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CENTRO DE BIOLOGA MOLECULAR

X ANIVERSARIO 1998-2008

1.- Si desea realizar algn estudio que no se encuentre en este CATLOGO, contacte con nuestro Servicio Cientfico de Asesoramiento. 2.- Todos los test diagnsticos incluidos dentro del programa European Molecular Genetics Quality Network (EMQN) se realizan segn sus recomendaciones y controles de sensibilidad y especificidad. 3.- C.B.M. Genetaq est incluida en varios programas de calidad como el de la International Society for Forensic Genetics y el Quality Control for Molecular Diagnostics. Tambin usa controles de referencia del National Institute for Biological Standards and Control (NIBSC). 4.- Genetaq tiene la certificacin de AENOR ISO9001-2000 y la certificacin DGE Data para la proteccin de datos. 5.- Los tiempos de realizacin de prueba son orientativos. Para las pruebas genticas dependen en gran medida de los resultados previos obtenidos y del propio paciente, ya que las diferencias interindividuales pueden requerir alteracin y puesta a punto de nuevos protocolos.

C.B.M. GENETAQ C/Frailes 28, 29012, Mlaga Telf. 952657605 www.genetaq.com

Rev 36 05/05/2009

MICROBIOLOGA MOLECULAR
Adenovirus M-1001 Bacterias patgenas M-1002 Bartonella henselae M-1003 BK / JC poliomavirus c.v. M-1004 Bordetella sp M-1005 Borrelia M-1006 Brucella M-1007 Chlamydia pneumoniae M-1008-1 Chlamidya psitacci M-1008-2 Chlamydia trachomatis M-1008-3 Clamidia: semen M-1008-4 CMV c.v. M-1009-1 CMV M-1009-2 S.P (EDTA) 2 ml 3 das 4C Real Time PCR S.P (EDTA), orina 2 ml 3 das 4C Real Time PCR Semen 5 ml 3 das 4C Nested PCR Escobilln en seco 3 das 4C Nested PCR S.P (EDTA) 2 ml 3 das 4C Nested PCR Exudado nasofarngeo 3 das 4C Nested PCR S.P (EDTA), LCR 2 ml 3 das 4C Nested PCR S.P. (EDTA), LCR, lquido articular 2 ml 3 das 4C Nested PCR Exudado farngeo 2 ml 3 das 4C Nested PCR S.P. (EDTA), suero, orina, tejido 2 ml 3 das 4C Real Time PCR S.P. (EDTA), aspirado, biopsia 2 ml 3 das 4C Nested PCR S.P. (EDTA), suero, LCR 2 ml 5 das 4C PCR LCR, aspirado nasofarngeo, hisopo conjuntival, orina 2 ml 3 das -20C Nested PCR

C.B.M. GENETAQ C/Frailes 28, 29012, Mlaga Telf. 952657605 www.genetaq.com

Rev 36 05/05/2009

CMV Resistencia M-1009-3 Coxsackievirus A y B M-1010 Coxiella M-1011 Criptococcus M-1012 Criptosporidium M-1013 EBV C.V. M-1014 Echovirus M-1015 Enterovirus M-1016 Estudio Ginecolgico completo: HPV, HSV 2 y Clamidia (EGC) M-1017 Haemophilus influenza M-1018 HBV C.V. M-1019-1 HBV M-1019-2 HBV Genotipo M-1019-3 Suero 2 ml 5 das -20C Nested PCR/ Secuenciacin Suero 2 ml 5 das -20C Nested PCR Suero 2 ml 10 das -20C Real Time PCR S.P (EDTA), LCR 2 ml 4 das 4C Nested PCR Escobilln en seco 5 das 4C Nested PCR Suero 5 ml 3 das -20C Nested PCR Suero 5 ml 3 das -20C Nested PCR S.P (EDTA) 2 ml 3 das 4C Real Time PCR Heces 6 das 4C Nested PCR LCR 2 ml 3 das 4C Nested PCR S.P. (EDTA) 2 ml 3 das 4C Nested PCR Suero 5 ml 3 das -20 C Nested PCR S.P (EDTA) 2 ml 10 das 4C Secuenciacin

C.B.M. GENETAQ C/Frailes 28, 29012, Mlaga Telf. 952657605 www.genetaq.com

Rev 36 05/05/2009

HBV Semen capacitado en mismo da M-1019-4 HBV Semen capacitado M-1019-5 HBV Semen M-1019-6 HBV Resistencia a Lamivudina M-1019-7 HBV Resistencia a Lamivudina, Entecavir, Emtricitabina, Adefovir y Telbivudina M-1019-8 HCV C.V. M-1020-1 HCV M-1020-2 HCV Secuenciacin M-1020-3 HCV Genotipificacin M-1020-4 HCV Semen M-1020-5 HCV Semen capacitado M-1020-6 HCV Semen capacitado en mismo da M-1020-7 HDV Semen capacitado 2 ml 1 da -20C Nested PCR Semen capacitado 2 ml 2 das -20C Nested PCR Semen 2 ml 2 das -20C Nested PCR Suero 2 ml 5 das -20C Hibridacin Suero 2 ml 5 das -20C Secuenciacin Suero 2 ml 3 das -20C Nested PCR Suero 2 ml 10 das -20C Real Time PCR Suero 2 ml 6 das -20C Secuenciacin Suero 2 ml 6 das -20C Secuenciacin Semen 5 ml 2 das -20C Nested PCR Semen capacitado 2 ml 2 das -20C Nested PCR Semen capacitado 2 ml 1 da -20C Nested PCR

C.B.M. GENETAQ C/Frailes 28, 29012, Mlaga Telf. 952657605 www.genetaq.com

Rev 36 05/05/2009

M-1021 Herpes virus I M-1022-1 Herpes virus II M-1022-2 Herpes virus VI M-1022-3 Herpes virus VII M-1022-4 Herpes virus VIII M-1022-5 HEV M-1023 HGV M-1024 HIV1 C.V. M-1025-1 HIV1 M-1025-2 HIV1 Semen capacitado M-1025-3 HIV1 Semen capacitado en mismo da M-1025-4 HIV Resistencia a inhibidores M-1025-5 Hongos patgenos

Suero

2 ml

5 das

-20C

Nested PCR

Escobilln en seco, LCR, S.P. (EDTA)

2 ml

3 das

4C

Nested PCR

Escobilln en seco, LCR, S.P. (EDTA)

2 ml

3 das

4C

Nested PCR

Escobilln en seco, LCR, S.P. (EDTA)

2 ml

3 das

4C

Nested PCR

Escobilln en seco, LCR, S.P. (EDTA)

2 ml

3 das

4C

PCR

Escobilln en seco, LCR, S.P. (EDTA)

2 ml

3 das

4C

Nested PCR

S.P. (EDTA)

5 ml

5 das

4C

Nested PCR

Suero

5 ml

5 das

-20C

Nested PCR

Suero

5 ml

10 das

-20C

Real Time PCR

S.P. (EDTA)

5 ml

3 das

4C

Nested PCR

Semen capacitado

5 ml

2 das

-20C

Nested PCR

Semen capacitado

5 ml

1 da

-20C

Nested PCR

Suero

5 ml

15 das

-20C

Secuenciacin

C.B.M. GENETAQ C/Frailes 28, 29012, Mlaga Telf. 952657605 www.genetaq.com

Rev 36 05/05/2009

M-1026-1 Hongos patgenos secuenciacin M-1026-2 HSV Semen M-1027-1 HSV 1-2 M-1027-2 Influenza A/B M-1028 Influenza A/B y Parainfluenza 1, 2, 3 M-1059 LCMV M-1029 Legionella pneumophila M-1030 Leishmania sp M-1031 Leptospira M-1032 Listeria M-1033 Micobacterium Avium M-1034-1 M. Genovense M-1034-2 M. Tuberculosis

S.P. (EDTA), LCR, Biopsia

5 ml

5 das

4C

Nested PCR

S.P. (EDTA), LCR, Biopsia

5 ml

15 das

4C

Secuenciacin

Semen

5 ml

2 das

-20C

Nested PCR

S.P. (EDTA), LCR, Escobilln en seco

2 ml

5 das

4C

Nested PCR

Exudado nasofarngeo

6 das

4C

Nested PCR

Exudado nasofarngeo

6 das

4C

Nested PCR

Suero, LCR

5 ml

15 das

4C

Nested PCR

S.P. (EDTA)

2 ml

10 das

4C

Nested PCR

S.P. (EDTA), M.O. (EDTA)

2 ml

15 das

4C

Nested PCR

S.P. (EDTA), LCR, Escobilln en seco

5 ml

5 das

4C

Hibridacin y Real Time PCR

S.P. (EDTA), LCR, Escobilln en seco

5 ml

5 das

4C

Hibridacin y Real Time PCR

S.P. (EDTA), LCR, Escobilln en seco

5 ml

5 das

4C

Hibridacin y Real Time PCR

S.P. (EDTA), LCR, Escobilln en seco

5 ml

5 das

4C

Hibridacin y Real Time PCR

C.B.M. GENETAQ C/Frailes 28, 29012, Mlaga Telf. 952657605 www.genetaq.com

Rev 36 05/05/2009

M-1034-3 Meningococo M-1035 Micoplasma M-1036 Microsporidium M-1037 Mycobacterium spp. M-1034-4 Neisseria gonorrhoeae M-1038-1 Neisseria meningitidis M1038-2 Neumococo M-1039 Papiloma virus deteccin y tifipifcacin M-1040-1 Papiloma virus secuenciacin M-1040-2 Papiloma virus Semen M-1040-3 Papiloma virus deteccin M-1040-4 Papiloma virus tifipicacin M-1040-5

LCR, Orina, Esputo

5 ml

5 das

4C

Real Time PCR

S.P. (EDTA), LCR

2 ml

4 das

4C

Nested PCR

S.P. (EDTA), Tejido de pulmn

2 ml

5 das

4C

PCR

Heces

5 das

4C

PCR

LCR, Orina, Esputo

2 ml

5 das

4C

Hibridacin

Orina

2 ml

3 das

4C

Nested PCR

S.P. (EDTA), LCR, Suero

2 ml

4 das

4C

Real Time PCR

S.P. (EDTA), LCR

2 ml

4 das

4C

Nested PCR

Escobilln en seco

5 das

4C

Nested PCR/ RFLP/ Hibridacin

Escobilln en seco

5 das

4C

Secuenciacin

Semen

5 ml

2 das

-20C

Nested PCR/ RFLP/ Hibridacin

Escobilln en seco

5 das

4C PCR

Escobilln en seco

5 das

4C RFLP Secuenciacin y/o

Parainfluenza 1, 2, 3

C.B.M. GENETAQ C/Frailes 28, 29012, Mlaga Telf. 952657605 www.genetaq.com

Rev 36 05/05/2009

M-1041 Paramixovirus (paperas) M-1042 Parvovirus B19 M-1043 Plasmodium ssp M-1044 Pneumocystis carinii M-1045 Proteus mirabilis M-1046 Rickettsias M-1047 Rotavirus M-1048 Rubeola M-1049 Salmonella Typhi M-1050-1 Salmonella Typhimurium y S. Enteriditis M-1050-2 Sarampin M-1051 Secuenciacin DNA Ribosomal 16s M-1052 Toxoplasma

Exudado nasofarngeo

3 das

4C

Nested PCR

Suero, LCR

5 ml

3 das

-20C

Nested PCR

Suero, LCR

5 ml

3 das

-20C

Nested PCR

S.P. (EDTA)

5 ml

5 das

4C

Nested PCR

S.P. (EDTA)

5 ml

3 das

4C

Nested PCR

Heces, LCR

2 ml

15 das

4C

Nested PCR

S.P. (EDTA)

5 ml

15 das

4C

Nested PCR

Heces

5 das

4C

RT-Nested PCR

S.P. (EDTA)

5 ml

15 das

4C

Nested PCR

S.P. (EDTA), Heces

5 ml

5 das

4C

Nested PCR

Heces

5 das

4C

Nested PCR

S.P. (EDTA), LCR, L. Amnitico

5 ml

15 das

4C

Nested PCR

DNA

3 das

-20C

PCR/Secuenciacin

C.B.M. GENETAQ C/Frailes 28, 29012, Mlaga Telf. 952657605 www.genetaq.com

Rev 36 05/05/2009

M-1053 Treponema pallidum M-1054 Tropheryma Whippelii M-1055 Tripanosoma Cruzi M-1056 Varicela M-1057 Virus Respiratorio Sincitial (RSVA y B) M-1058

S.P. (EDTA), LCR, L. Amnitico

2 ml

3 das

4C

Nested PCR

S.P. (EDTA), Suero

2 ml

3 das

4C

Nested PCR

S.P. (EDTA)

2 ml

3 das

4C

PCR

S.P. (EDTA)

2 ml

5 das

4C

PCR

S.P. (EDTA), LCR, L. Amnitico

2 ml

3 das

4C

Nested PCR

S.P. (EDTA), LCR, Escobilln en seco

2 ml

3 das

4C

Nested PCR

C.B.M. GENETAQ C/Frailes 28, 29012, Mlaga Telf. 952657605 www.genetaq.com

Rev 36 05/05/2009

GENTICA MOLECULAR
1.- ENFERMEDADES HEREDITARIAS
3M, Sndrome G-1001 ACE G-1002 Polimorfismo I/D en intrn 16 S.P (EDTA) 2 ml 15 das 4C PCR-RFLP Secuenciacin gen CUL7 S.P. (EDTA) 6 ml 3 meses 4C Secuenciacin

Acondrognesis G-1003 Secuenciacin COL2A1 S.P. (EDTA) 5 ml 30 das 4C Secuenciacin

Acondroplasia G-1004 Mutacin G1138A S.P. (EDTA) 3 ml 5 das 4C Secuenciacin

Adrenoleucodistrofia G-1005 Secuenciacin intrn-exn gen ABCD1 S.P (EDTA) 5 ml 25 das 4C Secuenciacin

Alagille, Sndrome de G-1006-1 Screening exones 1-6, 9, 12, 17, 20, 23 y 24 gen JAG1 G-1006-2 Secuenciacin intrn-exn gen JAG1 Albinismo G-1007-1 Tipo I Secuenciacin intrn-exn gen Tirosinasa G-1007-2Tipo 2 OCA2 Delecin 2.7 kb G-1007-3 Tipo 2 OCA2 Secuenciacin Aldolasa B G-1008 Mutaciones A149P y A174D S.P (EDTA) 5 ml 20 das 4C Secuenciacin S.P (EDTA) S.P (EDTA) S.P. (EDTA) 2 ml 2 ml 2 ml 10 das 10 das 15 das 4C 4C 4C Secuenciacin PCR Secuenciacin S.P. (EDTA) S.P. (EDTA) 3ml 3 ml 25 das 45 das 4C 4C Secuenciacin Secuenciacin

Alfa Antitripsina (AAT) G-1009 Variantes con disminucin moderada Z y S y leve, M2y M1 (Ala) S.P (EDTA) 2 ml 20 das 4C Multiplex PCR

Alport, Sndrome de G-1010 Secuenciacin exn-intrn del gen COL4A5 S.P (EDTA) 5 ml 25 das 4C Secuenciacin

Alzheimer: Presenilina 1 y 2

C.B.M. GENETAQ C/Frailes 28, 29012, Mlaga Telf. 952657605 www.genetaq.com

Rev 36 05/05/2009

G-1011-1 Secuenciacin exones 4, 5, 6 y 7 e intrn 8 del gen PS1 G-1011-2 Secuenciacin exones 5, 6 y 8 del gen PS2. Alzheimer G-1012 Apo-E, PS1, 2, APP16, 17, TAU

S.P (EDTA) S.P (EDTA)

5 ml 5 ml

15 das 15 dias

4C 4C

Secuenciacin Secuenciacin

S.P (EDTA) S.P (EDTA)

5 ml 5 ml

15 das 15 das

4C 4C

Secuenciacin Secuenciacin

G-1012-1 Apo-E, PS1, 2, APP16, 17 Amiloidosis TTR G-1013-1 Secuenciacin exn-intrn del gen TTR G-1013-2 Mutacion puntual del gen TTR Anlisis de Unin. G-1014 Estudio de ligamiento

S.P (EDTA) S.P (EDTA)

5 ml 3ml

15 das

4C

Secuenciacin Secuenciacin

10 das 4C

CONSULTAR

Anemia de Diamond Blackfan G-1015 Secuenciacin exn-intrn del gen RPS19 S.P (EDTA) 5 ml 25 das 4C Secuenciacin

Anemia falciforme G-1215 Mutacion p.Glu6Val gen HBB S.P. (EDTA) 2 ml 10 das 4C Secuenciacin

Angiotensingeno G-1212 Apo B G-1017-1 G-1017-2 G-1017-3 Apo E G-1018 Genotipificacion S.P (EDTA) 2 ml 5 das 4C RFLP Arg3500Gln Arg3500Gln, Arg3500Trp, His3543Tyr Secuenciacin S.P (EDTA) S.P. (EDTA) S.P. (EDTA) 2 ml 3 ml 6 ml 15 das 25 das 50 das 4C 4C 4C Secuenciacin Secuenciacin Secuenciacin S.P. (EDTA) 3 ml 15 das 4C Secuenciacin

APP exn 16 y 17 G-1019 Secuenciacin. exones 16 y 17 S.P (EDTA) 2 ml 15 das 4C Secuenciacin

Aracnodactilia contractual congnita. Sndrome de Beals G-1020-1 Secuenciacin exones 15. 22-33 y 35-36 gen FBN2 G-1020-2 Secuenciacin resto de exones gen FBN2 Artrogriposis Distal S.P. (EDTA) S.P. (EDTA) 6 ml 6 ml 3 meses 4C 3-6 meses 4C Secuenciacin Secuenciacin

C.B.M. GENETAQ C/Frailes 28, 29012, Mlaga Telf. 952657605 www.genetaq.com

Rev 36 05/05/2009

Tipo 1: TPM2 (R91G) G-1021-1 Tipo 2b: TNNI2 (166del, 175del, R156X, R174Q) TNNT3 (R63H) G-1021-3 Secuenciacin exn-intrn del gen MYH3 G-1021-4 Mutacion puntual (Tipo 1: TPM2 (R91G) AT1R Angiotensina II Tipo 1 Receptor G-1022 Polimorfismo A1166C

S.P (EDTA) S.P (EDTA)

2 ml 2 ml

10 das 30 das

4C 4C

Secuenciacin Secuenciacin

S.P (EDTA)

2 ml

15 das

4C

Secuenciacin

Ataxia de Friedreich G-1023 Expansin GAA S.P (EDTA) S.P (EDTA) Ataxias cerebelosa SCA 1 G-1024-1 Expansin CAG Ataxias cerebelosa SCA 2 G-1024-2 Expansin CAG Ataxias cerebelosa SCA 3 G-1024-3 Expansin CAG Ataxia cerebelosa SCA 4 G-1024-4 SCA4 S.P. (EDTA) 3 ml 10 das 4C Secuenciacin S.P (EDTA) 2 ml 15 das 4C GeneScan S.P (EDTA) 2 ml 15 das 4C GeneScan S.P (EDTA) 2 ml 15 das 4C GeneScan 2 ml 30 ml 15 das 4C GeneScan/TP-PCR Southern Blot

Consultar 4C

Ataxias cerebelosa SCA 6 G-1024-5 Expansin CAG Ataxias cerebelosa SCA 7 G-1024-6 Expansin CAG Ataxias cerebelosa SCA 8 G-1024-7 Expansin CAG Ataxia episdica tipo I G-1210 Secuenciacin gen KCNA1 S.P. (EDTA) 3 ml 20 das 4C Secuenciacin S.P (EDTA) 2 ml 15 das 4C GeneScan S.P (EDTA) 2 ml 15 das 4C GeneScan S.P (EDTA) 2 ml 15 das 4C GeneScan

Ataxias cerebelosa SCA 10 G-1024-8 Expansin ATTCT Ataxia Teleangiectasia- Luois-Bar, Sndrome de S.P (EDTA) 2 ml 15 das 4C GeneScan

C.B.M. GENETAQ C/Frailes 28, 29012, Mlaga Telf. 952657605 www.genetaq.com

Rev 36 05/05/2009

G-1235

Secuenciacin gen ATM

S.P. (EDTA)

10 ml

3-4 meses 4C

Secuenciacin

Atrofia Dentotuberal (DRPLA) G-1025 Expansin CAG S.P (EDTA) 2 ml 15 das 4C Multiplex PCR/ GeneScan

Atrofia Muscular espinal G-1026 Estudio SMN1/2 S.P (EDTA) 2 ml 15 das 4C MLPA/GeneScan

Atrofia Muscular Espinobulbar (SBMA) G-1027 Expansin CAG S.P (EDTA) 2 ml 15 das 4C GeneScan

Bartter, Sndrome de. Tipo II y III G-1028-1 Secuenciacin del exn 7 del gen CLCNKB, y de 2 fragmentos solapantes correspondientes al exn 2 del gen KCNJ1 G-1028-2 Secuenciacin intrn-exn de los genes CLCNKB y KCNJ1 S.P (EDTA) 2 ml 15 das 4C Secuenciacin

S.P (EDTA)

2 ml

15 das

4C

Secuenciacin

Batten, Sndrome de. Lipofucinosis G-1029-1 Delecin 1kb del gen CLN3 G-1029-2 Mutacion R151X, PPT1 Beare-Stevenson Cutis Gyrata G-1030 Estudio 2 mutaciones gen FGFR2 S.P. (EDTA) 3 ml 15 das 4C Secuenciacin S.P (EDTA) 2 ml 5 das 4C GeneScan

Beckwith -Wiedermann, Sndrome de G-1031 Anormalidades de metilacin en el gen KCNQ1OT1, H19DMR, KvDMR, CDKN1C y IGF2 Disoma Uniparental S.P (EDTA) 2 ml 25 das 4C MLPA

Berardinelli, Sndrome de G-1032 Secuenciacin completa intron-exn del gen AGPAT2 S.P. (EDTA) 2 ml 30 das 4C Secuenciacin

Biotinidasa, Deficiencia de G-1033 G98:d7i3, 456Q H, 538R C, 444D H, y 444D H:171A T S.P (EDTA) 2 ml 20 das 4C ARMS-PCR

Blefarofimosis G-1034 Bmp 15 Secuenciacin gen FOXL2 S.P. (EDTA) 3 ml 30 das 4C Secuenciacin

C.B.M. GENETAQ C/Frailes 28, 29012, Mlaga Telf. 952657605 www.genetaq.com

Rev 36 05/05/2009

G-1035-1 Sindrome Hiperestimulacion Ovarica G-1035-2 Fallo Ovarico Prematuro G-1035-3 Sindrome Ovarico Poliquistico Brugada, Sndrome de G-1036 C-KIT G-1227 CADASIL G-1037-1 Secuenciacin exn 3 y 4 del gen Noch 3 G-1037-2 Secuenciacin exn 2, 5 y 11 G-1037-3 Secuenciacin exones restantes Carney, Sndrome de G-1038 Gen PRKAR1A Mutacin puntual D816V Secuenciacin gen SCN5A

S.P. (EDTA)

3 ml

15 das

4C

Secuenciacin

S.P. (EDTA)

6 ml

3 meses 4C

Secuenciacin

S.P. (EDTA)

3 ml

15 das

4C

Secuenciacin

S.P (EDTA) S.P (EDTA) S.P (EDTA)

2 ml 2 ml 2 ml

10 das 10 das 10 das

4C 4C 4C

Secuenciacin Secuenciacin Secuenciacin

S.P. (EDTA)

3 ml

20 das

4C

Secuenciacin

Cavernomas cerebrales G-1039-1 Mutaciones 1363C>T, dG699 y Q698X del gen KRIT1 G-1039-2 Secuenciacin completa del gen KRIT1 Charcot Marie-Tooth G-1040-1 Duplicacin PMP 22 G-1040-2 Secuenciacin PMP 22 G-1040-3 MPZ G-1040-4 Conexina 32 Charcot Marie-Tooth Recesivo G-1041 Gen GADP1 S.P. (EDTA) 3 ml 15 das 4C Secuenciacin S.P (EDTA) S.P (EDTA) S.P (EDTA) S.P (EDTA) 5 ml 5ml 5 ml 5 ml 5 das 15 das 15 das 15 das 4C 4C 4C 4C GeneScan Secuenciacin Secuenciacin Secuenciacin S.P. (EDTA) S.P. (EDTA) 3 ml 3 ml 15 das 30 das 4C 4C Secuenciacin Secuenciacin

Charge, Sndrome de G-1042 Secuenciacin gen CHD7 S.P. (EDTA) 6 ml 2-3 meses 4C Secuenciacin

Cinca, Sndrome de G-1043 Secuenciacion del gen NLRP3 (CIAS1) S.P (EDTA) 5 ml 25 dias 4C Secuenciacin

Cistinosis G-1044-1 Estudio secuenciacin gnica y delecin CTNS G-1044-2 Mutacion puntual S.P (EDTA) 5 ml 15 das 4C Secuenciacin/PCR

C.B.M. GENETAQ C/Frailes 28, 29012, Mlaga Telf. 952657605 www.genetaq.com

Rev 36 05/05/2009

Citrulina, Deficiencia de G-1045-1 Mutacin Arg360Stop gen SLC25A13 G-1045-2 Screening gen SLC25A13 G-1045-3 Secuenciacin gen SLC25A13 Coffin Lowry, Sndrome de G-1218 Secuenciacin gen RPS6KA3 S.P. (EDTA) 3 ml 20 das 4C Secuenciacin S.P. (EDTA) S.P. (EDTA) S.P. (EDTA) 5 ml 5 ml 5 ml 5 das 20 das 40 das 4C 4C 4C Secuenciacin Secuenciacin Secuenciacin

Colagena 1 Polimorfismo en promotor Colestasis intraheptica G-1046 COMT G-1047 Polimorfismo Val158Met S.P (EDTA) 2 ml 15 das 4C PCR Gen ATP8B1. Mutacin I661T S.P (EDTA) 2 ml 10 das 4C Secuenciacin S.P (EDTA) 2 ml 15 das 4C PCR

Conos y Bastones, Degeneracin de (Leber congenital amaurosis) G-1048-1 Gen ABCA4. Dominante. Mutaciones 2888delG y R943Q G-1048-2 Gen CRX. Recesiva. Secuenciacin intrn-exn S.P (EDTA) S.P (EDTA) 2 ml 2 ml 15 das 15 das 4C 4C Secuenciacin Secuenciacin

Craneosinostosis G-1049 Secuenciacin exn 7 del FGFR1, el exn 7 del FGFR2 y los exones 6 y 8 del gen FGFR3 S.P (EDTA) 5 ml 15 das 4C Secuenciacin

Crohn, Sndrome de G-1050 Polimorfismos R702W, G908R y 1007fs. S.P. (EDTA) 2 ml 25 das 4C PCR

Crouzon, Sndrome de G-1051 Secuenciacin gen FGFR2 S.P. (EDTA) 5 ml 30 das 4C Secuenciacin

Currarino, Sndrome de G-1052 CYP2B6 G-1053 Secuenciacin intrn exn S.P. (EDTA) 3 ml 30 das 4C Secuenciacin Secuenciacin exn-intrn del gen HLXB9 S.P (EDTA) 5 ml 15 das 4C Secuenciacin

Dficit de Hormona del Crecimiento G-1209 Secuenciacin gen GH1 S.P. (EDTA) 3 ml 20 das 4C Secuenciacin

C.B.M. GENETAQ C/Frailes 28, 29012, Mlaga Telf. 952657605 www.genetaq.com

Rev 36 05/05/2009

Demencia frontotemporal G-1054-1 Estudio deleciones/duplicaciones MAPT-PGRN G-1054-2 Secuenciacin gen MAPT G-1054-3 Secuenciacin gen PGRN Di George, Sndrome de G-1055 Estudio delecin Catch22 S.P (EDTA) 5 ml 5 das 4C GeneScan S.P. (EDTA) S.P. (EDTA) S.P. (EDTA) 3 ml 5 ml 5 ml 15 das 35 das 40 das 4C 4C 4C MLPA Secuenciacin Secuenciacin

Diabetes Insipida ligada al cromosoma X G-1056 Secuenciacin exones 2 y 3 del gen AVPR2. S.P (EDTA) 5 ml 15 das 4C Secuenciacin

Diabetes mellitus, MODY tipo 1 G-1057-1 Secuenciacin gen HNF4A Diabetes mellitus, MODY tipo 2 G-1057-2 Secuenciacin gen GCK Diabetes mellitus, MODY tipo 3 G-1057-3 Secuenciacin gen HNF1A Diabetes mellitus, MODY tipo 4 G-1057-4 Secuenciacin gen IPF1 Diabetes mellitus, MODY tipo 5 G-1057-5 Secuenciacin gen HNF1B Diabetes mellitus, MODY tipo 6 G-1057-6 Secuenciacin gen NEUROD1 Disoma Uniparental G-1058 Displasia Ectodrmica ligada al X G-1059-1 MLPA gen EDA G-1059-2 Secuenciacin gen EDA Displasia Epifisaria Multiple G-1060 Screening exones 8-14 del gen COMP y ................exon 2 del gen MATN3 S.P (EDTA) 3 ml 25dias 4C Secuenciacion S.P. (EDTA) S.P. (EDTA) 3 ml 3 ml 15 das 20 das 4C 4C MLPA Secuenciacin S.P. (EDTA) 5 ml 35 das 4C Secuenciacin S.P. (EDTA) 5 ml 35 das 4C Secuenciacin S.P. (EDTA) 5 ml 35 das 4C Secuenciacin S.P. (EDTA) 5 ml 35 das 4C Secuenciacin S.P. (EDTA) 5 ml 35 das 4C Secuenciacin S.P. (EDTA) 5 ml 35 das 4C Secuenciacin

S.P (EDTA)

5 ml

5 das

4C

GeneScan

C.B.M. GENETAQ C/Frailes 28, 29012, Mlaga Telf. 952657605 www.genetaq.com

Rev 36 05/05/2009

Displasia Tanatofrica G-1231 Secuenciacin gen FGFR3 S.P. (EDTA) 10 ml 20-30 das 4C Secuenciacin

Distona mioclnica G-1061 Secuenciacin de los exones del 1 al 7 y el 9 del gen DYT11 S.P. (EDTA) 5 ml 20 das 4C Secuenciacin

Distona Progresiva Hereditaria, de torsin, idioptica familiar G-1062 DYT1 (TOR1 GAG delecin) S.P (EDTA) 2 ml 10 das 4C Secuenciacin

Distona Resistente a Dopamina G-1063 Secuenciacin DYT5 S.P. (EDTA) 3 ml 20 das 4C Secuenciacin

Distrofia facio-escapulo-humeral G-1064 Expansin regin D4Z4 gen FSHD S.P (EDTA) 10 ml 60 das 4C Southern blot

Distrofia oculofarngea G-1065 Expansin GCG S.P (EDTA) 2 ml 20 das 4C Secuenciacin

Distrofia Miotnica (Steiner) G-1066 Expansin gen DMPK S.P (EDTA) 2 ml 15 das 4C TP-PCR

Distrofia miotnica tipo 2, DM2 G-1067

S.P. (EDTA)

3 ml

15 das

4C

PCR

Distrofia muscular congnita, merosina deficiente Tipo1A (MDC1A) G-1068 Secuenciacin gen LAMA2 S.P. (EDTA) 5 ml 45 das 4C Secuenciacin

Distrofia Muscular de Duchenne/Becker G-1069-1 Anlisis de deleciones G-1069-2 Anlisis de Portadoras Distrofia Muscular de Cinturas (LGMD 1A) G-1070-1 Secuenciacin MYOT Distrofia Muscular de Cinturas (LGMD 1B) G-1070-2 Secuenciacin gen LMNA Distrofia Muscular de Cinturas (LGMD 2A) G-1070-3 Secuenciacin CAPN3 S.P (EDTA) 15 ml 15 das 4C Secuenciacin S.P. (EDTA) 3 ml 45 das 4C Secuenciacin S.P (EDTA) 15 ml 15 das 4C Secuenciacin S.P (EDTA) S.P (EDTA) 15 ml 15 ml 15 das 15 das 4C 4C Multiplex PCR MLPA

C.B.M. GENETAQ C/Frailes 28, 29012, Mlaga Telf. 952657605 www.genetaq.com

Rev 36 05/05/2009

Distrofia Muscular de Cinturas (LGMD 2B) G-1070-4 Secuenciacin DYSF Distrofia Muscular de Cinturas (LGMD 2D) G-1070-5 Secuenciacin SGCA S.P (EDTA) 15 ml 15 das 4C Secuenciacin S.P (EDTA) 15 ml 15 das 4C Secuenciacin

Distrofia Muscular Emery-Dreifuss, Autosmica dominante (EDMD2) G-1071-1 Secuenciacin gen LMNA S.P. (EDTA) 3 ml 45 das 4C Secuenciacin

Distrofia Muscular Emery-Dreifuss, Autosmica recesiva (EDMD3) G-1071-2 Secuenciacin gen LMNA Distrofia Muscular Emery-Dreifuss, Ligada al X (EDMD) G-1071-3 Secuenciacin gen EMD Ehlers-Danlos Tipo IV G-1072 Secuenciacin gen COL3A1 S.P. (EDTA) 9 ml 3 meses 4C Secuenciacin S.P. (EDTA) 3 ml 45 das 4C Secuenciacin S.P. (EDTA) 3 ml 45 das 4C Secuenciacin

ELAM-1 Molecula Adhesin 1 G-1073 Polimorfismo Ser128Arg S.P (EDTA) 2 ml 15 das 4C ARMS-PCR

Endocrinopata mltiple autoinmune Tipo I G-1074 Secuenciacin gen AIRE S.P. (EDTA) 5 ml 30 das 4C Secuenciacin

Epidermolisis bullosa G-1075-1 Autosmica dominante: Secuenciacin exones 73-76 gen Col7A1 G-1075-2 Autosmica dominante: Secuenciacin resto de exones G-1075-3 Autosmica recesiva: Delecione/Duplicacion gen Col7A1 Epilepsia G-1076-1 Anlisis de secuencia completa Gen LGI1 G-1076-2 Mutacin puntual Epilepsia generalizada con convulsiones febriles plus G-1077 Secuenciacin gen GABRG2 S.P. (EDTA) 3 ml 30 das 4C Secuenciacin S.P (EDTA) S.P (EDTA) 2 ml 2 ml 20 das 10 das 4C 4C Secuenciacin Secuenciacin S.P.(EDTA) S.P.(EDTA) S.P.(EDTA) 3 ml 6 ml 2 ml 10 das 50 das 20 das 4C 4C 4C Secuenciacin Secuenciacin MLPA

Epilepsia ligada al X G-1078 Secuenciacin gen ARX S.P.(EDTA) 3 ml 15 das 4C Secuenciacin

C.B.M. GENETAQ C/Frailes 28, 29012, Mlaga Telf. 952657605 www.genetaq.com

Rev 36 05/05/2009

Epilepsia mioclnica severa (SCN1A) G-1079 Anlisis de secuencia completa Gen SCN1A S.P (EDTA) 2 ml 45 das 4C Secuenciacin

Esclerosis lateral amiotrfica 4, Juvenil (ALS4) G-1205-1 Secuenciacin gen SETX Esclerosis lateral amiotrfica (ALS) G-1205-2 Secuenciacin gen SOD1 Esclerosis lateral amiotrfica Familiar (FALS, ALS1) G-1205-3 Secuenciacin gen ANG Esclerosis Tuberosa G-1080-1 Anlisis de deleciones TSC1 y TSC2 G-1080-2 Secuenciacin completa TSC1 y TSC2 G-1080-3 Analisis de deleciones TSC1 G-1080-4 Secuenciacion TSC1 G-1080-5 Analisis deleciones TSC2 G-1080-6 Secuenciacion TSC2 G-1080-7 Secuenciacion y analisis deleciones TSC1 y TSC2 F VII G-1081 F XII G-1082 F XIII G-1083 Factor II G-1084 G20210A S.P (EDTA) 2 ml 10 das 4C RealTime PCR Val34Leu S.P (EDTA) 2 ml 10 das 4C PCR C46T S.P (EDTA) 2 ml 10 das 4C PCR Arg353Gln /decanucletido en la posicin 323 S.P (EDTA) 2 ml 10 das 4C PCR S.P (EDTA) S.P (EDTA) S.P (EDTA) S.P (EDTA) S.P (EDTA) S.P (EDTA) S.P (EDTA) 2 ml 2 ml 3 ml 3 ml 3 ml 3 ml 6 ml 20 das 30 das 15 das 30 das 15 das 30 das 30 das 4C 4C 4C 4C 4C 4C 4C MLPA Secuenciacin MLPA Secuenciacion MLPA Secuenciacion Secuenciacion/MLPA S.P. (EDTA) 5 ml 30 das 4C Secuenciacin S.P. (EDTA) 5 ml 30 das 4C Secuenciacin S.P .(EDTA) 5 ml 30 das 4C Secuenciacin

Factor von Willebrand G-1085 Exones 3-19 S.P (EDTA) 2 ml 10 das 4C PCR

Farber , Sndrome de G-1086 Secuenciacin gen ASAH1 S.P. (EDTA) 5 ml 25 das 4C Secuenciacin

C.B.M. GENETAQ C/Frailes 28, 29012, Mlaga Telf. 952657605 www.genetaq.com

Rev 36 05/05/2009

Fenilcetonuria (PAH) G-1087 Secuenciacin exones 7, 8, 11 y 12 S.P (EDTA) 2 ml 15 das 4C Secuenciacin

Fibrosis Qustica G-1088-1 32 mutaciones + Poli T G-1088-2 Donantes: 32 mutaciones G-1088-3 F508 G-1088-4 Secuenciacin completa Fiebre Mediterranea Familiar G-1089-1 Secuenciacin exones 2,3,5,10 G-1089-2 Mutaciones: E148Q, P369S, F479L, M680I(G/C), M680I(G/A), I692del, M694V, M694I, K695R, V726A, A744S, R761H. G-1089-3 Mutacin puntual Fiebre Peridica (TRAPS) G-1090-1. Secuenciacin completa G-1090-2. Screening P46L, C55S, C70S, C70R, C70Y, R92Q Furhmann, Sndrome de G-1216 Secuenciacin gen WNT7A FV-506 F. Leiden G-1091 R506Q S.P (EDTA) 2 ml 3 das 4C Real Time S.P. (EDTA) 3 ml 20 ds 4C Secuenciacin S.P. (EDTA) ....S.P. (EDTA) 3 ml 3 ml 10 das 5 das 4C 4C Secuenciacin Secuenciacin S.P (EDTA) S.P (EDTA) 2 ml 2 ml 10 das 6 das 4C 4C Secuenciacin SSP-PCR S.P (EDTA) S.P (EDTA) S.P (EDTA) S.P (EDTA) 2 ml 2 ml 2 ml 2 ml 10 das 10 das 4 das 45 das 4C 4C 4C 4C GeneScan GeneScan PCR Secuenciacin

S.P (EDTA)

2 ml

5 das

4C

Secuenciacin

Gaucher, Sndrome de. Deficiencia Glucocerebrosidasa G-1228 Deteccin de mutaciones S.P. (EDTA) 5 ml 25 das 4C Secuenciacin

Gilbert, Sndrome de G-1092 Genotipo TA S.P (EDTA) 2 ml 15 das 4C GeneScan

Gitelman, Sndrome de G-1232 Secuenciacin gen SLC12A3 S.P. (EDTA) 5 ml 50 das 4C Secuenciacin

Glaucoma G-1093 Secuenciacin CYP1B1 S.P (EDTA) 2 ml 15 das 4C Secuenciacin

Glaucoma juvenil autosmica dominante

C.B.M. GENETAQ C/Frailes 28, 29012, Mlaga Telf. 952657605 www.genetaq.com

Rev 36 05/05/2009

G-1094

Secuenciacin myoc

S.P. (EDTA)

3ml

15 das

4C

Secuenciacin

Glicoprotena GPIb G-1095 Polimorfismo T145M S.P (EDTA) 2 ml 10 das 4C PCR

Glucogenosis Tipo Ia G-1207-1 Mutaciones Arg83Cys y Gln347X del gen G6PC G-1207-2 Secuenciacin del gen G6PC S.P .(EDTA) S.P. (EDTA) 2 ml 3 ml 10 das 30 das 4C 4C Secuenciacin Secuenciacin

Glucogenosis Tipo Ib G-1207-3 Mutaciones c.1042-1043 del CT y Gly339Cys G-1207-4 Secuenciacin del gen SLC37A4 S.P. (EDTA) S.P. (EDTA) 2 ml 3 ml 10 das 30 das 4C 4C Secuenciacin Secuenciacin

Glucogenosis Tipo 3 G-1096 Gen GDE, estudio de mutaciones S.P (EDTA) 2 ml 10 das 4C Secuenciacin

Glucosa 6-fosfato deshidrogenasa, deficiencia de G-1226 Secuenciacin intrn-exn gen G6PD S.P. (EDTA) 5 ml 25 das 4C Secuenciacin

Glud1 (Glutamato deshidrogenasa 1) G-1097-1 Screening exones 6, 7, 11 y 12 gen GLUD1 G-1097-2 Secuenciacin exn-intrn gen GLUD1 Glut1 G-1098 Secuenciacin exn 10 del gen SCL2A1 S.P (EDTA) 2 ml 10 das 4C Secuenciacin S.P (EDTA) S.P (EDTA) 3 ml 3 ml 20 das 40 das 4C 4C Secuenciacin Secuenciacin

Gorlin, Sndrome de G-1099 GPIIIa G-1100 Leu33Pro S.P (EDTA) 2 ml 10 das 4C PCR Secuenciacin completa del gen PTCH1 S.P. (EDTA) 3 ml 30 das 4C Secuenciacin

Granulomatosa crnica, enfermedad G-1101-1 Secuenciacin gen CYBB G-1101-2 Secuenciacin gen CYBA Hemocromatosis G-1102 Mutaciones C282Y, H63D, S65C S.P (EDTA) 2 ml 3 das 4C Real Time PCR S.P. (EDTA) S.P. 8EDTA) 3 ml 3 ml 20 das 30 das 4C 4C Secuenciacin Secuenciacin

C.B.M. GENETAQ C/Frailes 28, 29012, Mlaga Telf. 952657605 www.genetaq.com

Rev 36 05/05/2009

Hemocromatosis hereditaria tipo III G-1103 Mutacin Y250X gen TFR2 S.P.(EDTA) 3 ml 10 das 4C Secuenciacin

Hemofilia A G-1104 Inversin intrn 22A/Inversin intrn 1 S.P. (EDTA) 10 ml 60 das 4C PCR

Hemofilia B G-1105 Secuenciacin completa intrn-exn S.P. (EDTA) 10 ml 20 das 4C Secuenciacin

Hipercolesterolemia Familiar Dominante G-1106 Secuenciacin LDLR S.P. (EDTA) 3 ml 20 das 4C Secuenciacin

Hiperplasia Suprarrenal Congnita G-1107-1 Gen CYP21: Grandes deleciones, duplicaciones y conversiones gnicas.Secuenciacin mutaciones G-1107-2 Gen 11 hidroxilasa: Secuenciacin del gen G-1107-4 Dficit de 3 Hidroxiesteroide deshidrogenasa Tipo II (Secuenciacin gen HSD3B2) Hipertensin pulmonar primaria G-1211-1 Estudio de deleciones BMPR2 G-1211-2 Secuenciacin gen BMPR2 Hipertermia Maligna G-1108-1 Mutacin R1086H gen CACNA1S G-1108-2 Secuenciacin exones 2 al 18 gen RYR1 Hipertrofia cardiaca familiar G-1109-1 Secuenciacin -miosina G-1109-2 Secuenciacin troponina T S.P (EDTA) S.P (EDTA) 5 ml 5 ml 50 das 50 das 4C 4C Secuenciacin Secuenciacin S.P.(EDTA) S.P.(EDTA) 3 ml 5 ml 15 das 30 das 4C 4C Secuenciacin Secuenciacin S.P. (EDTA) S.P. (EDTA) 3 ml 3 ml 20 das 45 das 4C 4C MLPA Secuenciacin S.P (EDTA) S.P (EDTA) S.P. (EDTA) 2 ml 5 ml 5 ml 15 das 20 das 25 das 4C 4C 4C MLPA/Secuenciacin Secuenciacin Secuenciacin

Hipocondroplasia G-1110-1 Secuenciacin exones 9 y 15 del gen FGFR3 G-1110-2 Mutacin N540K Hipomagnesemia con hipocalcemia secundaria G-1206 Secuenciacion gen TRPM6 S.P (EDTA) 5 ml 45 dias 4C Secuenciacion S.P (EDTA) S.P (EDTA) 5 ml 5 ml 10 das 5 das 4C 4C Secuenciacin Secuenciacin

C.B.M. GENETAQ C/Frailes 28, 29012, Mlaga Telf. 952657605 www.genetaq.com

Rev 36 05/05/2009

Hirschsprung, Sndrome de G-1229 Secuenciacin gen RET S.P. (EDTA) 5 ml 50 das 4C Secuenciacin

Histiocitosis Familiar G-1111 Secuenciacin completa gen PRF1 S.P (EDTA) 5 ml 15 das 4C Secuenciacin

Hunter, Enfermedad de G-1112 Secuenciacin completa del gen IDS S.P (EDTA) 5 ml 15 das 4C Secuenciacin

Huntington, Enfermedad de G-1113 Expansin gen IT15 S.P (EDTA) 10 ml 15 das 4C TP-PCR

Ictiosis ligada al X G-1114 Estudio deleciones S.P. (EDTA) 3 ml Consultar 4C MLPA

Incontinencia pigmenti G-1115 Delecin exones 4-10 del gen NEMO S.P (EDTA) 5 ml 3 meses 4C Multiplex PCR

Insensibilidad andrognica, Sndrome de G-1223 Secuenciacin intrn-exn gen AR S.P. (EDTA) 3 ml 25 das 4C Secuenciacin

Jackson-Weiss, Sndrome de G-1205 Secuenciacin gen FGFR2 S.P. (EDTA) 5 ml 30 das 4C Secuenciacin

Kostmann, Sndrome de G-1116 Secuenciacin gen HAX 1 S.P (EDTA) 2 ml 15 das 4C Secuenciacin

Lange, Cornelia de G-1222 Secuenciacin intrn-exn gen NIPBL S.P. (EDTA) 5 ml 45 das 4C Secuenciacin

Langer Giedion, Sndrome de. Tricorrineofalntico tipo II G-1117 Estudio de deleciones S.P. (EDTA) 5 ml 15 das 4C MLPA

Leri Weill, Sndrome de - Haploinsuficiencia SHOX G-1118 Estudio deleciones S.P. (EDTA) 5 ml 15 das 4C MLPA

Lesch-Nyhan, Sndrome de G-1119 Secuenciacin exn-intrn gen HPRT1 S.P (EDTA) 5 ml 15 das 4C Secuenciacin

C.B.M. GENETAQ C/Frailes 28, 29012, Mlaga Telf. 952657605 www.genetaq.com

Rev 36 05/05/2009

Leucodistrofia Metacromtica G-1120 Secuenciacin del gen ARSA S.P.(EDTA) 3 ml 15 das 4C Secuenciacin

Lisencefalia ligada al X G-1121 Secuenciacin gen DCX S.P. (EDTA) 5 ml 15 das 4C MLPA

Lisencefalia Miller-Dieker G-1122 Anlisis de deleciones 17p13 S.P (EDTA) 5 ml 15 das 4C MLPA

Lipoproteinlipasa G-1123-1 Mutacin G188E G-1123-2 Secuenciacin exn- intrn del gen LPL G-1123-3 Estudio promotor Lowe, Sndrome de G-1124 Secuenciacin exn-intrn del gen OCRL S.P (EDTA) 5 ml 25 das 4C Secuenciacin S.P (EDTA) S.P (EDTA) S.P. (EDTA) 5 ml 5 ml 5 ml 5 das 15 das 10 das 4C 4C 4C Secuenciacin Secuenciacin Secuenciacin

Marfan, Sndrome de G-1125-4 Estudio de deleciones gen FBN1 G-1125-1 Secuenciacin zona codificante del gen FBN1 G-1125-2 Secuenciacin zona codificante del gen TGFBR1 G-1125-3 Secuenciacin zona codificante del gen TGFBR2 McARDLE, Enfermedad de G-1126-1 Secuenciacin exn-intrn del gen PYGM G-1126-2 Screening mutaciones: R49X, G204S, Y84X, W797R y 708/709del Menkes, Sndrome de G-1127-1 Secuenciacin exn-intrn del gen ATP7A G-1127-2 Mutacin puntual MHC II G-1128-1 Secuenciacin gen RFXAP G-1128-2 Secuenciacin gen RFXANK G-1128-3 Secuenciacin gen RFX5 G-1128-4 Secuenciacin gen CIITA S.P. (EDTA) S.P. (EDTA) S.P. (EDTA) S.P. (EDTA) 3 ml 3 ml 3 ml 3 ml 15 das 25 das 50 das 50 das 4C 4C 4C 4C Secuenciacin Secuenciacin Secuenciacin Secuenciacin S.P (EDTA) S.P (EDTA) 5 ml 5 ml 15 das 10 das 4C 4C Secuenciacin Secuenciacin S.P. (EDTA) S.P. (EDTA) 3 ml 3 ml 40 das 20 das 4C 4C Secuenciacin Secuenciacin S.P. (EDTA) S.P (EDTA) S.P (EDTA) S.P (EDTA) 3 ml 6 ml 5 ml 5 ml 20 das 4C MLPA Secuenciacin Secuenciacin Secuenciacin

6 meses 4C 45 das 45 das 4C 4C

C.B.M. GENETAQ C/Frailes 28, 29012, Mlaga Telf. 952657605 www.genetaq.com

Rev 36 05/05/2009

Miastenia congnita G-1129-1 CHRNA1 (G153S), CHAT (I3055), RAPSN (N88K exn 2) y CHRNE ( 1267delG exn 12 y 1293insG) G-1129-2 Dok7 Microdeleciones Cromosoma Y G-1130 (AZFa, AZFb, AZFc,DAZ) S.P (EDTA) 2 ml 5 das 4C Multiplex PCR S.P (EDTA) 5 ml 15 das 4C Secuenciacin

S.P. (EDTA)

5 ml

25 das

4C

Secuenciacin

Miocardiopata Espongiforme G-1219 Secuenciacin gen TAZ S.P. (EDTA) 3 ml 20 das 4C Secuenciacin

Miocardiopata Hipertrfica Familiar G-1217 Miopata Miotubular Ligada al X G-1131 Secuenciacin intrn-exn gen MTM1 S.P. (EDTA) 3 ml 20 das 4C Secuenciacin S.P. (EDTA) 9 ml 180 das 4C Secuenciacin

Morsier, Sndrome de. Displasia Septo-ptica G-1132 Secuenciacin gen HESX1 S.P. (EDTA) 3 ml 20 das 4C Secuenciacin

Mowat-Wilson, Sndrome de G-1133 Estudio de deleciones S.P. (EDTA) 3 ml 15 das 4C MLPA

MTHFR (Homocistenemia) G-1134 Mutaciones C677T y A1298C S.P (EDTA) 2 ml 3 das 4C RealTime

Muscular-Eye-Brain, Syndrome G-1135 NAT 1 G-1136 Alelos *3, *4, *10, *11, *14, *15, *17, y *22 S.P (EDTA) 2 ml 15 das 4C RealTime PCR Secuenciacin gen POMGnT1 S.P. (EDTA) 5 ml 15 das 4C MLPA

NAT 2 G-1137 Alelos *5A (C481T), *6A (G590A), y *7A (G857A) S.P (EDTA) 2 ml 15 das 4C RealTime PCR

Nefronoptisis G-1138-1 Analisis de Delecin G-1138-2 Secuenciacin NPHP1 S.P (EDTA) S.P (EDTA) 5-10 ml 5 ml 60 das 45 das 4C 4C Southern Blot Secuenciacin

C.B.M. GENETAQ C/Frailes 28, 29012, Mlaga Telf. 952657605 www.genetaq.com

Rev 36 05/05/2009

G-1138-3 Secuenciacin NPHP2

S.P. (EDTA)

3 ml

35 das

4C

Secuenciacin

Neurofibromatosis Tipo I G-1139-1 Secuenciacin intrn-exn gen NF1 G-1139-2 Estudio de deleciones/duplicaciones S.P (EDTA) S.P (EDTA) 5 ml 5 ml 45 das 15 das 4C 4C Secuenciacin MLPA

Neurofibromatosis Tipo II G-1140-1 Secuenciacin intrn-exn gen NFII G-1140-2 Estudio de deleciones/duplicaciones S.P (EDTA) S.P (EDTA) 5 ml 5 ml 45 das 15 das 4C 4C Secuenciacin MLPA

Neuropata Hereditaria sensible a la presin (HNPP) G-1141-1 Delecin PMP22 G-1141-2 Secuenciacion Neutropenia Congnita Severa G-1142 Secuenciacin intrn-exn gen ELA-2 S.P (EDTA) 5 ml 45 das 4C Secuenciacin S.P (EDTA) S.P (EDTA) 2 ml 2 ml 10 das 15 das 4C 4C GeneScan Secuenciacion

Noonan, Sndrome de G-1143 Mutacin gen PTPN11 S.P. (EDTA) 3 ml 25 das 4C Secuenciacin

Ondine, Sndrome de (Sndrome de Hipoventilacin) G-1144 Expansin Poli-Ala gen PHOX2B S.P (EDTA) S.P. (EDTA) 2 ml 5 ml 10 das 25 das 4C 4C GeneScan Secuenciacin

G-1144-1 Secuenciacin

Osteocondromatosis G-1145-1 Estudio de deleciones/duplicaciones gen EXT1 G-1145-2 Secuenciacin exn-intrn del gen EXT1 G-1145-3 Estudio de deleciones/duplicaciones gen EXT2 G-1145-4 Secuenciacin exn-intrn del gen EXT2 Osteoartritis G-1146 ER polimorfismos PvuII y XbaI S.P (EDTA) 5 ml 15 das 4C PCR S.P (EDTA) S.P (EDTA) S.P (EDTA) S.P (EDTA) 2 ml 5 ml 2 ml 5 ml 10 das 15 das 10 das 15 das 4C 4C 4C 4C MLPA Secuenciacin MLPA Secuenciacin

Osteognesis Imperfecta G-1147-1 Secuenciacin exn-intrn del gen Col 1A1 G-1147-2 Secuenciacin exn-intrn del gen Col 1A2 Osteoporosis
C.B.M. GENETAQ C/Frailes 28, 29012, Mlaga Telf. 952657605 www.genetaq.com

S.P (EDTA) S.P (EDTA)

5 ml 5 ml

30 das 30 das

4C 4C

Secuenciacin Secuenciacin

Rev 36 05/05/2009

G-1148

Genotipo del COL1A1 Ss

S.P. (EDTA)

2 ml

10 das

4C

PCR

OTC Ornitin carbamilasa G-1149 Secuenciacin exn-intrn del gen OTC S.P (EDTA) 5 ml 15 das 4C Secuenciacin

Otopalatodigital, Sndrome de G-1150 PAI 1 G-1151 Promotor 4G/5G S.P (EDTA) 2 ml 10 das 4C PCR Secuenciacin gen FLNA S.P. (EDTA) 5 ml 15 das 4C MLPA

Pancreatitis crnica G-1152 Mutacin N34S del gen SPINK1 S.P (EDTA) 5 ml 15 das 4C Secuenciacin

Pancreatitis hereditaria G-1153 Mutacin R122H del gen tripsingeno catinico S.P (EDTA) 5 ml 15 das 4C Secuenciacin

PANK2 (HARP sndrome (hipoprebetalipoproteinemia, acantocitosis, retinitis pigmentosa y degeneracin plidal) G-1154 Secuenciacin exn-intrn del gen PANK-2 S.P (EDTA) 2 ml 15 das 4C Secuenciacin

Parlisis peridica familiar G-1155-1 Hipokalmica: Secuenciacin exones 11 y 30 de CACNA1S y secuenciacin exn 12 de SCN4A. G-1155-2 Secuenciacin intrn-exn de SCN4A G-1155-3 Secuenciacin intrn-exn de CACNA1S G-1155-4 Hiperkalmica: Mutacin T704M G-1155-5 Mutaciones L6891, I693T, T704M, A1156T, M1360V, 1495F, M1592V, F1490L+M1493I G-1155-6 Secuenciacin exones 13,19,21-24 Paramiotona congnita G-1156 Secuenciacin gen SCN4A S.P. (EDTA) 3 ml 25 das 4C Secuenciacin

S.P (EDTA) S.P (EDTA) S.P (EDTA) S.P (EDTA) S.P (EDTA) S.P (EDTA)

2 ml 2 ml 2 ml 5 ml 2 ml 5 ml

15 das 15 das 15 das 3 das 10 das 15 das

4C 4C 4C 4C 4C 4C

Secuenciacin Secuenciacin Secuenciacin PCR Secuenciacin Secuenciacin

Paraplejia Espstica Familiar G-1157-1 Estudio duplicacin del gen PLP1 G-1157-2 Secuenciacin exn-intrn del gen SPG3 G-1157-3 Secuenciacin exn-intrn del gen SPG4 S.P (EDTA) S.P (EDTA) S.P (EDTA) 5 ml 5 ml 5 ml 15 das 15 das 15 das 4C 4C 4C MLPA Secuenciacin Secuenciacin

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Rev 36 05/05/2009

G-1157-4 Secuenciacin exn-intrn del gen SPG7 G-1157-5 Pelizaeus-Merzbacher-Like Disease: Estudio de deleciones/duplicaciones GJA12 G-1157-6 Secuenciacin exn-intrn del gen GJA12

S.P (EDTA) S.P (EDTA) S.P (EDTA)

5 ml 5 ml 5 ml

15 das 40 das 20 das

4C 4C 4C

Secuenciacin Southern Blot Secuenciacin

Parkinson G-1158 Estudio de mutaciones exn 31 y 41 del gen LRRK2 y exn 4 del gen PINK1 S.P. (EDTA) 2 ml 15 das 4C Secuenciacin

Park-1 G-1159-1 Exones 3 y 4 del gen alfa sinuclena Park-2 G-1159-1 Estudio de deleciones/duplicaciones del gen Park-2 G-1159-2 Secuenciacin exn-intrn del gen Park-2 Park-8 G-1160-1 Screening mutaciones gen LRRK2 G-1160-2 Secuenciacin intrn-exn gen LRRK2 Pfeiffer, Sndrome de G-1161 Secuenciacin FGFR1 (exn 7) y FGFR2 (exones 7,8,13,14 y 15) S.P. (EDTA) 5 ml 30 das 4C Secuenciacin S.P. (EDTA) S.P. (EDTA) 3 ml 6 ml 20 das 50 das 4C 4C Secuenciacin Secuenciacin S.P (EDTA) S.P (EDTA) 3 ml 3 ml 15 das 15 das 4C 4C MLPA Secuenciacin S.P. (EDTA) 3 ml 20 das 4C Secuenciacin

Polimorfismos de Rec. Estrognicos G-1162 Pompe, Sndrome de G-1163-1 Screening mutaciones Arg854X, Asp645Glu e IVS1-13 T>G del gen GAA G-1163-2 Secuenciacin del gen GAA Prader/Willi Sndrome de G-1164-1 Estudio de Metilacin G-1164-2 Disoma Uniparental Promotor eNOS G-1165 Polimorfismo T786C

S.P (EDTA)

5 ml

15 das

4C

PCR-RFLP

S.P.(EDTA) S.P. (EDTA)

3 ml 3 ml

15 das 30 das

4C 4C

Secuenciacin Secuenciacin

S.P (EDTA) S.P (EDTA)

5 ml 5 ml

10 das 10 das

4C 4C

PCR GeneScan

S.P (EDTA)

5 ml

15 das

4C

PCR-RFLP

Pseudoacondroplasia G-1166-1 Screening exn 13 del gen COMP S.P (EDTA) 3 ml 15 das 4C Secuenciacin

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Rev 36 05/05/2009

G-1166-2 Screening exones 8-14 y 15-19 del gen COMP G-1166-3 Secuenciacin exn-intrn del gen COMP Pseudoxantoma Elstico G-1167-1 Delecin 16.4Kb 23-29 ms secuenciacin exones 24 y 28 G-1167-2 Secuenciacin gen ABCC6 intrn-exn + delecin 16.4kb Prpura trombocitopnica trombtica G-1230 Secuenciacin gen ADAMTS 13

S.P (EDTA) S.P (EDTA)

3 ml 3 ml

25 das 40 das

4C 4C

Secuenciacin Secuenciacin

S.P (EDTA) S.P (EDTA)

5 ml 5 ml

15 das 25 das

4C 4C

Secuenciacin Secuenciacin

S.P. (EDTA)

5 ml

50 das

4C

Secuenciacin

QT largo, sndrome G-1168 LQT1. Secuenciacin intrn-exn del gen KCNQ1 S.P (EDTA) 5 ml 15 das 4C Secuenciacin

Querubinismo G-1224 Secuenciacin exn 9 gen SH3BP2 S.P. (EDTA) 3 ml 15 das 4 Secuenciacin

Retinitis pigmentosa dominante G-1169 RHO S.P (EDTA) 5 ml 20 das 4C Secuenciacin

Retinosquisis G-1170-1 Anlisis de mutaciones (E72K, G74V, G109R) G-1170-2 Secuenciacin gen RS1 S.P (EDTA) S.P (EDTA) 5 ml 5 ml 15 das 25 das 4C 4C Secuenciacin Secuenciacin

Rett, Sndrome de G-1171 Secuenciacin gen MECP2 S.P (EDTA) 5 ml 15 das 4C Secuenciacin

Retraso mental G-1172 Estudio de regiones Subtelomricas S.P (EDTA) 2 ml 10 das 4C MLPA

Rin poliqustico, Sndrome del G-1173-1 PKD1 y 2. Estudio Indirecto microsatlites G-1173-2 Secuenciacin intrn-exn genes PKD1 y/o PKD2 G-1173-3 Secuenciacin intrn-exn gen PKHD1 G-1173-4 Secuenciacion exones 15, 22, 27, 50, 55 y 59 PKHD1 G-1173-5 Secuenciacion exones 3, 5, 9, 16, 17, 18, 32, PKHD1 34, 36, 39, 57, 58 Y 61 G-1173-8 Secuenciacin intrn-exn gen PKD1 G-1173-9 Secuenciacin intrn-exn gen PKD2
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S.P (EDTA) S.P (EDTA) S.P (EDTA) S.P (EDTA) S.P (EDTA) S.P. (EDTA) S.P. (EDTA)

5 ml 5 ml 5 ml 5 ml 5 ml 5 ml 5ml

15 das 45 das 15 das 30 dias 30 dias 35 das 35 das

4C 4C 4C 4C 4C 4C 4C

Estudio indirecto Secuenciacin Secuenciacin Secuenciacion Secuenciacion Secuenciacin Secuenciacin

Rev 36 05/05/2009

Robinow, Sndrome de G-1225-1 Secuenciacin intrn-exn gen ROR2 Russel-Silver G-1220 Saethre-Chotzen, Sndrome de G-1174-1 Secuenciacin gen FGFR2 G-1174-2 Secuenciacin gen FGFR3 G-1174-3 Secuenciacin gen TWIST Selectina L G-1175 Polimorfismo F206L S.P (EDTA) 5 ml 15 das 4C PCR S.P. (EDTA) S.P. (EDTA) S.P. (EDTA) 5 ml 5 ml 5 ml 30 das 30 das 30 das 4C 4C 4C Secuenciacin Secuenciacin Secuenciacin S.P. (EDTA) 3 ml 20 das 4C MLPA S.P. (EDTA) 5 ml 45 das 4C Secuenciacin

Simpson-Golabi-Behmel, Sndrome de G-1176-1 Secuenciacin gen GPC3 G-1176-2 Estudio de deleciones G-1176-3 Secuenciacin y estudio de deleciones Sndrome Nefrtico Congnito G-1177-1 Secuenciacin regin codificante del gen NPHS1 G-1177-2 Secuenciacin regin codificante del gen NPHS2 Sndrome Velocardiofacial G-1178 Estudio deleciones 22q11 S.P (EDTA) 3 ml 7 das 4C MLPA S.P (EDTA) S.P (EDTA) 5 ml 5 ml 25 das 25 das 4C 4C Secuenciacin Secuenciacin S.P. (EDTA) S.P. (EDTA) S.P. (EDTA) 3 ml 3 ml 3 ml 25 das 15 das 25 das 4C 4C 4C Secuenciacin MLPA Secuenciacin + MLPA

Smith-Lemli-Opitz, Sndrome de G-1179 CONSULTAR

Sobresalto, Sndrome de. Hiperekplexia G-1183 Secuenciacin gen GLRA1 S.P. (EDTA) 3ml 30 das 4C Secuenciacin

Sordera Hereditaria G-1180-1 Estudio de mutaciones Conexina 26 y ADN mitocondrial A1555G G-1180-2 Screening genes GJB2 GJB6 y OTOF G-1180-3 Estudio de mutaciones ADN mitocondrial A1555G S.P (EDTA) S.P. (EDTA) S.P. (EDTA) 2 ml 3 ml 3 ml 15 das 20 das 10 das 4C 4C 4C Secuenciacin Secuenciacin + PCR Secuenciacin

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Rev 36 05/05/2009

Sordera Hereditaria AD G-1180-4 Mutaciones puntuales GJB2 / GJB6 Sotos, Sndrome de G-1181-1 NSD1 Estudio de delecin G-1181-2NSD1 Secuenciacin mutaciones NSD1 S.P (EDTA) S.P (EDTA) 5 ml 5 ml 15 das 15 das 4C 4C MLPA Secuenciacin S.P. (EDTA) 3 ml 15 das 4C Secuenciacin

SRY G-1182 Estudio de Delecin S.P (EDTA) 5 ml 5 das 4C Multiplex PCR

Talasemia Alfa G-1184 3.7, 4.2, 20.5, SEA, FIL y MED, S.P (EDTA) 2 ml 15 das 4C Multiplex PCR

Talasemia Beta G-1185 Secuenciacin del gen -globina S.P (EDTA) S.P. (EDTA9 2 ml 3 ml 15 das 20 das 4C 4C Secuenciacin MLPA

G-1185-1 Estudio de deleciones

Tay-Sachs, Enfermedad de- Gangliosidosis GM2 G-1186 +TATC1278, +1IVC12, +1IVS9, G269S, R247W y R249W S.P (EDTA) 10 ml 15 das 4C ARMS-PCR

Telangiectasia Hemorrgica Hereditaria (HHT1) G-1187-1 Telangiectasia Hemorrgica Hereditaria (HHT2) G-1187-2 Tirosinemia Ia G-1188 Secuenciacin exnica con sus regiones flanqueantes conteniendo IVS6-1 G>T, IVS7-6 T>G e IVS12+5G>A. S.P (EDTA) 2 ml 15 das 4C Secuenciacin S.P (EDTA) 2 ml 45 das 4C Secuenciacin S.P (EDTA) 2 ml 45 das 4C Secuenciacin

Thomsen, Miotona de G-1189-1 Secuenciacin exn-intrn CLCN1 G-4489-2 Mutacin puntual Townes Brocks, Sndrome de G-1233 Treacher-Collins, Sndrome de G-1190 S.P. (EDTA) 3 ml 30 das 4C Secuenciacin S.P. (EDTA) 5 ml 30 das 4C Secuenciacin S.P (EDTA) S.P (EDTA) 2 ml 2 ml 30 das 5 das 4C 4C Secuenciacin Secuenciacin

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Trombocitosis Familiar (TPO) G-1191 UMOD (uromodulin-associated kidney disease) G-1192 Secuenciacin exones 4,5 y 6 del gen UMOD S.P (EDTA) 2 ml 15 das 4C Secuenciacin S.P (EDTA) 2 ml 15 das 4C RFLP

Ua-Rtula, Sndrome de G-1193 Secuenciacin intrn-exn gen LMX1B S.P. (EDTA) 3 ml 30 das 4C Secuenciacin

Van der Woude, Sndrome de G-1194 VDR G-1195 VDR 2 G-1196 Fokl polimorfismo 5 Receptor Vitamina D S.P (EDTA) 2 ml 15 das 4C RFLP BsmaI polimorfismo intrn 7 Receptor Vitamina D S.P (EDTA) 2 ml 15 das 4C RFLP Secuenciacin intrn-exn gen IRF6 S.P. (EDTA) 5 ml 30 das 4C Secuenciacin

Vitreoretinopata exudativa familiar G-1197-2 Gen FZDA Von Hippel Lindau G-1198 Secuenciacin intrn-exn del gen VHL S.P (EDTA) 2 ml 15 das 4C Secuenciacin S.P. (EDTA) 3 ml 20 das 4C Secuenciacin

Waardenburg, Sndrome de G-1199 Walker-Warburg, Sndrome de G-1200 Secuenciacin del gen POMT1 S.P. (EDTA) 5 ml 15 das 4C MLPA S.P (EDTA) 2 ml 25 das 4C Secuenciacin

Williams, Sndrome de G-1201 Estudio de delecin S.P (EDTA) 5 ml 10 das 4C MLPA

Wilson, Sndrome de G-1202-1Secuenciacin exones 2, 14 y 18 G-1202-2 Secuenciacin completa ATP7B G-1202-3 1 Mutacin de ATP7B S.P (EDTA) S.P (EDTA) 5 ml 5 ml 15 das 45 das 4C 4C Secuenciacin Secuenciacin

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Rev 36 05/05/2009

Wolfram, Sndrome de G-1203Secuenciacin exones del 2 al 8 S.P. (EDTA) 5 ml 15 das 4C Secuenciacin

X-Frgil, Sndrome G-1204-1 Screening G-1204-2 Southern Blot Xantomatosis cerebrotendinosa G-1221 Secuenciacin gen CYP27A1 Zigosidad CONSULTAR S.P. (EDTA) 5 ml 25 das 4C Secuenciacin S.P (EDTA) S.P (EDTA) 10 ml 15 ml 7 das 45 das 4C 4C TP-PCR Southern blot

2.- ONCOLOGIA MOLECULAR


BRCA 1 y 2 O-1001-1 Secuenciacin intrn-exn de los genes BRCA 1 y 2 O-1001-2 Screening BRCA-1 y BRCA-2: Mutaciones consenso en cancer hereditario en poblacin espaola O-1001-3 Estudio deleciones/duplicaciones BRCA1 O-1001-4 Estudio deleciones/duplicaciones BRCA2 O-1001-9 Prdida allica (LOH) O-1001-4 BRCA 1 (anlisis de secuencia) O-1001-6 BRCA 2 (anlisis de secuencia) O-1001-7 BRCA 1 (screening mutaciones consenso en cncer hereditario en poblacin espaola) O-1001-8 BRCA 2 (screening mutaciones consenso en cncer hereditario en poblacin espaola) S.P. (EDTA) S.P (EDTA) S.P (EDTA) S.P (EDTA) S.P (EDTA)+ biopsia S.P.(EDTA) S.P.(EDTA) S.P. (EDTA) S.P. (EDTA) 10 ml 2 ml 2 ml 2 ml 5 ml 5 ml 5 ml 3 ml 3 ml 90 das 15 das 15 das 15 das 15 das 50 das 50 das 15 das 15 das 4C 4C 4C 4C 4C 4C 4C 4C 4C Secuenciacin Secuenciacin MLPA/GeneScan MLPA/GeneScan Microsatlites Secuenciacin Secuenciacin Secuenciacin Secuenciacin

Cncer de colon Polipsico (APC) O-1002-1 Secuenciacin completa exn 15 (90% de las mutaciones) S.P. (EDTA) O-1002-2 Screening: Fragmento del exn 15 conteniendo I1307K y E1317Q O-1002-3 Mutacin puntual Cncer de colon no polipsico O-1003-1 Secuenciacin intrn-exn del gen MLH 1 O-1003-2 Secuenciacin Intrn-exn del gen MSH 2 S.P (EDTA) S.P (EDTA) 10 ml 10 ml 90 das 90 das 4C 4C Secuenciacin Secuenciacin S.P (EDTA) S.P. (EDTA) 10 ml 2 ml 2 ml 45 das 15 das 10 das 4C 4C 4C Secuenciacin Secuenciacin Secuenciacin

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Rev 36 05/05/2009

O-1003-3 Secuenciacin Intrn-exn del gen MSH 6 O-1003-4 Inestabilidad cromosmica en cncer de colon: Estudio microsatlites O-1003-5 Mutacin puntual Cncer gstrico familiar O-1014 Cerb 2 O-1013 C-Myc O-1004 Secuenciacin completa Intrn-exn Secuenciacin gen CDH1

S.P (EDTA) S.P (EDTA) + Biopsia S.P. (EDTA)

10 ml

90 das 15 das

4C 4C 4C

Secuenciacin GeneScan Secuenciacin

2 ml

10 das

S.P. (EDTA)

3 ml

20 das

4C

Secuenciacin

Tejido en parafina

20 das

4C

Inmunohistoqumica y FISH

S.P. (EDTA)

2 ml

15 das 4C

Secuenciacin

Deteccin de clulas metastsicas: O-1005-1 Citoqueratina 19 Carcinoma de mama metasttico O-1005-2 Citoqueratina 20 Carcinoma de tiroides metastsico O-1005-3 PSA Cncer de Prstata metasttico S.P (EDTA) S.P (EDTA) S.P (EDTA) S.P (EDTA) 10 ml 10 ml 5 ml 2 ml 15 das 4C Nested PCR Nested PCR Nested PCR Nested PCR

15 das 4C 7 das 7 das 4C 4C

O-1005-4 Tirosinasa Melanoma metasttico GSTP1 Metilacion del promotor O-1006 MEN-1 O-1007-1 Secuenciacin intrn-exn del gen MEN1 MEN-2 O-1007-2 Secuenciacin exones 10,11,13-16 del gen RET O-1007-3 Secuenciacin exones 10 y 11 del gen RET Mutaciones del gen K-ras O-1008 Secuenciacin exn-intrn del gen K-ras Metilacin del promotor (cncer de prstata)

Orina tras masaje prosttico 10 das

4C

Metilacin-PCR

S.P (EDTA)

2 ml

15 das

4C

Secuenciacin

S.P (EDTA) S.P (EDTA)

2 ml 2 ml

15 das

4C

Secuenciacin Secuenciacin

15 das 4C

S.P (EDTA)

2 ml

15 das 4C

Secuenciacin

Mutaciones del gen p16 O-1009 Melanoma Hereditario. Secuenciacin exn 1, 2 y 3 S.P (EDTA) 2 ml 15 das 4C Secuenciacin

p53 O-1010-1 Secuenciacin intrn-exn O-1010-2 Prdida allica (LOH) S.P (EDTA) S.P (EDTA) + biopsia 2 ml 5 ml 15 das 15 das 4C 4C Secuenciacin Microsatlites

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Rev 36 05/05/2009

PTEN O-1011 Secuenciacin completa S.P. (EDTA) 5 ml 20 das 4C Secuenciacin

Retinoblastoma O-1012-1 Secuenciacin exn-intrn del gen RB1 O-1012-2 Deleciones/duplicaciones gen RB1 S.P (EDTA) S.P (EDTA) 2 ml 2 ml 15 das 15 das 4C 4C Secuenciacin MLPA

3.- HEMATOLOGIA MOLECULAR


AML inv (16) (p13a22): CBFB-MYH11 H-1001 Anlisis de la expresin del Gen mdr1 H-1002 Bcl-1 H-1003 Bcl-2 H-1004 Bcl-6 H-1006 Cromosoma Ph (BCR-ABL) H-1007-1 Cuantificacin H-1007-2 Deteccin S.P (EDTA), M.O. (EDTA) S.P (EDTA), M.O. (EDTA) 5 ml 5 ml 5 das 5 das 4C 4C Real Time PCR RT-Nested/PCR S.P. (EDTA) 2 ml 15 das 4C Nested PCR S.P. (EDTA) 2 ml 15 das 4C Nested PCR S.P. (EDTA) 2 ml 15 das 4C Nested PCR Multidrug resistance S.P (EDTA) 2 ml 15 das 4C Secuenciacin S.P. (EDTA), M.O. (EDTA) 5 ml 5 das 4C Real Time PCR

Estudio del reordenamiento t(11:18) H-1008-1 Linfoma Marginal cutneo S.P (EDTA) 2 ml 5 das 4C Nested PCR

Estudio del reordenamiento AML/ETO H-1008-2 Cualitativo S.P (EDTA), M.O. (EDTA) H-1008-12 Cuantitativo 5 ml 5 das 4C Nested PCR/RealTime

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Rev 36 05/05/2009

Estudio del reordenamiento CBFbeta MYH11 H-1008-3 Estudio del reordenamiento DEK/CAN H-1008-4 Estudio del reordenamiento E2A/PBX H-1008-5 Cualitativo S.P (EDTA) H-1008-13 Cuantitativo Estudio del reordenamiento MLL/AF4 H-1008-6 H-1008-14 Cualitativo S.P (EDTA) Cuantitativo 2 ml 5 das 4C Nested PCR/RealTime 2 ml 5 das 4C Nested PCR/RealTime S.P (EDTA) 2 ml 5 das 4C Nested PCR S.P (EDTA) 2 ml 5 das 4C Nested PCR/RealTime

Estudio del reordenamiento MYC/IgH H-1008-7 Estudio del reordenamiento NPM/ALK H-1008-8 Estudio del reordenamiento PLZF/RAR H-1008-9 H-1008-15 Cualitativo S.P (EDTA) Cuantitativo 2 ml 5 das 4C Nested PCR S.P (EDTA) 2 ml 5 das 4C Nested PCR S.P (EDTA) 2 ml 5 das 4C Nested PCR

Estudio del reordenamiento PML/RAR H-1008-10 H-1008-16 Cualititivo S.P (EDTA) Cuantitativo 2 ml 5 das 4C Nested PCR/RealTime

Estudio del reordenamiento TEL/AML1 H-1008-11 H-1008-17 Hipereosinofilia: H-1009 Leucemia Linfoblstica Aguda H-1010 BCR-abl, TEL-AML1, E2A-PBX1, MLL-AF4 Cualitativa/cuantitativa S.P (EDTA), M.O. (EDTA) 2 ml 10 das 4C Nested/PCR S.P (EDTA) 2 ml 5 das 4C Nested PCR Cualitativo S.P (EDTA) Cuantitativo 2 ml 5 das 4C Nested PCR/RealTime

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Rev 36 05/05/2009

Linfoma B. Clonalidad H-1011-1 Linfoma T. Clonalidad H-1011-2 Policitemia Vera H-1012-1 Gen BCR-X H-1012-2 Jak2 (V617F) Pruebas de quimerismos (STR y VNTRs) H-1013 S.P (EDTA), M.O. (EDTA) 5 ml 20 das 4C GeneScan S.P (EDTA) S.P (EDTA) 2 ml 2 ml 5 das 5 das 4C 4C Nested PCR Nested PCR S.P (EDTA) 2 ml 5 das 4C Nested/PCR/RealTime S.P (EDTA) 2 ml 5 das 4C Nested/PCR/RealTime

4.- ENFERMEDADES MITOCONDRIALES


Atrofia ptica de Leber MT-1001 Mutaciones G3460A, G11778A y T14484C Diabetes Mitocondrial t-RNA (Leu (UUR)) MT-1002 Mutacin A3.243G Encefalopata Mitocondrial Melas MT-1003 Mutaciones A3243, A3253, C3256, T3271 y T3291 Epilepsia Mioclnica MERRF MT-1004 Mutaciones A8344G y T8356C Leighs, Sndrome de MT-1005 Mutacin T8993G Madelung, Sndrome de MT-1006 Mutacin A8344G Narp MT-1007 Mutacin T8993G S.P. (EDTA) 2 ml 5 das 4C Secuenciacin S.P. (EDTA) 2 ml 5 das 4C Secuenciacin S.P. (EDTA) 2 ml 5 das 4C PCR S.P. (EDTA) 2 ml 5 das 4C Secuenciacin S.P. (EDTA) 2 ml 5 das 4C Secuenciacin S.P. (EDTA) 5 ml 10 das 4C Secuenciacin S.P. (EDTA) 2 ml 5 das 4C Secuenciacin

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Rev 36 05/05/2009

5.- FORENSE
Identificacin Gemelar F-1001 S.P (EDTA), 5 ml escobilln en seco, 15 das 4C GeneScan

Perfil Gentico F-1002 S.P (EDTA), 5 ml escobilln en seco, 15 das 4C GeneScan

Pruebas de Maternidad F-1003 S.P (EDTA), 5 ml escobilln en seco, 15 das 4C GeneScan

Pruebas de Paternidad F-1004 S.P (EDTA), 2 ml escobilln en seco, 15 das 4C GeneScan

6.- INMUNOLOGA
ESTUDIO MOLECULAR HLA B*5701 I-1001 ESTUDIO MOLECULAR HLA DQ2 I-1002 ESTUDIO MOLECULAR HLA DQ8 I-1003 ESTUDIO MOLECULAR HLA DQ2 Y HLA-DQ8 ASOCIADOS A ENFERMEDAD CELIACA I-1004 ESTUDIO MOLECULAR HLA DQ CLASE II TIPAJE (BAJA RESOLUCIN) I-1005 ESTUDIO MOLECULAR HLA DQ TIPAJE I-1006 S.P. (EDTA) 2 ml 5 das 4C PCR S.P. (EDTA) 2 ml 5 das 4C PCR S.P. (EDTA) 2 ml 5 das 4C PCR S.P. (EDTA) 2 ml 5 das 4C PCR S.P.(EDTA) 2 ml 5 das 4C PCR S.P. (EDTA) 2 ml 5 das 4C PCR

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Rev 36 05/05/2009

ESTUDIO MOLECULAR HLA DR4 I-1007 ESTUDIO MOLECULAR HLA DRB1 ASOCIADO A NARCOLEPSIA I-1008 ESTUDIO MOLECULAR HLA DRB1 CLASE II TIPAJE (BAJA RESOLUCIN) I-1009 ESTUDIO MOLECULAR HLA-B27 I-1010 S.P. (EDTA) 2 ml 5 das 4C PCR S.P. (EDTA) 2 ml 5 das 4C PCR S.P. (EDTA) 2 ml 5 das 4C PCR S.P. (EDTA) 2 ml 5 das 4C PCR

7.- OTRAS
Banco de ADN para donantes y muestras forenses V-1001 Cromosomopatas V-1002 V-1003 V-1004 1 cromosoma 13,18,21, X o Y 3 cromosomas 13,18,21, X o Y 5 cromosomas 13,18,21, X e Y S.P (EDTA), L. A S.P (EDTA), L. A S.P (EDTA), L. A. 2 ml 2 ml 2 ml 2 das 2 das 2 das 4C 4C 4C QF-PCR QF-PCR QF-PCR Consultar

PRNP (Creutzfeld-Jacob) V-1005-1 Estudio polimorfismos V-1005-2 Secuenciacin S.P. (EDTA) S.P. (EDTA) 2 ml 2 ml 10 das 15 das 4C 4C Secuenciacin Secuenciacin

8.-PERFILES GENTICOS
Para ms informacin, solicitar los catlogos especficos de PERFILES GENTICOS.
ANTIAGING P-1004-5 Complet hombre (69 SNPs) P-1004-6 Complet mujer (73 SNPs) P-1004-8 Basic (43/46 SNPs) P-1004-7 Basic 2 (25 SNPs) P-1004-14 Cardio-Profile (38 SNPs)
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S.P (EDTA) S.P (EDTA) S.P (EDTA) S.P (EDTA) S.P (EDTA)

3 ml 3 ml 3 ml 3 ml 3 ml

15 das 15 das 15 das 15 das 15 das

.....4C .....4C .....4C .....4C .....4C

Snapshot Snapshot Snapshot Snapshot Snapshot

Rev 36 05/05/2009

P-1004-15 Osteo-Profile (7 SNPs) P-1004-16 Prostata-Profile (5 SNPs) NUTRICHIP P-1004-2 Complet (40 SNPs) P-1004-4 Basic (25 SNPs) SPORT-PROFILE P-1004-9 Complet (45 SNPs) P-1004-10 Basic (25 SNPs) P-1004-11 Cardio (21 SNPs) P-1004-12 Detox (23 SNPs) P-1004-13 Muerte sbita (12 SNPs)

S.P (EDTA) S.P (EDTA)

3 ml 3 ml

15 das 15 das

.....4C .....4C

Snapshot Snapshot

S.P (EDTA) S.P (EDTA)

3 ml 3 ml

15 das 15 das

.....4C .....4C

Snapshot Snapshot

S.P (EDTA) S.P (EDTA) S.P (EDTA) S.P (EDTA) S.P (EDTA)

3 ml 3 ml 3 ml 3 ml 3 ml

15 das 15 das 15 das 15 das 15 das

.....4C .....4C .....4C .....4C .....4C

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GENTICA MOLECULAR
1.-ENFERMEDADES HEREDITARIAS
3M, Sndrome GEN: CUL7 LOCALIZACIN CROMOSMICA: 6p21.1 HERENCIA: autosmica recesiva El Sndrome 3M se caracteriza por un severo retraso del crecimiento pre y postnatal, dismorfismo facial e inteligencia normal. Adicionalmente los individuos presentan cuello corto, trapecio prominente, esternn deforme, trax corto, hiperlordosis y talones prominentes. Los varones con el sndrome 3M presentan hipogonadismo y, ocasionalmente, hipospadias. CUL7 es el nico gen asociado con el Sndrome 3M, en el cual se han identificado al menos 25 mutaciones diferentes en individuos afectos. Este gen codifica una protena llamada cullina-7, la cual desempea un papel importante en la degradacin de las protenas no deseadas en el sistema ubiquitina-proteasoma.

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3M SYNDROME GENE: CUL7 CHROMOSOMAL LOCALITATION: 6p21.1 MODE OF INHERITANCE: autosomal recessive 3-M syndrome is characterized by severe pre- and postnatal growth retardation, facial dysmorphism, and normal intelligence. Additional features of 3-M syndrome include short broad neck, prominent trapezii, deformed sternum, short thorax, hyperlordosis and prominent heels. Males with 3-M syndrome have hypogonadism and, occasionally, hypospadias. CUL7 is the only gene known to be associated with 3-M syndrome, at least 25 mutations in the CUL7 gene have been identified in people with this syndrome. The CUL7 gene provides instructions for making a protein called cullin-7. This protein plays a role in the cell machinery that breaks down (degrades) unwanted proteins, called the ubiquitinproteasome system.

VOLVER/ RETURN ACE GEN: ACE LOCALIZACIN CROMOSMICA: 17q23 FORMA DE HERENCIA: Ligado al X La enzima convertidora de angiotensina (ACE) es una metalopeptidasa de zinc que transforma angiotensina I (Ang I) en el pptido vasoactivo Ang II e inactiva a la bradikinina. La secuencia completa del aminocido deducida del cDNA contiene 1306 residuos y la secuencia de DNA contiene un polimorfismo que consiste en la presencia o ausencia de un fragmento de 250-pb. La ausencia de esta secuencia constituye una delecin (D), y su presencia, una insercin (I). El genotipo I/D ACE ha sido establecido como un factor de riesgo cardiovascular en poblacin seleccionada, pero la relacin con la hipertensin es controvertida. El genotipo ACE DD ha sido relacionado con la mitad de la variacin de los niveles de ACE en plasma e incremento en los niveles de Ang II podran jugar un papel importante en el aumento de la resistencia perifrica. ANGIOTENSIN CONVERTING ENZYME: CARDIOVASCULAR DISEASE RISK FACTOR GENE: ACE CHROMOSOMAL LOCATION: 17q23 MODE OF INHERITANCE: X-linked Angiotensin-converting enzyme (ACE) is a zinc metallopeptidase that converts angiotensin I (Ang I) into the vasoactive peptide Ang II, and inactivates bradykinin. The complete amino acid sequence deduced from the cDNA contains 1,306 residues, and the DNA sequence contains a polymorphism consisting of the presence or absence of a 250-bp fragment. The absence of the segment constitutes a deletion (D) and its presence, an insertion (I). The I/D ACE genotype has been established as a cardiovascular risk factor in selected populations, but the association with essential hypertension is controversial. ACE DD genotype has been associated with half the variance in ACE plasma levels and increased levels of Ang II could play a role in enhancing peripheral resistance. VOLVER/ RETURN Acondrognesis GEN: COL2A1 LOCALIZACIN CROMOSMICA:12q13.11-q13.2 INCIDENCIA: 1:40,000 1:60,000 MODO DE HERENCIA: Autosmica dominante Rev 36 05/05/2009

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Acondrognesis es un grupo de trastornos que afectan el desarrollo del cartlago y el hueso. Esta se caracteriza por pequea estatura, extremidades cortas, y otras anomalas esquelticas. Ocasiona graves problemas de salud por lo que bebs con acondrognesis generalmente mueren antes de nacer, nacen muertos, o mueren poco despus del nacimiento a causa de una insuficiencia respiratoria. En algunos casos, se ha conseguido una pequea tasa de supervivencia con intenso apoyo mdico. Acondrognesis tipo 2 es uno de trastornos que sufre el esqueleto como consecuencia de mutaciones en el gen COL2A1. Este gen codifica para la protena que forma el colgeno tipo II. Este tipo de colgeno se encuentran principalmente en el cartlago y el lquido vtreo. Es esencial para el desarrollo normal de los huesos y tejido conectivo. Las mutaciones en este gen tambin se asocian con condrodisplasia, osteoartritis de inicio temprano familiar, SED congnita, acondrognesis de Langer-Saldino, displasia de Kniest, el sndrome de Stickler tipo I y displasia tipo S Strudwick. ACHONDROGENESIS GENE: COL2A1 CHROMOSOMAL LOCATION: 12q13.11-q13.2 INCIDENCE: 1:40,000 and 1:60,000 MODE OF INHERITANCE: Autosomal dominant Achondrogenesis is a group of severe disorders that affect cartilage and bone development. These conditions are characterized by a small body, short limbs, and other skeletal abnormalities. As a result of serious health problems, infants with achondrogenesis usually die before birth, are stillborn, or die soon after birth from respiratory failure. Some infants, however, have lived for a short time with intensive medical support. Achondrogenesis type 2 is one of several skeletal disorders that result from mutations in the COL2A1 gene. This gene provides instructions for making a protein that forms type II collagen. This type of collagen is found mostly in cartilage and in the clear gel that fills the eyeball (the vitreous). It is essential for the normal development of bones and other tissues that form the body's supportive framework (connective tissues). Mutations in the COL2A1 gene interfere with the assembly of type II collagen molecules, which prevents bones and other connective tissues from developing properly. Mutations in this gene are associated with achondrogenesis, chondrodysplasia, early onset familial osteoarthritis, SED congenita, Langer-Saldino achondrogenesis, Kniest dysplasia, Stickler syndrome type I, and spondyloepimetaphyseal dysplasia Strudwick type. VOLVER/RETURN

ACONDROPLASIA GEN: FGFR3 LOCALIZACIN CROMOSOMICA: 4p16.3 HERENCIA: autosomica dominante La acondroplasia est caracterizada por un crecimiento seo anormal que da lugar a una baja estatura con un acortamiento desproporcionado de los huesos largos (brazos y piernas cortas), tamao de tronco normal y macrocefalia, entre otras irregularidades. Ms del 99% de los individuos con acondroplasia tiene una de las dos mutaciones descritas en el gen que codifica para el receptor 3 del factor de crecimiento fibroblstico (FGFR3). En cerca del 98%, la mutacin es G380R. Presenta una herencia autosmica dominante y aproximadamente el 80% de los casos es resultado de una mutacin de novo. ACHONDROPLASIA GEN: FGFR3 CHROMOSOMAL LOCATION: 4p16.3 MODE OF INHERITANCE: autosomal dominant Achondroplasia is characterized by abnormal bone growth that results in short stature with disproportionately short arms and legs, a large head. More than 99% of individuals with achondroplasia have one of two mutations in FGFR3. In Rev 36 05/05/2009

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about 98% of individuals, the mutation is a G380R substitution, resulting from a G-to-A point mutation at nucleotide 1138 of the FGFR3 gene. Achondroplasia is inherited in an autosomal dominant manner. Over 80% of individuals with achondroplasia have parents with normal stature and have achondroplasia as the result of a de novo gene mutation. VOLVER/RETURN Adrenoleucodistrofia GEN: ABCD1 LOCALIZACIN CROMOSMICA: Xq28 INCIDENCIA: 1:20,000 - 1:50,000 MODO DE HERENCIA: Ligado al cromosoma X X-ALD es un desorden que afecta a la materia blanca del sistema nervioso y la corteza suprarrenal. Se conocen 3 tipos de fenotipos en hombres. La forma cerebral de los nios se desarrolla habitualmente entre los 4 y 8 aos. Inicialmente se asocia a un desorden de dficit de atencin o hiperactividad; debilitacin progresiva del aprendizaje. El segundo fenotipo, adrenomieloneuropata. El tercer fenotipo, enfermedad de Addison, se presenta como insuficiencia adrenocortical primaria. Aproximadamente en el 20 % de mujeres portadoras desarrollan estos procesos que se asemejan a adrenomieloneuropatas, pero ms tarde (a partir de los 35 aos), y de una forma ms suave que en los hombres. Nuestro laboratorio ofrece la secuenciacin de DNA y anlisis de deleciones y reordenamientos del gen ABCD1 con un lmite de deteccin del 98% X-LINKED ADRENOLEUKODYSTROPHY GENE: ABCD1 CHROMOSOMAL LOCATION: Xq28 INCIDENCE: 1:20,000 and 1:50,000 MODE OF INHERITANCE: X-linked X-ALD is a disorder that affects the nervous system white matter and the adrenal cortex. Three main phenotypes are seen in males. The childhood cerebral form manifests most commonly between ages four and eight years. It initially resembles attention deficit disorder or hyperactivity; progressive impairment of cognition, behaviour. The second phenotype adrenomyeloneuropathy. The third phenotype, "Addison disease only," presents with primary adrenocortical insufficiency. Approximately 20% of females who are carriers develop neurologic manifestations that resemble adrenomyeloneuropathy, but have later onset (age 35 years or later) and milder disease than do affected males. Our laboratory offers DNA sequencing and large deletions and rearrangements analysis of the ABCD1 gene with a detection rate of 98%. VOLVER/RETURN Alagille, Sndrome de GEN: JAG1 LOCALIZACIN CROMOSMICA: 20p12.1-p11.23 MODO DE HERENCIA: Autosmica dominante Dos genes han sido asociados con el sndrome de Alagille, JAG1 y NOTCH2. La secuenciacin del gen JAG1 detecta mutaciones en cerca del 88% de los individuos con diagnstico clnico y mediante FISH se detecta microdelecin de 20p12 incluyendo el gen JAG1 completo en aproximadamente un 7% de los individuos afectos. Se han observado mutaciones en el gen NOTCH2 en menos de un 1% de los individuos con sndrome de Alagille.Nuestro laboratorio ofrece la secuenciacin completa del gen JAG1 as como un screening de los exones 1-6,9,12,17,20,23 y 24 del gen donde se localizan dos tercios de las mutaciones. ALAGILLE SYNDROME GENE: JAG1 CHROMOSOMAL LOCATION: 20p12.1-p11.23 MODE OF INHERITANCE:autosomal dominant

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Alagille syndrome (AGS) is a complex multisystem disorder involving primarily the liver, heart, eyes, face, and skeleton. The clinical features are highly variable, even within families. The major clinical manifestations of AGS are cholestasis, characterized by bile duct paucity on liver biopsy; congenital cardiac defects, primarily involving the pulmonary arteries; posterior embryotoxon in the eye; typical facial features; and butterfly vertebrae. Renal and central nervous abnormalities also occur. Mortality is approximately 10%, with vascular accidents, cardiac disease, and liver disease accounting for most of the deaths. The diagnosis of AGS is primarily based on clinical findings. The two genes associated with AGS are JAG1 and NOTCH2. Sequence analysis of JAG1 detects mutations in over 88% of individuals who meet clinical diagnostic criteria; fluorescence in situ hybridization (FISH) detects a microdeletion of 20p12, including the entire JAG1 gene, in approximately 7% of affected individuals. Mutations in NOTCH2 are observed in fewer than 1% of individuals with AGS. Our laboratory offers DNA sequencing of the JAG1 gene with a detection rate of 98%.Sequence analysis detects mutations in about 88% of individuals with AGS. Two-thirds of the detectable mutations are identified by sequencing exons 1-6, 9, 12, 17, 20, 23, 24 . VOLVER/RETURN

Albinismo Tipo I GEN: TYR LOCALIZACIN CROMOSMICA: 11q HERENCIA: Autosmica recesiva TYR es el nico gen conocido asociado al albinismo culo cutneo tipo I. En nuestro laboratorio ofrecemos la secuenciacin completa del gen Tirosinasa, responsable de esta patologa. Tipo II: OCA2 GEN: OCA2 LOCALIZACIN CROMOSMICA: 15q INCIDENCIA: 1:35.700 HERENCIA: Autosmica recesiva El albinismo oculocutneo se caracteriza por la hipopigmentacin de la piel y el pelo y las caractersticas oculares varan encontrndolas en todos los tipos de albinismo, nistagmus, reduccin de la pigmentacin del iris, reduccin de la pigmentacin retinal, hipoplasia foveal asociada a reduccin de la agudeza visual, reduccin de la visin estereoscpica. Individuos con OCA1A tienen el pelo blanco, piel clara e iris translcidos que no oscurecen con la edad. En el momento del nacimiento, los individuos con OCA1B tienen el pelo blanco o amarillo claro que oscurece con la edad, piel blanca que desarrolla al tiempo cierto grado de pigmentacin e iris azul que cambia a gris o verdoso con el paso del tiempo. La mayora de la poblacin subsahariana afecta de albinismo oculocutneo tipo 2 presenta una delecin en homocigosis de 2.7 kb en el gen OCA2. ALBINISM Type I GEN: TYR CHROMOSOMAL LOCATION: 11q MODE OF INHERITANCE: Autosomal recessive TYR is the only gene known to be associated with oculocutaneous albinism type 1 .Our lab offers sequence analysis of TYR gene , including intron sequences. OCA2 (Oculocutaneous albinism type 2) GENE: OCA2 CHROMOSOMAL LOCATION: 15q INCIDENCE: 1 in 35.700
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MODE OF INHERITANCE: Autosomal recessive Oculocutaneous albinism type 1 (OCA1) is characterized by reduced synthesis of melanin in the skin, hair, and eyes, associated with ocular findings of nystagmus, reduced iris pigment with iris translucency, reduced retinal pigment, foveal hypoplasia with significantly reduced visual acuity usually in the range of 20/100 to 20/400, and misrouting of the optic nerves resulting in alternating strabismus and reduced stereoscopic vision. Individuals with OCA1A have white hair, white skin that does not tan, and fully translucent irises that do not darken with age. At birth, individuals with OCA1B have white or very light yellow hair that darkens with age, white skin that over time develops some generalized pigment and may tan with sun exposure, and blue irises that change to green/hazel or brown/tan with age. Visual acuity may be 20/60 or better in some individuals Oculocutaneous albinism type 2 (OCA2) is characterized by hypopigmentation of the skin and hair and the characteristic ocular changes found in all types of albinism, including nystagmus; reduced iris pigment with iris translucency; reduced retinal pigment with visualization of the choroidal blood vessels on ophthalmoscopic examination; foveal hypoplasia associated with reduction in visual acuity; and misrouting of the optic nerves at the chiasm associated with alternating strabismus, reduced stereoscopic vision, and an altered visual evoked potential (VEP).The majority of individuals of sub-Saharan African heritage with OCA2 are homozygous for a common 2.7-kb deletion. VOLVER/RETURN Aldolasa B GEN: ALDOB LOCALIZACIN CROMOSMICA: 9q HERENCIA: autosmica recesiva La intolerancia hereditaria a la fructosa es una enfermedad metablica autosmica recesiva causada por deficiencia de la aldolasa B. Los individuos afectos sufren dolor abdominal, vmitos, hipoglucemia despus de la ingesta de fructosa, sacarosa o sorbitol. La ingesta continua de estos azcares causa lesiones renales y hepticas, las cuales eventualmente derivan en cirrosis y algunas veces en muerte, particularmente en nios pequeos. En Espaa se han descrito dos mutaciones: A149P y A174D. ALDOLASE B GENE: ALDOB, Aldolase B CHROMOSOMAL LOCATION: 9q MODE OF INHERITANCE: Autosomal recessive Hereditary fructose intolerance (HFI) is an autosomal recessive metabolic disorder caused by aldolase (fructosediphosphate aldolase, B deficiency). Affected subjects suffer abdominal pain, vomiting, and hypoglycaemia after the ingestion of fructose, sucrose, or sorbitol. Continued ingestion of noxious sugars causes hepatic and renal injury, which eventually leads to liver cirrhosis and sometimes death, particularly in small infants. Since the gene coding for human aldolase B (ALDOB) was cloned,2 at least 22 different mutations associated with HFI have been described. In Spain, two major mutations have been found: A149P and A174D. Other mutations are available upon request. VOLVER/RETURN Alfa 1 antitripsina GEN: INHIBIDOR DE PROTEASA (PI o SERPINA1) LOCALIZACIN CROMOSMICA: 14q32.1 MODO DE HERENCIA: Autosmico recesivo El diagnstico de AAT consiste en demostrar la baja concentracin de AAT en plasma o la observacin de una variante deficiente de AAT por el inhibidor de proteasa (PI) o la deteccin de mutaciones en ambas copias del gen SERPINA1, que codifica la AAT. La deficiencia allica ms comn es PI*Z. El 95% AATD se debe a la presencia de los 2 alelos Z. Nuestro laboratorio ha desarrollado un anlisis por PCR para la deteccin de los alelos Z y S. ALPHA-1-ANTITRYPSIN DEFICIENCY GENE: protease inhibitor (PI or SERPINA1) Rev 36 05/05/2009

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CHROMOSOMAL LOCATION: 14q32.1 MODE OF INHERITANCE: autosomal recessive The diagnosis of AATD relies on demonstration of low plasma concentration of alpha-1-antitrypsin (AAT) and either observation of a deficient variant of the protein AAT by protease inhibitor (PI) typing or detection of mutations in both copies of the gene SERPINA1, which encodes AAT. PI*Z is the most common deficiency allele. Ninety-five percent of AATD results from the presence of two Z alleles. Our laboratory have been developed a PCR analysis for detection of Z and S allele. VOLVER/RETURN Alport, sndrome GEN: COL4A5 LOCALIZACIN CROMOSMICA: Xq22-26 INCIDENCIA: 1 POR 10000 MODO DE HERENCIA: Ligado al cromosoma X El sndrome de Alport se caracteriza por tener afeccin renal, coclear y ocular. La principal seal de este sndrome es la hematuria microscpica (microhematuria). Los hombres con el sndrome Alport ligado al cromosoma X (XLAS) padecen microhematuria desde una edad muy temprana. Alrededor del 90% de mujeres con XLAS tambin la tienen. Hay 2 mtodos para el diagnstico clnico: secuenciacin y anlisis de delecin/duplicacin. El anlisis de secuenciacin de COL4A5 identifica cerca del 80% de las mutaciones de individuos afectados con antecedentes familiares en herencia ligada al X. El anlisis de delecin/duplicacin del gen COL4A5 identifica deleciones (tpicamente multiexnicas) cercanas al 10% de individuos afectados con antecedentes familiares ligada al X. ALPORT SYNDROME GENE: COL4A5 CHROMOSOMAL LOCATION: Xq22-26 INCIDENCE: 1 per 10,000 (General population) MODE OF INHERITANCE: X-linked Alport syndrome is characterized by renal, cochlear, and ocular involvement. The hallmark of this syndrome is microscopic hematuria (microhematuria). Males with X-linked Alport syndrome (XLAS) have persistent microhematuria from early in life. Over 90% of females with XLAS have microscopic hematuria. For clinical testing there are two methods: sequence and deletion/duplication analysis. COL4A5 sequence analysis identifies mutations in about 80% of affected individuals whose family history is consistent with X-linked inheritance. COL4A5 deletion/duplication analysis identifies deletions (typically multi-exonic) in about 10% of affected individuals whose family history is consistent with X-linked inheritance. VOLVER/RETURN Alzheimer GEN: APOE, Apolipoprotena E LOCALIZACIN CROMOSMICA: 19q13.2 GEN: APP, Amyloid beta precursor protein LOCALIZACIN CROMOSMICA: 21q GEN: PS1, Presenilina-1 (Alzheimer disease 3) LOCALIZACIN CROMOSMICA: 14q24.3 GEN: PS2, Presenilina-2 (alzheimer disease 4) LOCALIZACIN CROMOSMICA: 1q La enfermedad del Alzheimer se caracteriza por la demencia que tpicamente comienza con una sutil prdida de memoria y lentamente se hace ms severa y, ocasionalmente, incapacita. Otros sntomas comunes son confusin, perdida de juicio, lenguaje confuso, nerviosismo, retiro y alucinaciones. La duracin clnica normal de la enfermedades de 8 a 10 aos, en un rango de 1 a 25 aos. Sobre el 25% de todos los enfermos de Alzheimer familiar en los que el 95% de los casos la enfermedad se inicia despus de los 65 aos y slo el 5% antes de esa edad. La asociacin de alelo APOE e4 con la enfermedad es significantiva; sin embargo el genotipo APOE no es totalmente Rev 36 05/05/2009

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especfico. Mientras que el genotipo de APOE puede tener un papel importante en el diagnstico de la enfermedad en enfermos sintomticos, parece no tener capacidad de diagnstico para pacientes que an no han desarrollado la enfermedad. Se reconocen tres formas de diagnstico temprano de la enfermedad (EOFAD) causado por mutaciones en uno de estos 3 genes (APP, PSEN1, PSEN2). La fuerte relacin entre el alelo APOE e4 y el Alzheimer, segn el control normal de la poblacin, es con el genotipo e4/e4. Este genotipo aparece en el 1% del control normal de poblacin y cercano al 19% los enfermos. En individuos que han sido diagnosticados clnicamente, la probabilidad de que el enfermo sea correctamente diagnosticado se incrementa hasta casi el 97% con la presencia del genotipo APOE e4/e4. Aproximadamente el 42% de personas con Alzheimer no tienen un alelo APOE e4. As, APOE e4 no es especfico para el Alzheimer. La ausencia de un alelo APOE e4 no anula el diagnstico de la enfermedad. Los 3 genes conocidos que se asocian a EOFAD: PSEN1 PSEN2 APP Mutaciones en PSEN1 se asocian con el Alzheimer tipo 3 (AD3) AD3 explica del 30 al 70% de EOFAD Mutaciones en este gen se asocian al tipo 4 (AD4) AD4 explica casi el 5% de todos los EOFAD Mutaciones en este gen se asocian al tipo 1 (AD1) AD1 explica no ms del 10-15% de las EOFAD

Debido a que el Alzheimer es genticamente heterogneo, el asesoramiento gentico de personas con la enfermedad y sus familias debera adaptarse a la informacin disponible para esa familia. ALZHEIMER GENE: APOE, Apolipoprotein E CHROMOSOMAL LOCATION: 19q13.2 GENE: APP, Amyloid beta precursor protein CHROMOSOMAL LOCATION: 21q GENE: PS1, Presenilin-1 (alzheimer disease 3) CHROMOSOMAL LOCATION: 14q24.3 GENE: PS2, Presenilin-2 (alzheimer disease 4) CHROMOSOMAL LOCATION: 1q Alzheimer disease (AD) is characterized by dementia that typically begins with subtle and poorly recognized failure of memory and slowly becomes more severe and, eventually, incapacitating. Other common findings include confusion, poor judgment, language disturbance, agitation, withdrawal, and hallucinations. The typical clinical duration of the disease is eight to ten years, with a range from one to 25 years. About 25% of all AD is familial of which about 95% is late-onset (after age 60-65 years) and 5% is early-onset (before age 65 years). The association of the APOE e4 allele with AD is significant; however, APOE genotyping is neither fully specific nor sensitive. While APOE genotyping may have an adjunct role in the diagnosis of AD in symptomatic individuals, it appears to have no role at this time in predictive testing of asymptomatic individuals. Three forms of early-onset familial AD (EOFAD) caused by mutations in one of three genes (APP, PSEN1, PSEN2) are recognized. The strongest association between the APOE e4 allele and AD, relative to the normal control population, is with the e4/e4 genotype. That genotype occurs in about 1% of the normal control population and in nearly 19% of the familial AD population. In individuals who have the clinical diagnosis of AD, the probability that AD is the correct diagnosis is increased to about 97% in the presence of the APOE e4/e4 genotype. Approximately 42% of persons with AD do not have an APOE e4 allele. Thus, APOE genotyping is not specific for AD. The absence of an APOE e4 allele does not rule out the diagnosis of AD The three genes known to be associated with early-onset familial Alzheimer disease: PSEN1
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PSEN2 APP

Mutations in PSEN1 are associated with Alzheimer disease type 3 (AD3). AD3 accounts for 30%-70% of EOFAD. Mutations in PSEN2 are associated with Alzheimer disease type 4 (AD4). Mutations in PSEN2 account for less than 5% of all EOFAD. Mutations in APP are associated with Alzheimer disease type 1 (AD1). AD1 accounts for no more than 10%-15% of EOFAD.

Because AD is genetically heterogeneous, genetic counseling of persons with AD and their family members must be tailored to the information available for that family. VOLVER/RETURN

Amiloidosis GEN: TTR (Transthyretin) LOCALIZACIN CROMOSMICA: 18q FORMA DE HERENCIA: Autosmica dominante. La amiloidosis se caracteriza por una lenta y progresiva neuropata sensomotora perifrica y neuropata autosmica as como cambios no neuropticos de neuropatologa, cardiomiopata, opacidades vtreas y amiloidosis CNS. Aparece entre los 30 o 40 aos, pero puede aparecer a ms edad. Tpicamente, la neuropatologa sensorial comienza en las extremidades inferiores como parestesia e hipertesia de los pies seguida de una neuropatologa motora con el paso de los aos. La secuenciacin del gen completo de TTR se puede llevar a cabo con eficiencia ya que consiste solamente en 4 exones, y todas las mutaciones hasta ahora identificadas estn presentes en los exones 2, 3 4. La secuenciacin directa detecta ms del 99% de los enfermos que padecen esta enfermedad por causa de mutaciones. AMYLOIDOSIS GENE: TTR (Transthyretin) CHROMOSOMAL LOCATION: 18q MODE OF INHERITANCE: Autosomal dominant Transthyretin (TTR) amyloidosis is characterized by a slowly progressive peripheral sensorimotor neuropathy and autonomic neuropathy as well as non-neuropathic changes of nephropathy, cardiomyopathy, vitreous opacities, and CNS amyloidosis. Onset is usually in the third or fourth decade, but may be later. Typically, sensory neuropathy starts in the lower extremities as paresthesia and hypesthesia of the feet and is followed by motor neuropathy within a few years.Sequence analysis of the entire TTR gene can be performed efficiently because it consists of only four exons, and all the hitherto-identified mutations are present in exons 2, 3, or 4. Direct sequencing detects more than 99% of diseasecausing (amyloidogenic) mutations. VOLVER/RETURN Anlisis indirecto Es importante aclarar que el anlisis indirecto no permite un diagnstico directo de la enfermedad y adems no puede ser utilizado para confirmar un diagnstico en paciente sin una historia familiar de la enfermedad. El anlisis indirecto puede ser usado para hacer predicciones sobre el estado de la enfermedad (incluyendo diagnsitco prenatal), hacer diagnstico en casos familiares previamente estudiados. Las posibles muestras son: sangre, amniocitos, tejidos Adjunto se debe enviar el informe del estudio molecular previo y la historia clnica familiar. LINKAGE ANALYSIS It is important to note that linkage analysis is not a direct diagnostic test and therefore cannot be used to make or
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confirm a diagnosis on a patient without a family history of the disease. Linkage analysis can be used to make predictions about disease status (including prenatal diagnosis) as long as there is a confirmed clinical diagnosis of the disease in the family, and that family member is available for testing. The certainty of results from linkage analysis is dependent upon the degree of informativeness of the family, the accurate diagnosis of the disease, and the accurate representation of relationships of the family members. Please call to discuss each case with us prior to sample collection to ensure that the appropriate samples are obtained. Samples may include blood, amniocytes, CVS, slides, or tissue. We also request that a pedigree and any pertinent clinical history be included with the samples. VOLVER/RETURN Anemia de Diamond Blackfan GEN: RPS19 (Ribosomal protein S19) LOCALIZACIN CROMOSOMICA: 19q13.2 INCIDENCIA: de 5 a 10 de cada 1.000.000 de nacimientos. HERENCIA: En la mayora de los casos de DBA suceden espordicamente. En siguientes generaciones el modo de herencia es autosmico dominante. DBA es una enfermedad sangunea por un fallo en la medula sea. Se caracteriza por no tener capacidad de producir glbulos rojos (necesarias para transportar el oxgeno en el cuerpo). Se diagnostica en pacientes de dos aos de edad, aunque la mayora de los casos se encuentran antes de los 4 meses. La verdadera causa no est clara, pero el problema parece ser un fallo en los primeros pasos de produccin de los glbulos rojos. En ms del 25% de nios afectados hay un defecto en el gen RPS19. DIAMOND-BLACKFAN ANEMIA GENE: RPS19 (Ribosomal protein S19) CHROMOSOMAL LOCATION: 19q13.2 INCIDENCE: 5 to 10 in 1,000,000 births MODE OF INHERITANCE: In most cases DBA occurs sporadically. In subsequent generations the pattern of inheritance is typically autosomal dominant Diamond Blackfan Anaemia (DBA) is a blood condition caused by a failure within the bone marrow. It is characterized by an inability to produce red blood cells (necessary to transport oxygen around the body). It is typically diagnosed before the patients 2nd birthday with the majority of cases found before 4 months old. The exact cause is not clear, but the problem seems to be a fault in one of the early steps of red blood cell production. In up to twenty-five per cent of affected children there is a fault within a gene called RPS19. VOLVER/RETURN

ANEMIA FALCIFORME GEN: HBB LOCALIZACION CROMOSMICA: 11p15.5 HERENCIA: autosmica recesiva La enfermedad de clulas falciformes se caracteriza por un grado variable de hemlisis y episodios intermitentes de oclusin vascular que dan como resultado isquemia tisular y disfuncin crnica y aguda de los rganos. Dolor y/o hinchazn de las manos o los pies son con frecuencia las primeras manifestaciones, y usualmente tiene lugar en nios y bebes. Las consecuencias de la hemlisis incluyen anemia, ictericia, predisposicin a crisis aplstica, coleolitiasis y retraso en el crecimiento y la maduracin sexual. La oclusin vascular y la isquemia tisular pueden generar en dao crnico y agudo de virtualmente cualquier rgano del cuerpo, pero ms significativamente el bazo, el cerebro, los pulmones y los riones. El trmino enfermedad de clulas falciformes engloba un grupo de desrdenes sintomticos asociados a mutaciones en el gen HBB, que codifica para la cadena beta de la hemoglobina, y se define por la presencia de hemoglobina S (Hb Rev 36 05/05/2009

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S). La anemia falciforme es la forma en la que estn presentes dos alelos Hb S. Las otras formas de la enfermedad de clulas falciformes son el resultado de heredar la Hb S junto a otra variante anormal de la globina b. La hemoglobina falciforme (Hb S) es el resultado de una mutacin puntual (Glu6Val) en la cual el codn que determina la posicin del aminocido 6b cambia de GAG, que codifica para el cido glutmico, a GTG, que codifica para la valina. La Hb S es una protena heterotetramrica compuesta por dos cadenas de hemoglobina alfa, dos cadenas de hemoglobina falciforme y cuatro grupos hemo. SICKLE CELL ANEMIA GENE: HBB CHROMOSOMAL LOCALITATION: 11p15.5 MODE OF INHERITANCE: autosomal recessive Sickle cell disease (SCD) is characterized by variable degrees of hemolysis and intermittent episodes of vascular occlusion resulting in tissue ischemia and acute and chronic organ dysfunction. Pain and/or swelling of the hands or feet are often the earliest manifestations of sickle cell disease and usually occur in infants and young children. Consequences of hemolysis include chronic anemia, jaundice, predisposition to aplastic crisis, cholelithiasis, and delayed growth and sexual maturation. Vascular occlusion and tissue ischemia can result in acute and chronic injury to virtually every organ of the body, most significantly the spleen, brain, lungs, and kidneys. The term sickle cell disease encompasses a group of symptomatic disorders associated with mutations in the HBB gene and defined by the presence of hemoglobin S (Hb S). Sickle cell anemia is the Hb SS form. The other forms of sickle cell disease result from co-inheritance of Hb S with other abnormal globin beta chain variants. Sickle hemoglobin (Hb S) results from a single point mutation (Glu6Val) in which the codon determining the amino acid at position 6 has changed from GAG coding for glutamic acid to GTG coding for valine. Hb S is a heterotetrameric protein made up of two hemoglobin alpha chains, two hemoglobin sickle-beta chains, and four heme moieties. VOLVER/RETURN

Angelman, sndrome GEN: UBE3A (ubiquitin protein ligase E3A) LOCALIZACIN CROMOSMICA: 15q11-q13 FORMA DE HERENCIA: delecin; disomia uniparental; impresin de defectos; algunas reordenamientos autosmicos dominantes. El sndrome de Angelman (AS) se caracteriza por un severo retraso del desarrollo o retraso mental, debilitacin severa de comunicacin, ataxia y un comportamiento nico como es la risa frecuente y excitabilidad. Microcefalia y ataques son normales tambin. Nuestro sensible ensayo de metilacin detecta el cromosoma 15 materno, la disocia uniparental del cromosoma 15 paterno e imprime los defectos. Aproximadamente el 78% de los casos con sndrome de Angelman se detectan mediante este anlisis. Este anlisis directo del DNA para los enfermos con este sndrome se recomienda para confirmar el diagnstico de pacientes con o sin antecedentes familiares. El cariotipo de unos padres de un hijo afectado y los estudios de metilacin de un feto son vlidos para un diagnstico prenatal. Otros estudios, incluyendo anlisis por deleciones FISH y estudios dismicos uniparentales (requieren muestras de sangre de los padres), se recomiendan despus de un positivo.

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ANGELMAN SYNDROME GENE: UBE3A (ubiquitin protein ligase E3A) CHROMOSOMAL LOCATION: 15q11-q13 MODE OF INHERITANCE: deletion; uniparental disomy; imprinting defects; some autosomal dominant rearrangements Angelman syndrome (AS) is characterized by severe developmental delay or mental retardation, severe speech impairment, gait ataxia, and a unique behavior that includes frequent laughing, smiling, and excitability. Microcephaly and seizures are also common. Angelman syndrome is caused by a deletion or disruption of the maternal chromosome 15q11-q13 gene region. Our methylation-sensitive assay detects deletions of the maternal chromosome 15, uniparental disomy of the paternal chromosome 15, and imprinting defects. Approximately 78% of Angelman syndrome cases are detectable using this assay. This direct DNA analysis for Angelman syndrome is recommended for the confirmation of a diagnosis in a patient with or without a family history of the condition. Karyotyping parents of an affected child and methylation studies of a fetus are available for prenatal diagnosis. Further studies, including FISH deletion analysis and uniparental disomy studies (which require parental blood samples), are recommended following a positive test result. VOLVER/RETURN ANGIOTENSINGENO GEN: AGT LOCALIZACION CROMOSMICA: 1q42.2 El gen AGT codifica para el angiotensingeno, uno de los principales componentes del sistema renina-angiotensinaaldosterona el cual desempea un papel fundamental en el control de la presin arterial. La relacin entre las variantes gnicas del AGT y la hipertensin ha sido extensamente estudiada. Una de las variantes ms estudiadas es el cambio aminoacdico Met235Thr, que ha sido relacionado con niveles plasmticos de angiotensingeno ms elevados y con mayor riesgo de desarrollo de hipertensin. ANGIOTENSINOGEN GENE: AGT CHROMOSOMAL LOCALITATION: 1q42.2 The regulation of arterial blood pressure (BP) is complex and under the control of different physiological systems. The reninangiotensinaldosterone system (RAAS) is one of the important regulatory systems. Genes encoding products of the RAAS are plausible candidate genes for modifying blood pressure. The angiotensinogen gene (AGT) is one of the few candidates that has been investigated extensively and its genetic variant in exon 2 shows a transition resulting in replacement of methionine by threonine at amino-acid position 235 (M235T). Positive associations between the AGT M235T polymorphism, plasma angiotensinogen levels, and essential arterial hypertension indicate a pathway by which the AGT gene determines arterial BP. VOLVER/RETURN Apo B GEN: apoB LOCALIZACIN CROMOSMICA: 2p24 HERENCIA: autosmica dominante La deficiencia familiar de apoB100 (FDB) junto con la hipercolesterolemia familiar pertenecen al tipo II/a de hiperlipidemia primaria segn la clasificacin de Fredrickson. FDB es una enfermedad autosmica dominante que resulta en hipercolesterolemia. Las manifestaciones clnicas son explicadas debido a la acumulacin en plasma de LDL debido a apoB100 defectuosa. Estos cambios en la apoB100 producen una menor afinidad por el receptor de LDL (responsable en el 80% de los casos). Las consecuencias son hipercolesterolemia, xantoma tendinoso y arterosclerosis prematura, la cual causa temprana enfermedad cardio y cerebrovascular y muerte temprana. La mutacin ms comn es la G10699A, la cual resulta en la sustitucin de Arg por Gln (R3500Q). Los portadores de la
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mutacin poseen slo el 32% de la media de unin al receptor LDL en cultivo de fibroblastos. La FDB es uno de los problemas genticos ms frecuentes que pueden ser tratados fenotpicamente mediante medicamentos que disminuyen los lpidos, dieta APOB R3500Q GENE: apoB CHROMOSOMAL LOCATION: 2p24 MODE OF INHERITANCE: autosomal dominant Familial defective apolipoprotein (apo) B 100 (FDB), together with familial hypercholesterolemia (FH), belong to the type II/a primary hyperlipidemia group based on Fredricksons classification. FDB is an autosomal dominant trait resulting in hypercholesterolemia. Clinical manifestations of FDB are explained by plasma accumulation of low density lipoproteins (LDL) bearing defective apoB100. This change lowers the protein affinity for LDL receptor (LDLR) which is responsible for 80% of its clearance from plasma. The consequences are hypercholesterolemia, tendinous xanthomata and premature atherosclerosis, which cause early onset of cardio- and cerebrovascular disease and early death. The most common mutation is G10699A, which results in substitution of Arg for Gln (R3500Q). The LDL particles from carriers of the R3500Q mutation posses only 32% of the average binding affinity for the LDLR in cultured fibroblasts. FDB is one of the few genetic problems which can be treated phenotypically by lipid lowering drugs and diet regimens, and thus its early diagnosis and treatment is greatly valuable. VOLVER/RETURN Aracnodactilia contractual congnita. Sndrome de Beals GEN: FBN2 LOCALIZACION CROMOSOMICA: 5q23-q31 HERENCIA: autosomica dominante La aracnodactilia contractural congnita (CCA, sndrome de Beals) es un trastorno del tejido conectivo caracterizado por contracturas de flexin mltiples, aracnodactilia, cifoscoliosis grave, pabellones auriculares anormales e hipoplasia muscular. A pesar de que los signos clnicos son similares al sndrome de Marfan (MFS), las contracturas articulares mltiples (especialmente del codo, la rodilla y los dedos) y las orejas arrugadas son caractersticos de la CCA y raramente se observan en el MFS. El nico gen asociado con la CCA es el gen FBN2 que codifica para la fibrilina-2, una protena de la matriz extracelular. La frecuencia de deteccin de mutaciones en individuos afectos tras el anlisis de la secuencia es del 27-75%, segn estudios. Muchos individuos con CCA tienen un padre afecto aunque el desorden tambin puede aparecer como consecuencia de una mutacin de novo. CONGENITAL CONTRACTURAL ARACHNODACTYLY GENE: FBN2 CHROMOSOMAL LOCATION: 5q23-q31 MODE OF INHERITANCE: autosomal dominant Congenital contractural arachnodactyly (CCA, Beals syndrome) is an autosomal dominantly inherited connective tissue disorder characterized by multiple flexion contractures, arachnodactyly, severe kyphoscoliosis, abnormal pinnae and muscular hypoplasia. Although the clinical features can be similar to Marfan syndrome (MFS), multiple joint contractures (especially elbow, knee and finger joints), and crumpled ears are characteristic of CCA and rarely found in MFS. FBN2 gene encoding the extracellular matrix microfibril, fibrillin 2, is the only gene known to be associated with CCA. Mutation detection frequency by sequence analysis in affected individuals is 27-75%. Many individuals with CCA have an affected parent, although a proband may have the disorder as a result of a de novo gene mutation. VOLVER/RETURN

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Artrogriposis distal tipo 1 genes: TPM2, TNNI2, TNNT3 y MYH3 LOCALIZACIN CROMOSMICA: 9p13.2, 11p15.5, 11p15.5, 17p11. INCIDENCIA: 1:3000 HERENCIA: autosmica dominante La artrogriposis distal es un grupo de enfermedades caracterizada por mltiples contracturas en las extremidades. En general la artrogriposis distal se caracteriza por ser no progresiva, presentar contracturas congnitas de dos o ms partes del cuerpo sin enfermedad muscular o neurolgica principal que afecta a la funcin de las extremidades. La caracterstica comn de las artrogriposis distales incluyen un consistente patrn de afectacin distal, un limitado patrn proximal, un patrn de herencia dominante y una amplia expresin fenotpica. Se han descrito 10 tipos distintos de artrogriposis distal de acuerdo a las caractersticas que compartan unos y otros. El prototipo es la artrogriposis distal tipo 1 que cursa con camptodactilia, deformidades en los pies aunque los hombros y cadera pueden estar tambin afectos. En nuestro laboratorio se ofrece el anlisis molecular de TNNI2 (166del, 175del, R156X, R174Q), TNNT3 (R63H) y TPM2 (R91G) como primer estudio pudiendo realizar la secuenciacin completa de estos genes en caso de obtener un resultado negativo en el estudio de mutaciones. ARTHROGRYPOSIS MULTIPLEX CONGENITA, DISTAL, TYPE I GENES: TPM2, TNNI2, TNNT3 and MYH3 CHROMOSOMAL LOCATION: 9p13.2, 11p15.5, 11p15.5, 17p11. INCIDENCE: 1:3000 MODE OF INHERITANCE: autosomal dominant The distal arthrogryposes are a group of disorders characterized by multiple congenital contractures of the limbs. In general, the distal arthrogryposes are characterized by nonprogressive, congenital contractures of two or more different body areas without primary neurological and/or muscle disease that affects limb function. Features common to all distal arthrogryposes include a consistent pattern of distal joint involvement, limited proximal joint involvement, an autosomal dominant inheritance pattern, and widely variable expressivity. Ten different distal arthrogryposes were recognized and classified hierarchically according to the proportion of features they share with one another. The prototypic distal arthrogryposis is distal arthrogryposis type 1, which is primarily characterized by camptodactyly and clubfoot, although the shoulders and hips may also be affected.In our laboratory is available mutation detection of TNNI2 (166del, 175del, R156X, R174Q), TNNT3 (R63H) y TPM2 (R91G) as a first screening but also the sequencing analysis of MYH3 gene as a second chance. VOLVER/RETURN Ataxia de Friedreich GEN: FRDA LOCALIZACIN CROMOSMICA: 9q13 FRECUENCIA DE PORTADORES: 1 CADA 120 HERENCIA: Autosmica recesiva La ataxia de Friedreich (FRDA) se caracteriza por una lenta y progresiva ataxia que empieza a aparecer antes de los 25 aos. Asociada genralmente a la ausencia de reflejos en los tendones, disartria, respuestas de Babinski y prdida de los sentidos de posicin y vibracin. Se estima que el 96% de los casos de esta ataxia tienen una repeticin demostrable de trinucletidos (GAA) homocigticos. La mayora de los portadores de la ataxia de Friedriech presentan un alelo expandido y otro dentro de los lmites. En pacientes en los que el historial familiar presenta esta ataxia se recomienda determinar el estado del portador. El diagnstico prenatal es posible en familias en las que la presencia de la repeticin trinucleotdica ha sido demostrada. Alrededor de 1% de alelos expandidos no son detectables por anlisis de PCR, por lo tanto se usan las tcnicas Southern Blot y/o TP-PCR; y la PCR slo detectan muestras con un tamao normal. FRIEDREICH ATAXIA GENE: FRDA CHROMOSOMAL LOCATION: 9q13 CARRIER FREQUENCY: 1 in 120
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MODE OF INHERITANCE: autosomal recessive Friedreich ataxia (FRDA) is characterized by slowly progressive ataxia with onset usually before the age of 25 years. It is typically associated with depressed tendon reflexes, dysarthria, Babinski responses, and loss of position and vibration senses. An estimated 96% of cases of Friedreich ataxia have a demonstrable homozygous trinucleotide repeat expansion (GAA). Most carriers of Friedreich ataxia have one expanded allele and one allele within normal limits. DNA analysis of patients with a family history of Friedreich ataxia is recommended to determine carrier status. Prenatal diagnosis is available for families in which the presence of a trinucleotide repeat expansion has been demonstrated. About 1% of expanded alleles are not detected by PCR analysis, therefore Southern blot and/or TP-PCR analysis is used to analyze samples with only one size normal repeat detected by PCR. VOLVER/RETURN Ataxia espinocerebelosa LOCALIZACIONES CROMOSMICAS: 6p23 (SCA1), 12q24 (SCA2), 14q32.1 (Machado-Joseph Disease, SCA3), 19p13 (SCA6), 3p21.1-p12 (SCA7), 13q21 (SCA8), 22q13 (SCA10), 5q31-33 (SCA12), 6q27 (SCA17), 9q13 (Friedreich Ataxia), 12p13.31 (Dentatorubral-Pallidoluysian Atrophy, a.k.a. DRPLA) MODO DE HERENCIA: autosmico dominante para todos, menos la ataxia de Friedreich que es recesiva. Las ataxias descritas arriba tienen como caracterstica comn la inestabilidad en el paso, falta de coordinacin, disartria, explosiva habla hiperreflexia. Si se sospecha de un sntoma en particular, primero se puede analizar ese especfico gen. Si es negativo, se continuara con el test completo de ataxia. Es posible el anlisis prenatal para familias en las que se ha demostrado la presencia de repeticiones trinucleotdicas. El anlisis directo de DNA de los genes de la ataxia se recomienda en pacientes que presenten los sntomas, con o sin historial familiar en ataxia. El anlisis de pacientes con historial familiar con el sndrome de ataxia de Friedreich se recomienda para determinar el estado del portador. Incluso se puede realizar el anlisis de pacientes asintomticos y con un positivo en el historial familiar de un autonmico dominante en ataxia. El test de prediccin de estos pacientes, incluido el prenatal, incorpora problemas complicados y riesgos. Por esta razn, recomendamos el asesoramiento gentico a travs de un proceso de pruebas. ATAXIA PANEL CHROMOSOMAL LOCATIONS: 6p23 (SCA1), 12q24 (SCA2), 14q32.1 (Machado-Joseph Disease, SCA3), 19p13 (SCA6), 3p21.1-p12 (SCA7), 13q21 (SCA8), 22q13 (SCA10), 5q31-33 (SCA12), 6q27 (SCA17), 9q13 (Friedreich Ataxia), 12p13.31 (Dentatorubral-Pallidoluysian Atrophy, a.k.a. DRPLA) MODE OF INHERITANCE: autosomal dominant for all but Friedreich Ataxia (recessive) The ataxias listed above have the common characteristics of wide-based unsteady gait, lack of coordination, dysarthria, scanning and explosive speech, and hyperreflexia. If a particular disorder is suspected, gene analysis of that specific disorder can be done first. If negative, the full ataxia panel will follow. Prenatal diagnosis is available for families in which the presence of a trinucleotide repeat expansion has been demonstrated. Direct DNA analysis of the ataxia genes is recommended for symptomatic patients, with or without a family history of ataxia. DNA analysis of patients with a family history of Friedreich ataxia is recommended to determine carrier status. DNA analysis of asymptomatic patients with a positive family history of an autosomal dominant ataxia is also possible. Predictive testing of these patients, including prenatal diagnosis, introduces complex issues and risks. For this reason we recommend genetic counseling throughout the testing process. VOLVER/RETURN ATAXIA EPISDICA TIPO 1 GEN: KCNA1 LOCALIZACION CROMOSMICA: 12q13.32 HERENCIA: autosmica dominante La ataxia episdica, un desorden que afecta al cerebelo, es un sndrome de ataxia intermitente hereditario raro. Los individuos afectados son normales entre los ataques pero se vuelven atxicos bajo condiciones estresantes y de
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cansancio. Hay dos formas diferentes, Ataxias Episdicas tipo 1 y tipo 2, ambas con aparicin temprana de los sntomas y ataques episdicos de ataxia que responden a la acetazolamida (AZM). La Ataxia Episdica tipo 1 (EA1), un desorden que implica tanto al sistema nervioso central como al perifrico, se caracteriza por ataques de ataxia y miokimia persistente, una forma de movimiento muscular involuntario. Los episodios de ataxia, con balanceo al andar y balbuceo al hablar, ocurren de manera espontnea o pueden verse provocados por un movimiento repentino, excitacin o ejercicio. Los ataques generalmente duran desde unos segundos hasta varios minutos, una o varias veces al da. La EA1 est causada por mutaciones en el gen KCNA1 que codifica para un canal de potasio. EPISODIC ATAXIA TYPE 1 GENE: KCNA1 CHROMOSOMAL LOCALITATION: 12q13.32 MODE OF INHERITANCE: autosomal dominant Episodic ataxia, a disorder affecting the cerebellum, is a rare inherited syndrome of intermittent ataxia. Affected individuals are normal between attacks but become ataxic under stressful conditions and with fatigue. There are two distinct forms, Episodic Ataxia type 1 and type 2, both with an early onset of symptoms and episodic attacks of ataxia responsive to acetazolamide (AZM). Episodic Ataxia type 1 (EA1), a disorder involving both the central and the peripheral nervous system, is characterized by attacks of ataxia and persistent myokymia, a form of involuntary muscular movement. Episodes of ataxia, with gait imbalance and slurring of speech, occur spontaneously or can be precipitated by sudden movement, excitement, or exercise. The attacks generally last from seconds to several minutes at a time and may recur many times a day. EA1 is caused by mutation in the potassium channel gene KCNA1. VOLVER/RETURN

Atrofia dentatorubropalidolusiana GEN: DRPLA LOCALIZACIN CROMOSMICA: 12p INCIDENCIA: MENOR A 1 POR 100,000 HERENCIA: Autosmico dominante con anticipacin DRPLA es una enfermedad progresiva caracterizada por ataxia, mioclono, epilepsia y un deterioro progresivo intelectual en nios. Y en adultos, ataxia, coreoatetosis y demencia o cambios de carcter. La edad principal de diagnstico es a los 30 aos (en un rango de edad de 1 a 62 aos). Tanto en casos familiares o espordicos de DRPLA hay una repeticin demostrable de trinucletidos (CAG) que se cree que es la causa de esta enfermedad. El anlisis directo de DNA del gen DRPLA se recomienda en pacientes que presentan sntomas, con o sin historial familiar de ataxia cerebelar y demencia. Hay anlisis de DNA de pacientes con un historial familiar positivo que no presentan los sntomas de DRPLA. La prueba para diagnosticar a estos pacientes, incluido el diagnstico prenatal, introduce complejas cuestiones y riesgos. Por esta razn recomendamos un asesoramiento gentico anterior al test de DRPLA. DENTATORUBRAL-PALLIDOLUYSIAN ATROPHY (DRPLA)
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GENE: DRPLA CHROMOSOMAL LOCATION: 12p INCIDENCE: < 1 in 100,000 MODE OF INHERITANCE: autosomal dominant with anticipation DRPLA is a progressive disorder characterized by ataxia, myoclonus, epilepsy, and progressive intellectual deterioration in children, and ataxia, choreoathetosis, and dementia or character changes in adults. The mean age of onset is 30 years (age range 1-62 years). In both familial and sporadic cases of DRPLA there is a demonstrable trinucleotide repeat expansion (CAG) believed to be the causative factor of the condition. Direct DNA analysis of the DRPLA gene is recommended for patients who show symptoms of the condition, with or without a family history of cerebellar ataxia and dementia. DNA analysis of patients with a positive family history who do not have signs or symptoms of DRPLA is also possible. Predictive testing of these patients, including prenatal diagnosis, introduces complex issues and risks. For this reason we recommend pre-test genetic counseling for DRPLA. VOLVER/RETURN Atrofia muscular espinal GEN: SMN LOCALIZACIN CROMOSMICA: 5q11.2 -13.3 FRECUENCIA DE PORTADORES: 1:40 a 1:60 HERENCIA: autosmica recesiva La atrofia muscular espinal (Spinal Muscular Atrophy o SMA) se caracteriza por una progresiva debilidad muscular causada por la degeneracin y prdida de las clulas del asta anterior (menos neuronas motoras) en la espina dorsal y en el cerebro. El comienzo de la debilidad va desde el nacimiento hasta la etapa adolescente o incluso adulta. En la mayora de los casos de atrofia muscular espinal existe una delecin de los exones 7 y/o 8 del gen SMN. Especficamente la delecin se presenta en el 98% de los pacientes con SMA tipo I (Werdnig-Hoffman), el 92% de los pacientes con SMA tipo II (intermedia) y el 88% de los pacientes con SMA III (Kugelberg-Welander). El anlisis de la delecin se realiza mediante la tcnica de MLPA. Es posible realizar el estudio de portadores y el diagnstico prenatal en familias con casos previos de SMA. SPINAL MUSCULAR ATROPHY GENE: SMN (survival of motor neuron 1) CHROMOSOMAL LOCATION: 5q11.2 -13.3 CARRIER FREQUENCY: 1 in 40 to 1 in 60 MODE OF INHERITANCE: autosomal recessive Spinal muscular atrophy (SMA) is characterized by progressive muscle weakness caused by degeneration and loss of the anterior horn cells (i.e., lower motor neurons) in the spinal cord and the brain stem nuclei. The onset of weakness ranges from before birth to adolescence or young adulthood. In almost all cases of spinal muscular atrophy there is a demonstrable homozygous deletion of exons 7 and/or 8 of the SMN gene. Specifically, 98% of patients with SMA type I (Werdnig-Hoffman) have the deletion; 92% of patients with SMA type II (intermediate) have the deletion, and 88% of patients with SMA type III (Kugelberg-Welander) have the deletion. Direct DNA analysis of the SMN gene is recommended for confirmation of a diagnosis, in place of the more invasive method of muscle biopsy confirmation. Carrier testing is also available. Prenatal diagnosis is available for families in which there is an affected child confirmed to have a homozygous deletion. VOLVER/RETURN Atrofia muscular espinobulbar GEN: androgen receptor LOCALIZACIN CROMOSMICA: Xq11-q12 INCIDENCIA: 1/50,000 HERENCIA: Ligada al X La enfermedad de Kennedy, tambin conocida como atrofia muscular y espinal (SBMA), es una enfermedad degenerativa neuromuscular que afecta a msculos distales implicados en movimientos voluntarios como andar, Rev 36 05/05/2009

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control de la cabeza o cuello y tragar, la SBMA es un raro tipo de atrofia muscular y espinal que aparece siendo el paciente adulto. Tanto los casos familiares como espordicos presentan una demostrable repeticin expansin de trinucletidos (CAG) en el exn 1. Se recomienda el anlisis de DNA en pacientes sintomticos con o sin antecedentes familiares. Se puede hacer el anlisis de DNA en los que si tienen antecedentes, pero sin seales, ni sntomas de la enfermedad. Las pruebas predictivas en estos pacientes, incluido el anlisis prenatal, aade riesgos. Por esta razn, se recomienda hacer un pre-test gentico. KENNEDY DISEASE (SBMA) GENE: androgen receptor CHROMOSOMAL LOCATION: Xq11-q12 INCIDENCE: 1/50,000 MODE OF INHERITANCE: X-linked Kennedy Disease, also known as Spinal and Bulbar Muscular Atrophy (SBMA), is a degenerative neuromuscular disorder that affects proximal muscles involved in voluntary activities such as walking, head and neck control and swallowing. SBMA is a rare adult-onset subtype of Spinal Muscular Atrophy. Both familial and sporadic cases of SBMA exhibit a demonstrable trinucleotide repeat expansion (CAG) in exon 1. Direct DNA analysis of the SBMA gene is now recommended for symptomatic patients with or without a family history of the disorder. DNA analysis of patients with a positive family history who do not have signs or symptoms of SBMA is also possible. Predictive testing of these patients, including prenatal diagnosis, introduces complex issues and risks. For this reason we recommend pre-test genetic counseling for SBMA. VOLVER/RETURN Bartter sndrome tipo II y III GENES: KCNJ1 y CLCNKB LOCALIZACIN CROMOSMICA: 11q21-25 y 1p36 INCIDENCIA: 1.7:100,000 HERENCIA: autosmica recesiva Los pacientes con sndrome de Bartter prenatal presentan frecuentemente polihidroamnios, retraso del crecimiento y suelen ser prematuros. En algunos casos, se ha descrito retraso mental. Tambin es comn la incapacidad de los riones para retener agua y sal originan una prdida de fluido urinario, por lo que la poliuria es tpica. La prdida de volumen incrementa la sed y la respuesta normal es el aumento de la ingesta de lquido. Si los pacientes no reciben suficiente agua y sal, la deshidratacin y la alteracin del estado mental pueden presentarse. En los casos severos de sndrome de Bartter, es probable la presentacin de vmitos, la debilidad muscular debido a la incapacidad de los riones en retener potasio, calcio y magnesio, la aparicin de palpitaciones, espasmos. BARTTER SYNDROME TYPE II and III GENE: KCNJ1 y CLCNKB CHROMOSOMAL LOCATION: 11q21-25 y 1p36 INCIDENCE: 1.7:100,000 MODE OF INHERITANCE: autosomal recessive Patients with antenatal Bartter syndrome often present with polyhydramnios and growth retardation and were delivered prematurely. The inability of the kidney tubules to retain salt and water results in urinary fluid loss, so polyuria is common. The resulting volume depletion increases thirst, and the normal response is to increase fluid intake. If patients cannot receive sufficient salt and water, dehydration and altered mental status can occur. In severe cases of Bartter syndrome, vomiting is not uncommon, producing further volume depletion. Inability of the kidney tubules to retain potassium, calcium, or magnesium can lead to muscle weakness, spasms, tetany, or palpitations. A few patients with severe cases of antenatal Bartter syndrome have also had mental retardation. VOLVER/RETURN Batten, sndrome. Lipofuscinosis GEN: CLN3 Rev 36 05/05/2009

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LOCALIZACIN CROMOSMICA: 16p12.1 INCIDENCIA: 1:25,000 HERENCIA: autosmica recesiva JNCL se manifiesta en sus inicios entre los 4 y los 10 aos. La primera seal clnica es la rpida y progresiva prdida de visin, resultando una completa ceguera de 2 a 4 aos. Epilepsia con procesos generalizados tnico-clnicos o procesos mioclnicos, que aparecen de los 5 a los 18 aos. La esperanza de vida vara desde la adolescencia hasta los treinta aos. La mutacin comn es una delecin en 1-kb que elimina los exones 7-8. BATTEN SYNDROME (JUVENILE NEURONAL CEROID-LIPOFUSCINOSES) GENE: CLN3 CHROMOSOMAL LOCATION: 16p12.1 INCIDENCE: 1:25,000 MODE OF INHERITANCE: autosomal recessive The onset of JNCL is usually between ages four and ten years. Rapidly progressing visual loss resulting in total blindness within two to four years is often the first clinical sign. Epilepsy with generalized tonic-clonic seizures, complexpartial seizures, or myoclonic seizures typically appears between ages five and 18 years. Life expectancy ranges from the late teens to the 30's. The common mutation is a 1-kb deletion that removes exons 7-8. VOLVER/RETURN

BEARE-STEVENSON CUTIS GYRATA GEN: FGFR2 LOCALIZACIN CROMOSMICA: 10q26 HERENCIA: autosmica dominante El Sndrome Beare-Stevenson cutis gyrata se caracteriza por anormalidades de la piel y la fusin prematura de ciertos huesos del crneo (craneosinostosis). Esta fusin temprana impide el crecimiento normal del crneo, afectando a la forma de la cabeza y la cara. Esto tambin repercute en el crecimiento del cerebro, causando retraso intelectual y del desarrollo. El cutis gyrata, caracterstico de este desorden, se presenta como un aspecto arrugado de la piel, en particular sobre la cara, cerca de los odos, y en las palmas y las plantas de los pies. El sndrome de Beare-Stevenson puede estar causado por una o dos mutaciones del gen FGFR2 (Tyr375Cys y Ser372Cys). Esta gen codifica el receptor del factor de crecimiento de fibroblastos 2.

BEARE-STEVENSON syndrome GENE: FGFR2 CHROMOSOMAL LOCALITATION: 10q26 MODE OF INHERITANCE: autosomal dominant Beare-Stevenson cutis gyrata syndrome is a genetic disorder characterized by skin abnormalities and the premature fusion of certain bones of the skull (craniosynostosis). This early fusion prevents the skull from growing normally and affects the shape of the head and face, also affects the growth of the brain, causing delayed development and intellectual disability. A skin abnormality called cutis gyrata is also characteristic of this disorder. The skin has a wrinkled appearance, particularly on the face, near the ears, and on the palms and soles of the feet. Beare-Stevenson syndrome can be caused by one of two FGFR2 mutations (Tyr375Cys and Ser372Cys). VOLVER/RETURN

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BeckwithWiedemann, Sndrome de GEN: KCNQ1OT1 LOCALIZACIN CROMOSOMICA: 11p15.5 INCIDENCIA: 1 in 13,700 FORMA DE HERENCIA: BWS es un desorden del crecimiento caracterizado por la macrosoma (tamao del cuerpo grande), macroglosa, visceromegalia, tumores en embriones (por ejemplo tumor de Wilms, hepatoblastoma, neuroblastoma, rabdomiosarcoma), onfalocele, hipoglicemia neonatal, pliegues/orificios de los odos, citomegalia adrenocortical y anormalidades en los riones. Las pruebas gentico moleculares de nuestro laboratorio permiten observar: 1) La prdida de metilaciones observada en el 50% de los individuos. 2) El aumento de metilaciones observada del 2 al 7% de los individuos. 3) Disoma uniparental paterna observada en el 10-20%. BECKWITH-WIEDEMANN SYNDROME GENE: KCNQ1OT1 CHROMOSOMAL LOCATION: 11p15.5 INCIDENCE: 1 in 13,700 MODE OF INHERITANCE: autosomal dominant BWS is a disorder of growth characterized by macrosomia (large body size), macroglossia, visceromegaly, embryonal tumors (e.g., Wilms tumor, hepatoblastoma, neuroblastoma, rhabdomyosarcoma), omphalocele, neonatal hypoglycemia, ear creases/pits, adrenocortical cytomegaly, and renal abnormalities. Molecular genetic testing available in our laboratory are: (1) loss of methylation observed in 50% of individuals; (2) gain of methylation observed in 2 - 7%; (3) paternal uniparental disomy observed in 10-20%. VOLVER/RETURN Berardinelli, sndrome GEN: AGPAT2 LOCALIZACIN CROMOSMICA: 9q34.3 INCIDENCIA: 1 cada 12 millones en USA, 1 cada milln en Noruega, 1 cada 500,000 en Portugal FORMA DE HERENCIA: autosmico recesivo La lipodistrofia congnita de Berardinelli-Seip (BSCL) se diagnostica generalmente en el nacimiento o poco despus, debido a la ausencia de adipocitos funcionales, los lpidos se almacenan en otros tejidos, incluso en msculos e hgado. Los individuos afectados desarrollan resistencia a insulina. Virtualmente todos los individuos presentan hepatomegalia secundaria a esteatosis heptica. Todos estos pacientes presentan hipertrofia de los msculos esquelticos. En el 20-25% de los casos padecen hipertrofia cardiomioptica que es una importante causa de muerte por fallos cardiacos y mortalidad temprana. En nuestro laboratorio podemos secuenciar el gen AGPAT2. BERARDINELLI-SEIP CONGENITAL LIPODYSTROPHY GENE: AGPAT2 CHROMOSOMAL LOCATION: 9q34.3 INCIDENCE: 1 per 12 million in USA, 1 per million in Norway, 1 per 500,000 in Portugal MODE OF INHERITANCE: autosomal recessive Berardinelli-Seip congenital lipodystrophy (BSCL) is usually diagnosed at birth or soon thereafter. Because of the absence of functional adipocytes, lipid is stored in other tissues, including muscle and liver. Affected individuals develop insulin resistance. Hepatomegaly secondary to hepatic steatosis occurs in virtually all individuals. Skeletal muscle hypertrophy occurs in all affected individuals. Hypertrophic cardiomyopathy is reported in 20-25% of affected individuals and is a significant cause of morbidity from cardiac failure and early mortality. In our laboratory is avaible the sequencing analysis of AGPAT2 gene.

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VOLVER/RETURN Biotinidasa deficiencia GEN: BTD LOCALIZACIN CROMOSMICA: 3p25 INCIDENCIA: 1:137,401 en BD profunda; 1:109,921 en BD parcial; y 1:61,067 para la combinacin de ambas. La frecuencia de portadores es 1:120. HERENCIA: autosmica recesiva En los casos sin tratamiento, la deficiencia de biotinidasa profunda presenta normalmente hipotona, ataxia, retraso en el desarrollo, problemas de visin, prdida de audicin y anormalidades cutneas como alopecia, sarpullidos y candidiasis. Con la edad, debilidad motora, parlisis espstica y disminucin de la agudeza visual. Los individuos con deficiencia parcial de biotinidasa pueden tener hipotona, sarpullido y cada de pelo, particularmente en situaciones de estrs. Los problemas de visin, de audicin y de retraso del desarrollo no son reversibles cuando se comienza con la terapia de biotina. Se utiliza la tcnica de ARMS-PCR para detectar las mutaciones ms comunes: G98del3ins, Q456H, R538C, D444H, y la doble mutacin A171T:D444H, con una tasa de mutacin del 60%. BIOTINIDASE DEFICIENCY, BD GENE: BTD CHROMOSOMAL LOCATION: 3p25 INCIDENCE: 1:137,401 for profound BD; 1:109,921 for partial BD; and 1:61,067 for the combined incidence of profound and partial BD. Carrier frequency in the general population is about 1:120. MODE OF INHERITANCE: autosomal recessive In the untreated state, profound biotinidase deficiency is usually characterized initially by seizures, hypotonia, ataxia, developmental delay, vision problems, hearing loss, and cutaneous abnormalities such as alopecia, skin rash, and candidiasis. With age, motor limb weakness, spastic paresis, and decreased visual acuity occur. Individuals with partial biotinidase deficiency may have hypotonia, skin rash, and hair loss, particularly during times of stress. Once vision problems, hearing loss, and developmental delay occur, they are usually irreversible even with biotin therapy. ARMS PCR can be used to identify a panel of common BTD mutations (G98del3ins, Q456H, R538C, D444H, and the double mutation A171T:D444H) with a rate mutation of ~60%. VOLVER/RETURN BLEFAROFIMOSIS GEN: FOXL2 LOCALIZACION CROMOSOMICA: 3q23 HERENCIA: autosomica dominante El sndrome clsico de blefarofimosis (BPES) es una malformacin del prpado compleja invariablemente caracterizada por cuatro rasgos principales: blefarofimosis, ptosis, epicanto inverso y telecanto. Han sido descritos dos tipos de sndrome de blefarofimosis: BPES tipo I, incluye los cuatro rasgos principales y la infertilidad femenina causada por el fallo ovrico prematuro (POF); y BPES tipo II que incluye slo los cuatro rasgos principales. FOXL2 es el nico gen asociado actualmente con BPES. Entorno al 70% de los afectos presentan mutaciones en el nico exn codificante del gen FOXL2. Ocasionalmente, los individuos con BPES presentan cambios citogenticos como deleciones intersticiales y translocaciones que afectan a la localizacin 3q23. Las mutaciones son identificadas en aproximadamente el 80% de los individuos afectados mediante una combinacin de varias tcnicas: anlisis de la secuencia codificante y anlisis de deleciones por MLPA. Ms del 50% de los casos de BPES se estima que son causados por mutaciones de novo. BLEPHAROPHIMOSIS GENE: FOXL2 CHROMOSOMAL LOCATION: 3q23 MODE OF INHERITANCE: autosomal dominant

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Classic blepharophimosis syndrome (BPES) is a complex eyelid malformation invariably characterized by four major features: blepharophimosis, ptosis, epicanthus inversus, and telecanthus. Two types of blepharophimosis syndrome have been described: BPES type I includes the four major features and female infertility caused by premature ovarian failure (POF); BPES type II includes only the four major features. FOXL2 is the only gene currently known to be associated with BPES. About 70% of individuals with BEPS have a mutation in the single coding exon of FOXL2. Occasionally individuals with BPES have cytogenetic rearrangements, such as interstitial deletions and translocations involving 3q23. Mutations are identified in approximately 80% of affected individuals by using a combination of sequence analysis of the coding region (single exon) and deletion testing using methods such as multiplex ligation-dependent probe amplification (MPLA). The proportion of cases caused by de novo mutations is estimated to be more than 50%. VOLVER/RETURN Bmp15 GEN: Bmp15 LOCALIZACIN CROMOSMICA: Xp11.2 MODO DE HERENCIA: Ligada al cromosoma X La protena morfogentica de hueso-15 (BMP-15) es un factor de crecimiento de ovocito perteneciente a la superfamilia de factores de crecimiento transformantes. Es una protena necesaria para la fertilidad femenina ya que regula la proliferacin y diferenciacin de las clulas de la granulosa (CG), promueve la mitosis de las CG, suprime la expresin del receptor de la hormona estimulante del folculo (FSH) y estimula la expresin de su ligando. La protena BPM15 est relacionada con Fallo Ovrico Prematuro (POF), Sndrome de Hiperestimulacin Ovrica (OHSS) y Sndrome de Ovario Poliqustico (PCOS). Bmp15 GENE: Bmp15 CHROMOSOMAL LOCATION: Xp11.2 MODE OF INHERITANCE: X linked Bone morphogenetic protein-15 (BMP-15), an oocyte growth factor belonging to the transforming growth factorsuperfamily, has recently been shown to be necessary for normal female fertility in mammals. We have previously demonstrated that BMP-15 regulates granulosa cell (GC) proliferation and differentiation; namely, BMP-15 promotes GC mitosis, suppresses follicle-stimulating hormone (FSH) receptor expression, and stimulates kit ligand expression. Bmp15 protein is linked to Premature Ovarian Failure (POF), Ovarian Hyperstimulation Syndrome (OHSS) and Polycytisc Ovary Syndrome (PCOS). VOLVER/RETURN Brugada, Sndrome de GEN: SCN5A LOCALIZACION CROMOSOMICA: 3p21 HERENCIA: autosmica dominante El Sndrome de Brugada se caracteriza por anormalidades en el segmento ST en las derivaciones V1-V3 detectadas en el electrocardiograma y un riesgo alto de arritmias ventriculares y muerte sbita. SCN5A, el gen codificante de la subunidad a del canal de sodio, es el nico gen asociado actualmente con dicho sndrome. El estudio gentico molecular de SCN5A identifica mutaciones en, aproximadamente, el 20-25% de los individuos con el sndrome de Brugada. La proporcin de casos debidos a una mutacin de novo se estima que es el 1%. BRUGADA SYNDROME GENE: SCN5A CHROMOSOMAL LOCATION:3P21 MODE OF INHERITANCE: autosomal dominant
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Brugada syndrome is characterized by ST-segment abnormalities in leads V1-V3 on ECG (electrocardiogram) and a high risk of ventricular arrhythmias and sudden death. SCN5A, the gene encoding the -subunit of the sodium channel, is the only gene currently known to be associated with Brugada syndrome. Molecular genetic testing of SCN5A identifies mutations in approximately 20-25% of individuals with Brugada syndrome. The proportion of cases caused by de novo mutations is estimated at 1%. VOLVER/RETURN Cadasil GEN: NOTCH3 LOCALIZACIN CROMOSMICA: 19p13.2-p13.1 MODO DE HERENCIA: Autosmica dominante. La arteriopata autosmica dominante del cerebro con infartos subcorticales y leucoencefalopata (CADASIL) es una enfermedad hereditaria de pequeos vasos sanguneos que causa apopleja y demencia. Esta enfermedad causa repetidos ataques isqumicos y se relaciona a la mutacin del gen NOTCH3. Nuestro laboratorio ofrece la secuenciacin de DNA para la identificacin de mutaciones en el tercer y cuarto exn del gen NOTCH3 con un ndice de deteccin del 90% aproximadamente. En las pruebas negativas se contina el anlisis con la secuenciacin de los exones 2, 5 y 11. CADASIL GENE: NOTCH3 CHROMOSOMAL LOCATION: 19p13.2-p13.1 MODE OF INHERITANCE: autosomal dominant Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small vessel disease causing stroke and dementia. This condition causes repeated ischemic attacks and is related to mutations in the NOTCH3 gene. Our laboratory offers DNA sequencing for the identification of mutations in the third and fourth exn of NOTCH3 gene with a detection rate of approximately 90%. Negative test should be followed of 2, 5 and 11 exons sequencing. VOLVER/RETURN CARNEY, SNDROME DE GEN: PRKAR1A LOCALIZACION CROMOSOMICA: 17q23-q24 HERENCIA: Autosmica dominante El sndrome o complejo de Carney (CNC) se caracteriza por anormalidades en la pigmentacin de la piel, mixoma (cardaco, cutneo, mamario), tumores endocrinos o hiperactividad, tumores testiculares y swannomas. La presencia de manchas pigmentadas cutneas es la caracterstica representativa del CNC ms comn. El diagnstico del CNC se basa generalmente en los criterios clnicos de diagnstico. Mutaciones en el gen PRKAR1A, que codifica para la subunidad reguladora 1 alfa de la proteina quinasa A, y en el locus cromosmico 2p16, han sido determinadas como causantes del CNC (tipos 1 y 2, respectivamente). El anlisis de la secuencia de la regin codificante del gen PRKAR1A detecta entorno al 55% de las mutaciones. El anlisis de deleciones/duplicaciones localiza un 2% de las mutaciones del gen PRKAR1A. El CNC se hereda de manera autosmica dominante. Aproximadamente el 30% de los individuos afectos poseen una mutacin de novo.

CARNEY COMPLEX GENE: PRKAR1A CHROMOSOMAL LOCATION: 17q23-q24


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MODE OF INHERITANCE: autosomal dominant The Carney complex (CNC) is an autosomal dominant syndrome characterized by skin pigmentary abnormalities, myxomas, endocrine tumors or overactivity, and schwannomas. The diagnosis of CNC usually relies on clinical diagnostic criteria. Mutations in two genes, PRKAR1A and an unknown gene at chromosomal locus 2p16, are causative. Sequence analysis of the PRKAR1A coding region has a mutation detection rate of approximately 55%. Approximately 70% of individuals diagnosed with CNC have an affected parent; approximately 30% have a de novo mutation. VOLVER/RETURN Cavernomas cerebrales GEN: KRIT1 LOCALIZACIN CROMOSMICA: 7q21-q22 INCIDENCIA: 4-8:1000 MODO DE HERENCIA: Autosmica dominante Los Cavernomas Cerebrales (CCMs de sus siglas en ingls, Cerebral Cavernous Malformation) son malformaciones vasculares a modo de espacios vasculares dilatados, angiomas cavernosos cerebrales, que constan de una sola capa de endotelio sin parnquima cerebral. El dimetro de estas dilataciones va de unos pocos milmetros hasta varios centmetros incrementando el tamao y el nmero con el tiempo. CCMs puede aparecer en los lactantes y en nios, pero en la mayora de los casos manifestacin de los sntomas se produce entre la segunda y quinta dcadas de vida. Hasta el 25% de las personas con CCMs pueden permanecer asintomticas durante toda su vida. Aproximadamente el 50-75% de las personas con CCMs tienen sntomas, incluyendo convulsiones, dficits neurolgicos focales, dolores de cabeza y hemorragia cerebral. Los Cavernomas Cerebrales Familiares se definen como la aparicin de los propios cavernomas en al menos dos miembros de la familia y/o la presencia de patologas causada por la mutacin en uno de los genes asociados con CCM y/o la presencia de mltiples CCM. La falta de estudios de individuos homocigotos para la mutacin KRIT1 sugiere la posibilidad de que la homocigosis sea letal.

CEREBRAL CAVERNOUS MALFORMATION FAMILIAL GENE: KRIT1 CHROMOSOMAL LOCATION: 7q21-q22 INCIDENCE: 4-8:1000 MODE OF INHERITANCE:Autosomal dominant Cerebral cavernous malformations (CCMs) are vascular malformations consisting of closely clustered enlarged capillary channels (caverns) with a single layer of endothelium without normal intervening brain parenchyma or mature vessel wall elements. The diameters range from a few millimeters to several centimeters. The channels increase in size and number over time. CCMs have been reported in infants and children, but the majority of individuals present with symptoms between the second and fifth decades. Up to 25% of individuals with CCM remain symptom free throughout their lives. Approximately 50-75% of persons with CCM have symptoms, including seizures, focal neurologic deficits, nonspecific headaches, and cerebral hemorrhage. Familial cerebral cavernous malformation is defined as the occurrence of CCMs in at least two family members, and/or the presence of a disease-causing mutation in one of the genes associated with CCM and/or the presence of multiple CCMs. The lack of reported individuals homozygous for KRIT1 mutation suggests the possibility of homozygote lethality. VOLVER/RETIRN CharcotMarieTooth Rev 36 05/05/2009

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La enfermedad de Charcot-Marie-Tooth es una polineuropatologa sensoneural perifrica. Aproximadamente, afecta a 1 de cada 2500 individuos, la CMT es uno de los desrdenes del sistema nervioso heredables ms comunes. Se han reconocido las formas autosmica dominante, recesiva y ligada al X. CMT 1 Modo de herencia: autosmica dominante Las mutaciones puntuales de PMP22 aparecen en menos del 5% de los casos de CMT1 La neuropata de tipo 1 de Charcot-Marie-Tooth (CMT1) es una neuropata perifrica desmielinizante caracterizada por la debilidad del msculo distal y atrofia, prdida de sensibilidad y lenta conduccin nerviosa. Es normal que tenga un progreso lento y a menudo se relaciona con la deformidad de los pies (pes cavus) y BILATERAL FOOT DROP. CMT1A representa el 70-80% de todos los casos de CMT1 e implica anormalidades en el gen PMP22. Todas las personas con CMT1A tienen una duplicacin del gen PMP22. Y aproximadamente el 5-10% de los casos de CMT1 es de tipo 1B. Nuestro laboratorio ofrece la secuenciacin del DNA de los 6 exones codificantes del gen MPZ, con lo que detectamos >99% de los casos CMT1B. CMT 2 Modo de herencia: Todos los tipos de CMT2 presentan una herencia autosmica dominante, con la excepcin de CMT2B1, CMT2B2, CMT2H y CMT2K, los que son autosmicos recesivos. La mayora de los tipos autosmicos dominantes CMT2 han heredado la enfermedad debido a mutaciones de uno de los padres afectados. CMT2 es clnicamente igual que CMT1, aunque algo menos severa. Los nervios perifricos no presentan alargamiento ni hipertrofia. Los 15 subtipos de CMT2 son similares clnicamente y slo se pueden distinguir por gentica molecular. Los genes conocidos que se asocian con los tipos de CMT2 son el KIFI B y MFN2 (CMT2A), RAB7 (CMT2B), LMNA (CMT2B1), GARS (CMT2D), NEFL (CMT2E/1F), HSPB1 (CMT2F), MPZ (CMT2I/CMT2J), y GDAP1 (CMT2K). Nuestro laboratorio ofrece MPZ. Otros genes estn disponibles bajo peticin. CMT X Modo de herencia: Ligado al X La neuropata X de tipo 1 de Charcot-Marie-Tooth (CMTX1) se caracteriza por que una neuropata motora y sensorial que va de moderada a severa que afecta a hombres y normalmente de leve a sin sntomas en mujeres. Algunas familias presentan sordera. Pruebas gentico-moleculares del gen GJB1 (Cx32) detecta sobre el 90% de los casos de CMTX1. Estas pruebas estn clnicamente disponibles. CHARCOT-MARIE-TOOTH DISEASE Charcot-Marie-Tooth disease is a sensorineural peripheral polyneuropathy. Affecting approximately 1 in 2,500 individuals, CMT is the most common inherited disorder of the peripheral nervous system. Autosomal dominant, autosomal recessive, and X-linked forms have been recognized CMT 1 MODE OF INHERITANCE: autosomal dominant PMP22 point mutations; less than 5% of CMT1 Charcot-Marie-Tooth neuropathy type 1 (CMT1) is a demyelinating peripheral neuropathy characterized by distal muscle weakness and atrophy, sensory loss, and slow nerve conduction velocity. It is usually slowly progressive and often associated with pes cavus foot deformity and bilateral foot drop. CMT1A represents 70%-80% of all CMT1 and involves abnormalities of the PMP22 gene. All individuals with CMT1A have a duplication of PMP22. Approximately 5-10% of CMT1 is type 1B. Our laboratory offers DNA sequencing of all six coding exons in the MPZ gene, which detects >99% of individuals with CMT1B. CMT 2 MODE OF INHERITANCE: All types of CMT2 are inherited in an autosomal dominant manner with the exception of CMT2B1, CMT2B2, CMT2H, and CMT2K, which are inherited in an autosomal recessive manner. Most probands with autosomal dominant types of CMT2 have inherited the disease-causing mutation from an affected parent. CMT2 is clinically similar to CMT1, although typically less severe. Peripheral nerves are not enlarged or hypertrophic. The fifteen subtypes of CMT2 are similar clinically and are distinguished by molecular genetic findings. The genes known to be associated with the CMT2 types are KIF1B and MFN2 (CMT2A), RAB7 (CMT2B), LMNA (CMT2B1), GARS (CMT2D), NEFL (CMT2E/1F), HSPB1 (CMT2F), MPZ (CMT2I/CMT2J), and GDAP1 (CMT2K). Our laboratory offers MPZ. Other genes are available upon request. CMT X
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MODE OF INHERITANCE: X-linked manner Charcot-Marie-Tooth neuropathy X type 1 (CMTX1) is characterized by a moderate to severe motor and sensory neuropathy in affected males and usually mild to no symptoms in carrier females. Sensorineural deafness and central nervous system symptoms also occur in some families. Molecular genetic testing of the GJB1 (Cx32) gene detects about 90% of cases of CMTX1. Such testing is clinically available. VOLVER/RETURN

CharcotMarieTooth Recesivo GEN: GDAP1 LOCALIZACION CROMOSOMICA: 8q21.11 HERENCIA: autosmico recesivo El Charcot-Marie-Tooth tipo 4 (CMT4) comprende un grupo de neuropatas motoras y sensoriales progresivas que incluyen variantes axonales y desmielinizantes que se caracteriza por un patrn de herencia autosmico recesivo. Los individuos afectados tienen el fenotipo tpico CMT, consistente en debilidad muscular y atrofia asociada con la prdida sensorial. Ha sido clasificado en ocho subtipos en los cuales intervienen distintos genes: GDAP1 (CMT4A), MTMR2 (CMT4B1), CMT4B2 (CMT4B2), SH3TC2 (KIAA1985) (CMT4C), NDRG1 (CMT4D), EGR2 (CMT4E), PRX (CMT4F), FGD4 (CMT4H) y FIG1 (CMT4). Cerca del 25% de los casos de CMT4 han sido asociados con mutaciones en el gen GDPA1. En caso de resultado negativo se recomienda continuar el estudio mediante secuenciacin del resto de genes implicados. CHARCOT-MARIE-TOOTH NEUROPATHY TYPE 4 GENE: GDAP1 CHROMOSOMAL LOCATION: 8q21.11 MODE OF INHERITANCE: autosomal recessive Charcot-Marie-Tooth neuropathy type 4 (CMT4) is a group of progressive motor and sensory axonal and demyelinating neuropathies that are distinguished from other forms of CMT by autosomal recessive inheritance. Affected individuals have the typical CMT phenotype of muscle weakness and atrophy associated with sensory loss. The genes associated with eight CMT4 subtypes have been identified: GDAP1 (CMT4A), MTMR2 (CMT4B1), CMT4B2 (CMT4B2), SH3TC2 (KIAA1985) (CMT4C), NDRG1 (CMT4D), EGR2 (CMT4E), PRX (CMT4F), FGD4 (CMT4H), and FIG1 (CMT4J). About 25% of autosomal recessive CMT is attributable to mutations in GDAP1

VOLVER/RETURN CHARGE, Sndrome de GEN: CHD7 LOCALIZACIN CROMOSMICA: 8q12.1 HERENCIA: autosmica dominante Los individuos afectos con sndrome de CHARGE presentan de modo general aunque en diferentes combinaciones y distintos grados: coloboma, malformaciones cardiovasculares, atresia del coana, retraso en el crecimiento y en el desarrollo, anomalas genitales y del odo. El nico gen asociado con el sndrome de CHARGE es el CHD7 (chromodomain helicase DNA binding protein 7). El anlisis de la secuencia de las regiones codificantes del gen CHD7 detecta mutaciones en aproximadamente el 60-65% de los individuos diagnosticados con sndrome de CHARGE. La mayora de los individuos diagnosticados con sndrome de CHARGE se deben a mutaciones de novo.
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CHARGE SYNDROME GENE: CHD7 CHROMOSOMAL LOCALITATION: 8q12.1 MODE OF INHERITANCE: autosomal dominant CHARGE is a mnemonic that stands for coloboma, heart defect, atresia choanae, retarded growth and development, genital abnormality, and ear abnormality, which are frequently present in various combinations and to varying degrees in individuals with CHARGE syndrome. CHD7, encoding the chromodomain helicase DNA binding protein, is the gene currently known to be associated with CHARGE syndrome. Sequence analysis/mutation scanning of the CHD7 coding region detects mutations in approximately 60-65% of individuals diagnosed with CHARGE syndrome. Most individuals diagnosed with CHARGE syndrome represent simplex cases. VOLVER/RETURN Cinca, Sndrome de GEN: NLRP3 LOCALIZACIN CROMOSMICA: 1q44 INCIDENCIA: 100 casos a nivel mundial HERENCIA: autosmica dominante El sndrome CINCA es una enfermedad rara peditrica extraordinariamente rara multisistmica, inflamatoria y de curso crnico. Se caracteriza por la presencia de una triada caracterstica: rash (erupcin transitoria que recuerda la de la escarlatina, rubola, o prpura segn los casos, en el curso de ciertas enfermedades febriles no eruptivas, o como reaccin de intolerancia a un medicamento) cutneo, meningitis (inflamacin de las meninges, membranas que envuelven la mdula espinal y el cerebro) crnica (que tiene un curso prolongado por mucho tiempo) y artropata (nombre genrico de enfermedad articular). Presenta dos nombres, CINCA, del acrnimo ingls de Articular y Cutneo Neurolgico Infantil Crnico (Chronic Infantile Neurological Cutaneous and Articular) y NOMID en EE.UU, del acrnimo ingls de Enfermedad Neonatal Multisistmica Inflamatoria (Neonatal Onset Multisystemic Inflammatory Disease), por lo que es frecuente encontrar la denominacin CINCA/NOMID. Los pacientes tienen una morfologa caracterstica: baja estatura, cabeza ensanchada, nariz en silla de montar y extremidades cortas y gruesas con dedos unidos. La gran frecuencia de prematuridad asociada hace pensar en una infeccin fetal, aunque no ha sido posible encontrar ningn agente viral responsable y sigue siendo una enfermedad de origen desconocido. Los primeros sntomas se producen generalmente en el momento del nacimiento, excepto en unos pocos pacientes en los que las primeras manifestaciones aparecen ms tardamente durante la lactancia. En todos los casos estn fundamentalmente afectados el sistema nervioso, la piel y articulaciones. El primer sntoma en aparecer es el rash cutneo, que se caracteriza por ser una urticaria no pruriginosa (que producen picor), que vara durante el da. Las articulaciones ms comnmente afectadas son rodillas, tobillos y pies, mientras que codos, muecas y manos estn normales. Las manifestaciones neurolgicas se deben a la meningitis crnica y son: cefaleas (dolor de cabeza), convulsiones y espasticidad (contracciones involuntarias persistentes de un msculo) de miembros inferiores, sntomas que indican la irritacin menngea. Muchos pacientes presentan atrofia cerebral y bajo cociente intelectual. Con el tiempo va apareciendo la afectacin de los rganos sensoriales: inflamacin ocular con atrofia (disminucin de volumen y peso de un rgano) ptica, pseudopapiledema (inflamacin anormal de la papila de modo que aparece elevada), uvetis (inflamacin de la vea, cara posterior pigmentada del iris) crnica, sordera y ronquera. Se acompaa de fiebre, linfadenopatas (inflamacin de los ndulos linfticos) y hepatoesplenomegalia (hgado y bazo anormalmente grandes). Radiogrficamente se observan modificaciones que afectan a las epfisis (extremos de los huesos largos), metfisis (cartlago de crecimiento de los huesos largos) y cartlagos de crecimiento, que asemejan tumoraciones seas, que provocan una artropata y deformidad de las grandes articulaciones. La biopsia (operacin que consiste en extirpar en el individuo vivo un fragmento de rgano o de tumor con objeto de someterlo a examen microscpico) de piel se caracteriza por
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hidradenitis neutroflica de las glndulas ecrinas (glndulas cuyo canal excretor desemboca directamente en la superficie de la piel).El pronstico a largo plazo no es bueno, debido a la sordera y afectacin visual progresivas y al empeoramiento de las manifestaciones dependientes del sistema nervioso central (sistema formado por el encfalo y la mdula espinal). CHRONIC INFANTILE NEUROLOGICAL CUTANEOUS AND ARTICULAR SYNDROME GENE: NLRP3 CHROMOSOMAL LOCATION: 1q44 INCIDENCE: Despite its rarity (about 100 caseshave been reporterd worldwide) MODE OF INHERITANCE: autosomal dpminant Chronic infantile neurological cutaneous and articular (CINCA) syndrome also referred to as NOMID (neonatal onset multisystemic inflammatory disease), was recently recognized as a unique entity that associates 3 cardinal sings: a maculopapular urticarial skin rash that is often present at birth but whose presence varies with time; a rtucular sings of variable expression including transient swelling without sequelae between crises or unpredictable anomalies of growth cartilage suggestive of a pseudo-tumor, wich, when biopsied, reveals disorganized cartilage with no inflammatory cells; central nervous system involvement with headaches. Lumbar puncture almost always provides evidence of chronic meningitis with neutrophils and sometimes eosinophils. Generally, the infants are born pretem anddysmature; a placenta anormaly with inflammation was observed in some cases. Laboratory tests reveal signs of a non-specific inflammatory syndrome with anemia, polynuclear leukocytosis, thrombocystosis, elevated erythrocyte sedimentation rate (ESR) and elevated concentrations of inflammatory proteins. No autoantibodies or immune deficiency are detected. VOLVER/RETURN Cistinosis GEN: CTNS LOCALIZACIN CROMOSMICA: 17p INCIDENCIA: 1:100.000 y 1:200.000 HERENCIA: autosmica recesiva La cistinosis nefroptica se caracteriza por un pobre crecimiento, sndrome tubular renal de Fanconi, raquitismo hipofosfatmico, disfuncin glomerular, e implicacin de otros tejidos y rganos. En individuos sin tratamiento, el defecto en el crecimiento se hace notorio desde los 6 9 meses de edad. Los signos del sndrome tubular renal de Fanconi se presentan a los 6 meses de edad incluyendo poliuria, polidipsia, deshidratacin y acidosis. Cristales en la crnea pueden aparecer al ao de vida siendo presentes siempre despus de los 16 meses. La cistinosis intermedia se caracteriza por las tpicas presentaciones fenotpicas de la cistinosis nefropatica pero a una edad ms tarda. La cistinosis no nefroptica presenta slo fotofobia. En el norte de Europa y EEUU aproximadamente el 40% de los individuos con cistinosis nefroptica son homocigotos para una delecin de 57 kb. En los individuos de 15 -25 aos con cistinosis intermedia y no nefroptica, la delecin puede presentarse en heterocigosis. CYSTINOSIS GENE: CTNS CHROMOSOMAL LOCATION: 17p INCIDENCE: between 1 in 100.000 and 1 in 200.000 MODE OF INHERITANCE: autosomal recessive Nephropathic cystinosis is characterized by poor growth, renal tubular Fanconi syndrome, hypophosphatemic rickets, impaired glomerular function, and involvement of other tissues and organ systems. In untreated individuals, growth failure is generally noticed at six to nine months of age. Signs of renal tubular Fanconi syndrome appear as early as six months of age and include polyuria, polydipsia, dehydration, and acidosis. Corneal crystals can be present before one year of age, and are always present after 16 months of age, at least in untreated individuals with nephropathic cystinosis. In untreated individuals, glomerular function gradually deteriorates, resulting in renal failure at approximately ten years of age. Intermediate cystinosis is characterized by all the typical early manifestations of nephropathic cystinosis, but at a later age. Renal glomerular failure occurs in all affected individuals, usually between Mutations in CTNS cause all three types of cystinosis. In the United States and northern European populations, approximately 40% of individuals with nephropathic cystinosis are homozygous for a 57-kb deletion. In individuals with intermediate and Rev 36 05/05/2009

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non-nephropathic cystinosis, the deletion can be present in the heterozygous state15 and 25 years of age. Nonnephropathic cystinosis is characterized by photophobia only. VOLVER/RETURN CITRULINA, DEFICIENCIA DE GEN: SLC25A13 LOCALIZACIN CROMOSMICA: 7q21.3 HERENCIA: Autosomica recesiva La citrulina es una protena mitocondrial que participa en diversas rutas metablicas. Los dos fenotipos de la deficiencia de citrulina son la citrulinemia tipo II (CTLN2), caracterizada por aparicin en la edad adulta, episodios recurrentes de hiperamonemia y sntomas neurosiquiatricos asociados; y la colestasis neonatal intraheptica por deficiencia de citrulina (NICCD), caracterizada por colestasis neonatal transitoria y disfuncin heptica variable. Se conoce un nico gen, el SLC25A13 que codifica para la citrulina, asociado a la deficiencia de esta protena. La mayora de las mutaciones en SLC25A13 dan lugar a una protena truncada. El anlisis de la secuencia de los exones y las regiones flanqueantes identifica variaciones en SLC25A13 en ms del 95% de los individuos en los que se sospecha una deficiencia de citrulina. CITRIN DEFICIENCY GENE: SLC25A13 CHROMOSOMAL LOCATION: 7q21.3 MODE OF INHERITANCE: autosomal recessive Citrin is a mitochondrial protein and plays a role in various methabolic pathways. The two phenotypes of citrin deficiency are citrullinemia type II (CTLN2) and neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). CTLN2 is characterized by adult-onset (usually between ages 20 and 50 years), recurring episodes of hyperammonemia and associated neuropsychiatric symptoms. Children younger than age one year with NICCD have transient intrahepatic cholestasis and variable hepatic dysfunction. SLC25A13 is the only gene known to be associated with citrin deficiency. Most SLC25A13 mutations cause truncation of the citrin protein. Sequence analysis of the exons and flanking regions identifies SLC25A13 variants in more than 95% of individuals suspected of having citrin deficiency. VOLVER/RETURN COFFIN LOWRY, SNDROME DE GEN: RPS6KA3 LOCALIZACION CROMOSMICA:Xp22.2-p22.1 HERENCIA: dominante ligada al X El sndrome de Coffin-Lowry (CLS) est caracterizado por un retraso mental de severo a profundo en hombres. El rango intelectual en mujeres con mutaciones en heterocigosis va desde la normalidad hasta un retraso profundo. El diagnstico de CLS en hombres se establece por distintos rasgos fsicos y mentales propios de la patologa: retraso del desarrollo severo, caractersticas craneofaciales y en las manos, y hallazgos radiogrficos. Las mujeres portadoras podran estar medianamente afectadas. El estudio molecular del gen RPS6KA3, el nico asociado hasta el momento a la patologa, que codifica para una serina/treonina quinasa, puede ser usado para confirmar el diagnstico. Mediante secuenciacin se identifican mutaciones en el 35-40% de los pacientes. El CLS presenta una herencia dominante ligada al cromosoma X. Entre el 70 y el 80% de los afectos no presentan historia familiar previa.

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COFFIN LOWRY SYNDROME GENE:RPS6KA3 CHROMOSOMAL LOCALITATION: Xp22.2-p22.1 MODE OF INHERITANCE: X-linked dominant Coffin-Lowry syndrome (CLS) is usually characterized by severe-to-profound mental retardation in male. Intellect ranges from normal to profoundly retarded in heterozygous females. The diagnosis of CLS is established in males with severe developmental delay, characteristic craniofacial and hand findings, and radiographic findings. Carrier females may be mildly affected. Molecular genetic testing of RPS6KA3, the only gene yet published to be associated with CLS, which encodes a growth factor-regulated serine/threonine kinase, can be used to confirm but not to rule out the diagnosis of typical CLS. Sequence analysis identifies mutations in approximately 35%-40% of probands. CLS is inherited in an X-linked dominant manner. Approximately 70%-80% of probands have no family history of CLS.

VOLVER/RETURN

Colestasis intraheptica GEN: ATP8B1 LOCALIZACIN CROMOSMICA: 18q21 INCIDENCIA: 1/50.000-100.000 HERENCIA: Autosmica recesiva Las alteraciones en el gen ATP8B1, que codifica la colestasis intraheptica familiar 1 (CIF1), han sido asociadas a la colestasis intraheptica benigna recurrente (BRIC, de sus siglas en ingls) sndrome caracterizado por mltiples episodios de prurito e ictericia. Aproximadamente el 80% de los individuos afectos con BRIC1 de origen europeo con alteraciones en el gen ATP8B1 presentan la mutacin I661T. El cuadro clnico se caracteriza por ictericia, esteatorrea, retardo del crecimiento, y una actividad srica disminuda o normal de gamaglutamiltranspeptidasa (GGT) a pesar de niveles aumentados de fosfatasa alcalina (FAL). Intrahepatic Cholestasis GENE: ATP8B1 CHROMOSOMAL LOCATION: 18q21 INCIDENCE: 1/50.000-100.000 MODE OF INHERITANCE: autosomal recessive The alterations in the gene ATP8B1, coding for intrahepatic cholestasis family 1 (CIF1), have been associated with benign recurrent intrahepatic cholestasis (BRIC, its acronym in English) syndrome characterized by multiple episodes of itching and jaundice. Approximately 80% of individuals affected with BRIC1 of European origin with alterations in the gene ATP8B1 have the mutation I661T. The clinical picture is characterized by jaundice, steatorrhea, growth retardation, and decreased serum activity or normal gamaglutamiltranspeptidasa (GGT) despite increased levels of alkaline phosphatase (AFL). VOLVER/RETURN Conos y bastones degeneracin GEN: ABCA4 LOCALIZACIN CROMOSMICA: 1p22 GEN: CRX
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LOCALIZACIN CROMOSMICA: 19q13.3 Las distrofias de conos y bastones (CRDs) son distrofias hereditarias de la retina. Se incluyen en el grupo de la retinitis pigmentosa, y, de forma ms general, en el de las retinopatas pigmentarias. Como tal, se caracterizan por la presencia de depsitos de pigmentos en la retina, visibles en la exploracin del fundus, que se localizan predominantemente en la regin de la mcula. A diferencia de las retinitis pigmentosas tpicas (tambin conocidas como distrofias de bastncono, RCDs), que son el resultado de una prdida primaria de funcin de los fotorreceptores de los bastones, seguida por una prdida secundaria de la funcin de los fotorreceptores de los conos; las CRDs reflejan una secuencia de hechos totalmente opuesta, con una implicacin primaria de los conos, o con una prdida de funcin concomitante de conos y bastones. Esto explica la naturaleza de los sntomas de las CRDs, agudeza visual disminuida, defectos en la visin de los colores, fotoaversin y disminucin de la sensibilidad en el centro del campo visual, seguido por una prdida de la visin perifrica y ceguera nocturna. Por tanto, el curso clnico de las CRDs suele ser ms grave y rpido que el de las distrofias de bastn-cono. Provocan una ceguera legal ms temprana (agudeza visual inferior a 20/200) e invalidez. En la etapa final, sin embargo, las CRDs no son diferentes de las RCDs. Las CRDs no suelen ser sindrmicas, aunque pueden formar parte de diversos sndromes, tales como el de Bardet-Bield y la ataxia cerebelar SCA7. Las CRDs tienen una prevalencia estimada de 1/40000. Las CRDs no sindrmicas son genticamente heterogneas, con 10 genes clonados y tres loci identificados. Sigue sin estar claro el porcentaje de pacientes para el que los genes clonados aportan una explicacin. De todas maneras, entre los genes ya clonados se han identificado cuatro genes principales para las CRDs: ABCA4, que provoca la enfermedad de Stargardt, adems del 30 a 60% de las CRDs autosmicas recesivas; CRX y GUCY2D, que son responsables de muchos casos de CRDs autosmicas dominantes; y RPGR, que provoca cerca de 2 tercios de las RPs ligadas al cromosoma X, adems de un porcentaje no determinado de las CRDs ligadas al X. Por tanto, hay una gran heterogeneidad en los genes responsables y los mecanismos implicados en las CRDs. LEBER CONGENITAL AMAUROSIS GENE: ABCA4 CHROMOSOMAL LOCATION: 1p22 GENE: CRX (CONE-ROD HOMEOBOX-CONTAINING GENE) CHROMOSOMAL LOCATION: 19Q13.3 Specifically, the ABCA4 (photoreceptor-specific ATP-binding cassette transporter 4) gene encodes for a retinal protein exclusively localized at the rims of the outer segments of rod and cone photoreceptors. Mutations in the ABCA4 gene have been associated with autosomal recessive Stargardt disease (STGD) and have been implicated in several retinal phenotypes, such as retinitis pigmentosa (RP), conerod dystrophy (CRD), fundus flavimaculatus (FFM), and agerelated macular dystrophy (AMD). These clinical manifestations depend on the nature of the ABCA4 mutation and on the remaining protein activity. Thus, a grading system explaining these phenotypes has been proposed: Two null mutations lead to RP, two severe mutations to arCRD, two mild or moderate mutations to STGD/FFM and one milder heterozygotic mutation to AMD. Some investigators have found that 50% of the CRD families with the mutation had two recurrent changes (2888delG and R943Q). Our lab offers those mutations but also complete gene sequencing upon request. Leber congenital amaurosis (LCA) is the earliest and most severe form of all inherited retinal dystrophies, responsible for congenital blindness. Disease-associated mutations have been hitherto reported in seven genes. These genes are all expressed preferentially in the photoreceptor cells or the retinal pigment epithelium but they are involved in strikingly different physiologic pathways resulting in an unforeseeable physiopathologic variety. This wide genetic and physiologic heterogeneity that could largely increase in the coming years, hinders the molecular diagnosis in LCA patients. Although LCA is generally thought to be inherited in an autosomal recessive fashion, some autosomal dominant pedigrees have been reported. VOLVER/RETURN Craneosinostosis GENES: FGFR1, FGFR2, FGFR3 LOCALIZACIN CROMOSMICA: FGFR1: 8p11.2-p11.1; FGFR2: 10q26; FGFR3: 4p16.3 INCIDENCIA: 1/2000-1/2500 de los nacimientos MODO DE HERENCIA: autosmica dominante Rev 36 05/05/2009

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Los ocho desrdenes considerados como parte del espectro de la craneosinostosis ligado al FGFR son los sndromes de Pfeiffer, de Apert, de Crouzon, de Beare-Stevenson, sinostosis relacionada a FGFR2, de Jackson-Weiss, de Crouzon con acantosis nigricans y de Muenke (sinostosis coronaria relacionada a FGFR3). Todos, excepto el sndrome de Muenke y la sinostosis relacionada con FGFR2, se caracterizan por una craneosinostosis bicorona o crneo en cloverleaf, distintas caractersticas faciales, malformaciones en manos y pies; El sndrome de Muenke y la sinostosis relacionada con FGFR2 se caracterizan por la craniosinostosis uni o bicorona.

FGFR-RELATED CRANIOSYNOSTOSIS SYNDROMES GENE: FGFR1, FGFR2, FGFR3 CHROMOSOMAL LOCATION: FGFR1: 8p11.2-p11.1; FGFR2: 10q26; FGFR3: 4p16.3 INCIDENCE: 1/2000-1/2500 live births MODE OF INHERITANCE: autosomal dominant The eight disorders considered as part of the FGFR-related craniosynostosis spectrum are Pfeiffer syndrome, Apert syndrome, Crouzon syndrome, Beare-Stevenson syndrome, FGFR2-related isolated coronal synostosis, Jackson-Weiss syndrome, Crouzon syndrome with acanthosis nigricans, and Muenke syndrome (FGFR3-related isolated coronal synostosis). All but Muenke syndrome and FGFR2-related isolated coronal synostosis are characterized by bicoronal craniosynostosis or cloverleaf skull, distinctive facial features, and variable hand and foot findings; Muenke syndrome and FGFR2-related isolated coronal synostosis are characterized only by uni- or bicoronal craniosynostosis. VOLVER/RETURN Crohn, sndrome GEN: CARD15/NOD2 LOCALIZACIN CROMOSMICA: 16q12 INCIDENCIA: 6/100000 La enfermedad de Crohn se piensa que es el resultado de varios efectos combinados, factores ambientales y genticos. La principal hiptesis postula que se debe a una respuesta innata inmune a antgenos discretos. Esta alteracin produce la inflamacin del tracto gastrointestinal. Esta enfermedad afecta tanto a jvenes como adultos, as, una presentacin temprana de la enfermedad conlleva un aumento de la morbilidad y mortalidad. Se han descrito tres mutaciones principalmente: R702W, G908R, y 1007 frameshift ligadas a fenotipo de Crohn. CROHN SYNDROME GENE: CARD15/NOD2 CHROMOSOMAL LOCATION: 16q12 INCIDENCE: 6/100000 Crohns disease (CD) is thought to result from combined effects of environmental agents and a genetically susceptible host. A central role for the innate immune responses to discrete antigens has been postulated. A perturbation in the immune response to luminal bacteria leads to inflammation in the gastrointestinal tract. The disease can affect both children and adults. Early presentation of the disease in the first decades of life carries significant morbidity and mortality. A high risk for complications associated with early onset of the disease is thought to reflect longer lifetime duration of disease and medication use, effects of the disease during periods of growth and development, and possibly a more severe phenotype of the disease as a result of a specific genotype-causing predisposition to early onset of the disease. Three main mutations (R 702W, G908 R, and 1007 frameshift) have been described in CD and have been linked to the phenotype of the disease. VOLVER/RETURN CROUZON, SINDROME DE GEN: FGFR2
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LOCALIZACIN CROMOSMICA: 10q26 HERENCIA: autosmica dominante El Sndrome de Crouzon es un desorden gentico caracterizado la fusin prematura de algunos huesos del crneo (craneosinostosis), lo cual impide el crecimiento normal del mismo afectando, por tanto, a la forma de la cabeza y de la cara. Como caractersticas generales los individuos afectos presentan hipertelorismo ocular, proptosis, estrabismo externo, hipoplasia mediofacial y prognatismo mandibular. La severidad de estos signos vara entre los afectados. El riesgo de hipertensin intracraneal es elevado. Los individuos con el sndrome Crouzon, por lo general, poseen una inteligencia normal. El sndrome de Crouzon est causado por mutaciones en el gen FGFR2, el cual codifica para el receptor del factor de crecimiento de fibroblastos 2. La mayora de las mutaciones son missense.

CROUZON SYNDROME GENE: FGFR2 CHROMOSOMAL LOCALITATION: 10q26 MODE OF INHERITANCE: autosomal dominant Crouzon syndrome is a genetic disorder characterized by by the premature fusion of certain skull bones (craniosynostosis). This early fusion prevents the skull from growing normally and affects the shape of the head and face. Clinical features of Crouzon syndrome are ocular hypertelorism, significant proptosis, external strabismus, midface hypoplasia and mandibular prognathism. The severity of these signs and symptoms varies among affected people. Risk of intracranial hypertension is high. People with Crouzon syndrome are usually of normal intelligence. Mutations in the FGFR2 (fibroblast growth factor receptor 2) gene cause Crouzon syndrome. Most FGFR2 mutations are missense mutations. VOLVER/RETURN Currarino, sndrome GEN: HLXB9 LOCALIZACIN CROMOSMICA: 7q36 INCIDENCIA: 1,3:10.000 HERENCIA: autosmica dominante El sndrome de Currarino implica sacro en forma de hoz, masa presacral y malformaciones anorectales. Mutaciones en el gen HLBX9 se relacionan con el Currarino. CURRARINO SYNDROME GENE: Homeobox HB9 (HLXB9) CHROMOSOMAL LOCATION: 7q36 INCIDENCE: 1,3:10.000 liveborns MODE OF INHERITANCE: Autosomal dominant The Currarino triad involves the association of partial sacral agenesis with intact first sacral vertebra ('sickle-shaped sacrum'), a presacral mass, and anorectal malformation (Currarino et al., 1981). The specific sacral anomaly is distinct to this syndrome. Ross et al. (1998) demonstrated mutations in the homeobox gene HLXB9 as the cause of the Currarino syndrome. In the families they studied, some individuals had the typical scimitar, or sickle-shaped, hemisacrum but were asymptomatic, whereas others had the full Currarino syndrome.

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VOLVER/RETURN Dficit de la hormona del crecimiento GEN: GH1 LOCALIZACIN CROMOSMICA: 17q22-q24 HERENCIA: autosmica recesiva/dominante. La hormona del crecimiento (GH) es una hormona multifuncional producida en la pituitaria anterior que promueve el crecimiento postnatal del tejido esqueltico y los tejidos blandos. La secrecin y liberacin de la GH son procesos complejos dependientes de multitud de factores. Cualquier desorden tanto gentico como adquirido que afecte a la secrecin de la GH o a su accin, da lugar a un fenotipo patolgico caracterizado por una baja estatura proporcionada y por deficiencia aislada de GH (IGHD) o por deficiencia combinada de hormonas pituitarias (CPHD). El gen GH1, que codifica para la GH, es el gen ms estudiado en los casos de IGHD. Se han detectado mutaciones en alrededor del 12.5% de los casos familiares de IGHD y del 10% en los casos espordicos. Estas mutaciones causan diferentes tipos de IGHD clasificados como IA, IB, II y III. La forma ms severa, la IGHD IA, se caracteriza por la total ausencia de GH, se hereda de manera autosmica recesiva y los pacientes portan grandes deleciones que eliminan al gen entero o, en un pequeo nmero de casos, mutaciones nonsense. Las formas menos severas, que se caracterizan por niveles muy bajos pero detectables de GH, son la IGHD IB, autosmica recesiva (que es la forma ms comn), y la IGHD II, autosmica dominante. En estas formas los pacientes portan sustituciones nucleotdicas que afectan al splicing del ARNm. La IGHD III se hereda ligada al X pero la base molecular se desconoce. En la mayora de los afectados con IGHD no se detectan mutaciones en GH1. Ya que varios factores intervienen en la secrecin de GH, probablemente las formas genticas de deficiencia de GH pueden resultar de mutaciones en otros genes tales como GHRH, GHRHR, PIT-1, PROP-1, HESX1, LHX3 y LHX4. GROWTH HORMONE DEFICIENCY GENE: GH1 CHROMOSOMAL LOCALITATION: 17q22-q24 MODE OF INHERITANCE: autosomal recessive/dominant Growth hormone (GH) is a multifunctional hormone produced in the anterior pituitary that promote postnatal growth of skeletal and soft tissues. GH secretion and release are complex phenomena depending on several intrinsic and extrinsic factors. Any genetic or acquired disorder that impairs GH secretion or action causes a pathological phenotype characterized by harmonic short stature with isolated Gh deficiency (IGHD) or combined pituitary hormone deficiency (CPHD). GH1, the GH encoding gene, is the most extensively studied gene in IGHD. Mutations in the GH1 gene have been detected in about 12.5% of familial and 10% of sporadic IGHD. These mutations cause different types of IGHD classified as IA, IB, II and III. The most severe form of IGHD (IGHD IA), characterized by the total absence of GH, has an autosomal recessive manner of inheritance and the patients carry gross deletions removing the entre GH1 or, in a few cases, nonsense mutations. The milder forms (characterized by a very low but detectable amount of GH) include IGHD IB, autosomal recessive, (that is the most common form) and IGHD II, autosomal dominant. In these forms patients carry nucleotide substitutions affecting mRNA splicing. IGHD III is inherited as an X-linked recessive trait, but its molecular basis is, to date, unknown. In most IGHD patients no GH1 mutation is found. Since several factors take part in GH secretion, it is likely that genetic forms of GH deficiency can result from mutations in other gene such as GHRH, GHRHR, PIT-1, PROP-1, HESX1, LHX3 and LHX4. VOLVER/RETURN
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DiGeorge, sndrome GEN: Regin cromosmica de DiGeorge (DGCR) LOCALIZACIN CROMOSMICA: 22q11 HERENCIA: Autosmica dominante Las personas que presentan el sndrome de delecin de 22q11.2 pueden padecer un amplio rango de enfermedades como problemas congnitos de corazn (74% de los enfermos); malformaciones (tetraloga de Fallot, arco artico interrumpido, defectos ventriculares y del tronco arterioso); anormalidades palatales (69%); incompetencia velofarngea (VPI) y hendidura en el paladar; caractersticas faciales especiales (presentes en la mayora de la poblacin caucsica); y dificultades de aprendizaje (70-90%). El 77% de los individuos tienen una inmunodeficiencia adems de los sntomas clnicos. Otros problemas que pueden presentar: hipocalcemia (50%); problemas de alimentacin (30%); anomalas renales (37%); sordera (ambos conductos y sensineural); anomalas en laringe, trquea y esfago; deficiencia de la hormona de crecimiento; desrdenes del sistema inmunolgico y anormalidades en el esqueleto. DIGEORGE SYNDROME GENE: DiGeorge chromosomal region (DGCR) CHROMOSOMAL LOCATION: 22q11 INCIDENCE: MODE OF INHERITANCE: Autosomal dominant manner Individuals with the 22q11.2 deletion syndrome (del 22q11.2) have a range of findings, including congenital heart disease (74% of individuals), particularly conotruncal malformations (tetralogy of Fallot, interrupted aortic arch, ventricular septal defect, and truncus arteriosus); palatal abnormalities (69%), particularly velopharyngeal incompetence (VPI), submucosal cleft palate, and cleft palate; characteristic facial features (present in the majority of Caucasian individuals); and learning difficulties (70-90%). Seventy-seven percent of individuals have an immune deficiency regardless of their clinical presentation. Additional findings include: hypocalcemia (50%), significant feeding problems (30%), renal anomalies (37%), hearing loss (both conductive and sensorineural), laryngotracheoesophageal anomalies, growth hormone deficiency, autoimmune disorders, seizures (without hypocalcemia), and skeletal abnormalities. VOLVER/RETURN Diabetes inspida GEN: AVPR2 LOCALIZACIN CROMOSMICA: Xq28 INCIDENCIA: Se desconoce prevalencia de NDI, pero se asume rara MODO DE HERENCIA: Ligada al X La diabetes inspida nefrognica (NDI) se caracteriza por su incapacidad de concentrar la orina, lo que resulta en poliuria y polidipsia. Los nios afectados sin tratar suelen tener una pobre alimentacin y retraso en el crecimiento, con una aparicin temprana de deshidratacin severa asociada a enfermedad, estatura corta y dilatacin de urteres y vejiga. Cerca del 95% de los individuos con NDI ligada al X tienen una mutacin en el gen AVPR2. Nuestro laboratorio ofrece la secuenciacin completa del gen. DIABETES INSIPIDUS GENE: AVPR2 CHROMOSOMAL LOCATION: Xq28 INCIDENCE: The exact prevalence of NDI is not known but it is assumed to be rare MODE OF INHERITANCE: X-linked Nephrogenic diabetes insipidus (NDI) is characterized by inability to concentrate the urine, which results in polyuria (excessive urine production) and polydipsia (excessive thirst). Affected untreated infants usually have poor feeding and failure to thrive, and rapid onset of severe dehydration with illness, hot environment, or the withholding of water. Short stature and secondary dilatation of the ureters and bladder from the high urine volume is common in untreated
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individuals. About 95 % of individuals with X-linked NDI have a mutation in AVPR2 gene, we offer completed sequencing of this gene. VOLVER/RETURN Diabetes mellitus, tipo MODY GENES: HNF4A, GCK, HNF1A, IPF1, HNF1B y NEUROD1 LOCALIZACIN CROMOSMICA: HNF4A: 20q12-q13.1 GCK: 7p14-p13 HNF1A: 12q24.31 IPF1: 13q12.1 HNF1B: 17q12 NEUROD1: 2q32 HERENCIA: autosmica dominante La diabetes tipo MODY (Maturity onset diabetes of the young) pertenece a un subtipo monognico de diabetes mellitus, caracterizado por comienzo precoz, habitualmente antes de los 25 aos, herencia autosmica dominante y disfuncin primaria de la clula beta pancretica. El MODY supone del 1 al 5% de todos los casos de diabetes en los pases industrializados. Es debida a un defecto gentico de la secrecin de la insulina y a una alteracin en la diferenciacin y en el desarrollo de la clula . La diabetes tipo MODY es genticamente heterognea y resulta de mutaciones en estado heterocigoto en al menos seis genes diferentes: MODY tipo 1, el gen afectado es el HNF4A, el cual codifica un factor de transcripcin identificado como el factor hepatonuclear 4. MODY tipo 2, el gen afectado es el GCK, el cual codifica el enzima glicoltico, la glucoquinasa que interniene como sensor de glucosa en la regulacin de la secrecin de insulina. MODY tipo 3, el gen afectado es el HNF1A, el cual codifica el factor de transcripcin identificado como factor hepatonuclear 1. Este gen tambin se conoce como el factor de transcripcin del hepatocito 1 (TCF1). MODY tipo 4, el gen afectado es el IPF1, el cual codifica el factor promotor de la insulina 1. MODY tipo 5, el gen afectado es el HNF1B, el cual codifica el factor de trasncripcin identificado como factor hepatonuclear 1 . MODY tipo 6, el gen afectado es el NEUROD1/BETA2 que interviene en el desarrollo pancretico y en la transcripcin del gen de la insulina.

Diabetes mellitus, MODY GENE: HNF4A, GCK, HNF1A, IPF1, HNF1B y NEUROD1 CHROMOSOMAL LOCALITATION: HNF4A: 20q12-q13.1 GCK: 7p14-p13 HNF1A: 12q24.31 IPF1: 13q12.1 HNF1B: 17q12 NEUROD1: 2q32 MODE OF INHERITANCE: autosomal dominant Maturity onset diabetes of the young is characterized by early onset diabetes inherited in an autosomal dominant pattern. Classic MODY presents before age 25, is nonketotic, and is generally not insulin-requiring. Mutations in five genes can cause MODY. These genes encode hepatocyte nuclear factor-4 alpha (HNF-4 alpha, MODY1), glucokinase (MODY2), hepatocyte nuclear factor-1 alpha (HNF-1 alpha, MODY3), insulin promoter factor-1 (IPF-1, MODY4), hepatocyte nuclear factor-1 beta (HNF-1 beta, MODY5), and gene NEUROD1, MODY6 (It induces the neural development).

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VOLVER/RETURN

Disoma uniparental La disoma uniparental se presenta cuando un individuo hereda dos copias de un par de cromosomas procedente de un progenitor y ninguna copia del otro. La disoma uniparental puede ocurrir en enfermedades raras recesivas, o problemas de desarrollo debido a los efectos del imprinting. Nuestro laboratorio ofrece el anlisis de UDP para varios cromosomas. UNIPARENTAL DISOMY Uniparental disomy (UPD) arises when an individual inherits two copies of a chromosome pair from one parent and no copy from the other parent. When this abnormality is inherited, it may lead to health concerns in a child. UPD can result in rare recessive disorders, or developmental problems due to the effects of imprinting. UPD may also occur with no apparent impact on the health and development of and individual. Our laboratory offers UPD testing for several chromosomes. VOLVER/RETURN

Distona Mioclnica GEN: DYT11/SGCE LOCALIZACIN CROMOSMICA: 7q21-q22 HERENCIA: autosmica dominante La Distona Mioclnica es un trastorno del movimiento caracterizado por una combinacin rpidas y breves contracciones musculares (mioclona) y/o torsin sostenida y movimientos repetitivos que se traducen en posturas anormales (distona). Las contracciones mioclnicas tpicas afectan con mayor frecuencia al cuello, tronco y extremidades superiores con menos participacin de las piernas. Aproximadamente el 50% de los individuos afectados tienen distona focal y segmentaria, apareciendo como la distona cervical y/o calambre del escribiente. La otra caracterstica importante no motora son problemas psiquitricos como la depresin, ansiedad, trastorno obsesivocompulsivo (OCD), los trastornos de la personalidad, adicciones, y ataques de pnico. La aparicin de los sntomas se produce generalmente en la niez o la adolescencia temprana, pero oscila entre los seis meses de vida a los 38 aos. La mayora de los adultos afectados presentan una reduccin drstica de la mioclona en respuesta a la ingesta de alcohol. La enfermedad es compatible con una vida activa normal. Las mutaciones en el gen SGCE (locus DYT11), que codifica la protena psilon-sarcoglicano, aparecen en la mayora de los casos de Distona Mioclnica familiar. MYOCLONUS-DYSTONIA GENE: DYT11/SGCE CHROMOSOMAL LOCATION: 7q21-q22 MODE OF INHERITANCE: autosomal dominant Myoclonus-dystonia (M-D) is a movement disorder characterized by a combination of rapid, brief muscle contractions (myoclonus) and/or sustained twisting and repetitive movements that result in abnormal postures (dystonia). The myoclonic jerks typical of M-D most often affect the neck, trunk, and upper limbs with less common involvement of the legs. Approximately 50% of affected individuals have additional focal or segmental dystonia, presenting as cervical dystonia and/or writer's cramp. The most prominent non-motor features have been psychiatric problems including depression, anxiety, obsessive-compulsive disorder (OCD), personality disorders, addiction, and panic attacks. Symptom onset is usually in childhood or early adolescence but ranges from six months to 38 years. Most affected adults report a dramatic reduction in myoclonus in response to alcohol ingestion. The disease is compatible with an active life of normal span. Mutations in the SGCE gene (locus DYT11), which encodes the protein epsilon-sarcoglycan, are identified in many individuals with familial M-D tested to date
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VOLVER/RETURN Distona Progresiva Hereditaria; de torsin temprana GEN: TOR1A LOCALIZACIN CROMOSMICA: 9q34 INCIDENCIA: 1/10,000 to 1/30,000 HERENCIA: autosmica dominante Las contracciones distnicas musculares causadas en la postura de pies, piernas y brazos son los sntomas comunes de presentacin. La distona es el primer sntoma evidente con acciones especficas como son al escribir o al andar, con el tiempo aparecen las contracciones de las distintas regiones del cuerpo. La severidad de la enfermedad varia dentro de la misma familia. Calambres al escribir pueden ser un signo. DYT1 es una de las ms comunes distonias de aparicin temprana que se diagnostica realizando el anlisis molecular de la delecin de tres pares de bases (GAG) en el gen TOR1A. EARLY-ONSET PRIMARY DYSTONIA (DYT1) GENE: TOR1A CHROMOSOMAL LOCATION: 9q34 INCIDENCE: 1/10,000 to 1/30,000 MODE OF INHERITANCE: autosomal dominant Dystonic muscle contractions causing posturing of a foot, leg, or arm are the most common presenting symptom. Dystonia is usually first apparent with specific actions, e.g., writing or walking. Over time, the contractions frequently (but not invariably) become evident with less specific actions and spread to other body regions. No other neurologic abnormalities are present, except for postural arm tremor. Disease severity varies considerably even within the same family. Isolated writer's cramp may be the only sign. DYT1 is one of the more common early-onset primary dystonias. DYT1 is diagnosed by molecular genetic testing of the TOR1A gene revealing a 3-base pair GAG deletion in most affected individuals. VOLVER/RETURN Distona Resistente a Dopamina GEN: DYT5/GCH1 LOCALIZACIN CROMOSMICA: 14q22.1-q22.2 INCIDENCIA: 1:1,000,000 HERENCIA: Autosmica dominante La Distona Resistente a Dopamina (GTPCH1- resistente a DRD) se caracteriza por la aparicin de distona durante la niez y baja respuesta a dosis orales de levodopa. La edad media de inicio es aproximadamente de seis aos. Este trastorno generalmente presenta dificultad progresiva para caminar y, ms tarde, desarrollo de parkinsonismo. Los sntomas fluctan durante el da, desde una movilidad relativa por la maana hasta una incapacidad progresiva por la tarde y en la noche, o despus de hacer ejercicio. En ocasiones, los sntomas iniciales son distona en el brazo, temblor postural de la mano, o la lentitud de movimientos. En muchos individuos aparecen reflejos tendinosos en las piernas, clonus de tobillo y/o el dedo del pie estriatal (extensin distnica del dedo gordo del pie). En general, se observa la progresin gradual de distona generalizada aunque no aparecen alteraciones ni intelectuales, del cerebelo, sensoriales ni autonmicas. GTP CYCLOHYDROLASE 1-DEFICIENT DOPA-RESPONSIVE DYSTONIA GENE: DYT5/GCH1 CHROMOSOMAL LOCATION: 14q22.1-q22.2 INCIDENCE: 1:1,000,000 MODE OF INHERITANCE: autosomal dominant GTP cyclohydrolase 1-deficient dopa-responsive dystonia (GTPCH1-deficient DRD) is characterized by childhood-onset dystonia and a dramatic and sustained response to low doses of oral administration of levodopa. The average age of onset is approximately six years. This disorder typically presents with gait disturbance caused by foot dystonia, later Rev 36 05/05/2009

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development of parkinsonism, and diurnal fluctuation of symptoms. Initial symptoms are often gait difficulties attributable to flexion-inversion (equinovarus posture) of the foot. Occasionally, initial symptoms are arm dystonia, postural tremor of the hand, or slowness of movements. Brisk deep-tendon reflexes in the legs, ankle clonus, and/or the striatal toe (dystonic extension of the big toe) are present in many affected individuals. In general, gradual progression to generalized dystonia is observed. Intellectual, cerebellar, sensory, or autonomic disturbances do not occur. VOLVER/RETURN

Displasia Ectodrmica ligada al X GEN: EDA LOCALIZACION CROMOSOMICA: Xq12-q13.1 HERENCIA: Recesivo ligado al X La displasia ectodrmica hipohidrotica (HED) se caracteriza por hipotricosis (escasez de cuero cabelludo y pelos), hipohidrosis (sudoracin reducida), e hipodoncia (ausencia congnita de piezas dentales). Comnmente afecta a varones con una herencia recesiva ligada al X, aunque existen otras formas con herencia mendeliana autosmica dominante y recesiva. Los pacientes afectos pueden presentar intolerancia al calor, fiebre, hipertermia grave e incluso muerte sbita. El gen EDA es el nico gen asociado a la Displasia Ectodrmica ligada al X. El 95% de los individuos con HED presentan la forma ligada al cromosoma X. En varones con Displasia ectodrmica ligada al X, secuenciando los ocho exones que codifican la ectodisplasina-A, se identifican alrededor de un 95% de las mutaciones, incluyendo las delecciones y mutaciones puntuales. El anlisis de la secuencia del gen EDA no detecta ciertos tipos de mutaciones en mujeres. Sin embargo, es necesario un anlisis especializado (anlisis de delecciones por MLPA) si la mujer presenta sntoma clnicos que sugieran que es portadora. Las formas autosmicas dominante y recesiva de la displasia ectodrmica hipohidrtica han sido asociadas con mutaciones en los genes EDAR y EDARADD. En un 5% de los casos de HED se detectan mutaciones en estos genes. X-Linked Hypohidrotic Ectodermal Dysplaisa GENE: EDA CHROMOSOMAL LOCATION: Xq12-q13.1 MODE OF INHERITANCE: X-linked recessive inheritance Hypohidrotic ectodermal dysplasia (HED) is characterized by hypotrichosis (sparseness of scalp and body hair), hypohidrosis (reduced ability to sweat), and hypodontia (congenital absence of teeth). It commonly affects males with an X-linked recessive inheritance, although variants exist with mendelian autosomal dominant and recessive patterns. The early recognition of the disorder is important, since the children can present with heat intolerance, fever, severe hyperthermia and even sudden death. EDA is the only gene known to be associated with X-linked HED. Ninety-five percent of individuals with HED (Hypohidrotic ectodermal dysplasia) have the X-linked form. In males with X-linked HED, direct sequencing of the eight exons of ectodysplasin-A using genomic DNA identifies about 95% of mutations, including missense and nonsense mutations and deletions. Sequence analysis of EDA cannot detect certain types of deletion mutations in females. Therefore, specialized testing (deletion testing) to identify a deletion is necessary if the female has clinical findings suggesting that she is a carrier. VOLVER/RETURN DISPLASIA EPIFISARIA MLTIPLE GEN: COMP y MATN3 LOCALIZACIN CROMSOMICA: 19p 12 (COMP) 2p24-p23 (MATN3) HERENCIA: autosmica dominante La displasia epifisaria mltiple (MED) aparece tempranamente (niez), por lo general con dolor en las caderas y/o rodillas despus de la actividad fsica. La altura que alcanzan en la edad adulta, est por debajo del rango de
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normalidad. Los miembros son relativamente cortos en comparacin con el tronco. El dolor y el progreso de la deformidad de las uniones, dan como resultado una osteoartritis de inicio temprano, en particular de las uniones grandes que llevan el peso. Presenta una herencia autosmica dominante. Muchos individuos con MED han heredado el alelo mutante de uno de los padres. La displasia epifisaria mltiple (MED) est causada por mutaciones en 5 genes: COMP, COL9A1, COL9A2, COL9A3 y MATN3. Las mutaciones en COMP estn localizadas en los exones 8-14 y en los exones 15-19. Todas las mutaciones en MATN3 son mutaciones puntuales encontradas dentro del exn 2, el cual codifica el dominioA de la matrilina-3 (molcula de la matriz cartilaginosa) MULTIPLE EPIPHYSELA DISPLASIA GENE: COMP and MATN3 CHROMOSOMAL LOCATION: 19p 12 (COMP), 2p 24-p23 (MATN3) MODE OF INHERITANCE: autosomal dominant Autosomal dominant multiple epiphyseal dysplasia (MED) presents early in childhood, usually with pain in the hips and/or knees after exercise. Adult height is either in the lower range of normal or mildly shortened. The limbs are relatively short in comparison to the trunk. Pain and joint deformity progress, resulting in early-onset osteoarthritis, particularly of the large weight-bearing joints. Dominant MED is inherited in an autosomal dominant manner. Many individuals with dominant MED have inherited the mutant allele from one parent. Mutations in five genes have been shown to cause autosomal dominant MED: COMP, COL9A1, COL9A2, COL9A3 and MATN3 Mutations in COMP are located in the exons encoding the type III repeats (exons 8-14) and C-terminal domain (exons 15-19) With one exception, all MED-causing mutations in MATN3 are missense mutations found within exon 2, which encodes the single A-domain of matrilin-3. VOLVER/RETURN

Distrofia facioescapulohumeral GEN: D4Z4 LOCALIZACIN CROMOSMICA: 4q35 INCIDENCIA: 4 10/100,000 HERENCIA: autosmica dominante La distrofia facio-escapulo-humeral se presenta normalmente antes de los 20 aos con debilidad en los msculos faciales y estabilizacin de la escpula o de los dorsiflexores del pie. La severidad es muy variable. La debilidad aparece lenta y progresivamente y en el 20% de los afectos eventualmente requieren silla de ruedas. El diagnstico de FSHD se realiza analizando la delecin de 3,3 Kb en el gen D4Z4 presente en el 95% de los casos de FSHD. FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY GENE: D4Z4 CHROMOSOMAL LOCATION: 4q35 INCIDENCE: four and ten per 100,000 MODE OF INHERITANCE: autosomal dominant Facioscapulohumeral muscular dystrophy (FSHD) typically presents before age 20 years with weakness of the facial muscles and the stabilizers of the scapula or the dorsiflexors of the foot. Severity is highly variable. Weakness is slowly progressive and about 20% of affected individuals eventually require a wheelchair. Life expectancy is not shortened. FSHD is diagnosed by a molecular genetic test showing a deletion of integral copies of a 3.3-kb DNA repeat motif named D4Z4. Molecular genetic testing detects about 95% of affected individuals and is clinically available.

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VOLVER/RETURN Distrofia muscular-oculofarngea GEN: PABPN1 LOCALIZACIN CROMOSMICA: 14q INCIDENCIA: 1:10,000 de la forma autosmica recesiva HERENCIA: autosmica dominante y recesiva La distrofia muscular oculo-farngea es de aparicin tarda (normalmente despus de los 45). La clnica se presenta con prpados cados, dificultades para tragar e historia familiar con implicacin de dos o ms generaciones. El diagnstico molecular est basado en el anlisis del nmero de repeticiones del triplete GCG en el gen PABPN1, donde los individuos afectos presentan ms de 6 repeticiones. OCULOPHARYNGEAL MUSCULAR DYSTROPHY GENE: PABPN1 (Poly(A) binding protein, nuclear 1) CHROMOSOMAL LOCATION: 14q INCIDENCE: 1:10,000 of autosomal-recessive MODE OF INHERITANCE: In either an autosomal dominant or an autosomal recessive manner Oculopharyngeal muscular dystrophy (OPMD) is characterized by late-onset (usually after the age of 45 years) eyelid drooping (ptosis, defined as either vertical separation of at least one palpebral fissure that measures less than 8 mm at rest), swallowing difficulty (dysphagia, defined as swallowing time greater than seven seconds when drinking 80 mL of ice-cold water), and a positive family history with involvement of two or more generations. Diagnosis of OPMD is based on clinical criteria. PABPN1, encoding the polyadenylate binding protein nuclear 1, is the only gene known to be associated with OPMD. VOLVER/RETURN Distrofia muscular miotnica (Steiner) GEN: DMPK (dystrophia myotonica protein kinase) LOCALIZACIN CROMOSMICA: 19q13.3 INCIDENCIA: 1 en 8,000 MODO DE HERENCIA: autosmica dominante con anticipacin La distrofia miotnica tipo 1 (DM1) es un trastorno multisistmico que afecta al msculo esqueltico y liso incluso al ojo, corazn, sistema endocrino y sistema nervioso central. Los sntomas clnicos, que van desde leves a severos, han sido clasificados en 3 fenotipos: leve, clsico y congnito. Al menos el 98% de casos DM1 presentan una repeticin y expansin demostrable de trinucletidos (CTG). Se recomienda para la confirmacin del diagnstico del paciente con o sin antecedentes familiares por medio del anlisis de DNA del gen DMPK. Las pruebas presintomticas de pacientes con antecedentes son posibles, como en diagnstico prenatal de fetos con familiares afectados. Se recomienda consejo gentico anteriormente a las pruebas de casos presintomticos. MYOTONIC MUSCULAR DYSTROPHY GENE: DMPK (dystrophia myotonica protein kinase) CHROMOSOMAL LOCATION: 19q13.3 INCIDENCE: 1 in 8,000 MODE OF INHERITANCE: autosomal dominant with anticipation Myotonic dystrophy type 1 (DM1) is a multi-system disorder that affects skeletal and smooth muscle as well as the eye, heart, endocrine system, and central nervous system. The clinical findings, which span a continuum from mild to severe, have been categorized into three somewhat overlapping phenotypes: mild, classic, and congenital. At least 98% of cases of myotonic dystrophy exhibit a demonstrable trinucleotide repeat expansion (CTG). Direct DNA analysis of the myotonic dystrophy gene is now recommended for the confirmation of a diagnosis in a patient with or without a family history of the condition. Presymptomatic testing of individuals with a confirmed family history is also possible, as is the prenatal diagnosis of a fetus from a family with a known trinucleotide repeat expansion. Genetic counseling is recommended prior to testing in presymptomatic cases.

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VOLVER/RETURN DISTROFIA MIOTNICA TIPO 2 GEN: ZNF9 LOCALIZACIN CROMOSMICA: 3q21.3 HERENCIA: autosmica dominante La distrofia miotnica tipo 2 (DM2) se caracteriza por miotona en el 90% de las personas afectadas, disfuncin muscular (debilidad, dolor y rigidez) en el 82 % de los individuos, y menos comnmente, por defectos en la conduccin cardaca, cataratas subcapsulares posteriores iridiscentes, diabetes mellitus tipo 2 resistente a insulina y fallo testicular. CNBP (ZNF9) es el nico gen asociado con la DM2. El intrn 1 del gen CNBP contiene un complejo de repeticiones, (TG) n (TCTG) n (CCTG) n. La expansin de las repeticiones de CCTG causan la DM2. El nmero de repeticiones de CCTG en los alelos expandidos oscila entre aproximadamente 75 a ms de 11.000, con una media de aproximadamente 5.000 repeticiones. La tasa de deteccin de las expansiones CCTG en el gen CNBP es de ms del 99% con la combinacin de PCR, Southern blot, y triple PCR (TP-PCR). No se han detectado mutaciones de novo. MYOTONIC DYSTROPHY TYPE 2 GENE: ZNF9 CHROMOSOMAL LOCALITATION: 3q21.3 MODE OF INHERITANCE: autosomal dominant Myotonic dystrophy type 2 (DM2) is characterized by myotonia (90% of affected individuals) and muscle dysfunction (weakness, pain, and stiffness) (82%), and less commonly by cardiac conduction defects, iridescent posterior subcapsular cataracts, insulin insensitive type 2 diabetes mellitus, and testicular failure. CNBP (ZNF9) is the only gene known to be associated with myotonic dystrophy type 2. CNBP intron 1 contains a complex repeat motif, (TG)n(TCTG)n(CCTG)n. Expansion of the CCTG repeat causes DM2. The number of CCTG repeats in expanded alleles ranges from approximately 75 to more than 11,000, with a mean of approximately 5000 repeats. The detection rate of a CNBP CCTG expansion is more than 99% with the combination of routine PCR, Southern blot analysis, and the "PCR repeat assay." De novo mutations have not been reported. VOLVER/RETURN

DISTROFIA MUSCULAR CONGNITA, MEROSINA DEFICIENTE TIPO 1A (MDC1A) GEN: LAMA2 LOCALIZACIN CROMOSMICA: 6q22-q23 HERENCIA: autosmica recesiva El trmino Distrofia Muscular Congnita (CMD) se refiere a un grupo de trastornos hereditarios en los cuales la debilidad muscular est presente desde el nacimiento. Los nios afectados presentan bajo tono muscular y contracturas. La debilidad muscular tiende a ser estable en el tiempo, pero las complicaciones de la distrofia suelen ser ms graves con el tiempo. Aproximadamente el 50% de las CMD estn causadas por una deficiencia completa de una protena de la matriz extracelular, la merosina. Esta deficiencia est causada por mutaciones en el gen LAMA2 que codifica para merosina, tambin denominada laminina alfa-2. El gen LAMA2 tiene 64 exones y las mutaciones se distribuyen a lo largo de toda la secuencia codificante de 9,5 Kb. No se han observado mutaciones ms frecuentes en este gen.

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CONGENITAL MUSCULAR DYSTROPHY WITH MEROSIN DEFICIENCY GENE: LAMA2 CHROMOSOMAL LOCALITATION: 6q22-q23 MODE OF INHERITANCE: autosomal recessive The term congenital muscular dystrophy (CMD) refers to a group of inherited disorders in which muscle weakness is present at birth. Affected infants typically appear "floppy" with low muscle tone and contractures. Muscle weakness tends to be stable over time, but the complications of the dystrophy become more severe with time. Approximately 50% of CMD is caused by complete merosin deficiency, an extracellular matrix protein also called laminin alpha2. This deficiency is caused by mutations in LAMA2 gene. The LAMA2 gene has 64 exons and mutations are distributed throughout the very large coding sequence of 9.5 Kb. No common mutations are observed in LAMA2. VOLVER/RETURN

Distrofia muscular de Duchenne/Becker GEN: Dystrophin LOCALIZACIN CROMOSMICA: Xp21.2 FRECUENCIA DE PORTADORES: 1 CADA 1500 mujeres INCIDENCIA: ~1:3,500 hombres (DMD); ~1:30,000 hombres (BMD) HERENCIA: Recesivo ligado al cromosoma X Las distrofias de Duchenne o Becker son enfermedades que afectan principalmente a los msculos esquelticos y cardiacos. La distrofia muscular de Duchenne (DMD) normalmente presenta en la temprana infancia retraso y debilidad muscular. DMD tiene una rpida evolucin, la mayora de los enfermos deben usar silla de ruedas hasta la edad de 12 aos. Pocos sobreviven ms de 30 aos, como principales causas de muerte estn las complicaciones respiratorias y cardiopticas. La distrofia muscular de Becker (BMD) se caracteriza por una posterior debilidad muscular, y pueden andar hasta los 20 aos.

Las mujeres portadoras de la mutacin DMD tienen un mayor riesgo de cardiomiopata y problemas cardiovasculares. Entre un 60-70% de estos casos tienen una delecin demostrable en uno a ms exones del gen de la distrofina. Se recomienda el anlisis directo de DNA de los genes de DMD y BMD para confirmar el diagnstico, en lugar de una tcnica tan invasiva como la biopsia muscular. Tambin se puede realizar el test del portador para mujeres en riesgo. El diagnstico prenatal es posible en familias en las que se hayan demostrado la presencia de la delecin. DUCHENNE or BECKER MUSCULAR DYSTROPHY GENE: Dystrophin CHROMOSOMAL LOCATION: Xp21.2 CARRIER FREQUENCY: 1 in 1500 females INCIDENCE: ~1 in 3,500 male live births (DMD); ~1 in 30,000 male live births (BMD) MODE OF INHERITANCE: X-linked recessive Duchenne and Becker muscular dystrophies are progressive muscle diseases primarily affecting skeletal and cardiac muscle. Duchenne muscular dystrophy (DMD) usually presents in early childhood with delayed milestones and proximal muscle weakness. DMD is rapidly progressive, with most affected individuals being wheelchair bound by age 12. Few survive beyond the third decade, with respiratory complications and cardiomyopathy being common causes of death. Becker muscular dystrophy (BMD) is characterized by later-onset skeletal muscle weakness, and individuals remain ambulatory into their 20s. Carrier females of DMD mutations are at increased risk for dilated cardiomyopathy and cardiac conduction defects. An estimated 60-70% of cases of Duchenne and Becker muscular dystrophy have a
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demonstrable deletion of one or more exons in the dystrophin gene. Direct DNA analysis of the Duchenne/Becker muscular dystrophy gene is recommended for confirmation of a diagnosis, in place of the more invasive method of muscle biopsy confirmation. Carrier testing for at-risk females is also available. Prenatal diagnosis is available for families in which the presence of a deletion has been demonstrated. VOLVER/RETURN Distrofia muscular de cinturas La distrofia muscular de cintura (LGMD) ha sido reconocida como un termino descriptivo, reservado generalmente a los nios o preadultos con distrofia muscular que se diferencian de las distrofinopatas ligadas al cromosoma X que son mucho ms comunes. Las personas con LGMD presentan debilidad y prdida de musculatura mayor en la proximal que en la distal. La mayora de pacientes de LGMD presentan escaso msculo cardiaco y bulbar, aunque hay excepciones dependiendo de subtipo gentico. Inicialmente, la progresin y distribucin de la debilidad y prdida de musculatura varan considerablemente entre los distintos pacientes y subtipos. En algunos casos, para demostrar la total o parcial deficiencia de una protena en particular puede seguirse mediante estudios de las mutaciones del correspondiente gen. Pruebas gentico moleculares para MYOT, CAPN3, LMNA y SGCA son posibles con bases clnicas. Adems, pruebas para BYSF se pueden llevar a cabo en individuos de ascendencia libio-juda. LGMD1A GEN: MYOT, Miotilina LOCALIZACIN CROMOSMICA: 5q31 HERENCIA: Autosmica dominante Las mutaciones de dos grandes pedigres han sido investigadas. Los pacientes presentan debilidad en los msculos proximales de piernas y brazos a una edad principal de inicio de 27 aos, posteriormente el progreso incluye a los msculos distales. La miotilina es una protena sarcomrica y ha sido descrita como la causante de esta patologa (gen LGMD1A). LGMD1B GEN: LMNA, Laminina A/C LOCALIZACIN CROMOSMICA: 1q21.2 HERENCIA: Autosmica dominante Mutaciones en el gen LMNA dan lugar al menos a once condiciones allicas diferentes entre las que se encuentran la distrofia muscular de cinturas 1B(LGMD1B), las formas autosmicas dominante y recesiva de la distrofis muscular de Emery-Dreifuss y el Charcot-Marie-Tooth tipo 2B1. LGMD2A GEN: CAPN3, Calpana LOCALIZACIN CROMOSMICA: 15q HERENCIA: Autosmica recesiva La prueba de protenas inmunoblot no es especfica ni sensible, la protena Calpana 3 puede ser relativamente inestable en el msculo,lo que dificulta la interpretacin de los resultados. El diagnstico se hace directamente por pruebas de mutaciones o anlisis preliminar de la protena por inmunoblot, seguido de la deteccin de la mutacin. LGMD2B GEN: DYSF, Disferlina LOCALIZACIN CROMOSMICA: 2p13 HERENCIA: Autosmica recesiva Los pacientes de esta enfermedad presentan debilidad primaria en msculos proximales y distales, la ltima se conoce como Miopata Distal de Miosina. La debilidad del msculo puede ser suave y los pacientes pueden presentar importantes inflamaciones en la biopsia del msculo, resultando ser una enfermedad autoinmune. stos enfermos que no responden a terapias inmuno-reguladoras se pueden diagnosticar por pruebas de disferlina. LGMD2D GEN: SGCA, Alfa-sarcoglicano
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LOCALIZACIN CROMOSMICA: 17q12 HERENCIA: Autosmica recesiva El diagnstico molecular se logra por deteccin inmunolgica de las protenas -sarcoglicano en biopsias musculares. La mutacin de un nico gen de la -sarcoglicano conlleva una deficiencia bioqumica secundaria de todas estas protenas del msculo. Por ejemplo, individuos con mutaciones en la protena -sarcoglicano presentan marcadas deficiencias o ausencia de las protenas alfa-, beta-, gamma- y delta-sarcoglicano del msculo. LIMB-GIRDLE MUSCULAR DYSTROPHY Limb-girdle muscular dystrophy (LGMD) has long been recognized as a purely descriptive term, generally reserved for childhood- or adult-onset muscular dystrophies that are distinct from the much more common X-linked dystrophinopathies. Individuals with LGMD generally show weakness and wasting restricted to the limb musculature, proximal greater than distal. Most individuals with LGMD show relative sparing of the heart and bulbar muscles, although exceptions occur, depending on the genetic subtype. Onset, progression, and distribution of the weakness and wasting vary considerably among individuals and genetic subtypes In some cases, demonstration of complete or partial deficiencies for any particular protein can then be followed by mutation studies of the corresponding gene. Molecular genetic testing for MYOT, CAPN3, LMNA and SGCA is available on a clinical basis. In addition, testing for DYSF is available for individuals of Libyan Jewish ancestry. LGMD1A GENE: MYOT , Myotilin CHROMOSOMAL LOCATION: 5q31 MODE OF INHERITANCE: Autosomal dominant Mutations in two large pedigrees have been reported. Individuals show proximal leg and arm weakness with a mean age of onset of 27 years, later progressing to include distal weakness. Myotilin is a sarcomeric protein and it has been described as the causative gene in LGMD1A. LGMD1B GENE: LMNA, Lamin A/C CHROMOSOMAL LOCATION: 1q21.2 MODE OF INHERITANCE: Autosomal dominant Mutations in LMNA result in at least eleven allelic conditions including LGMD1B, autosomal dominant and autosomal recessive Emery-Dreifuss muscular dystrophy, Dunnigan-type familial partial lipodystrophy (FPLD), mandibuloacral dysplasia, and Charcot-Marie-Tooth type 2B1. LGMD2A GENE: CAPN3, Calpain CHROMOSOMAL LOCATION: 15q MODE OF INHERITANCE: Autosomal recessive The protein immunoblot test is not highly specific or sensitive; calpain 3 may be relatively unstable in muscle, leading to difficulties in interpretation. Diagnosis has been made by direct mutation testing or preliminary immunoblot analysis of calpain 3 protein, followed by mutation detection. LGMD2B GENE: DYSF, Disferlin CHROMOSOMAL LOCATION: 2p13 MODE OF INHERITANCE: Autosomal recessive Affected individuals can show either a primarily proximal or primarily distal distribution of weakness; the latter is known as "Miyoshi distal myopathy".The muscle weakness may be mild and individuals can show significant inflammation on muscle biopsy, resulting in misclassification as autoimmune disease. Individuals with myositis who do not respond to immuno-modulation therapy can be considered for dysferlin testing. LGMD2G GENE: SGCA,Alpha-sarcoglycan CHROMOSOMAL LOCATION: 17q12 MODE OF INHERITANCE: Autosomal recessive
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Molecular diagnosis is accomplished by immunological detection of the sarcoglycan proteins in muscle biopsy. Mutation in any single sarcoglycan gene leads to secondary biochemical deficiency of all sarcoglycan proteins in muscle. For example, individuals with mutations in alpha-sarcoglycan show marked deficiency or absence of alpha-, beta-, gamma-, and delta-sarcoglycan on immunostaining of muscle. VOLVER/RETURN DISTROFIA MUSCULAR EMERY-DREIFUSS GENES: LMNA y EMD LOCALIZACION CROMOSOMICA: 1q21.2-q21.3 (LMNA), Xq28 (EMD) HERENCIA: autosmica dominante (EDMD2), autosmica recesiva (EDMD3) y ligada al X (EDMD) La Distrofia Muscular Emery-Dreifuss (EDMD) es un tipo de distrofia muscular que afecta principalmente al msculo esqueltico y al msculo cardaco. La EDMD se caracteriza por contracturas en las articulaciones que comienzan al inicio de la niez; debilidad y atrofia muscular de progresin lenta (en un principio de distribucin hmero-peroneal y progresando posteriormente hacia las cinturas escapular y plvica); y problemas cardacos que pueden manifestarse como palpitaciones, presncope y sncope, baja tolerancia al ejercicio y paro cardaco congestivo. Los diferentes tipos de Distrofia Muscular Emery-Dreifuss se distinguen por su modelo de herencia:
Distrofia Muscular Emery-Dreifuss ligada al X (XL-EDMD). El gen asociado es EMD, que codifica para la emerina. Distrofia Muscular Emery-Dreifuss Autosmica Dominante (EDMD2). El gen asociado es LMNA, que codifica para las

lamininas A y C de la lmina nuclear. Distrofia Muscular Emery-Dreifuss Autosmica Recesiva (EDMD3). El gen LMNA tambin est asociado con este tipo de EDMD.

EMERY-DREIFUSS MUSCULAR DYSTROPHY GENES: LMNA and EMD CHROMOSOMAL LOCALITATION: 1q21.2-q21.3 (LMNA), Xq28 (EMD) MODE OF INHERITANCE: autosomal dominant (EDMD2), autosomal recessive (EDMD3) and X-linked (EDMD) Emery-Dreifuss muscular dystrophy (EDMD) is characterized by the clinical triad of joint contractures that begin in early childhood, slowly progressive muscle weakness and wasting initially in a humero-peroneal distribution that later extends to the scapular and pelvic girdle muscles, and cardiac involvement that may manifest as palpitations, presyncope and syncope, poor exercise tolerance, and congestive heart failure. The types of Emery-Dreifuss muscular dystrophy are distinguished by their pattern of inheritance: X-linked EDMD (XLEDMD); Autosomal dominant EDMD (EDMD2); and Autosomal recessive EDMD (EDMD3). The two genes known to be associated with EDMD are EMD, encoding emerin and causing XL-EDMD, and LMNA, encoding lamins A and C and causing autosomal dominant EDMD (AD-EDMD) and autosomal recessive EDMD (AREDMD). VOLVER/RETURN

EHLERS-DANLOS TIPO IV GEN: COL3A1 LOCALIZACIN CROMOSMICA: 2q31 HERENCIA: autosmica dominante
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El Sndrome de Ehlers-Danlos tipo vascular (tambin conocido como EDS tipo IV) se caracteriza porque los individuos que lo padecen presentan una piel delgada y translcida en la cual aparecen moratones fcilmente, una apariencia facial caracterstica y fragilidad arterial, intestinal y uterina. La ruptura arterial puede estar precedida por aneurisma, fstula arteriovenosa o diseccin. Los recin nacidos pueden presentar pie zambo y/o luxacin congnita en la cadera. En la infancia son comunes la hernia inguinal, neumotorax y la dislocacin recurrente o subluxacin. Las mujeres embarazadas con EDS tipo IV tienen un 12% de riesgo de muerte por ruptura arterial periparto o ruptura uterina. Una cuarta parte de los individuos con EDS tipo IV experimenta importantes problemas de salud a los 20 aos de edad y ms del 80 % a los 40 aos de edad. La edad media a la cual se produce la muerte es de 48 aos. COL3A1 es el nico gen asociado con EDS tipo vascular, codifica las cadenas de procolgeno tipo III, importante componente estructural de la piel, vasos sanguneos y rganos huecos. La mayora de las mutaciones identificadas son el resultado de la sustitucin de otros aminocidos por residuos de glicina en los tripletes [Gly-X-Y]343 del dominio helicoidal triple del colgeno tipo III.

EHLERS-DANLOS SYNDROME IV GENE: COL3A1 CHROMOSOMAL LOCALITATION: 2q31 MODE OF INHERITANCE: autosomal dominant Ehlers-Danlos syndrome, vascular type (also known as EDS IV) is characterized by thin, translucent skin; easy bruising; characteristic facial appearance; and arterial, intestinal, and/or uterine fragility. Arterial rupture may be preceded by aneurysm, arteriovenous fistulae, or dissection. Neonates may present with clubfoot and/or congenital dislocation of the hips. In childhood, inguinal hernia, pneumothorax, and recurrent joint dislocation or subluxation are common. Pregnancy for women with the vascular type of EDS has as much as a 12% risk for death from peripartum arterial rupture or uterine rupture. One-fourth of individuals with EDS, vascular type experience a significant medical problem by age 20 years and more than 80% by age 40 years. The median age of death is age 48 years. COL3A1 is the only gene associated with EDS, vascular type. The COL3A1 gene encodes the chains of type III procollagen, a major structural component of skin, blood vessels, and hollow organs. The majority of identified mutations result in substitution of other amino acids for glycine residues in the [Gly-X-Y]343 triplets of the triple helical domain of the type III collagen molecule. The vascular type of EDS is inherited in an autosomal dominant manner. VOLVER/RETURN

ENDOCRINOPATA MLTIPLE AUTOINMUNE TIPO I GEN: AIRE LOCALIZACIN CROMOSMICA: 21q22.3 HERENCIA: autosmica recesiva Los individuos afectos por endocrinopata mltiple autoinmune tipo I , en la mayora de los casos, presentan los primeros sntomas en la niez o en la adolescencia. Esta afeccin se caracterizada por tres rasgos especficos: candidiasis cutaneomucosa (infeccin fngica que afecta a la piel y mucosas), hipoparatiroidismo (mal funcionamiento de la glndula paratiroides), y enfermedad de Addison (mal funcionamiento de las glndulas suprarrenales). Los individuos afectos presentan, tpicamente, al menos dos de estos rasgos, y muchos presentan los tres, manifestndose
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como fatiga, debilidad muscular, prdida de peso, hipotensin . Las complicaciones de este desorden afectan a la piel y las uas, las gnadas (ovarios y testculos), los ojos, al tiroides, y al sistema digestivo. Esta causado por mutaciones en el gen AIRE, el cual codifica una protena llamada regulador autoinmune. Esta protena ayuda al sistema inmunitario a distinguir las clulas y protenas del cuerpo de los agentes invasores externos, por tanto, las mutaciones en este gen desarrollan procesos autoinmunitarios.Han sido identificadas ms de 60 mutaciones del gen AIRE que producen la Endocrinopata mltiple autoinmune tipo I.

AUTOIMMUNE POLYENDOCRINOPATHY SYNDROME TYPE I GENE: AIRE CHROMOSOMAL LOCALITATION: 21q22,3 MODE OF INHERITANCE: autosomal recessive Autoimmune polyendocrynopathy syndrome, type 1 is a autoimmune disease. In most cases, the signs and symptoms of autoimmune polyglandular syndrome, type 1 begin in childhood or adolescence. This condition is characterized by three specific features: mucocutaneous candidiasis (a fungal infection that affects the skin and mucous membranes), hypoparathyroidism (a malfunction of the parathyroid glands), and Addison disease (a malfunction of the small hormone-producing glands on top of each kidney (adrenal glands)). Affected individuals typically have at least two of these features, and many have all three. It disease can cause fatigue, muscle weakness, weight loss, low blood pressure....Complications of this disorder can affect the skin and nails, the gonads (ovaries and testicles), the eyes, the thyroid, and the digestive system. Mutations in the AIRE gene cause autoimmune polyglandular syndrome, type 1. The AIRE gene provides instructions for making a protein called the autoimmune regulator. Specifically, it helps the body distinguish its own proteins and cells from those of foreign invaders (such as bacteria and viruses).More than 60 mutations in the AIRE gene have been identified in individuals with autoimmune polyendocrynopathy syndrome, type 1.

VOLVER/RETURN

Enfermedad de Tay-Sachs-Gangliosidosis GM2 GEN: HEX A LOCALIZACIN CROMOSMICA: 15q23-q24 INCIDENCIA: entre 1/250 y 1/300 para portadores HERENCIA: autosmica recesiva La enfermedad de Tay-Sachs, deficiencia de hexosaminidasa A, se caracteriza por una progresiva debilidad, prdida de destreza motora, disminucin de la atencin y sobresaltos. Estos sntomas comienzan entre los 3 y 6 meses de edad con una progresiva evidencia de neurodegeneracin, incluyendo ataques, ceguera, espasticidad, incapacidad total eventual y muerte normalmente antes de los 4 aos. El panel de las mutaciones ms frecuentes es: +TATC1278, +1IVC12, +1IVS9, G269S R247W y R249W. TAY-SACHS DISEASE GENE: HEX A

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CHROMOSOMAL LOCATION: 15q23-q24 INCIDENCE: carrier frequency (between 1/250 and 1/300). MODE OF INHERITANCE: autosomal recessive Tay-Sachs disease (acute infantile), the prototype hexosaminidase A deficiency, is characterized by progressive weakness, loss of motor skills, decreased attentiveness, and increased startle response beginning between three and six months of age with progressive evidence of neurodegeneration, including seizures, blindness, spasticity, eventual total incapacitation, and death, usually before age four years. The panel of the six most common mutations comprises: +TATC1278, +1IVC12, +1IVS9, G269S R247W and R249W. VOLVER/RETURN Epidermolisis bullosa GEN: COL7A1 LOCALIZACIN CROMOSMICA: 3p21.3 INCIDENCIA: 6.5/1000000 en poblacin EEUU. La frecuencia de portadores: 1/370 HERENCIA: Hay tres subtipos: epidermolisis bullosa recesiva tipo Hallopeau-Siemens, epidermolisis bullosa recesiva tipo no-Hallopeau-Siemens y epidermolisis bullosa dominante. En la epidermolisis bullosa recesiva tipo Hallopeau-Siemens, forma clsica de epidermolisis bullosa, las ampollas estn presentes desde antes del nacimiento. Es posible que se produzca la fusin entre la lengua y la parte baja de la boca ocasionando una disminucin de la cavidad oral. La erosin esofgica puede causar disfagia. Las erosiones en las crneas pueden conducir a la prdida de visin. Las ampollas en manos y pies pueden generar cicatrices que fusionan los dgitos en la parte media de las manos y pies. El riesgo de carcinoma de clulas escamosas est entorno al 90%. Por el contrario, en la epidermolisis bullosa recesiva tipo no-Hallopeau-Siemens las ampollas estn localizadas en manos, pies, rodillas y codos, con o sin implicacin de las reas de flexin y el tronco, y sin la severidad que presenta la epidermolisis bullosa recesiva tipo Hallopeau-Siemens. En la epidermolisis bullosa dominante las ampollas son frecuentes en la mitad o lmites de las manos, pies, rodillas y codos. La distrofia en las uas, especialmente en la del dedo gordo del pie, es una caracterstica especial de este tipo de epidermolisis bullosa. El gen implicado en los tres casos es el COL7A1. La secuenciacin de los exones 73, 74 y 75 de este gen detecta el 75% de los casos de epidermolisis bullosa dominante. La secuenciacin completa del gen tiene una tasa de deteccin del 95% de los casos de epidermolisis bullosa dominante y recesiva. Para el estudio de grandes deleciones y duplicaciones se usa la tcnica de MLPA. DYSTROPHIC EPIDERMOLYSIS BULLOSA GENE: COL7A1 CHROMOSOMAL LOCATION: 3p21.3 INCIDENCE: 6.5 per million live births in the US population. The carrier frequency: 1/370 MODE OF INHERITANCE: Dystrophic epidermolysis bullosa (DEB) includes three subtypes: recessive DEB, Hallopeau-Siemens type (RDEB-HS); recessive DEB, non-Hallopeau-Siemens type (non-HS RDEB); and dominant DEB (DDEB). In RDEB-HS, the classic severe form of DEB, blisters affecting the whole body are present in the neonatal period. Oral involvement may lead to fusion of the tongue to the floor of the mouth and progressive diminution of the size of the oral cavity. Esophageal erosions can lead to webs and strictures that can cause severe dysphagia. Corneal erosions can lead to scarring and loss of vision. Blistering of the hands and feet followed by scarring fuses the digits into "mitten" hands and feet, a hallmark of this disorder. The lifetime risk of aggressive squamous cell carcinoma is over 90%. In contrast, the blistering in non-HS RDEB is localized to hands, feet, knees, and elbows with or without involvement of flexural areas and the trunk, and without the severe, mutilating scarring seen in classic RDEB-HS. In DDEB, blistering is often mild and limited to hands, feet, knees, and elbows, but nonetheless heals with scarring. Dystrophic nails, especially toenails, are common and may be the only manifestation of DDEB. The only gene known to be associated with DEB is COL7A1. Sequencing of exons 73, 74, and 75 of COL7A1 detects mutations in 75% of families with DDEB; sequencing of all coding exons detects mutations in about 95% of individuals with either DDEB or RDEB. Using methods such as MLPA, we analysed deletions/duplications in COL7A1 gene. VOLVER/RETURN Rev 36 05/05/2009

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Epilepsia GEN: LGI1 LOCALIZACIN CROMOSMICA: 10q24 INCIDENCIA: desconocida pero muy baja HERENCIA: autosmica dominante Se caracteriza por cuadro de epilepsia, problemas auditivos como zumbidos, repiques, distorsin del sonido, estruendo as como afasia receptiva. El 50% de los casos de epilepsia estn asociados a mutaciones en el gen LGI1. EPILEPSY (AUTOSOMAL DOMINANT PARTIAL EPILEPSY WITH AUDITORY FEATURES) GENE: LGI1 CHROMOSOMAL LOCATION: 10q24 INCIDENCE: unknown but likely to be very low MODE OF INHERITANCE: autosomal dominant ADPEAF is characterized by localization-related epilepsy with auditory symptoms and/or receptive aphasia as prominent ictal manifestations. The most common auditory symptoms are simple unformed sounds such as humming, buzzing, or ringing; less common forms are distortions (e.g., volume changes) or complex sounds (e.g., specific songs or voices). VOLVER/RETURN EPILEPSIA GENERALIZADA CON CONVULSIONES FEBRILES PLUS GEN: GABRG2 LOCALIZACIN CROMOSMICA: 5q31.1-q33.1 HERENCIA: autosmica dominante La Epilepsia Generalizada con Convulsiones Febriles Plus (GEFSP) es una sndrome epilptico familiar caracterizado por la heterogeneidad gentica y fenotpica. Se asocia con mutaciones en los genes que codifican las subunidades de los canales de sodio neuronales regulados por voltaje (SCN1A(GEFSP1), SCN2A(GEFSP4), SCN1B(GEFSP2)) y en los genes que codifican los receptores regulados por ligando del cido gamma aminobutrico o GABA (GABRG2(GEFSP3), GABRD) Los nios afectos presentan convulsiones febriles que posteriormente evolucionan en una epilepsia con convulsiones febriles. Se ha confirmado que estos genes presentan un papel en la herencia autosmica dominante de la GEFSP familiar. Los fenotipos de los miembros afectados pueden depender de los tipos y ubicaciones de estas mutaciones genticas. Nuestro laboratorio dispone del anlisis de secuencia del gen GABRG2. GENERALIZED EPILEPSY WITH FEBRILE SEIZURES PLUS GENE: GABRG2 CHROMOSOMAL LOCALITATION: 5q31.1-q33.1 MODE OF INHERITANCE: autosomal dominant Generalized epilepsy with febrile seizures plus (GEFS+) is a familial epilepsy syndrome characterized by phenotypic and genetic heterogeneity. It was associated with mutations in the neuronal voltage-gated sodium channel subunit gene (SCN1A, SCN2A, SCN1B) and ligand-gated gamma aminobutyric acid receptors genes (GABRG2, GABRD). Children with febrile seizures that later develop ongoing epilepsy with a febrile seizures. These genes have been confirmed as having a role in autosomal dominant GEFS+ families. In addition, the phenotypes of the affected members may depend on the types and locations of these gene mutations. Sequencing analysis of GABRG2 is available in our laboratory. Rev 36 05/05/2009

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VOLVER/RETURN Epilepsia ligada al X GEN: ARX LOCALIZACIN CROMOSMICA: Xp21 HERENCIA: Recesiva ligada al X La epilepsia mioclnica ligada al X asociada a discapacidad intelectual (XMESID) es una rara enfermedad recesiva ligada al X relacionada con epilepsia mioclnica y discapacidad intelectual en los nios. XMESID se asocia con una mutacin en el gen ARX. Las mutaciones de ARX se asocian con una amplia gama de fenotipos; estudios funcionales en el futuro puede aportar informacin sobre las convulsiones mioclnicas y espasmos infantiles. X-LINKED MYOCLONIC EPILEPSY GENE: ARX CHROMOSOMAL LOCATION: Xq21 MODE OF INHERITANCE:Recesive X linked X-linked myoclonic epilepsy with generalized spaticity and intellectual disability (XMESID) is a rare X-linked recessive myoclonic epilepsy with spasticity and intellectual disability in boys. Hyperreflexia is found in carrier women. XMESID is associated with a missense mutation in ARX. This disorder is allelic with X-linked infantile spasms where polyalanine tract expansions are the commonly observed molecular defect. Mutations of ARX are associated with a wide range of phenotypes; functional studies in the future may lend insights to the neurobiology of myoclonic seizures and infantile spasms. VOLVER/RETURN Epilepsia mioclnica severa SCN1A GEN: SCN1A LOCALIZACIN CROMOSMICA: 2q24 INCIDENCIA: 1/20.000-1/40.000 en la poblacin general La epilepsia mioclnica grave de la infancia (EMGI) o sndrome de Dravet constituye una de las formas de epilepsia ms graves de la infancia. En la mayor parte de los casos el cuadro se caracteriza por su inicio en el primer ao de vida, con crisis febriles, desarrollo normal previo al inicio de las crisis, gran variedad en la fenomenologa crtica a lo largo de la evolucin, resistencia temprana al tratamiento, normalidad inicial del EEG y deterioro neurolgico progresivo con ataxia y piramidalismo. La reciente descripcin, como probable responsable del proceso, de una mutacin de la subunidad a de un canal neuronal de sodio dependiente de voltaje (SCN1A) en el cromosoma 2q24 va a permitir el cribado en las fases iniciales de la enfermedad, as como el estudio de la correlacin entre el fenotipo y el genotipo del sndrome. En nuestro laboratorio se realiza la secuenciacin completa del gen SCN1A. SCN1A-RELATED SEIZURE DISORDERS GENE: SCN1A CHROMOSOMAL LOCATION: 2q24 INCIDENCE: 1/20.000-1/40.000 Severe myoclonic epilepsy begins during the first year of life. Development is normal prior to the onset of seizures. Affected infants develop either generalized or unilateral clonic seizures without prodromal signs. Myoclonic jerks and partial seizures usually appear later. Psychomotor retardation and other neurologic deficits occur in affected children. The occurrence of status epilepticus is frequent, either convulsive (often febrile), or as obtundation status. The latter consist of an impairment of consciousness, variable in intensity, the presence of fragmentary and segmental erratic myoclonias, sometimes associated with a slight increase of the muscular tone. Convulsive seizures can either initiate or occur during or terminate these status. They are prolonged for several hours or days. In 2001 Claes and colleagues found new mutations in the sodium-channel gene SCN1A in all of the studied 7 probands with severe myoclonic epilepsy in infancy. In our laboratory, SCN1A gen is studied by sequencing analysis.
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VOLVER/RETURN ESCLEROSIS LATERAL AMIOTRFICA GEN: SETX, SOD1 y ANG LOCALIZACIN CROMOSMICA: 9q34 (SETX), 21q22.1 (SOD1), 14q11.2 (ANG) HERENCIA: autosmica dominante y recesiva La Esclerosis Lateral Amiotrfica (ALS) es una enfermedad neurodegenerativa progresiva que afecta a las neuronas motoras superiores (UMN) e inferiores (LMN). Los individuos afectos presentan, tpicamente, debilidad focal asimtrica de las extremidades, disartria y disfagia. Tambin presentan una perdida de la capacidad de caminar, de la fuerza y el uso de las manos y los brazos. La respiracin se vuelve difcil porque los msculos del sistema respiratorio se debilitan. La mayora de las personas con esclerosis lateral amiotrfica mueren de insuficiencia respiratoria. La edad de inicio de ALS es de aproximadamente 56 aos en los individuos sin historia familiar conocida y de 46 aos en individuos con ms de un miembro de la familia afectado (ALS familiar o FALS). Aproximadamente un 10% de las personas afectadas de Esclerosis Lateral Amiotrfica tienen una condicin familiar, que es causada por una mutacin heredada. Mutaciones en los genes ALS2,SETX, SOD1 y VAPB causan la Esclerosis Lateral Amiotrfica. Variaciones en los genes ANG, DCTN1, NEFH, PRPH, SMN1 y SMN2 incrementa el riesgo de desarrollar dicha enfermedad. Cerca del 90 % de los casos de Esclerosis Lateral Amiotrfica son espordicos y no hereditarios. ESCLEROSIS LATERAL AMIOTRFICA GEN: SOD1 LOCALIZACIN CROMOSMICA:21q22.1 HERENCIA: autosmica dominante ALS1 est causada por mutaciones en SOD1, que representan aproximadamente el 20% de todos los casos de FALS(Esclerosis Lateral Amiotrfica Familiar) y de aproximadamente el 3% de la ALS espordica. ESCLEROSIS LATERAL AMIOTRFICA 4, Juvenil (ALS4) GEN: SETX LOCALIZACIN CROMOSMICA: 9q34 HERENCIA: autosmica dominante Es una forma de progresin lenta de la enfermedad que normalmente afecta a personas menores de 25 aos, caracterizado por debilidad distal y atrofia muscular. ESCLEROSIS LATERAL AMIOTRFICA FAMILIAR, (FALS, ALS1) GEN: ANG LOCALIZACIN CROMOSMICA:14q11.2 HERENCIA: autosmica dominante. La esclerosis lateral amiotrfica Familiar (FALS) representa aproximadamente el 10-15% de todos los casos diagnosticados de ALS. Este gen est implicado en la aparicin de FALS en edades adultas, de herencia autosmica dominante, cuyas mutaciones estn presentes en ms de un 1% de los pacientes afectos. Por lo tanto, esta prueba es especialmente importante para los pacientes de ALS que se han presentado resultados negativos para las mutaciones SOD1. AMYOTROPHIC LATERAL SCLEROSIS GENE: SETX, SOD1 y ANG CHROMOSOMAL LOCALITATION: 9q34 (SETX), 21q22.1 (SOD1), 14q11.2 (ANG) MODE OF INHERITANCE: autosomal dominant and recessive

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Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease involving both the upper motor neurons (UMN) and lower motor neurons (LMN). Affected individuals typically present with asymmetric focal weakness of the extremities, dysarthria and dysphagia. Individuals with this disorder lose their strength, the ability to walk, and use of their hands and arms. Breathing becomes difficult because the muscles of the respiratory system weaken. Most people with amyotrophic lateral sclerosis die from respiratory failure. The mean age of onset of ALS in individuals with no known family history is 56 years and in individuals with more than one affected family member (familial ALS or FALS) is age 46 years. About 10 percent of people with amyotrophic lateral sclerosis have a familial form of the condition, which is caused by an inherited genetic mutation. Mutations in the ALS2,SETX, SOD1 and VAPB genes cause amyotrophic lateral sclerosis. Variations of the ANG, DCTN1, NEFH, PRPH, SMN1 and SMN2 genes increase the risk of developing amyotrophic lateral sclerosis. About 90 percent of amyotrophic lateral sclerosis cases are sporadic and are not inherited. ALS1 caused by mutations in the SOD1 gene is typically inherited in an autosomal dominant manner. ALS2 caused by mutations in the ALS2 gene (autosomal recessive). ALS4 caused by mutations in the SETX gene (autosomal dominant). ALS4 is a slowly progressive form of the disease that typically affects people under age 25. ALS8 caused by mutations in the VAPB (autosomal dominant). AMYOTROPHIC LATERAL SCLEROSIS GEN: SOD1 CHROMOSOME LOCATION: 21q22.1 INHERITANCE: Autosomal dominant ALS1 is caused by mutations in SOD1, which represent approximately 20% of all cases of FALS (Familiar amyotrophic lateral sclerosis) and approximately 3% of sporadic ALS. AMYOTROPHIC LATERAL SCLEROSIS 4,JUVENILE (ALS4) GEN: SETX CHROMOSOME LOCATION: 9q34 INHERITANCE: Autosomal dominant It is a way to slow progression of the disease that usually affects individuals younger than 25 years, characterized by distal weakness and muscle atrophy. ALS4 is associated with mutations in the SETX gene that encodes the protein senataxin with an autosomal dominant pattern. FAMILIAR AMYOTROPHIC LATERAL SCLEROSIS (FALS,ALS1) GEN: ANG CHROMOSOME LOCATION: 14q11.2 INHERITANCE: Autosomal dominant. Familiar amyotrophic lateral sclerosis (FALS) represents approximately 10-15% of all diagnosed cases of ALS. This gene is implicated in the occurrence of fals-aged adults, autosomal dominant inheritance, whose mutations are present in more than 1% of the patients. Therefore, this test is particularly important for ALS patients who have tested negative for SOD1 mutations. VOLVER/RETURN

Esclerosis tuberosa GENES: TSC1 y TSC2 Rev 36 05/05/2009

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LOCALIZACIN CROMOSMICA: 9q34 (TSC1) y 16p13.3 (TSC2) HERENCIA: autosmica dominante La esclerosis tuberosa se caracteriza por alteraciones en la piel (mcula hipomelantica, angifibroma facial, placas faciales fibrosas), cerebro (ndulos subependimales, apopleja, retraso en el desarrollo y mental), rin (angiomiolipomas, quistes) y corazn (rabdomiomas y arritmias). Dos tercios de los individuos con TSC tienen una mutacin de novo. La distribucin de mutaciones es del alrededor del 30% para el TSC1 y del 50% para TSC2 para los casos familiares y del 15% y 70% para casos simples. Un pequeo porcentaje de casos presentan grandes deleciones, bien parciales del gen, bien completos, como en el caso de Sndrome de genes contiguos. Nuestro laboratorio ofrece la secuenciacin completa de ambos genes del 80% aproximadamente. Tambin est disponible el estudio de grandes deleciones/duplicaciones para TSC1 y TSC2.

TUBEROUS SCLEROSIS GENE: TSC1 and TSC2 CHROMOSOMAL LOCATION: 9q34 (TSC1) and 16p13.3 (TSC2) MODE OF INHERITANCE: autosomal dominant Tuberous sclerosis complex (TSC) involves abnormalities of the skin (hypomelanotic macules, facial angiofibromas, shagreen patches, fibrous facial plaques, ungual fibromas), brain (cortical tubers, subependymal nodules, seizures, mental retardation/developmental delay), kidney (angiomyolipomas, cysts), and heart (rhabdomyomas, arrhythmias). Two-thirds of individuals with TSC have a di-novo mutation. Our laboratory offers sequencing of the entire coding regions for TSC1 and TSC2 , which yields a detection rate of approximately 80%, and MLPA to detect deletions/duplications of one or more exons of the TSC1/TSC2 genes. VOLVER/RETURN Factor II GEN: F2 LOCALIZACIN CROMOSMICA: 11p11-q12 INCIDENCIA: 1-2% de la poblacin caucsica HERENCIA: autosmica dominante La protombina es el precursor de la trombina (la forma activa del factor II) en la cascada de coagulacin. Una mutacin en el gen de la protombina produce una elevacin de los niveles de protombina funcional en plasma, lo que se asocia con un incremento en el riesgo de trombosis. Las personas con riesgo de portar la mutacin en el gen de la protombina son aquellas que tienen una historia familiar de temprana aparicin de ataque, trombosis en las venas, tromboembolismo, hiperhomocistinemia y abortos mltiples, adems el riesgo de trombosis aumenta con el uso de anticonceptivos orales, golpes o ciruga. Se recomienda realizar conjuntamente el estudio del factor II y V en los pacientes con alto riesgo para comenzar lo antes posible el tratamiento antitrombtico. PROTHROMBIN PROTHROMBIN GENE: F2 CHROMOSOMAL LOCATION: 11p11-q12 INCIDENCE: 1-2% of the Caucasian population MODE OF INHERITANCE: autosomal dominant Prothrombin is the precursor of thrombin (the activated form of factor II) in the clotting cascade. A mutation in the gene for prothrombin causes an elevation of the level of functional prothrombin in plasma, which is associated with an increased risk of thrombosis. Persons who are at risk to carry the prothrombin mutation are those with a family history of early onset stroke, deep vein thrombosis, thromboembolism, pregnancy associated with thrombosis/embolism, hyperhomocystinemia, and multiple miscarriage. Individuals with the mutation are at increased risk of thrombosis in the setting of oral contraceptive use, trauma, and surgery. Direct DNA analysis of the Factor V (see above) and prothrombin mutations are now recommended for at-risk patients because of the importance of therapy and antithrombotic prophylaxis.

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VOLVER/RETURN Factor von Willebrand GEN: vWF LOCALIZACIN CROMOSMICA: 12p13.2 INCIDENCIA: 1/100 HERENCIA: Tipos 1, 2 plaquetario: autosmica dominante, tipo 3: autosmica recesiva. El factor von Willebrand es la alteracin hereditaria de la coagulacin ms comn descrita en humanos, aunque puede ser adquirida como resultado de otras condiciones mdicas. Hay cuatro tipos, el tipo 1 que representa 60-80% de los casos de von Willebrand, es un defecto cuantitativo no teniendo claro el alcance de la enfermedad, el tipo 2 en el 20-30% es un defecto cualitativo y la tendencia a sangrar vara de un individuo a otro. El tipo 3 es la forma ms severa con sangrado severo de la mucosa. No se detecta antgeno vWF y puede aparecer con valores muy bajos de factor VIII. El tipo plaquetario est producido por ganancia de funcin de los receptores vWF. Nuestro laboratorio ofrece la secuenciacin de los exones del 3 al 19 en un primer screening. Otros exones pueden secuenciarse bajo peticin expresa. VON WILLEBRAND FACTOR GENE: vWF CHROMOSOMAL LOCATION: 12p13.2 INCIDENCE: 1/100 MODE OF INHERITANCE: autosomal dominant and type 3: autosomal recessive. vWD is the most common hereditary coagulation abnormality described in humans, although it can also be acquired as a result of other medical conditions. There are four hereditary types of vWD described - type 1, type 2, type 3, and platelet-type. Type 1 vWD (60-80% of all vWD cases) is a quantitative defect but may not have clearly impaired clotting, most patients usually end up leading a nearly normal life. Type 2 vWD (20-30%) is a qualitative defect and the bleeding tendency can vary between individuals. There are normal levels of vWF, but the multimers are structurally abnormal, or subgroups of large or small multimers are absent. Type 3 is the most severe form of vWD (homozygous for the defective gene) and may have severe mucosal bleeding, no detectable vWF antigen, and may have sufficiently low factor VIII that they have occasional hemarthoses (joint bleeding), as in cases of mild hemophilia. Platelet-type vWD is an autosomal dominant type of vWD caused by gain of function mutations of the vWF receptor on platelets; specifically, the alpha chain of the glycoprotein Ib receptor (GPIb). Our lab offers sequencing of exons 3-19 . Other exons sequencing are available under request. VOLVER/RETURN

Farber, Enfermedad de GEN: ASAH1 LOCALIZACION CROMOSOMICA: 8p22-p21.3 HERENCIA: autosmica recesiva Los individuos afectados por la enfermedad de Farber (lipogranulomatosis de Farber) acumulan cantidades dainas de lpidos en las clulas y tejidos de todo el cuerpo, en particular alrededor de las uniones. Se caracteriza por la trada: ndulos subcutneos, artritis y afectacin larngea. Est causada por mutaciones en el gen ASAH1. Dicho gen codifica la enzima ceramidasa cida que se encuentra en los lisosomas Mutaciones en dicho gen provocan un dficit de esta ceramidasa cida, lo cual impide a los lisosomas degradar la ceramida correctamente. Esta ceramida se acumulara en los lisosomas de las clulas y de los tejidos del pulmn, hgado, colon, msculos esquelticos, cartlago, y hueso. La severidad de la enfermedad depende de la cantidad de acumulacin de ceramida.

FARBER, DISEASE
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GENE: ASAH1 CHROMOSOMAL LOCATION: 8p22-p21.3 MODE OF INHERITANCE: autosomal recessive Farber lipogranulomatosis is a rare inherited condition involving the breakdown and use of fats in the body (lipid metabolism). In affected individuals, harmful amounts of lipids accumulate in cells and tissues throughout the body, particularly around the joints. Three classic signs are seen with Farber lipogranulomatosis: a hoarse voice, small lumps of fat under the skin and in other tissues (lipogranulomas), and swollen and painful joints. Other problems that can occur include difficulty breathing, hepatosplenomegaly, and mental retardation. Mutations in the ASAH1 gene cause Farber lipogranulomatosis. The ASAH1 gene provides instructions for making an enzyme called acid ceramidase. This enzyme is found in the lysosomes. The ceramide accumulation in Farber lipogranulomatosis results from an inability to break down ceramides in the lysosomes. Mutations in the ASAH1 gene lead to a shortage of functional acid ceramidase, which prevents lysosomes from breaking down ceramides properly. Without the activity of acid ceramidase, ceramides can build up in the lysosomes of cells and tissues in the lung, liver, colon, muscles used for movement (skeletal muscles), cartilage, and bone. This buildup causes the signs and symptoms of Farber lipogranulomatosis, and the severity of the disease depends on the amount of ceramide accumulation. VOLVER/RETURN Fenilcetonuria GEN: Fenilalanina hidroxilasa (PAH) LOCALIZACIN CROMOSMICA: 12q INCIDENCIA: frecuencia de portadores 1:50 HERENCIA: autosmica recesiva La fenilcetonuria est causada por la deficiencia de la hidroxilasa fenilalanina que produce una intolerancia en la ingesta de fenilalanina. Sin restriccin en la dieta de fenilalanina, muchos nios con fenilcetonuria desarrollan profundo e irreversible retraso mental. El 30% de los casos se produce por 4 mutaciones detectadas en los exones 7, 8, 11 y 12 del gen PAH. PHENYLKETONURIA GENE: phenylalanine hydroxylase (PAH) CHROMOSOMAL LOCATION: 12q CARRIER FREQUENCY: 1 in 50 Caucasians MODE OF INHERITANCE: autosomal recessive Phenylketonuria (PKU) is caused by a deficiency in phenyalanine hydroxylase (PAH) which results in intolerance to the dietary intake of the essential amino acid phenylalanine. Without dietary restriction of phenylalanine, most children with PKU develop profound and irreversible mental retardation. There are four hot spots in the phenylalanine hydroxylase gene account for approximately 30% of all mutant alleles. Our laboratory offers direct molecular testing for these four hot spots, including 7, 8 11 and 12 exons sequencing. Direct DNA analysis of the phenylalanine hydroxylase gene is available for the identification of carriers for persons with a family history of PKU, following mutation identification in the proband. Furthermore, prenatal diagnosis is available when the PKU mutations have been identified in the family. Please note that testing a person who does not have a family history of PKU does not significantly change the risk to be a carrier of the condition. VOLVER/RETURN Fibrosis qustica GEN: CFTR (regulador transmembrana de la fibrosis qustica) LOCALIZACIN CROMOSMICA: 7q31 INCIDENCIA: portadores 1:25 MODO DE HERENCIA: Autosmica recesiva
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La fibrosis qustica afecta al epitelio del aparato respiratorio, pncreas, intestino, testculos, sistema hepatobiliar, glndulas exocrinas resultando una enfermedad multisistmica. La mayor causa de muerte en enfermos de fibrosis qustica es por enfermedad pulmonar. La mayora de los casos tienen una mutacin en el gen CFTR. Especficamente, nuestro panel de 32 mutaciones detecta ms del 90% de mutaciones en la poblacin europea. Ahora, adems completamos el estudio con la secuenciacin completa del gen CFTR. El ndice de deteccin vara en otras razas. El anlisis directo de DNA del gen de fibrosis qustica se recomienda para la confirmacin del diagnstico de un paciente con o sin precedentes familiares. El diagnstico prenatal es posible para familias con casos confirmados de fibrosis, o cuando hay sospecha de que el feto est afectado (por ejemplo; intestino ecognico). Adems, el Colegio Americano de Obstetricia y Ginecologa (ACOG) recomienda a los portadores de FQ un screening con todas sus parejas cuando al menos uno de ellos sea caucsico. Se puede realizar para personas de otras razas. CYSTIC FIBROSIS GENE: CFTR (cystic fibrosis transmembrane conductance regulator) CHROMOSOMAL LOCATION: 7q31 CARRIER FREQUENCY: 1 in 25 MODE OF INHERITANCE: autosomal recessive Cystic fibrosis affects epithelia of the respiratory tract, exocrine pancreas, intestine, male genital tract, hepatobiliary system, and exocrine sweat glands, resulting in complex multisystem disease. Pulmonary disease is the major cause of morbidity and mortality in CF. The majority of cases of cystic fibrosis have a demonstrable mutation in the CFTR gene. Specifically, our panel of 32 mutations detects up to 90% of mutations in the European population. Moreover, we now study the complete sequence of CFTR gen. Detection rates for individuals of other ethnicities vary. Direct DNA analysis of the cystic fibrosis gene is recommended for the confirmation of a diagnosis in a patient with or without a family history of CF. Prenatal diagnosis is available for a family with a confirmed case of cystic fibrosis, or when there is a suspicion that the fetus is affected (i.e. echogenic bowel). In addition, the American College of Obstetrics & Gynecology (ACOG) recommends CF carrier screening to all couples in which at least one person is Caucasian. Cystic fibrosis carrier screening should also be available to couples of other ethnic backgrounds. VOLVER/RETURN Fiebre mediterrnea familiar GEN: MEFV (Pyrin) LOCALIZACIN CROMOSMICA: 16p13.3 INCIDENCIA: portadores 1:7 (armenios, turcos y rabes); 1:28 (Sefarditas) HERENCIA: Autosmica recesiva La fiebre mediterrnea (FMF) es una enfermedad gentica que se caracteriza por ataques cortos y repetidos de fiebre, acompaados de dolor abdominal, pecho, articulaciones y erupciones como eritemas. Las 12 principales mutaciones que causan la FMF y un polimorfismo/mutacin aparecen aproximadamente en el 85% de armenios, sefardes, rabes o turcos. El anlisis de DNA se recomienda en pacientes con sntomas de esta enfermedad para confirmar el diagnstico. Incluso se recomienda el anlisis de DNA en posibles portadores en parejas en las que al menos uno de ellos tenga gran riesgo. Podemos secuenciar los exones 2, 3, 5 y 10 del gen FMF y detectar con una estimacin del 97% todas las mutaciones conocidas. FAMILIAL MEDITERRANEAN FEVER GENE: MEFV CHROMOSOMAL LOCATION: 16p13.3 CARRIER FREQUENCY: 1 in 7 (Armenian, Turkish, Arabic); 1 in 28 (Sephardic Jewish) MODE OF INHERITANCE: autosomal recessive Familial Mediterranean Fever (FMF) is a genetic disorder characterized by short, recurrent bouts of fever, accompanied by pain in the abdomen, chest, or joints, and an erysipelas-like erythema. The twelve most common mutations reported to cause FMF and one polymorphism/mutation account for approximately 85% of abnormal alleles in Armenian, Sephardic Jewish, Arabic, or Turkish populations. DNA analysis is recommended for patients who have signs or symptoms suggestive of this disorder to confirm the clinical diagnosis. Direct DNA analysis of the FMF disease gene is also recommended for carrier screening of couples in which at least one person is at high risk. Sequencing of exons 2, Rev 36 05/05/2009

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3, 5, and 10 of the FMF gene is available and detects an estimated 97% of all known mutations. VOLVER/RETURN Fiebre Peridica (TRAPS) GEN:TNFRSF1A LOCALIZACIN CROMOSMICA:12p13.2 HERENCIA: autosmica dominante El sndrome peridico asociado al receptor del factor de necrosis tumoral (TRAPS) es una enfermedad que se engloba dentro de los sndromes hereditarios de fiebre peridica, los cuales constituyen a su vez el principal subgrupo dentro de las enfermedades autoinflamatorias sistmicas. El TRAPS se caracteriza por episodios inflamatorios prolongados, recurrentes, en los que se objetiva fiebre y parmetros analticos inflamatorios elevados que pueden acompaarse de clnica articular, cutnea, ocular y abdominal. TRAPS (Familial Hibernian Fever) GENE: TNFRSF1A CHROMOSOMAL LOCATION: 12p13,2 MODE OF INHERITANCE: autosomal dominant This disorder usually presents in childhood and is characterized by periodic fevers that last from a few days to several weeks, abdominal symptoms (pain, diarrhea/constipation, occasionally peritonitis), pleuritis, arthralgia, myalgia, conjunctivitis/periorbital edema, and tender, migratory, erythematous skin lesions. Patients with TRAPS generally do not respond to treatment with colchicine, although relief with corticosteroid treatment has been reported. VOLVER/RETURN SNDROME DE FUHRMANN GEN: WNT7A LOCALIZACION CROMOSMICA: 3p25 HERENCIA: autosmica recesiva Este sndrome se caracteriza principalmente por curvatura femoral, aplasia o hipoplasia de los perons y poli-, oligo- y sindactilia. La mayora de los pacientes tenan tambin una pelvis hipoplsica, con dedos y uas tambin hipoplsicos. En algunos casos se presenta dislocacin congnita de la cadera, ausencia o fusin de los tarsos, ausencia de varios metatarsos e hipoplasia y aplasia de los dedos de los pies. El sndrome est provocado por mutaciones en el gen WNT7A, que desarrolla un importante papel en el desarrollo de las extremidades. FUHRMANN SYNDROME GENE:WNT7A CHROMOSOMAL LOCALITATION: 3p25 MODE OF INHERITANCE: autosomal recessive This syndrome is characterized by fibular aplasia or hypoplasia, femoral bowing and poly-, syn-, and oligodactyly. Most patients also present hypoplasia of pelvis, as well as variable digital abnormalities, as well as absent/dysplastic nails. In some cases congenital dislocation of hips, absence or coalescence of tarsal bones, absence of various metatarsals, hypoplasia of fingers and fingernails, and postaxial polydactyly, are present. It is caused by mutations in the WNT7A gene, which is crucial for limb development. VOLVER/RETURN Factor V Leiden
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GEN: FV LOCALIZACON CROMOSMICA: 1q21-25 INCIDENCIA: 2-8% de la poblacin caucsica HERENCIA: autosmica dominante La principal enfermedad hereditaria de coagulacin se debe a una mutacin especfica en el gen del factor V llamado mutacin de Leiden (Arg506Gln). Las personas heterocigticas para la mutacin de Leiden tienen 7 veces ms riesgo de sufrir trombosis que las personas sanas y las homocigticas, 80 veces ms. Las personas en riesgo de portar la mutacin en el factor V son las que tienen historial familiar con diagnstico temprano, sufren trombosis en vena, trombo embolismos, embolias o trombosis en el embarazo, hiperhomocistenemia y aborto mltiple. Individuos con la mutacin incrementan el riesgo de trombosis con el uso de pldoras anticonceptivas, traumas y cirugas. Se recomienda el anlisis directo de DNA de las mutaciones del Factor V y la protrombina en pacientes en riesgo debido a la importancia de la terapia y la profilaxis antitrombtica. FACTOR V LEIDEN GENE: FV CHROMOSOMAL LOCATION: 1q21-25 INCIDENCE: 2-8% of the Caucasian population MODE OF INHERITANCE: autosomal dominant The most common hereditary blood clotting disorder is due to a specific mutation in the gene for factor V called the Leiden mutation (Arg506Gln). Persons who are heterozygous for the Leiden mutation have a 7-fold increased risk for thrombosis, and those who are homozygous have an 80-fold increased risk for thrombosis. Persons who are at risk to carry the factor V mutation are those with a family history of early onset stroke, deep vein thrombosis, thromboembolism, pregnancy associated with thrombosis/embolism, hyperhomocystinemia, and multiple miscarriage. Individuals with the mutation are at increased risk of thrombosis in the setting of oral contraceptive use, trauma, and surgery. Direct DNA analysis of the Factor V and prothrombin (see below) mutations are now recommended for at-risk patients because of the importance of therapy and antithrombotic prophylaxis. VOLVER/RETURN

Gilbert, sndrome GEN: UGT1A1 LOCALIZACIN CROMOSMICA: 2q37 INCIDENCIA: 1:10 HERENCIA: autosmica recesiva El sndrome de Gilbert es una alteracin hereditaria multifactorial asociada a un elevado nivel de bilirrubina (hiperbilirrubinemia no conjugada) en sangre y por lo general no presenta sntomas, aunque puede aparecer una leve ictericia en condiciones de esfuerzo excesivo, estrs, insomnio, cirugas, ayuno, cuando hay infecciones o tras la ingesta de algunos medicamentos como el paracetamol, ya que la concentracin de bilirrubina en la sangre aumenta en estas situaciones. El sndrome cursa fatiga y depresin en algunos casos. El sndrome de Gilbert est asociado al polimorfismo (TA)7 en el promotor del gen UGT1A1. GILBERT SINDROME GENE: UGT1A1 CHROMOSOMAL LOCATION: 2q37 INCIDENCE: 1 in 10 MODE OF INHERITANCE: autosomal recessive Gilbert syndrome is a benign form of unconjugated hyperbilirubinemia that has long been regarded to be a manifestation of an abnormality of bilirubin glucuronide formation. Recently, homozygous A(TA)7TAA variation in promoter of UGT1A1 gene was found to be associated with neonatal hyperbilirubinemia. This (TA)7 polymorphism, associated with Gilbert syndrome, is the only allele found up to now in white populations, while two other variants (TA) 5 and (TA)8 have been identified in black populations. Recently, it has been described several cases of subjects affected Rev 36 05/05/2009

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by Gilberts syndrome who are heterozygous for the (TA)8 allele in the promoter region of the UGT1A1 gene. This polymorphism, as well as the (TA)7 one, is associated with an increased level of bilirubin and a significant reduction of transcription activity of the UGT1A1 gene. VOLVER/RETURN Glaucoma GEN: CYP1B1 LOCALIZACIN CROMOSMICA: 2p22-p21 INCIDENCIA: 1/5,000-22,000 en los paises occidentales, 1/2500 paises orientales HERENCIA: autosmica recesiva El glaucoma primario congnito se caracteriza por una elevada presin intraocular, aumento del globo ocular, edema y opacificacin corneal con ruptura de la membrana de Descemet, disminucin de la esclera anterior y atrofia del iris, fotofobia, blefaroespasmo y lagrimeo. El diagnstico se realiza en el primer ao de vida. Segn cuando se comienza el tratamiento la agudeza visual se puede reducir. Nuestro laboratorio ofrece la secuenciacin completa del CYP1B1. PRIMARY CONGENITAL GLAUCOMA GENE: CYP1B1 CHROMOSOMAL LOCATION: 2p22-p21 INCIDENCE: 1/5,000-22,000 newborns in western countries, 1/2500 in the Middle East MODE OF INHERITANCE: autosomal recessive Primary congenital glaucoma is characterized by elevated intraocular pressure (IOP), enlargement of the globe (buphthalmos), edema, and opacification of the cornea with rupture of Descemet's membrane, thinning of the anterior sclera and atrophy of the iris, anomalously deep anterior chamber, structurally normal posterior segment except for progressive optic atrophy, and photophobia, blepharospasm, and excessive tearing (hyperlacrimation). Typically, the diagnosis is made in the first year of life. Depending on when treatment is instituted, visual acuity may be reduced and/or visual fields may be restricted. In untreated cases, blindness invariably occurs. Sequence analysis of the two coding exons of CYP1B1 is available in our laboratory. VOLVER/RETURN Glaucoma juvenil autosmico dominante GEN: MYOC LOCALIZACIN CROMOSMICA:1q23-q24 INCIDENCIA:1:12500 HERENCIA:Autosmica dominante El gen MYOC codifica una glicoprotena extracelular denominada miocilina. Se expresa en distintos rganos humanos incluido el ojo. Determinadas mutaciones de este gen originan glaucoma, una neuropata ptica producida por apoptosis de las clulas ganglionares de la retina. El glaucoma juvenil autosmico dominante aparece entre los diez aos de edad y antes de la tercera o cuarta dcada de la vida. Se caracteriza de un aumento de la presin intraocular que puede derivar en ceguera. GLAUCOMA, DOMINANT (JUVENIL ONSET) GENE: MYOC CHROMOSOMAL LOCATION: 1q23-q24 INCIDENCE: 1:12500 MODE OF INHERITANCE: autosomal dominant The MYOC gene encodes a extracellular glycoprotein called miocilina. It is expressed in different organs including the human eye. Certain mutations of this gene originated glaucoma, optic neuropathy caused by apoptosis of retinal ganglion cells. Glaucoma dominant appears between the age of ten and by the third or fourth decade of life. It is characterized by an increase in intraocular pressure which can lead to blindness. VOLVER/RETURN
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GLUCOGENOSIS TIPO I La glucogenosis tipo I (GSDI) se caracteriza por la acumulacin de glucgeno y grasa en el hgado y los riones, dando lugar a hepatomegalia y renomegalia. El diagnstico de GSDI est basado en hallazgos clnicos, concentraciones anormales en sangre/plasma de glucosa,lactato, cido rico, triglicridos y lpidos, y anlisis moleculares. Las mutaciones en el gen G6PC(GSDIa) son responsables del 80% de las GSDI y las del gen SLC37A4 (GSDIb) lo son del otro 20%. Nuestro laboratorio dispone de pruebas genticas para ambos genes. Glucogenosis Tipo Ia (GSDIa) GEN: G6PC LOCALIZACION CROMOSOMICA: 17q21 HERENCIA: autosmica recesiva Mutaciones en el gen G6PC se dan en cerca del 80% de los casos de glucogenosis tipo I. Mediante secuenciacin se detectan mutaciones en casi el 100% de los individuos en algunos grupos tnicos homogneos mientras que en poblaciones ms heterogneas esta tasa baja al 94% ya que ambas mutaciones podran no ser detectadas en algunos individuos con GSDIa clnica y enzimticamente confirmada. Nuestro laboratorio dispone de un screening de las mutaciones ms frecuentes: pArg83Cys (32% de la poblacin caucsica con GSDIa y en el 93-100% de los judos) y p.Gln347X (21% de los caucsicos afectos), as como el estudio de toda la secuencia codificante del gen G6PC. Glucogenosis Tipo Ib (GSDIb) GEN: SLC37A4 LOCALIZACION CROMOSOMICA: 11q23.3 HERENCIA: autosmica recesiva Mutaciones en el gen SLC37A4 se dan en cerca del 20% de los casos de glucogenosis tipo I. Nuestro laboratorio dispone de un screening de las mutaciones ms frecuentes en la poblacin caucsica: c.1042_1043delCT y p.Gly339Cys , as como el estudio de toda la secuencia codificante del gen SLC37A4. GLYCOGEN STORAGE DISEASE TYPE I Glycogen storage disease type I (GSDI) is characterized by accumulation of glycogen and fat in the liver and kidneys, resulting in hepatomegaly and renomegaly. The diagnosis of GSDI is based on clinical presentation, abnormal blood/plasma concentrations of glucose, lactate, uric acid, triglycerides, and lipids, and molecular genetic testing. Mutations in G6PC (GSDIa) are responsible for 80% of GSD1 and mutations in SLC37A4 (GSDIb) are responsible for 20% of GSD1. Molecular testing is clinically available for both genes. Glycogen storage disease type Ia (GSDIa) GENE: G6PC CHROMOSOMAL LOCALITATION: 17q21 MODE OF INHERITANCE: autosomal recessive Mutations in G6PC (GSDIa) are responsible for 80% of GSD1.Sequence analysis of G6PC detects mutations in up to 100% of affected individuals in some homogeneous populations , but in mixed populations (e.g., in the US) detection rate is approximately 94% because both mutations could not be detected in some individuals with clinically and enzymatically confirmed GSDIa. Targeted mutation analysis:p.Arg83Cys (Caucasian 32%, Jewish 93%-100%) and p.Gln347X (Caucasian 21%) and sequencing analysis is available in our laboratory. Rev 36 05/05/2009

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Glycogen storage disease type Ib (GSDIb) GENE: SLC37A4 CHROMOSOMAL LOCALITATION: 11q23.3 MODE OF INHERITANCE: autosomal recessive Mutations in SLC37A4 (GSDIb) are responsible for 20% of GSD1. Targeted mutation analysis: c.1042_1043delCT and p.Gly339Cys (Caucasian 50%) and sequencing analysis is available in our laboratory. VOLVER/RETURN Glucogenosis tipo III GEN: AGL LOCALIZACIN CROMOSMICA: 1p21 INCIDENCIA: rara HERENCIA: autosmica recesiva La glucogenosis tipo III tambin llamada enfermedad de Forbes y Cori est causada por una deficiencia de la enzima ramificadora del glucgeno. El mal funcionamiento de la enzima conlleva una acumulacin de glucgeno. Clnicamente la GDD-III se caracteriza por hepatomegalia e hipoglucemia y los pacientes normalmente presentan una estatura corta. Los pacientes con alteraciones en hgado y msculo presentan GSD tipo IIIa y entorno al 15% de los casos con slo alteracin en hgado se clasifica como GSD tipo IIIb. GLYCOGEN STORAGE DISEASE TYPE III GENE: AGL CHROMOSOMAL LOCATION: 1p21 INCIDENCE: rare MODE OF INHERITANCE: autosomal recessive GSD-III, which is also called Forbes disease and Coris disease, is caused by a deficiency of the glycogen debranching enzyme. The lack of activity of this enzyme results in an incomplete breakdown of glycogen and glycogen accumulates. Because stored glycogen has very short outer chains, as in a phosphorylase limit dextrin, GSD-III is also called limit dextrinosis. Clinically, GSD-III is characterized by hepatomegaly and hypoglycemia, and patients typically are short in stature. Additionally, most patients have disease involving both liver and muscle, which is termed type IIIa disease. However, in about 15% of the patients, GSD-III appears to involve only the liver, which is classified as type IIIb disease. Furthermore, during infancy and childhood, hepatomegaly, hypoglycemia, hyperlipidemia, and short stature are predominant features. The liver-related symptoms in most GSD-III patients improve with age and are usually resolved after puberty. In patients having muscular involvement, muscle weakness can occur, ranging in severity from not apparent or very minimal during early childhood to severe after the third or fourth decade of life. The patients serum creatine kinase level can be used to determine muscle involvement; however, a normal level does not rule out the presence of muscle enzyme deficiency. VOLVER/RETURN Glut1 GEN: SCL2A1 LOCALIZACIN CROMOSMICA: 1p35-p31.3 INCIDENCIA: desconocida HERENCIA: autosmica recesiva La deficiencia del transportador de glucosa tipo 1 se caracteriza por ataques infantiles anticonvulsionante seguido de una desaceleracin del crecimento de la cabeza, retraso en el crecimiento motor y mental, espasticidad, ataxia, opsoclonus, disartria. Los nios afectos son normales en el nacimiento, peso e ndice Apgar normal. Los ataques normalmente comienzan a los 1-4 meses. Los ataques ocurren de 5 maneras diferentes: tnico o clnico generalizado, mioclnico, ausencia atpica, atnica y sin clasificar. La secuenciacin del exn 10 del gen SLC2A1 est disponible en
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nuestro laboratorio. GLUCOSE TRANSPORTER TYPE 1 DEFICIENCY SYNDROME GENE: SCL2A1 CHROMOSOMAL LOCATION: 1p35-p31.3 INCIDENCE: unknown MODE OF INHERITANCE: autosomal dominant Glucose transporter type 1 deficiency syndrome (Glut1-DS) is characterized by infantile seizures refractory to anticonvulsants, followed by deceleration of head growth, delays in mental and motor development, spasticity, ataxia, dysarthria, opsoclonus, and other paroxysmal neurologic phenomena, often occurring prior to meals. Affected infants appear normal at birth following an uneventful pregnancy and delivery. Birth weight and Apgar scores are normal. Seizures usually begin between age one and four months. Apneic episodes and abnormal episodic eye movements simulating opsoclonus may precede the onset of seizures by several months. Five seizure types occur: generalized tonic or clonic, myoclonic, atypical absence, atonic, and unclassified. The frequency of seizures varies among affected individuals. Varying degrees of cognitive impairment, ranging from learning disabilities to severe mental retardation, are characteristic. SLC2A1 is the only gene known to be associated with Glut1-DS. Sequence analysis of exon 10 is available in our laboratory. VOLVER/RETURN Gorlin, Sndrome de GEN: PTCH1 LOCALIZACIN CROMOSMICA: 9q22.3 HERENCIA: Autosmica dominante El sndrome de Nevus de Clulas Basales (SNCB) es un desorden en el que aparecen mltiples alteraciones, las ms frecuentes son la presencia de carcinomas de clulas basales nevoides en la piel, por lo general a partir de la tercera dcada de vida en adelante, queratoquistes odontognicos en los huesos maxilares, a partir de la segunda dcada de vida, y otras alteraciones seas. Aproximadamente el 60% de las personas tienen un aspecto reconocible con macrocefalia, prognatismo y amplia raz nasal. La mayora de las personas tienen anomalas esquelticas (por ejemplo, cifosis, espina bfida, vrtebras en forma de cua). El 90% de los individuos afectados presentan calcificacin ectpica, en la hoz del cerebro en particular. Aparecen fibromas ovricos y cardacos en aproximadamente el 2% y el 20% de los individuos, respectivamente. El 5% de los nios SNCB desarrollan meduloblastoma (tumor neuroectodrmico primitivo [PNET]), generalmente del subtipo desmoplsico. El pico de incidencia es a los dos aos de vida sin que la esperanza de vida, en s, sea significativamente diferente de la media. GORLIN SYNDROME, BASAL CELL NEVUS SYNDROME GENE: PTCH1 CHROMOSOMAL LOCATION: 9q22.3 MODE OF INHERITANCE: autosomal dominant Nevoid basal cell carcinoma syndrome (NBCCS) is characterized by the development of multiple jaw keratocysts, frequently beginning in the second decade of life, and/or basal cell carcinomas (BCCs) usually from the third decade onward. Approximately 60% of individuals have a recognizable appearance with macrocephaly, bossing of the forehead, coarse facial features, and facial milia. Most individuals have skeletal anomalies (e.g., bifid ribs, wedgeshaped vertebrae). Ectopic calcification, particularly in the falx, is present in more than 90% of affected individuals by age 20 years. Cardiac and ovarian fibromas occur in approximately 2% and 20% of individuals respectively. Approximately 5% of children with NBCCS develop medulloblastoma (primitive neuroectodermal tumor [PNET]), generally the desmoplastic subtype. Peak incidence is at age two years. Life expectancy in NBCCS is not significantly different from average. VOLVER/RETURN Granulomatosa Crnica, Enfermedad de GEN: CYBB
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LOCALIZACIN CROMOSMICA: Xp21.1 INCIDENCIA: 1/250.000 HERENCIA: Recesivo ligado al X Autosmica recesiva 40-50% La deficiencia del gen CYBB est asociada con la Enfermedad Granulomatosa Crnica. En esta enfermedad se produce un decrecimiento de la actividad NADPH oxidasa de las clulas fagocticas; los neutrfilos pueden fagocitar bacterias al interior de sus vacuolas pero no matarlas. Esto provoca una mayor susceptibilidad a infecciones bacterianas severas, junto con la formacin de abscesos y granulomas. CHRONIC GRANULOMATOUS DISEASE GENE: CYBB CHROMOSOMAL LOCATION:Xp21.1 INCIDENCE: 1/250.000 MODE OF INHERITANCE: 50-60% X-linked recessive 40-50% Autosomal recessive CYBB deficiency is associated with chronic granulomatous disease (CGD). In this disorder, there is decreased activity of phagocyte NADPH oxidase; neutrophils are able to phagocytize bacteria but cannot kill them in the phagocytic vacuoles. The cause of the killing defect is an inability to increase the cell's respiration and consequent failure to deliver activated oxygen into the phagocytic vacuole. ENFERMEDAD GRANULOMATOSA CRNICA GEN: CYBA LOCALIZACION CROMOSMICA: 16q24 HERENCIA: autosmica recesiva La enfermedad granulomatosa crnica es un raro desorden hereditario causado por la total ausencia o un importante descenso en la produccin de superxido en los fagocitos, lo que da lugar a un grave defecto en la defensa y la consecuente predisposicin a infecciones microbianas. El enzima responsable de la generacin de superxido, la NADPH oxidasa, est formado por al menos 5 componentes. La ausencia de, o un defecto en, al menos una de cuatro de estas protenas (p22phox, p47phox, p67phox, o gp91phox) da lugar a los tipo conocidos de granulomatosis crnica. Una de las formas ms raras de la enfermedad es debida a defectos en el gen CYBA que codifica para la p22phox, el cual junto con gp91phox forma el flavocitocromo b558, el centro cataltico de la NADPH oxidasa. La forma de enfermedad granulomatosa crnica causada por mutaciones en el gen CYBA representa entorno al 5% de todos los casos de granulomatosis crnica. Deleciones, inserciones, mutaciones missense, nonsense y de splicing han sido descritas asociadas a la enfermedad granulomatosa crnica. Por tanto, el anlisis del gen CYBA implica su secuenciacin completa, dada la distribucin de las mutaciones. CHRONIC GRANULOMATOUS DISEASE GENE:CYBA CHROMOSOMAL LOCALITATION: 16q24 MODE OF INHERITANCE: autosomal recessive Chronic granulomatous disease (CGD) is a rare inherited disorder caused by nonexistent or severely decreased phagocyte superoxide production that results in a severe defect in host defense and consequent predisposition to microbial infection. The enzyme responsible for generating the superoxide, NADPH oxidase, involves at least 5 protein components. The absence of, or a defect in, any 1 of 4 of these proteins (p22phox, p47phox, p67phox, or gp91phox) gives rise to the known types of chronic granulomatous disease. One of the rarest forms of the disease is due to defects in the CYBA gene encoding p22phox, which together with Rev 36 05/05/2009

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gp91phox forms flavocytochrome b558, the catalytic core of NADPH oxidase. The form of CGD caused by mutation in the CYBA gene represents about 5% of all CGD cases. Deletions, insertions, missense, nonsense and splicing mutations in the CYBA gene have been reported to be associated with chronic granulomatous disease. Therefore, analysis of CYBA gene involves its complete sequencing, given the distribution of mutations associated with CGD. VOLVER/RETURN Hemocromatosis GEN: HFE LOCALIZACIN CROMOSMICA: 6p21.3 INCIDENCIA:1:200 a 1:400 FRECUENCIA DE PORTADORES: 1/7 A 1/10 de los caucsicos HERENCIA: Autosmica recesiva La hemocromatosis se caracteriza por una alta e inapropiada absorcin de hierro en la mucosa gastrointestinal, resultando un excesivo almacenamiento de hierro, particularmente en el hgado, piel, pncreas, corazn, articulaciones y testculos. Los sntomas iniciales son dolor abdominal, debilidad, letargo y prdida de peso. La hemocromatosis hereditaria (HCC) se puede detectar por anlisis de DNA. Aproximadamente el 95% de todos los alelos de hemacromatosis presentan una mutacin (C282Y) y dos polimorfismos (H63D, S65C). La prueba de HHC se puede realizar tanto a personas con o sin antecedentes familiares. La deteccin y el diagnstico temprano es importante para tratar la enfermedad y prevenir daos multiorgnicos debido al acumulo de hierro. El anlisis de mutaciones de DNA es el nico mtodo fiable para el diagnstico de portadores de HHC. HEREDITARY HEMOCHROMATOSIS GENE: HFE CHROMOSOMAL LOCATION: 6p21.3 INCIDENCE: 1 in 200 to 1 in 400 CARRIER FREQUENCY: 1/7 to 1/10 Caucasians MODE OF INHERITANCE: Autosomal recessive Hemochromatosis is characterized by inappropriately high absorption of iron by the gastrointestinal mucosa, resulting in excessive storage of iron, particularly in the liver, skin, pancreas, heart, joints, and testes. Abdominal pain, weakness, lethargy, and weight loss are early symptoms. Hereditary hemochromatosis (HHC) may be detected using direct DNA analysis. One mutation (C282Y) and two polymorphisms (H63D, S65C) account for approximately 95% of all hemochromatosis alleles. Testing for HHC is available for the detection of affected persons with or without a family history of this condition. Early detection and presymptomatic diagnosis is important for therapeutic intervention to prevent multi-organ damage from iron overload. DNA mutation analysis is the only reliable method of carrier detection for HHC. VOLVER/RETURN Hemocromatosis hereditaria tipo III GEN: TFR2 LOCALIZACION CROMOSOMICA: 7q22 HERENCIA: autosomica recesiva La hemocromatosis hereditaria relacionada a TFR2 (TFR2-HHC) se caracteriza por una absorcin de hierro intestinal aumentada que causa acumulacin de hierro en el hgado, el corazn, el pncreas y los rganos endocrinos. El nico gen asociado a TFR2-HHC es el TFR2 que codifica para el receptor de la transferrina-2. El anlisis de mutaciones puntuales (p.Arg30ProfsX31, p.Met172Lys, p.Tyr250X, p.Ala621_Gln624del in TFR2) permite identificar mutaciones en cerca del 50% de los individuos con TFR2-HHC.

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HEMOCHROMATOSIS, TYPE 3 GENE: TFR2 CHROMOSOMAL LOCATION: 7q22 MODE OF INHERITANCE: autosomal recessive TFR2-related hereditary hemochromatosis (TFR2-HHC) is characterized by increased intestinal iron absorption resulting in iron accumulation in the liver, heart, pancreas, and endocrine organs. TFR2-HHC is inherited in an autosomal recessive manner. TFR2 (it codifies tranferrin receptor 2) is the only gene associated with TFR2-HHC. A targeted mutation analysis (p.Arg30ProfsX31, p.Met172Lys, p.Tyr250X, p.Ala621_Gln624del in TFR2) identifies mutations in 50% of individuals known to have TFR2-HHC. VOLVER/RETURN Hemofilia A GEN: F8 LOCALIZACIN CROMOSMICA: Xq28 INCIDENCIA: 1/4,000 hombres HERENCIA: recesiva ligada al X La hemofilia A se caracteriza por la deficiencia de factor VIII, el cual resulta en un prolongado sangrado tras extracciones de sangre, de dientes, cirugas. El anlisis molecular del factor VIII detecta la invensin 22-A presente en el 45% de los casos de hemofilia A. HEMOPHILIA A GENE: F8 CHROMOSOMAL LOCATION: Xq28 INCIDENCE: 1/4,000 live male births worldwide MODE OF INHERITANCE: X-linked recessive Hemophilia A is characterized by deficiency in factor VIII, which results in prolonged oozing after injuries, tooth extractions, or surgery, renewed bleeding after initial bleeding has stopped, and delayed bleeding. In severe hemophilia A, spontaneous joint bleeding is the most frequent symptom. The age of diagnosis and frequency of bleeding episodes are related to the factor VIII clotting activity. Molecular genetic testing of the factor VIII (F8) gene identifies a intrn 22-A gene inversion accounts for 45% of severe hemophilia A. Such testing is available in our laboratory. VOLVER/RETURN Hemofilia B GEN: F9 LOCALIZACIN CROMOSMICA: Xq27.1-q27.2 INCIDENCIA: 1/20,000 hombres HERENCIA: ligada al X La hemofilia B se caracteriza por la deficiencia del factor IX el cual resulta en un prolongado sangrado tras extracciones de sangre, de dientes, cirugas. El anlisis molecular del factor IX detecta posibles mutaciones en el 99% de los casos de hemofilia B. HEMOPHILIA B GENE: F9 CHROMOSOMAL LOCATION: Xq27.1-q27.2 INCIDENCE: 1/20,000 live male births worldwide MODE OF INHERITANCE: X-linked Hemophilia B is characterized by deficiency in factor IX, which results in prolonged oozing after injuries, tooth extractions, or surgery, renewed bleeding after initial bleeding has stopped, and delayed bleeding. In severe hemophilia
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B, spontaneous joint bleeding is the most frequent symptom. The age of diagnosis and frequency of bleeding episodes are related to the factor IX clotting activity. Molecular genetic testing of the factor IX (F9) gene identifies disease-causing mutations in more than 99% of individuals with hemophilia B. VOLVER/RETURN Hipercolesterolemia Familiar Dominante GEN: LDLR LOCALIZACIN CROMOSMICA:19p13.3 INCIDENCIA: Homocigoto 1:1,000,000 Heterocigoto 1:500 HERENCIA: Autosmica dominante Hipercolesterolemia familiar (FH) es una enfermedad autosmica dominante se define a nivel molecular por la presencia de mutaciones en el gen LDLR que codifica los receptores de lipoprotenas de baja densidad y se caracteriza por el aumento en las concentraciones plasmticas de colesterol transportado en las lipoprotenas de baja densidad (c-LDL), asociado al depsito de colesterol en los tendones y al aumento de riesgo de cardiopatas prematuras, especialmente cardiopata isqumica, FH muestra una gran variabilidad en la expresin fenotpica, que puede verse influida por factores como la edad, sexo, dieta, el tipo de mutaciones en LDLR u otros genes. FAMILIAL HYPERCHOLESTEROLEMIA GENE: LDLR CHROMOSOMAL LOCATION:19p13.3 INCIDENCE: Homocygous 1:1,000,000 Heterocygous 1:500 MODE OF INHERITANCE: Autosomal dominant Familial hypercholesterolemia (FH) is an autosomal dominant disease defined at the molecular level by the presence of mutations in the low-density lipoprotein receptor (LDLR) gene and characterized by markedly elevated low-density lipoprotein cholesterol (LDLc) levels, tendon xanthomata and increased risk of coronary heart disease (CHD). FH shows great variability in phenotypic expression, which may be influenced by factors such as age, gender, diet, type of LDLR mutations or other genes. VOLVER/RETURN Hiperplasia suprarrenal congnita 21-HIDROXILASA GEN: CYP21A2 LOCALIZACIN CROMOSMICA: 6p21.3 INCIDENCIA: 1:15,000 HERENCIA: autosmica recesiva El defecto en la biosntesis de andrgeno adrenal resulta en la virilizacin en todos los individuos y prdida de sal en algunos casos. En la forma clsica con deficiencia severa y aparicin prenatal se distingue de la forma no clsica por la presentacin moderada y aparicin postnatal. Los recien nacidos que nacen con este defecto sufren el riesgo constante de crisis de prdidas de sal. Los afectos de la forma no clsica presentan signos de hiperandrogenismo. La deteccin de las nueve mutaciones y deleciones ms frecuentes estn presentes en el 80-98% de los casos. 11 HIDROXILASA GEN: CYP11B LOCALIZACIN CROMOSMICA: 8q2122 INCIDENCIA: 1/200 000 HERENCIA: autosmica recesiva Mientras que ms del 90% de los casos son originados por la deficiencia de 21-hidroxilasa, el 5-8% est relacionados con alteraciones en la 11--hidroxilasa. En la forma clsica de la enfermedad se produce una disminucin o ausencia de secrecin de cortisol estimulando la secrecin de ACTH la cual produce una acumulacin de precursores de
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esteroides que produce un mal funcionamiento de la ruta de sntesis de los andrgenos. Los signos tpicos son maculinizacin de mujeres. En la forma no clsica se producen ciclos menstruales anormales, hirsutismo y acn. CONGENITAL ADRENAL HYPERPLASIA 21-HYDROXYLASE-DEFICIENT GENE: CYP21A2 CHROMOSOMAL LOCATION: 6p21.3 INCIDENCE: 1:15,000 live births for the classic form MODE OF INHERITANCE: autosomal recessive In 21-OHD CAH, excessive adrenal androgen biosynthesis results in virilization in all individuals and salt wasting in some individuals. A classic form with severe enzyme deficiency and prenatal onset is distinguished from a nonclassic form with moderate enzyme deficiency and postnatal onset. The classic form is further divided into the simple virilizing form (~25% of affected individuals) and the salt-wasting form, in which aldosterone production is inadequate (>75% of individuals). Newborns with salt-wasting 21-OHD CAH are at risk for life-threatening salt-wasting crises. Individuals with the nonclassic form of 21-OHD CAH have only moderate enzyme deficiency and present postnatally with signs of hyperandrogenism; females with the nonclassic form are not virilized at birth. Molecular genetic testing of the CYP21A2 for a panel of nine common mutations detects about 80%-98% of disease-causing alleles in affected individuals and carriers. Entire sequence may detect mutations rarer in affected individuals in whom the mutations are not identified by targeted mutation analysis or deletion/duplication analysis. 11HYDROXYLASEDEFICIENT GENE: CYP11B CHROMOSOMAL LOCATION: 8q2122 INCIDENCE: 1/200 000 in the general Caucasian population MODE OF INHERITANCE: autosomal recessive Whereas >90% of cases of CAH are caused by 21-hydroxylase deficiency, steroid 11-hydroxylase deficiency accounts for 58% of cases. In classic 11-hydroxylase deficiency decreased or absent cortisol secretion stimulates ACTH secretion which, in turn, leads to accumulation of steroid precursors that are shunted into the androgen synthesis pathway. Typical signs of androgen excess include masculinization of female external genitalia and precocious pseudopuberty in both sexes. A non-classic form of 11-hydroxylase deficiency has been reported that causes milder androgen excess than the classic form. This may produce menstrual cycle abnormalities, hirsutism and acne in previously asymptomatic women. These problems resemble those found in women suffering from polycystic ovary syndrome. Whereas the frequency of non-classic 11- hydroxylase deficiency is not known, it has been hypothesized that some women thought to have polycystic ovary syndrome might in fact have non-classic 11-hydroxylase deficiency. Entire gene sequencing may detect mutations in CYP11B gene. VOLVER/RETURN

Hipertensin arterial pulmonar GEN: BMPR2 LOCALIZACION CROMOSOMICA: 2q33-q34 HERENCIA: autosmica dominante La hipertensin arterial pulmonar (PAH) relacionada con el gen BMPR2 se caracteriza por obstruccin y obliteracin de las pequeas arterias pulmonares. Cuando un nmero suficiente de vasos se encuentran ocluidos, la resistencia al flujo de sangre de los pulmones aumenta, y el ventrculo derecho trata de compensarlo generando un aumento de presin para mantener el flujo de sangre pulmonar. Cuando el ventrculo derecho no puede compensarlo debido al incremento de la resistencia se acaban produciendo daos cardacos progresivos. La edad a la que se suele diagnosticar ronda los 36 aos y la supervivencia tras el diagnstico ronda los 2.8 aos. Los individuos con hipertensin arterial pulmonar relacionada con el gen BMPR2 tienen idnticos sntomas, signos y
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pronstico clnico que aquellos diagnosticados de PAH idioptica. Las mutaciones en el gen BMPR2 en individuos con PAH confirman el diagnstico establecido por hallazgos clnicos. En cerca del 80% de los individuos con PAH familiar aparecen mutaciones en el gen BMPR2, de las cuales, el 37% son mutaciones puntuales en la regin codificante y cerca del 48% son deleciones/duplicaciones intragnicas detectadas por MLPA u otros mtodos similares. Por lo tanto, entre los individuos con PAH familiar, cerca del 30% de las mutaciones son detectables por secuenciacin y aproximadamente el 34% por anlisis de deleciones/duplicaciones. Ambas pruebas estn disponibles en nuestro laboratorio. BMPR2-related pulmonary arterial hypertension GENE: BMPR2 CHROMOSOMAL LOCALITATION: 2q33-q34 MODE OF INHERITANCE: autosomal dominant BMPR2-related pulmonary arterial hypertension (PAH) caused by mutations in the gene BMPR2, is characterized by widespread obstruction and obliteration of the smallest pulmonary arteries. When a sufficient number of vessels are occluded, the resistance to blood flow through the lungs increases, and the right ventricle attempts to compensate by generating higher pressure to maintain pulmonary blood flow. When the right ventricle can no longer compensate for the increased resistance, progressive heart failure ensues. The mean age at diagnosis is 36 years. Mean survival after diagnosis is 2.8 years. Individuals who have BMPR2-related PAH have identical symptoms, signs, and clinical course as those with idiopathic PAH. The diagnosis of PAH can be established clinically by confirming the presence of pulmonary arterial hypertension (i.e., mean pulmonary artery pressure >25 mmHg at rest or >30 mmHg during exercise) and excluding other known causes of pulmonary hypertension (PH). The presence of a BMPR2 mutation in an individual with PAH confirms the diagnosis of BMPR2-related PAH. BMPR2 mutations are detected in about 80% of individuals with familial PAH. Of those mutations detected, 37% were point mutations in the coding region and 48% were intragenic deletion/duplications detected by MLPA or other comparable methods. Therefore, among all individuals with familial PAH, an estimated 30% of mutations are detectable by sequence analysis and 34% by deletion/duplication analysis.

VOLVER/RETURN

HIPERTERMIA MALIGNA GEN: CACNA1S y RYR1 LOCALIZACIN CROMOSMICA: 1q32 (CACNA1S) , 19q13.1(RYR1) HERENCIA: autosmica dominante La susceptibilidad a hipertermia maligna (MHS) es un desorden farmacogentico de regulacin del calcio del msculo esqueltico que da lugar al hipermetabolismo incontrolado de dicho msculo. Las manifestaciones de la hipertermia maligna (MH) son provocadas por ciertos anestsicos voltiles (ej. halotane, isoflurano, sevoflurano, desflurano, enflurano) solos o en conjuncin con relajantes musculares despolarizantes (succinilcolina). Hasta la fecha, tres genes han sido relacionados con la MHS. La MHS1 ha sido asociada con mutaciones en el gen RYR1, el cual codifica para el receptor de rianodina tipo 1; mutaciones en este gen son detectadas hasta en un 70% de familias con MHS. La MHS3 ha sido asociada con mutaciones en el gen CACNA2D1, el cual codifica para las subunidades alfa-2/delta del canal de calcio tipo L sensible a dihidropiridina; mutaciones en este gen han sido detectadas en muy pocos individuos. La MHS5 ha sido asociada con mutaciones en el gen CACNA1S que codifica para un canal de calcio del msculo esqueltico; las mutaciones en dicho gen suponen un 1% de todas las MHS, Rev 36 05/05/2009

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siendo R1086H la mutacin ms comn en este gen. La mayora de los individuos diagnosticados para MHS tiene un padre con MHS, sin embargo, el padre puede no haber experimentado un episodio de MH. La proporcin de individuos con MHS causada por una mutacin de novo no se conoce. MALIGNANT HYPERTHERMIA SUSCEPTIBILITY GENE: CACNA1S and RYR1 CHROMOSOMAL LOCATION: 1q32 (CACNA1S) , 19q13.1(RYR1) MODE OF INHERITANCE: autosomal dominant Malignant hyperthermia susceptibility (MHS) is a pharmacogenetic disorder of skeletal muscle calcium regulation resulting in uncontrolled skeletal muscle hypermetabolism. Manifestations of malignant hyperthermia (MH) are triggered by certain volatile anesthetics (i.e., halothane, isoflurane, sevoflurane, desflurane, enflurane) either alone or in conjunction with depolarizing muscle relaxants (succinylcholine). To date, three MHS genes have been identified. MHS1 is associated with mutations in the gene RYR1 encoding ryanodine receptor type 1; molecular genetic testing detected mutations in 25-70% of families with MHS. MHS3 is associated with mutations in the gene CACNA2D1 encoding dihydropyridine-sensitive L-type, calcium channel alpha-2/delta subunits; very few individuals have been reported with this mutation. MHS5 is associated with mutations in the gene CACNA1S; mutations in the CACNA1S gene account for 1% of all MHS (mutation R1086H). Most individual diagnosed with MHS have a parent with MHS; however the parent may not have experienced an episode of MH. The proportion of individuals with MHS caused by de novo mutations is unknown. VOLVER/RETURN

Hipoacondroplasia GEN: FGFR3 LOCALIZACIN CROMOSMICA: 4p16.3 INCIDENCIA: 1:15,000 - 40,000 HERENCIA: autosmica dominante La hipoacondroplasia es un displasia esqueltica caracterizada por corta estatura, desproporcin en brazos y piernas, manos y pies pequeos, laxitud media y macroencefalia. Dos mutaciones (C1620A y C1620G) en el exn 10 del gen FGFR3 parecen ser la causa de la hipoancondroplasia. Nuestro laboratorio ofrece el anlisis de estas mutaciones responsables del 70% y el 30% de los casos as como la secuenciacin de los exones 9 y 15 para detectar la presencia de mutaciones raras encontradas en menos del 2% de los casos. HYPOCHONDROPLASIA GENE: FGFR3 CHROMOSOMAL LOCATION: 4p16.3 INCIDENCE: one in 15,000 - 40,000 MODE OF INHERITANCE: autosomal dominant Hypochondroplasia is a skeletal dysplasia characterized by short stature; stocky build; disproportionately short arms and legs; broad, short hands and feet; mild joint laxity; and macrocephaly. Two FGFR3 mutations (C1620A and C1620G) result in a lysine-for-asparagine substitution at codon 540 (N540K) in exon 10 and have been shown to cause hypochondroplasia Our laboratory analysed C1620A and C1620G mutations with a relative frequencies of 70% and 30%, respectively. Sequence analysis of FGFR3 exons 9 and 15 detects other rare FGFR3 mutations that account for fewer than 2% of FGFR3 mutations associated with hypochondroplasia. VOLVER/RETURN

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Hipomagnesemia con hipocalcemia secundaria GEN: TRPM6 LOCALIZACION CROMOSOMICA: 9q12-q22.2 HERENCIA: autosomica recesiva La Hipomagnesemia con hipocalcemia secundaria est causada por mutaciones en el gen TRPM6. La proteina TRPM6 es miembro de la familia de los canales ionicos de transicin (transient receptor potential cation channel, subfamily M, member 6). Se expresa en el epitelio intestinal o en las clulas del rin. Es crucial para la homeostasis del magnesio. Los bajos niveles de magnesio sricos son probablemente debidos a un defecto en la reabsorcion intestinal de magnesio. La secrecion renal de magnesio es normal. La hipocalcemia se desarrolla en los casos de hipomagnesemia grave como consecuencia de una actividad ineficaz de la hormona paratiroidea.

HYPOMAGNESEMIA WITH SECONDARY HYPOCALCEMIA GENE: TRPM6 CHROMOSOMAL LOCALITATION: 9q12-q22.2 MODE OF INHERITANCE: autosomal recessive Hypomagnesemia with secondary hypocalcemia is caused by mutation in the TRPM6 gene. This disorder is inherited in an autosomal recessive manner. The TRPM6 protein is a member of the long transient receptor potential channel (TRPM) family. TRPM6 is expressed in intestinal epithelia and kidney cells. TRPM6 is crucial for magnesium homeostasis. The low levels of serum magnesium were probably due to a defect in the intestinal reabsorption of magnesium. Renal magnesium secretion was normal. They commented that the hypocalcemia is to be expected since it develops in instances of any severe hypomagnesemic state, as a result of unresponsiveness to parathyroid hormone. VOLVER/RETURN Histiocitosis Familiar GEN: PRF1 LOCALIZACIN CROMOSMICA: 10q22 INCIDENCIA: 1/ 50,000 HERENCIA: autosmica recesiva La linfohistiocitosis hemofagoctica familiar se caracteriza por la proliferacin e infiltracin de macrfagos hiperactivados y linfocitos T. Es una enfermedad aguda con fiebre prolongada y hepatoesplenomegalia, normalmente dentro de los primeros aos de vida y ocasionalmente en el tero. Se pueden presentar inicalmente alteraciones neurolgicas o aparecer ms tarde. Estas incluyen aumento de la presin intracraneal, irritabilidad, rigidez de cuello, hipotona, convulsiones, ataxia, hemiplejia y coma. Es posible realizar la secuenciacin completa del gen PRF1 para detectar posibles mutaciones causantes de la enfermedad. HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL GENE: PRF1 CHROMOSOMAL LOCATION: 10q22 INCIDENCE: 1/ 50,000 births MODE OF INHERITANCE: autosomal recessive Familial hemophagocytic lymphohistiocytosis (FHLH) is characterized by proliferation and infiltration of hyperactivated macrophages and T-lymphocytes. FHLH is characterized by acute illness with prolonged fever and hepatosplenomegaly, usually within the first few months of life and on occasion in utero. Neurologic abnormalities may be present initially or may develop later. These may include increased intracranial pressure, irritability, neck stiffness, hypotonia, hypertonia, convulsions, cranial nerve palsies, ataxia, hemiplegia, quadriplegia, blindness, and coma. Entire
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gene sequencing of PRF1 gene is avaible in our laboratory. VOLVER/RETURN Hunter enfermedad GEN: IDS LOCALIZACIN CROMOSMICA: Xq28 INCIDENCIA: 1/150000 HERENCIA: Ligada al X La enfermedad de Hunter, tambin conocida como mucopolisacaridosis tipo II, es una enfermedad rara del metabolismo caracterizada por una inadecuada produccin de enzima iduronato sulfatasa, la cual es necesaria para la ruptura de azcares complejos producidos en el cuerpo. Los sntomas incluyen retraso en el crecimiento, rigidez en las articulaciones, rasgos faciales muy marcados. En los casos severos, los pacientes experimentan problemas cardiacos y respiratorios, agrandamiento de hgado y bazo, y dficit neurolgicos. Puede producirse la muerte prematura en estos casos severos. Nuestro laboratorio ofrece la secuenciacin completa del gen IDS. HUNTER DISEASE GENE: IDS CHROMOSOMAL LOCATION: Xq28 INCIDENCE: 1/150000 MODE OF INHERITANCE: X-linked Hunter syndrome, also known as mucopolysaccharidosis II, is a rare inborn error of metabolism characterized by inadequate production of an enzyme known as iduronate sulfatase, which is needed to break down complex sugars produced in the body. Symptoms include growth delay, joint stiffness, and coarsening of facial features. In severe cases, patients experience respiratory and cardiac problems, enlargement of the liver and spleen, and neurological deficits. The disorder can lead to premature death in severe cases. Sequencing of complete IDS gene is available. VOLVER/RETURN Huntington, Sndrome de GEN: huntingtin LOCALIZACIN CROMOSMICA: 4p16.3 INCIDENCIA: 3-7 por 100,000 (de los descendientes de Europa occidental) HERENCIA: Autosmico dominante con anticipacin La enfermedad de Huntington (HD) afecta progresivamente al sistema motor, cognitivo y problemas psiquitricos. Aparece principalmente entre los 35 y 44 aos y la media de supervivencia es de 15-18 aos. Al menos el 98% de los casos presentan una demostrable repeticin de trinucletidos (CAG). Para pacientes sin antecedentes familiares se recomienda el anlisis directo de DNA. El diagnstico predictivo en pacientes presintomticos aade riesgos. Por esta razn, se recomienda una prueba inicial gentica y una evaluacin neurolgica. Se requiere un consentimiento firmado antes de realizar las pruebas. HUNTINGTON DISEASE GENE: huntingtin CHROMOSOMAL LOCATION: 4p16.3 INCIDENCE: 3-7 per 100,000 (Western European descent) MODE OF INHERITANCE: autosomal dominant with anticipation Huntington disease (HD) is a progressive disorder of motor, cognitive, and psychiatric disturbances. The mean age of onset is 35 to 44 years and the median survival is 15 to 18 years after onset. At least 98% of both familial and sporadic cases of HD have a demonstrable trinucleotide repeat expansion (CAG). Direct DNA analysis of the Huntington disease gene is now recommended for patients without a family history of HD who have signs or symptoms suggestive of this disorder. Predictive testing for presymptomatic patients introduces complex issues and risks. For this reason, pre-test genetic counseling and neurological evaluation are strongly recommended in HD. A signed consent is required to accompany any samples for predictive testing.
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VOLVER/RETURN Ictiosis ligada al X GEN: ARSC1/STS LOCALIZACIN CROMOSMICA: Xp22.32 INCIDENCIA:rara HERENCIA: ligada al X La protena codificada por este gen cataliza la conversin de los precursores de esteroides sulfatados a los estrgenos durante el embarazo. Esta protena se encuentra en el retculo endoplasmtico, donde acta como un homodmero. Las mutaciones en este gen causan Ictiosis ligada al X. La ictiosis ligada al cromosoma X es una enfermedad hereditaria rara de la piel, que afecta a varones. Se forman escamas de gran tamao, oscuras y finas y se localizan preferentemente en cuello y tronco. Las mujeres embarazadas de fetos con ictiosis ligada a X tienen una incidencia elevada de complicaciones obsttricas y mortalidad perinatal. Se han descrito diversas asociaciones, entre las que se incluyen alteraciones del sistema nervioso central, oculares, genitales y condrodisplasia punctata, pero la gran mayora de los pacientes no presentan ninguna de ellas y su esperanza de vida es normal. X-linked Icthyosis GENE: ARSC1/STS CHROMOSOMAL LOCATION: Xp22.32 INCIDENCE: "rare" or "uncommon MODE OF INHERITANCE: X-linked The protein encoded by this gene catalyzes the conversion of sulfated steroid precursors to estrogens during pregnancy. The encoded protein is found in the endoplasmic reticulum, where it acts as a homodimer. Mutations in this gene are known to cause X-linked ichthyosis (XLI). X-linked ichthyosis is a rare hereditary disease of the skin, which affects men only. Those affected have larges, darks and thin scaled primarily in the neck and trunk. Pregnant women of X-linked ichthyosis babies have a high incidence of obstetric complications and perinatal mortality. Various associations have been described, including alterations in the central nervous system, eyes, genitals and chondrodysplasia punctata, but the majority of patients do not exhibit any of them and their life expectancy is normal. VOLVER/RETURN Incontinencia pigmenti GEN: NEMO LOCALIZACIN CROMOSMICA: Xq28 INCIDENCIA: rara HERENCIA: Ligada al X dominante La incontinencia pigmenti afecta a la piel, el pelo, los dientes y las uas. Se caracteriza por lesiones en la piel desarrolladas en cuatro etapas: 1) ampollas (desde el nacimiento a los 4 meses), 2) brote de verrugas (durante unos meses), 3) hiperpigmentacin macular en forma de remolino (desde los 6 meses a la adolescencia) seguida de 4) hipopigmentacin lineal. La alopecia, hipodontia, forma anormal de los dientes, y distrofia en las uas son otros de los sntomas observados. Algunos pacientes presentan defecto vascular en la retina, retraso cognitivo y mental pueden aparecer ocasionalmente. Se ha descrito la delecin de los exones 4-10 en el gen NEMO como causante de la patologa. INCONTINENTIA PIGMENTI GENE: NEMO CHROMOSOMAL LOCATION: Xq28 INCIDENCE: "rare" or "uncommon MODE OF INHERITANCE: X-linked dominant IP is a disorder that affects the skin, hair, teeth, and nails. Characteristic skin lesions evolve through four stages: (1)
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blistering (from birth to about four months of age), (2) a wart-like rash (for several months), (3) swirling macular hyperpigmentation (from about six months of age into adulthood), followed by (4) linear hypopigmentation. Alopecia, hypodontia, abnormal tooth shape, and dystrophic nails are observed. Some individuals with IP have retinal vascular abnormalities predisposing to retinal detachment in early childhood. Cognitive delays/mental retardation are occasionally seen. Deletion 4-10 exons of NEMO gene carried out by PCR. VOLVER/RETURN JACKSON-WEISS, SINDROME GEN: FGFR2 LOCALIZACION CROMOSMICA: 10q26 HERENCIA: autosmica dominante El Sndrome de Jackson-Weiss es un trastorno gentico caracterizado por la fusin prematura de algunos huesos del crneo (craneosinostosis) y anormalidades en los pies. Esta fusin prematura impide el normal crecimiento del crneo afectando, por tanto, a la forma de la cabeza y la cara; como caractersticas generales los individuos afectos presentan un crneo deforme con acroturricefalia, hipertelorismo con exoftalmos, frente abombada e hipoplasia facial media. Las personas con el Sndrome de Jackson-Weiss poseen usualmente una inteligencia y vida normales. Este sndrome est causado por mutaciones en el gen FGFR2.

JACKSON-WEISS SYNDROME GENE: FGFR2 CHROMOSOMAL LOCALITATION: 10q26 MODE OF INHERITANCE: autosomal dominant Jackson-Weiss syndrome is a genetic disorder characterized by foot abnormalities and the premature fusion of certain skull bones (craniosynostosis). This early fusion prevents the skull from growing normally and affects the shape of the head and face. Abnormal growth of these bones leads to a misshapen skull, widely spaced eyes, a bulging forehead, and midface hypoplasia. People with Jackson-Weiss syndrome usually have normal intelligence and a normal life span. Jackson-Weiss syndrome is caused by mutations in the FGFR2 gene. VOLVER/RETURN

Kostmann, Sndrome de GEN: HAX1 LOCALIZACIN CROMOSMICA: 1q21.3 HERENCIA: Autosmica recesiva La agranulocitosis gentica infantil o neutropenia congnita severa (enfermedad de Kostmann) se caracteriza por infecciones severas y neutropenia debida a una alteracin del desarrollo mieloide. Es una enfermedad autosmica recesiva que cursa con infecciones recurrentes e inmunodeficiencia producida por un defecto en la maduracin de los neutrfilos, con detencin del desarrollo a nivel del estado promielocito-mielocito y neutropenia de menos de 200/mm3. SEVERE CONGENITAL NEUROPENIA GENE: HAX1 CHROMOSOMAL LOCATION: 1q21.3
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MODE OF INHERITANCE: Autossomal recesssive Kostmann syndrome, or severe congenital neutropenia (SCN), is characterized by neuropenia and severe infections due to a developmental abnormality myeloid. It is an autosomal recessive disease that presents with recurrent infections and inmunodeficiency caused by a disorder of neutrophil production arrested development at the stage promielocito mielocito and neutropenia less than 200/mm3. VOLVER/RETURN CORNELIA DE LANGE GEN: NIPBL LOCALIZACION CROMOSMICA: 5p13.1 HERENCIA: autosmica dominante El sndrome Cornelia de Lange (CdLS) se caracteriza por caractersticas faciales distintivas, retraso en el crecimiento, retraso mental, hirsutismo y defectos de reduccin de las extremidades superiores que varan desde anormalidades sutiles de las falanges hasta oligodactilia. NIPBL, que codifica para la protena Nipped B-Like, es uno de los dos genes que actualmente se conocen asociados al CdLS. Mutaciones en NIPBL han sido identidficadas en el 50% de los individuos con CdLS. La gran mayora de los afectos tiene una mutacin de novo; menos del 1% de los individuos diagnosticados con CdLS relacionado con NIPBL tienen un padre afecto. El otro gen asociado con el CdLS es SMC1L1 (SMC1A). Mutaciones en este gen han sido identificadas en un pequeo porcentaje de individuos diagnosticados con el CdLS; en este caso el CdLS se hereda ligado al X. CORNELIA DE LANGE SYNDROME GENE:NIPBL CHROMOSOMAL LOCALITATION: 5p13.1 MODE OF INHERITANCE: autosomal dominant Cornelia de Lange syndrome (CdLS) is characterized by distinctive facial features, growth retardation (prenatal onset; <5th centile throughout life), mental retardation, hirsutism, and upper limb reduction defects that range from subtle phalangeal abnormalities to oligodactyly. NIPBL, encoding the Nipped B-Like protein, is one of the two genes currently known to be associated with CdLS. Mutations in NIPBL are identified in 50% of individuals with CdLS. The vast majority of affected individuals have a de novo mutation; fewer than 1% of individuals diagnosed with NIPBL-related CdLS have an affected parent. The other gene associated with CdLS is SMC1L1 (SMC1A), encoding the Structural maintenance of chromosome 1-like 1 protein. Mutations in SMC1L1 are identified in a small percentage of individuals with a clinical diagnosis of CdLS; in this case, CdLS is inherited in an X-linked manner. VOLVER/RETURN

LANGER GIEDION, Sndrome de GEN: TRPS1 y EXT1 LOCALIZACIN CROMOSMICA: 8q24.11-q24.13


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HERENCIA: autosmica dominante El sndrome de Langer-Giedion, tambin conocido como sndrome Tricorrineofalngico tipo II, se describe como un sndrome gentico de delecin ya que es el resultado de la prdida de al menos dos genes: TRPS1 y EXT1, situados prximos en el cromosoma 8. Combina las caractersticas clnicas del sndrome Tricorrineofalngico tipo I y la exostosis mltiple tipo I, que son causadas por mutaciones en los genes TRPS1 y EXT1, respectivamente. Los individuos con Sndrome de Langer Giedion, adems de la exostosis mltiple, presentan rasgos faciales muy caractersticos que engloban una cabellera escasa, una nariz bulbosa con un septum grueso, un filtrum prominente y un labio superior muy fino. Las personas afectadas tambin presentan una baja estatura, las epfisis de los huesos largos de forma cnica y, en ocasiones, retraso mental. El anlisis de deleciones se realiza por MLPA.

LANGER GIEDION SYNDROME GENE: TRPS1 and EXT1 CHROMOSOMAL LOCALITATION: 8q24.11-q24.13 MODE OF INHERITANCE: autosomal dominant Langer-Giedion syndrome, sometimes referred to as trichorhinophalangeal syndrome type II (TRPS2), is often described as a contiguous gene deletion syndrome because it results from the loss of several genes that are close together on chromosome 8, involving loss of functional copies of the TRPS1 and EXT1 genes. TRPS2 combines the clinical features of trichorhinophalangeal syndrome type I and multiple exostoses type I, which are caused by mutations in the TRPS1 and EXT1 genes, respectively. In addition to multiple exostoses, people with Larger Giedion Syndrome have distinctive facial features that include sparse scalp hair, a rounded nose, a long flat area between the nose and the upper lip (philtrum), and a thin upper lip. Affected individuals also have short stature, the ends of their long bones (epiphyses) are cone-shaped and mental retardation.

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Leri Weill sndrome GEN: SHOX y SHOXY LOCALIZACIN CROMOSMICA: Xpter-p22.32 y Ypter-p11.2 INCIDENCIA: 1:4000 HERENCIA: pseudoautosomal dominante La haploinsuficiencia ligada a SHOX comprende desde la discondrosteosis Leri-Weill a las formas ms severas de discondrosteosis. La forma clsica cursa con corta estatura, mesomelia, deformidad tipo Madelung. El gen SHOX se localiza en la regin psedoautosomal de los cromosomas X e Y. El 100 % de los casos de haploinsuficiencia de SHOX
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muestra deleciones o mutaciones en este gen as como el 70% de los casos LWD. SHOX-RELATED HAPLOINSUFFICIENCY DISORDERS GENE: SHOX and SHOXY CHROMOSOMAL LOCATION: Xpter-p22.32 and Ypter-p11.2 INCIDENCE: 1:4000 MODE OF INHERITANCE: pseudoautosomal dominant manner Short stature homeobox (SHOX)-related haploinsufficiency disorders range from Leri-Weill dyschondrosteosis (LWD) at the more severe end of the spectrum to SHOX-related short stature at the mild end of spectrum. The classic clinical triad in LWD is short stature, mesomelia, and Madelung deformity. Mesomelia, in which the middle portion of a limb is shorted in relation to the proximal portion, is the most frequent clinical finding. Madelung deformity includes abnormal alignment of the radius, ulna, and carpal bones at the wrist; it typically develops in mid-to-late childhood and is more common and severe in females. Individuals with SHOX-related short stature have disproportionate short stature and/or wrist abnormalities consistent with those described in Madelung deformity. The SHOX genes located on the pseudoautosomal regions of the X and Y chromosomes are the only genes known to be associated with SHOX-related haploinsufficiency. Molecular genetic testing detects SHOX deletions/mutations in 100% of individuals with SHOXrelated haploinsufficiency and in about 70% of individuals with features of LWD. VOLVER/RETURN Lesch Nyhan sndrome GEN: HPRT1 LOCALIZACIN CROMOSMICA: Xq INCIDENCIA: 1:380.000 HERENCIA: Ligada al X El sndrome de Lesch-Nyhan se caracteriza por una disfuncin motora que parece parlisis cerebral, alteracin del comportamiento y cognitivo, superproduccin de cido rico, hipotona, y retraso del desarrollo, el cual se hace evidente desde los 3 a los 6 meses. La mayora de los individuos afectos no camina. LESCH-NYHAN SYNDROME GENE: HPRT1 (Hypoxanthine phosphoribosyltransferase 1) CHROMOSOMAL LOCATION: Xq INCIDENCE: 1 per 380.000 MODE OF INHERITANCE: X-linked Lesch-Nyhan syndrome is characterized by motor dysfunction that resembles cerebral palsy, cognitive and behavioral disturbances, and uric acid overproduction (hyperuricemia). The most common presenting features are hypotonia and developmental delay, which are evident by three to six months of age. Affected individuals are delayed in sitting, and most never walk. Within the first few years, extrapyramidal involvement (e.g., dystonia, choreoathetosis, opisthotonus) and pyramidal involvement (e.g., spasticity, hyperreflexia, and extensor plantar reflexes) become evident VOLVER/RETURN Leucodistrofia Metacromtica GENES: ARSA LOCALIZACIN CROMOSMICA: 22q13.33 INCIDENCIA: entre 1:40,000 y 1:160,000 HERENCIA: Autosmica recesiva La deficiencia de Arilsulfatasa A (Leucodistrofia Metacromtica o MLD) es un trastorno que afecta a la ruptura de compuestos sulfatados afectando principalmente al tejido nervioso, los riones y testculos. Los tres subtipos clnicos de MLD son MLD-infantil, que comprende el 50-60% de los casos; menores MLD, que comprende alrededor de 20-30% y MLD-adultos, que comprende alrededor de 15-20%. La edad de comienzo dentro de una familia suele ser similar. Todas las personas pierden las funciones intelectuales y motoras. La muerte est causada en la mayora de los casos por neumona u otras infecciones.

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METACHROMATIC LEUCODYSTROPHY GENE: ARSA CHROMOSOMAL LOCATION: 22q13,33 INCIDENCE: between one in 40,000 and one in 160,000 MODE OF INHERITANCE: Autosomal recessive Arylsulfatase A deficiency (metachromatic leukodystrophy or MLD) is a disorder of impaired breakdown of sulfatides that occur throughout the body, but are found in greatest abundance in nervous tissue, kidneys, and testes. The three clinical subtypes of MLD include late-infantile MLD, comprising 50-60% of cases; juvenile MLD, comprising about 20-30%; and adult MLD, comprising about 15-20%. Age of onset within a family is usually similar. All individuals eventually lose motor and intellectual functions. The disease course may be from three to ten or more years in the late infantile-onset form and up to 20 years or more in the juvenile- and adult-onset forms. Death most commonly results from pneumonia or other infection. VOLVER/RETURN Lisencefalia Ligada al cromosoma X GENES: DCX LOCALIZACIN CROMOSMICA: Xq22.3-q23 HERENCIA: Ligada al cromosoma X Lisencefalias son malformaciones cerebrales causadas por una alteracin de la migracin neuronal, que se manifiestan como sndromes epilpticos y trastornos motores graves con alta mortalidad. Cuando la alteracin se produce en el cromosoma X, se puede afectar el gen XLIS, tambin llamado DCX o el gen ARX. La alteracin del gen XLIS se hereda en forma dominante, con un fenotipo leve en la mujer (se puede observar doble corteza), compatible con un desarrollo intelectual normal o lmite; y en el hombre se manifiesta con lisencefalia grave, retardo mental y convulsiones. La malformacin es mayor en el territorio anterior o frontal, sin compromiso de otras estructuras cerebrales ni dismorfias. DOUBLE CORTEX SYNDROME, X-LINKED LISSENCEPHALY GENES: DCX CHROMOSOMAL LOCATION: Xq22.3-q23 MODE OF INHERITANCE: X-linked Lissencephaly is a brain malformation caused by defective neuronal migration and characterized by epilepsy and severe psychomotor retardation, with high mortality. When disruption occurs on the X chromosome, the gene may be involved XLIS, also called DCX or the ARX gene. The alteration of the gene is inherited XLIS in dominant form, with a mild phenotype in women (can be seen double crust), which is compatible with a normal or limit intellectual development and manifests itself in humans with lissencephaly severe mental retardation and seizures. The malformation is higher in the territory earlier or frontal without commitment from other brain structures or dismorfias. VOLVER/RETURN

Lisencefalia Miller-Dieker GENES: LIS1 LOCALIZACIN CROMOSMICA: 17p13 La lisencefalia es una malformacin cerebral rara caracterizada por la ausencia de las circunvoluciones cerebrales normales en el cortex cerebral y microcefalia. Est causado por un defecto en la migracin neuronal durante el desarrollo embrionario. Los sntomas de la enfermedad puede incluir apariencia facial inusual, espasmo muscular, retardo severo psicomotor. Manos y dedos pueden estar deformados. La lisencefala puede estar asociada con otras patologas como el sndrome de Miller-Dieker y el Walker-Warburg. El test realizado en nuestro laboratorio detecta deleciones/duplicaciones de varios exones en los genes implicados en la lisencefalia, incluyendo a LIS1 (PAFAH1B1, Lisencefalia clsica tipo 1 y Sndrome de Miller-Dieker), DCX (Sndrome del doble crtex y Lisencefalia ligada al X), POMT1 (Sndrome de Walker/Warburg), POMGnT1 (Enfermedad msculoojo-cerebro) y FLNA (heterotopia nodular periventricular y sndrome otopalatodigital). Rev 36 05/05/2009

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MILLER-DIEKER LISSENCEPHALY GENES: LIS1 CHROMOSOMAL LOCATION: 17p13 Lissencenphaly, which literally means "smooth brain," is a rare, gene-linked brain malformation characterized by the absence of normal convolutions (folds) in the cerebral cortex and an abnormally small head (microcephaly). It is caused during embryonic development by defective neuronal migration, the process in which nerve cells move from their place of origin to their permanent location. Symptoms of the disorder may include unusual facial appearance, difficulty swallowing, failure to thrive, muscle spasms, seizures, and severe psychomotor retardation. Hands, fingers, or toes may be deformed. Lissencephaly may be associated with other diseases including isolated lissencephaly sequence, MillerDieker syndrome, and Walker-Warburg syndrome. This assay is designed to detect deletions/duplications of one or more exons of the Lissencephaly genes, such as LIS1 (PAFAH1B1, classical type 1 lissencephaly, Miller-Dieker syndrome), DCX (Double cortex syndrome, X-linked lissencephaly), POMT1 (Walker/Warburg Syndrome), POMGnT1 (Muscle-Eye-Brain disease) and FLNA (periventricular nodular heterotopia, frontometaphyseal dysplasia and otopalatodigital syndrome). VOLVER/RETURN Lipoproteinlipasa GEN: LPL LOCALIZACIN CROMOSMICA: 8p22 INCIDENCIA: 1/1,000,000 HERENCIA: autosmica recesiva La deficiencia de lipoprotein-lipasa normalmente se presenta en la juventud y es caracterizada por hipertriglicemia con episodios de dolor abdominal, pancreatitis aguda, erupciones cutneas y hepatoesplenomegalia. Los sntomas se resuelven con una restriccin en la dieta de las grasa 20gr/da o menos. El anlsis de la mutacin G188E en el gen LPL est disponible en nuestro laboratorio. FAMILIAL LIPOPROTEIN LIPASE DEFICIENCY GENE: LPL CHROMOSOMAL LOCATION: 8p22 INCIDENCE: 1/1,000,000 MODE OF INHERITANCE: autosomal recessive Familial lipoprotein lipase (LPL) deficiency usually presents in childhood and is characterized by hypertriglyceridemia with episodes of abdominal pain, recurrent acute pancreatitis, eruptive cutaneous xanthomata, and hepatosplenomegaly. Clearance of chylomicrons from the plasma is impaired, causing triglycerides to accumulate in plasma and the plasma to have a milky ("lactescent" or "lipemic") appearance. Symptoms resolve with restriction of dietary fat to 20 grams/day or less. The molecular testing avaible are G188E mutation and sequencing of LPL gene. VOLVER/RETURN Lowe, sndrome GEN: OCRL LOCALIZACIN CROMOSMICA: Xq INCIDENCIA: 1:500.000 HERENCIA: Ligada al X recesiva El sndrome de Lowe o sndrome oculocerebrorenal se caracteriza por la implicacin del sistema nervioso central, ojos y riones. Las cataratas aparecen en los nios afectos y en el 50% de los casos se desarrolla glaucoma. La hipotona generalizada tiene un origen central (cerebro) y se da desde el nacimiento. Este sndrome est causado la deficiencia de actividad de la enzima polifosfato 5-fosfatasa OCRL-1 que codifica el gen OCRL. La deteccin de las mutaciones causantes de este gen se realiza mediante secuenciacin del gen OCRL. LOWE SYNDROME
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GENE: OCRL (enzyme inositol polyphosphate 5-phosphatase OCRL-1) CHROMOSOMAL LOCATION: Xq INCIDENCE: 1 in 500.000 MODE OF INHERITANCE: X-linked recessive manner Lowe syndrome (oculocerebrorenal syndrome) is characterized by involvement of the eyes, central nervous system, and kidneys. Dense congenital cataracts are found in all affected boys and infantile glaucoma in about 50%. All boys have impaired vision; corrected acuity is rarely better than 20/100. Generalized hypotonia is noted at birth and is of central (brain) origin. Deep tendon reflexes are usually absent. Hypotonia may slowly improve with age, but normal motor tone and strength are never achieved. Motor milestones are delayed. Lowe syndrome is caused by markedly reduced activity of the enzyme inositol polyphosphate 5-phosphatase OCRL-1, which is encoded by the gene OCRL. The diagnosis is established in affected individuals by demonstrating reduced (<10% of normal) activity of inositol polyphosphate 5-phosphatase OCRL-1 in cultured skin fibroblasts. VOLVER/RETURN Marfan, sndrome GEN: FBN1 LOCALIZACIN CROMOSMICA: 15q21.1 HERENCIA: Autosmica dominante El sndrome de Marfan es una enfermedad sistmica que afecta a los tejidos con una variabilidad clnica muy elevada. Los principales sntomas afectan a los ojos, esqueletos y sistema cardiovascular. Las mutaciones en el gen FBN1 estn asociadas a una amplia gama de fenotipos, desde caractersticas aisladas del sndrome a severa y progresiva enfermedad en varios rganos en recin nacidos. El 75% de los enfermos tienen un padre afecto. Alrededor del 25% de los afectados sufren la enfermedad como resultado de una mutacin de novo en el gen. Pruebas genticas del gen FBN1 detectan mtaciones en el 70-93% de los individuos afectos.Nuestro laboratorio dispone tanto del anlisis de secuencia como el estudio de deleciones/duplicaciones del gen FBN1. GEN: TGFBR1 LOCALIZACIN CROMOSMICA: 9q33-34 GEN: TGFBR2 LOCALIZACIN CROMOSMICA: 3p22 Mutaciones en los genes TGFBR1 y TGFBR2 han sido detectadas en individuos con caractersticas propias del sndrome de Marfan. Esta patologa ha sido denominada Sndrome de Marfan Tipo II.Nuestro laboratorio dispone del anlisis de secuencia de ambos genes. MARFAN SYNDROME GENE: Fibrillin 1 (FBN1) CHROMOSOMAL LOCATION: 15q21.1 MODE OF INHERITANCE: Autosomal dominant manner Marfan syndrome is a systemic disorder of connective tissue with a high degree of clinical variability. Cardinal manifestations involve the ocular, skeletal, and cardiovascular systems. FBN1 mutations associate with a broad phenotypic continuum, ranging from isolated features of Marfan syndrome to neonatal presentation of severe and rapidly progressive disease in multiple organ systems. About 75% of individuals diagnosed with Marfan syndrome have an affected parent. About 25% of probands with Marfan syndrome have the disorder as the result of a de novo gene mutation. Molecular genetic testing of the FBN1 gene detects 70-93% of mutations and is available in our clinical laboratory. GENE: Transforming growth factor, beta receptor I (activin A receptor type II-like kinase, 53kDa) TGFBR1 CHROMOSOMAL LOCATION: 9q33-34 GENE: Transforming growth factor, beta receptor 2 (70-80 kDa) TGFBR2

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CHROMOSOMAL LOCATION: 3p22 Because TGF-beta signaling has a prominent role in vascular and craniofacial development in mouse models (Sanford et al., 1997; Azhar et al., 2003) and because conditional knockout of TGFBR2 in neural crest cells causes cleft palate and defects of the calvaria (Ito et al., 2003), Loeys et al. (2005) considered TGFBR2 as a candidate gene in LDS. They sequenced all exons of the TGFBR2 gene and identified heterozygous mutations in 6 of the 10 families with LDS. No mutations in TGFBR2 were found in the 4 other families with a clinically indistinguishable phenotype. Therefore Loeys et al. (2005) sequenced all exons of the TGFBR1 gene and found a unique missense mutation in each family. Individuals with Marfan syndrome and mutations in TGFBR2 or TGFBR1 are designated Marfan syndrome type II.Molecular genetic testing of the TGFBR1 and TGFBR2 genes are available in our clinical laboratory.

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McARDLE, Enfermedad de GEN: PYGM LOCALIZACIN CROMOSMICA: 11q13.2 HERENCIA:Autosmica recesiva La enfermedad por almacenamiento de glucgeno tipo V ,tambin conocida como deficiencia de glucgeno fosforilasa en los msculos o enfermedad de McArdle, es una miopata metablica caracterizada por intolerancia al ejercicio que se manifiesta por fatiga rpida, mialgia y calambres en los msculos ejercitados, adems, en aproximadamente el 50% de los individuos cursa con episodios de mioglobinuria que puede resultar en un fallo renal agudo. El nico gen asociado con GSDV (Glycogen Storage Disease Type V) es el PYGM. En nuestro laboratorio est disponible tanto el anlisis de las mutaciones ms frecuentes halladas en este gen (R49X,G204S,Y84X,W797R y 708/709del) como la secuenciacin completa del mismo. McARDLE disease GENE: PYGM CHROMOSOMAL LOCATION: 11q13.2 MODE OF INHERITANCE: autosomal recessive manner Glycogen storage disease type V (GSDV, McArdle disease) is a metabolic myopathy characterized by exercise intolerance manifested by rapid fatigue, myalgia, and cramps in exercising muscles, and, in about 50% of individuals, episodes of myoglobinuria that can result in acute renal failure. Symptoms usually are precipitated by isometric exercise and sustained aerobic exercise. Most individuals learn to improve their exercise tolerance exploiting the "second wind" phenomenon with relief of myalgia and fatigue after a few minutes of rest. Onset of GSDV typically occurs in the second to third decade of life. Individuals may present with exercise intolerance; acute renal failure; hyper-CK-emia; or clumsiness, lethargy, slow movement, or laziness in pre-adolescents. Clinical variability exists; some individuals have mild symptoms manifesting as tiredness or poor stamina without cramps. PYGM, the gene encoding myophosphorylase, is the only gene associated with GSDV. Targeted mutation analysis of the most common mutations (R49X,G204S,Y84X,W797R and 708/709del) and sequence analysis of the entire coding region are available on our laboratory. VOLVER/RETURN

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Menkes, enfermedad GEN: ATP7A LOCALIZACIN CROMOSMICA: Xq12-q13 INCIDENCIA: 1/100,000 HERENCIA: ligada al X recesiva La enfermedad de Menkes se caracteriza por una baja concentracin de cobre en algunos tejidos como resultado de la mala absorcin intestinal, la acumulacin de cobre en otros tejidos y la dficit de actividad de las enzimas dependientes de cobre como la dopamina beta hidroxilasa y la lisil oxidasa. Los nios con forma clsica de Menkes aparentemente son sanos hasta los 2 o 3 meses de vida, cuando le aparece la hipotona, ataques y no progresan en el crecimiento. El diagnstico se realiza cuando los nios afectos sufren cambios neurolgicos y en el pelo (baja pigmentacin, acortamiento, escasez, spero y retorcido). En el periodo neonatal puede aparecer hipoglucemia, inestabilidad en la temperatura corporal y la muerte ocurre a los 3 aos de edad. La secuenciacin del gen ATP7A permite detectar las mutaciones responsables de la enfermedad. MENKES DISEASE GENE: ATP7A CHROMOSOMAL LOCATION: Xq12-q13 INCIDENCE: 1/100,000 MODE OF INHERITANCE: X-linked recessive Menkes disease and OHS are characterized by low concentrations of copper in some tissues as a result of impaired intestinal copper absorption, accumulation of copper in other tissues, and reduced activity of copper-dependent enzymes such as dopamine beta hydroxylase (DBH) and lysyl oxidase. Infants with classic Menkes disease appear healthy until age two to three months, when loss of developmental milestones, hypotonia, seizures, and failure to thrive occur. The diagnosis is usually suspected when infants exhibit typical neurologic changes and concomitant characteristic changes of the hair (short, sparse, coarse, twisted, often lightly pigmented). Temperature instability and hypoglycemia may be present in the neonatal period. Death usually occurs by three years of age. Direct sequence analysis of the ATP7A coding region and flanking intron is available in our laboratory. VOLVER/RETURN Miastenia congnita GEN: CHRNA1 LOCALIZACIN CROMOSMICA: 2q31-q32 GEN: CHAT LOCALIZACIN CROMOSMICA:10q11.2 GEN: RAPSN LOCALIZACIN CROMOSMICA:11p11.2-p11.1 GEN:CHRNE LOCALIZACIN CROMOSMICA:17p13.1 GEN: Dok7 LOCALIZACIN CROMOSMICA: 4p16.2 HERENCIA: Autosmica recesiva o, en algunos casos, autosmica dominante Desorden que causa debilidad muscular que afectar a la unin neuromuscular. En algunos tipos de miastenia congnita los sntomas pueden ser leves, pero puede aparecer debilidad repentina o incluso episodios de insuficiencia respiratoria. CONGENITAL MYASTHENIC GENE: CHRN1 CHROMOSOMAL LOCATION: 2q31-q32 GENE: CHAT CHROMOSOMAL LOCATION: 10q11.2 GENE: RAPSN CHROMOSOMAL LOCATION: 11p11.2-q11.1 Rev 36 05/05/2009

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GENE: CHRNE CHROMOSOMAL LOCATION: 17p13.1 GENE: Dok7 CHROMOSOMAL LOCATION: 4p16.2 MODE OF INHERITANCE: Autosomal recessive, or, less frequently, autosomal dominant manner Disorder that causes muscle weakness that affect the neuromuscular junction. In some types of congenital myasthenic syndrome, myasthenic symptoms may be mild, but sudden severe exacerbations of weakness or even sudden episodes of respiratory insufficiency may occur. They may be precipitated by fever, infections, or excitement and are most frequently seen in individuals with CMS with episodic apnea (CMS-EA) or endplate rapsyn deficiency (EP rapsyn deficiency). VOLVER/RETURN MHC II GEN: RFXAP LOCALIZACIN CROMOSMICA: 13q14 GEN: RFXANK LOCALIZACIN CROMOSMICA: 19p12 GEN: RFX5 LOCALIZACIN CROMOSMICA: 1q21 GEN: CIITA LOCALIZACIN CROMOSMICA: 16p13 HERENCIA: autosmica recesiva El dficit de expresin de molculas de clase II del complejo mayor de histocompatibilidad es una inmunodeficiencia primaria combinada de herencia autosmica recesiva. La precocidad en el diagnstico es vital, dada su elevada letalidad en los primeros 2 aos de vida, as como su potencial tratamiento mediante trasplante de progenitores hematopoyticos. Consiste en una ausencia de molculas MHC-II en la superficie de las clulas que habitualmente las expresan, confiriendo una inmunodeficiencia grave celular y humoral, con susceptibilidad extrema a infecciones bacterianas, virales, fngicas y protozoarias. Los genes afectados no son exactamente los que codifican a las molculas del MHC-II, sino aqullos relacionados con las protenas que promueven la transcripcin de dichas molculas. La alteracin final puede ser el producto de la mutacin de 4 grupos de genes diferentes, dando lugar a los 4 grupos actualmente descritos para esta enfermedad, que se denominan grupo A (gen CIITA ), B (gen RFX5 ), C (gen RFXAP ) o D (gen RFXANK ). MHC II GENE: RFXAP CHROMOSOMAL LOCATION: 13q14 GENE: RFXANK CHROMOSOMAL LOCATON: 19p12 GENE: RFX5 CHROMOSOMAL LOCATION: 1q21 GENe: CIITA CHROMOSOMAL LOCATION: 16p13 MODE OF INHERITANCE: autosomal recessive Major histocompatibility complex class II deficiency is an autosomal recessive primary combined immunodeficiency. Early diagnosis is essential due to high mortality in the first 2 years of life and the possibility of bone marrow transplantation. It consists of a lack of MHC-II molecules on the surface of cells that usually express, conferring a cellular and humoral immune severe, extreme susceptibility to bacterial, viral, fungal and protozoal infections. The genes involved are not exactly the ones that encode molecules of the MHC-II, but those related proteins that promote transcription of these molecules. The alteration may be the end product of the mutation of 4 groups of different genes, giving rise to the 4 groups currently described for this disease, which is called group A (gene CIITA), B (RFX5 gene), C (gene RFXAP) or D (RFXANK gene).

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VOLVER/RETURN Microdeleciones del cromosoma Y Las microdeleciones del cromosoma Y en pacientes con infertilidad se encuentran entre el 3,5 % y el 55 % de los casos aunque la mayora de los estudios las informan por debajo del 15 %. En hombres oligozoosprmicos no seleccionados la frecuencia de deleciones est en el 2,9 %, y aumenta al 11,6 % en la oligozoospermia idioptica, llegando al 14,3 % cuando adems se restringe a oligozoospermia severa (<5x106/ml). En hombres azoosprmicos no obstructivos la frecuencia de deleciones es de 10,5 %, pero aumenta al 18 % si slo se tienen en cuenta los casos idiopticos. Cuatro diferentes loci conocidos como azoospermia factor, AZF (regiones AZFa, b, c y d) han sido mapeados en el cromosoma Y como reguladores de la espermatognesis. Las deleciones en estas regiones afectan genes candidatos como DBY, RBMY, DAZ y USP9Y, originando testiculopata severa en el hombre infrtil. Las microdeleciones ms frecuentes se dan en la regin AZFc con el 59,6 % e los casos, seguida de la regin AZFb con el 15,8 %. Las deleciones amplias que afectan dos o tres regiones AZF se encuentran en el 13,6 % de los casos, y en el 6 % se localizan fuera de los intervalos AZF. El anlisis se realiza mediante dos multiplex PCR de las regiones AZF: AZFc: sY277, sY283, el gen SRY: sY14, AZFa: sY84, AZFb: sY143 y AZFc: sY254 Y-CHROMOSOME DNA ASSAY FOR MICRODELETIONS Almost 30% of males with impaired spermatogenesis have a Yq microdeletion. Our laboratory tests for 8 different microdeletions of the Y-chromosome, any one of which could interfere with spermatogenesis or cause spermatogenic arrest. We test for the presence of one marker (Sy277) within the DAZ (Deleted in AZoospermia) gene, four markers (Sy127, Sy1227, Sy85, and Sy243) within the AZF (AZoospermia Factor) gene, plus SRY, Amelogenin Y (Sy276), and ZFY(Sy238). This assay should be performed in conjunction with routine chromosome studies for evaluation of male infertility. VOLVER/RETURN

MIOCARDIOPATA ESPONGIFORME GEN: TAZ LOCALIZACION CROMOSMICA: Xq28 HERENCIA: ligada al X La miocardiopata espongiforme (no compactacin del miocardio ventricular izquierdo) es una miocardiopata congnita resultado de la interrupcin del desarrollo embrionario endomiocrdico normal, que se caracteriza por la presencia de prominentes trabeculaciones y espacios intratrabeculares profundos en la pared ventricular. Las manifestaciones clnicas varan entre fallo cardaco, arritmias y tromboembolismo sistmico. La mayora de los afectados son detectados en la infancia o la adolescencia. Mutaciones en el gen TAZ que codifica para la tafazzina, una protena implicada en el metabolismo de la cardiolipina, han sido relacionadas con la miocardiopata espongiforme. SPONGY CARDIOMYOPATHY GENE:TAZ CHROMOSOMAL LOCALITATION: Xq28 MODE OF INHERITANCE: X-linked Isolated left ventricular noncompaction, also known as spongy myocardium or spongy cardiomyopathy, is a congenital disease caused by an arrest in the left ventricular myocardial embriogenesis that makes the ventricular wall to persist thickened with multiple trabecular formations and deep sinusoidal recesses. It is clinically characterized by heart failure, cardiac arrhythmia and systemic embolic events. Most of the affected subjects are detected during childhood or adolescence. It has been linked to mutations in the TAZ gene, which encodes tafazzin, a protein involved in the metabolism of
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cardiolipin. VOLVER/RETURN

Miopata Miotubular Ligada al X GEN: MTM1 LOCALIZACIN CROMOSMICA: Xq28 HERENCIA: Ligada al cromosoma X La miopata miotubular ligada al X (XLMTM) se caracteriza por debilidad muscular que vara de leve a grave. La XLMTM severa (clsica) se presenta prenatalmente con polihidramnio, demasiado lquido amnitico, y disminucin del movimiento fetal y en los recin nacidos se caracteriza por hipotona y dificultad respiratoria. Los hombres afectados tpresentan dependencia crnica de ventilacin y problemas motores, es bastante frecuente que no puedan caminar. La muerte en la infancia es comn como consecuencia de la afectacin severa de la musculatura respiratoria. Los hombres con casos moderados de XLMTM presentan menores anomalas motoras que los casos graves; alrededor del 40% no requieren ventilacin de apoyo. Los casos de XLMTM leves pueden requerir soporte ventilatorio slo en el perodo neonatal, son capaces de caminar y presentan menos casos de facies miopticas. Las enfermedades musculares de XLMTM no son progresivas; la fuerza muscular mejora lentamente con el tiempo. Mujeres portadoras de XLMTM son por lo general asintomtica, aunque se han descritos muy pocos casos de heterocigotos. X-LINKED MYOTUBULAR MYOPATHY GENE: MTM1 CHROMOSOMAL LOCATION: Xq28 MODE OF INHERITANCE: X-linked X-linked myotubular myopathy (XLMTM) is characterized by muscle weakness that ranges from severe to mild. Severe (classic) XLMTM presents prenatally with polyhydramnios and decreased fetal movement and in newborns with hypotonia and respiratory distress. Affected males have chronic ventilator dependence and grossly delayed motor milestones; they often fail to walk. Death in infancy is common. Males with moderate XLMTM achieve motor milestones more quickly than males with the severe form; about 40% require no ventilator support or intermittent support. Males with mild XLMTM may require ventilatory support only in the newborn period; they have minimally delayed motor milestones, are able to walk, and lack myopathic facies. The muscle disease of XLMTM is not progressive; muscle strength improves slowly over time. Female carriers of XLMTM are generally asymptomatic, although rare manifesting heterozygotes have been described. VOLVER/RETURN

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DISPLASIA SEPTO-PTICA (SNDROME DE MORSIER) GEN: HESX1 LOCALIZACION CROMOSMICA: 3p21.2-p21.1 HERENCIA: autosmica dominante El sndrome de Morsier o displasia septo-ptica (SOD) es un desorden clnicamente heterogneo definido por la combinacin de hipoplasia del nervio ptico, hipoplasia de la glndula pituitaria y, con frecuencia, anormalidades de la lnea media del cerebro, incluyendo ausencia del cuerpo calloso y septum pellucidum. La etiologa de la SOD no se conoce completamente. La mayora de los casos son espordicos y diferentes factores han sido sugeridos como su causa. Tambin han sido descritos casos familiares. La etiologa precisa de la SOD es muy probablemente multifactorial, compuesta por la contribucin de factores ambientales junto al importante papel de genes cruciales en el desarrollo como HESX1, SOX2 y SOX3, donde se han sido identificadas mutaciones en pacientes con SOD. SEPTO-OPTIC DYSPLASIA (MORSIER SYNDROME) GENE: HESX1 CHROMOSOMAL LOCALITATION: 3p21.2-p21.1 MODE OF INHERITANCE: autosomal dominant Septo-optic dysplasia (SOD), also known as Morsier Syndrome, is a highly heterogeneous condition comprising a variable phenotype of optic nerve hypoplasia, midline brain abnormalities including absence of the corpus callosum and septum pellucidum, and pituitary hypoplasia with consequent endocrine deficits. The majority of cases are sporadic and several aetiologies have been suggested to account for the pathogenesis of the condition. However, a number of familial cases have been described and the identification of mutations in key developmental genes including HESX1 , SOX2 and SOX3 in patients with SOD and associated phenotypes suggests that a genetic causation is likely in the more common sporadic cases of the condition. The precise aetiology of SOD is most likely multifactorial involving contributions from environmental factors in addition to an important role for crucial developmental genes. The variability of the penetrance and phenotypes within a single SOD pedigree may also suggest a complex interaction between genetics and the environment, and at present, the understanding of these interactions is rudimentary. Further study of these critical factors may shed light on the aetiology of this complex disorder. VOLVER/RETURN MOWAT WILSON, Sndrome de GEN: ZEB2 LOCALIZACION CROMOSOMICA: 2q22 HERENCIA: autosmica dominante El Sndrome de Mowat-Wilson (MWS) se caracteriza por unos rasgos faciales distintivos, anomalas estructurales incluyendo la enfermedad de Hirschsprung, anomalas genitourinarias (en particular hipospadias en el hombre), defectos congnitos del corazn que afectan a las arterias pulmonares y/o vlvulas, defectos del ojo (microftalmia y la anomala de Axenfeld) y diferencias funcionales que incluyen retraso mental de moderado a severo, retraso del crecimiento con microcefalia y convulsiones. El MWS est causado por mutaciones y deleciones en el gen ZEB2, que codifica para la protena ZEB2 (Zing finger Ebox Binding homeobox 2), la cual desempea un importante papel en el desarrollo de la cresta neural. El anlisis de la secuencia de los 9 exones codificantes, splice junctions y de las regiones intrnicas flanqueantes del gen ZEB2 permite detectar las mutaciones en aproximadamente un 81% de los individuos con un diagnstico clnico de MWS. Un 2% de los individuos presentan deleciones de tamao intermedio que pueden ser detectadas por MLPA.
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El sndrome de Mowat-Wilson es tpicamente el resultado de una mutacin dominante de novo. MOWAT WILSON, SYNDROME GENE: ZEB2 CHROMOSOMAL LOCALITATION: 2q22 MODE OF INHERITANCE: autosomal dominant Mowat-Wilson syndrome (MWS) is characterized by distinctive facial features; structural anomalies including Hirschsprung disease, genitourinary anomalies (particularly hypospadias in males), congenital heart defects (abnormalities of the pulmonary arteries and/or valves), eye defects (microphthalmia and Axenfeld anomaly); and functional differences including moderate to severe mental retardation, seizures, and growth retardation with microcephaly. Mutations and deletions in the gene ZEB2 cause MWS. The protein encoded by this gene, ZEB2 (Zing finger E-box Binding homeobox 2), plays an important role in the development of the neural crest. Sequencing of all nine coding exons, splice junctions, and immediate intronic flanking regions of the ZEB2 gene detects mutations in approximately 81% of individuals with a clinical diagnosis of MWS. An 2% of persons have intermediatesized deletions that can be detected by MLPA. Mowat-Wilson syndrome is typically the result of a de novo dominant mutation. VOLVER/RETURN MTHFR GEN: metilenotetrahidrofolato reductasa LOCALIZACIN CROMOSMICA: 1p36.3 HERENCIA: autosmica recesiva Hay factores genticos de riesgo que involucran a la predisposicin de individuos a sufrir trombosis. stos incrementan los niveles de homocistena en plasma, que se asocia con la variante de 2 nucletidos en el gen de la MTHFR. La variante termolbil de MTHFR 677C>T provoca un consumo de flico, que es un cofactor requerido para la remetilacin de homocistena. Homocigticos de la variante de MTHFR 677C>T se asocian desde una leve a moderada hiperhomocisteinemia. El riesgo de los tromboflicos se otorga en heterocigotos o homocigotos de la variante termolbil de MTFHT 677C>T. En otras variantes tambin son causas de riesgo de sufrir trombosis. El anlisis de DNA del gen MTHFR se recomienda en todos los individuos con antecedentes de trombosis o variante conocida de MTHFR. METHYLENETETRAHYDROFOLATE REDUCTASE (MTHFR) GENE: methylenetetrahydrofolate reductase CHROMOSOMAL LOCATION: 1p36.3 MODE OF INHERITANCE: autosomal recessive Genetic risk factors are involved in the predisposition of individuals to venous thrombosis. These include increased plasma homocysteine levels, which are associated with two nucleotide variants in the methylenetetrahydrofolate reductase (MTHFR) gene. The MTHFR 677C>T thermolabile variant results in a decreased utilization of folate, which is a cofactor required for homocysteine remethylation. Homozygocity for the MTHFR 677C>T variant is associated with mild to moderate hyperhomocysteinemia. The thrombophilic risk conferred by heterozygosity or homozygosity for the MTHFR 677C>T thermolabile variant remains to be defined. The other variant, A1298C, is involved on thrombophilic risk as well. Direct DNA analysis of the MTHFR gene is recommended for all individuals with a family history of venous thrombosis or a known MTHFR variant.

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VOLVER/RETURN MEB, Sndrome GEN: POMGnT1 LOCALIZACIN CROMOSMICA: 1p34.1 HERENCIA: Autosmica recesiva La anomala gentica causante del sndrome MEB (Muscle-Eye-Brain) se trata de mutaciones en el gen de la POMGnT1, el cual codifica a una enzima que interviene en la transformacin de protenas en glicoprotenas al unirlas con un azcar especfico (O-manosa). Esta O-glicosilacin con manosa es una rara transformacin proteica que slo se observa para algunas glicoprotenas del cerebro, del nervio y del msculo esqueltico. MEB Syndrome GENE: PMGnT1 CHROMOSOMAL LOCATION: 1p34.1 MODE OF INHERITANCE: Autosomal recessive The genetic abnormality causing the syndrome SEM (Muscle-Eye-Brain Disease) is mutations in the gene of POMGnT1 which encodes an enzyme involved in the transformation of proteins in glycoproteins to link them with a specific sugar (OR-mannose). This O-glycosylation with mannose transformation is a rare protein that is observed only for certain glycoproteins of the brain, nerve and skeletal muscle. VOLVER/RETURN NAT GEN: N-ACETYLTRANSFERASA 1 y 2 LOCALIZACIN CROMOSMICA: 8p23.1-p21.3 Diferentes estudios epidemiolgicos sugieren que las variaciones en la N-acetilacin de las aminas aromticas intervienen en la predisposicin a varios tipos de cncer relacionados con los carcingenos aromticos. Ocho polimorfismos de NAT1 se han identificado, estando el alelo 10* relacionado con incremento del riesgo de cncer de colon y vejiga. NAT2 est relacionado con reacciones de activacin/inactivacin de numerosos xenobiticos, incluyendo aminas aromticas, heterocclicas y numerosas drogas farmacuticas. Algunas variantes allicas de NAT2 son las responsables de descenso en los niveles enzimticos de NAT2 y estn asociados a incremento en el riesgo de determinados tipos de cncer y reacciones adversas a medicamentos. NAT GENE: N-ACETYLTRANSFERASE 1 and 2 CHROMOSOMAL LOCATION: 8p23.1-p21.3 A number of epidemiologic studies suggest that genetic variation in the N-acetylation of aromatic amines may infer predisposition to various cancers related to aromatic amine carcinogens. Although genetic polymorphism for the NAT2 N-acetyltransferase has been well established on phenotypic and genetic grounds as the basis of rapid, intermediate, and slow acetylation, a genetic polymorphism for NAT1 was first discovered. Eight different human NAT1 alleles were identified: NAT1*3, -*4, -*5, -*10, -*11, -*14, -*15, and -*16. The NAT1*10 allele has been associated with increased risk of colon and urinary bladder cancers and with higher levels of N-acetyltransferase activity and DNA adducts in aromatic amine tumor target organs such as colon and urinary bladder. N-Acetyltransferase 2 (NAT2) encoded by the NAT2 gene is involved in activation/inactivation reactions of numerous xenobiotics, including aromatic amines, heterocyclic amines, and numerous pharmaceutical drugs. Several allelic variants of NAT2 are responsible for decreased NAT2 enzyme levels and are reported to be associated with increased risk for several cancers and adverse drug reactions. VOLVER/RETURN Rev 36 05/05/2009

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Nefronoptosis Juvenil tipo I


Se caracteriza por atrofia tubular renal y fibrosis intersticial progresiva. Actualmente existen mas de 24 mutaciones descritas a lo largo del gen. En el 30% de los casos de los individuos con nefroneptosis juvenil, se ha identificado una delecin de 290kb. En nuestro laboratorio recomendamos el estudio de delecin como tcnica de screening y secuenciacin del gen tras resultado negativo de la delecin.

Juvenile nephronophthisis (nephronophthisis type 1). A homozygous ~290-kb deletion of NPHP1 is the causative molecular defect in approximately 30% of individuals with juvenile nephronophthisis. Juvenile nephronophthisis is characterized by renal tubular atrophy and progressive interstitial fibrosis with later development of medullary cysts. Some individuals with juvenile nephronophthisis and NPHP1 deletions have the molar tooth sign on cranial imaging. The number of individuals with this feature in the absence of other findings of Joubert syndrome (e.g., hypotonia, developmental delay, and eye movement abnormalities), though it has not been determined, is likely to be low. Some individuals with NPHP1 molecular defects have retinal dystrophy in combination with juvenile nephronophthisis, termed Senior-Lken syndrome.

VOLVER/RETURN

Neurofibromatosis tipo 1 GEN: NF1 LOCALIZACIN CROMOSMICA: 17q11.2 INCIDENCIA: 1 en 3000 - 1 en 4000 MODO DE HERENCIA: autosmica dominante NF1 se caracteriza por la aparicin de manchas caf con leche, neurofibromas mltiples drmicos y problemas de apredizaje. Menos comn pero potencialmente ms serias son las manifestaciones que incluyen neurofibromas plexiformes y gliomas pticos. La mayora de los casos de NF1 presentan nuevas mutaciones. Los casos familiares tienden a tener una nica mutacin en el gen NF1. Por esta razn nuestro laboratorio ofrece anlisis de unin, pero tambin secuenciacin gnica completa y anlisis de deleciones en el gen. NEUROFIBROMATOSIS TYPE 1 GENE: NF1 CHROMOSOMAL LOCATION: 17q11.2 INCIDENCE: 1 in 3000 to 1 in 4000 MODE OF INHERITANCE: autosomal dominant NF1 is characterized by multiple cafe au lait spots, axillary and inguinal freckling, multiple discrete dermal neurofibromas, iris Lisch nodules, and learning disabilities. Less common but potentially more serious manifestations include plexiform neurofibromas and optic gliomas. The majority of cases of Neurofibromatosis type 1 (NF-1) represent new mutations. Familial cases of NF-1 tend to each have a unique mutation in the NF1 gene. For these reasons, our laboratory offers linkage analysis but also sequencing and deletions analysis for the diagnosis of NF-1. VOLVER/RETURN Neurofibromatosis tipo 2 GEN: NF2 LOCALIZACIN CROMOSMICA: 22q12.2
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INCIDENCIA 1:33,000-40,000 HERENCIA: autosmica dominante La neurofibromatosis tipo 2 se caracteriza por tumores de las clulas de Schwann en la regin vestibular bilateral con sntomas asociados de prdida de audicin, tinitus y disfuncin en el equilibrio. La edad de aparicin es de los 18 a 24 aos. Los individuos afectos desarrollan schwannomas en los nervios craneales y perifricos, meningiomas, astrocitomas, ependitomas. Nuestro laboratorio ofrece el anlisis de mutaciones y deleciones del gen NF2 causantes de la enfermedad. NEUROFIBROMATOSIS TYPE II GENE: NF2 CHROMOSOMAL LOCATION: 22q12.2 INCIDENCE 1:33,000-40,000 MODE OF INHERITANCE: autosomal dominant NF2 is characterized by bilateral vestibular schwannomas with associated symptoms of tinnitus, hearing loss, and balance dysfunction. The average age of onset is 18 to 24 years. Affected indivduals may also develop schwannomas of other cranial and peripheral nerves, meningiomas, and rarely, ependymomas and astrocytomas. Posterior subcapsular lens opacities that rarely progress to a visually significant cataract are the most common ocular findings. Mononeuropathy that occurs in childhood is an increasingly recognized finding; it frequently presents as a persistent facial palsy, a squint (third nerve palsy), or hand/foot drop. For these reasons, our laboratory offers linkage analysis but also sequencing and deletions analysis for the diagnosis of NF2. VOLVER/RETURN

Neuropata hereditaria sensible a la presin GEN: PMP22 LOCALIZACIN CROMOSMICA: 17p11.2 INCIDENCIA: 5/100,000 HERENCIA: autosmica dominante La neuropata hereditaria sensible a la presin presenta parlisis perineal. El primer ataque normalmente ocurre entre la 2 y 3 dcada de vida. La recuperacin de la neuropata aguda es prcticamente completa, si no es as, el resultado es la inestabilidad normalmente de la zona media. Algunos pacientes tienen afectacin media-moderada. Esta patologa se produce por la delecin del gen PMP22 detectndose en el 80% de los casos, el 20% restante sufre mutaciones puntuales en este gen.

HEREDITARY NEUROPATHY WITH LIABILITY TO PRESSURE PALSIES GENE: PMP22 CHROMOSOMAL LOCATION: 17p11.2 INCIDENCE: 5/100,000 MODE OF INHERITANCE: autosomal dominant HNPP is characterized by repeated focal pressure neuropathies such as carpal tunnel syndrome and peroneal palsy with foot drop. The first attack usually occurs in the second or third decade. Recovery from acute neuropathy is often complete; when recovery is not complete, the resulting disability is usually mild. Some affected individuals also have
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signs of a mild-to-moderate peripheral neuropathy. Molecular genetic testing for a contiguous gene deletion of chromosome 17p11.2 that includes the PMP22 gene detects about 80% of affected individuals. The remaining 20% of affected individuals have a variety of point mutations in PMP22 that may lead to frameshifts or other functional changes in the protein. VOLVER/RETURN Neutropenia congnita severa GEN: ELA2 LOCALIZACIN CROMOSMICA: 19p13.3 HERENCIA: autosmica dominante La neutropenia relacionada con ELA2 incluye neutropenia congnita y neutropenia cclica ambos son enfermedades hematolgicas primarias caracterizadas por fiebre recurrente, inflamacin de la piel y la zona orofarngea y adenopata cervical. La tasa de deteccin de mutacin en el gen ELA2 es del 100% en la neutropenia cclica y del 80% en la neutropenia congnita. CONGENITAL NEUTROPENIA GENE: ELA2 CHROMOSOMAL LOCATION: 19p13.3 MODE OF INHERITANCE: autosomal dominant ELA2-related neutropenia includes congenital neutropenia and cyclic neutropenia, both of which are primary hematologic disorders characterized by recurrent fever, skin and oropharyngeal inflammation, and cervical adenopathy. Molecular testing of the ELA2 gene, the only gene known to be associated with ELA2-related neutropenia, is available on a clinical basis. For individuals with well-documented cyclic neutropenia and known affected family members, the mutation detection rate is as high as 100%. For individuals with congenital neutropenia, the mutation detection rate is as high as 80%. ELA2-related neutropenia is inherited in an autosomal dominant manner. One parent of a proband is expected to be affected. De novo mutations have also been identified; their frequency is unknown. Each child of an individual with an ELA2 mutation has a 50% chance of inheriting the mutation. VOLVER/RETURN Noonan, Sndrome de GEN: PTPN11 LOCALIZACIN CROMOSMICA: 12q24 HERENCIA: Autosmica dominante Sndrome de Noonan (SN) se caracteriza por baja estatura; defectos congnitos del corazn; cuello con pliegues, forma inusual del trax (pectus excavatum), retraso mental de grado variable, rasgos faciales caractersticos (ojos de base amplia o inclinados hacia abajo, orejas de implantacin baja o de forma anormal...). Frecuentemente se observan varios tipos de defectos de coagulacin y displasias linfticas. En el 50-80% de las personas afectadas por este sndrome aparecen cardiopatas congnitas. La estenosis de vlvula pulmonar, junto a la displasia, es el defecto ms comn del corazn y aparece en 20-50% de las personas. La cardiomiopata hipertrfica, que se encuentra en el 20-30% de las personas, pueden estar presentes desde el momento del nacimiento o aparecer ya en la infancia o niez. Otros defectos estructurales observado con frecuencia incluyen defectos en los septos auricular y ventricular, rama estenosis de la arteria pulmonar y tetraloga de Fallot. La longitud al nacer suele ser normal aunque ya de adultos se acerca al lmite inferior de lo normal. Leve retraso mental se ve en hasta un tercio de las personas. Tambin pueden aparecer hasta en un 95% de los afectos anomalas oculares, incluyendo estrabismo, los defectos de refraccin, ambliopa y nistagmo. Son varios los genes que han sido asociados con el sndrome de Noonan como son PTPN11, KRAS, SOS1 y RAF1. Aproximadamente el 50% de los individuos afectos presentan mutaciones en el gen PTPN11, entre un 3-17% en el gen RAF1, un 10% en el gen SOS1 y menos del 5% en el gen KRAS. Los defectos en estos genes hacen que ciertas Rev 36 05/05/2009

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protenas involucradas en el crecimiento y desarrollo se vuelvan hiperactivas. NOONAN SYNDROME GENE: PTPN11 CHROMOSOMAL LOCATION: 12p24 MODE OF INHERITANCE: autosomal dominant Noonan syndrome (NS) is characterized by short stature; congenital heart defect; broad or webbed neck; unusual chest shape with superior pectus carinatum, inferior pectus excavatum, and apparently low-set nipples; developmental delay of variable degree; cryptorchidism; and characteristic facies. Varied coagulation defects and lymphatic dysplasias are frequently observed. Congenital heart disease occurs in 50-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20-50% of individuals. Hypertrophic cardiomyopathy, found in 20-30% of individuals, may be present at birth or appear in infancy or childhood. Other structural defects frequently observed include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Length at birth is usually normal. Final adult height approaches the lower limit of normal. Mild mental retardation is seen in up to one-third of individuals. Ocular abnormalities, including strabismus, refractive errors, amblyopia, and nystagmus, occur in up to 95% of individuals. PTPN11, KRAS, SOS1 and RAF1 are the only genes known to be associated with Noonan syndrome. Molecular genetics testing identifies mutations in the PTPN11 gene in 50% of affected individuals and is available on a clinical basis. Molecular genetic testing identifies mutations in the RAF1 gene in 3%-17% of affected individuals and is available on a clinical basis. Molecular genetic testing identifies mutations in the KRAS gene in fewer than 5% of affected individuals and is available on a clinical basis. Molecular genetic testing identifies mutation in the SOS1 gene in about 10% of individuals with Noonan syndrome and is available on a clinical basis. VOLVER/RETURN Ondine, Sndrome GEN: PHOX2B LOCALIZACIN CROMOSMICA: 4p12 HERENCIA: autosmica dominante El diagnstico del sndrome de Hipoventilacin congnita (CCHS) se establece sobre criterios clnicos y anlisis molecular como confirmatorio. Todos los individuos con fenotipo CCHS son heterocigotos para una mutacin en el gen POHX2B aunque se desconoce si otros genes diferentes pueden estar implicados. El 92% de los casos de CCHS presentan una expansin de 25-33 repeticiones de Poli-Ala en el alelo afecto, y puede ser detectado mediante ensayo por PCR con ADN modificado con bisulfito. Tan solo el 8% de los casos que no presentan expansin exhiben otra mutacin sobre la secuencia codificante del gen. Nuestro laboratorio ofrece el anlisis para el estudio de repeticiones Poli-Ala en PHOX2B. El anlisis de la regin codificante del gen tambin est disponible bajo peticin especfica. ONDINE SYNDROME (Congenital Central Hypoventilation Syndrome) GENE: PHOX2B CHROMOSOMAL LOCATION: 4p12 MODE OF INHERITANCE: autosomal dominant Diagnosis of CCHS is established by clinical findings and confirmatory molecular genetic testing. All individuals with the comprehensive CCHS phenotype are heterozygous for a mutation in the PHOX2B gene. Whether mutations in genes other than PHOX2B are pathogenic is unknown. The PHOX2B polyalanine repeat expansion of 25-33 repeats on the affected allele, accounting for 92% of cases, can be detected with a PCR-based assay. Sequence analysis of the entire coding region and intron-exon boundaries of PHOX2B can detect mutations in the 8% of individuals with the CCHS phenotype who do not have an expansion mutation. Our lab offers polyalanine repeat expansion test. Sequence analysis of the entire coding region is available upon request. VOLVER/RETURN

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Osteocondromatosis GEN: EXT1 y EXT2 LOCALIZACIN CROMOSMICA: 8q24.11-q24.13 y 11p12-p11 INCIDENCIA: 1:100,000 HERENCIA: autosmica dominante. Penetrancia del 95% La exostosis multiple hereditaria se caracteriza por el crecimiento de mltiples osteomas (tumor benigno derivado del tejido seo) el cual se puede producir en cualquier hueso aunque con mayor incidencia en cadera y rodilla. La exostosis se puede asociar a una reduccin en el crecimiento esqueltico, deformidad osa, restriccin del movimiento de las articulaciones, acortamiento de la estatura y prematura osteoartrosis. La enfermedad se diagnostica entorno a los 12 aos y el riesgo de aparicin de osteosarcoma aumenta con la edad. Para el diagnstico molecular de exostosis se realiza la secuenciacin de los genes EXT1 y EXT2. HEREDITARY MULTIPLE EXOSTOSES GENE: EXT1 and EXT2 CHROMOSOMAL LOCATION: 8q24.11-q24.13 and 11p12-p11 INCIDENCE: one in 100,000 MODE OF INHERITANCE: autosomal dominant. Penetrance is 95% HME is characterized by growths of multiple exostoses, benign cartilage-capped bone tumors that grow outward from the metaphyses of long bones. Exostoses can be associated with a reduction in skeletal growth, bony deformity, restricted motion of joints, shortened stature, premature osteoarthrosis, and compression of peripheral nerves. The median age of diagnosis is three years; nearly all affected individuals are diagnosed by twelve years of age. The risk for malignant degeneration to osteochondrosarcoma increases with age, although the lifetime risk of malignant degeneration is low (~1%). Sequence analysis of the EXT1 and EXT2 genes is available in our laboratory. VOLVER/RETURN Osteogenesis imperfecta GEN: COL1A1 y COL1A2 LOCALIZACIN CROMOSMICA: 17q21.3-q22 y 7q22.1 INCIDENCIA: 6-7/100,000 HERENCIA: autosmica dominante La osteognesis imperfecta es un grupo de enfermedades caracterizadas por la aparicin de fracturas con mnima o ausente trauma, dentinognesis imperfecta y en el adulto, prdida de audicin. Las caractersticas clnicas tienen un amplio rango que va desde la letalidad perinatal a individuos con severas deformidades en los huesos, incapacidad de movimiento y corta estatura a individuos prcticamente asintomticos con una predisposicin media a las fracturas y estatura normal. Las fracturas aparecen en todos los huesos pero son ms frecuentes en las extremidades. La dentinognesis imperfecta se caracteriza por presentar dientes negros o marrones y de fcil ruptura. La secuenciacin completa de los genes COL1A1 y COL1A2 se realiza en nuestro laboratorio. COL1A1/2-RELATED OSTEOGENESIS IMPERFECTA GENE: COL1A1 and COL1A2 CHROMOSOMAL LOCATION: 17q21.3-q22 and 7q22.1 INCIDENCE: 6-7/100,000 MODE OF INHERITANCE: OI types I-V are inherited in an autosomal dominant manner OI is a group of disorders characterized by fractures with minimal or absent trauma, dentinogenesis imperfecta (DI), and, in adult years, hearing loss. The clinical features of OI represent a continuum ranging from perinatal lethality to individuals with severe skeletal deformities, mobility impairments, and very short stature to nearly asymptomatic individuals with a mild predisposition to fractures, normal stature, and normal lifespan. Fractures can occur in any bone, but are most common in the extremities. DI is characterized by grey or brown teeth that may appear translucent and wear down and break easily. Genomic DNA sequence analysis is avaible in our laboratory. Rev 36 05/05/2009

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VOLVER/RETURN OTC GEN: OTC LOCALIZACIN CROMOSMICA: Xp21.1 HERENCIA: Ligada al X Las enfermedades relacionadas con el ciclo de la urea son producidas por defectos en el metabolismo del nitrgeno. Las mujeres portadoras de la enfermedad desarrollan hiperamonemia durante su vida y necesitan tratamiento crnico. La aparicin de sntomas neurolgicos podran sugerir una enfermedad relacionada con el ciclo de la urea as como una historia familiar dado el tipo de herencia que presenta. OTC ORNITIN CARBAMILASE GENE: OTC CHROMOSOMAL LOCATION: Xp21.1 MODE OF INHERITANCE: X-linked The urea cycle disorders (UCD) result from defects in the metabolism of the extra nitrogen produced by the breakdown of protein and other nitrogen-containing molecules. Absence of OTC activity in males is as severe as CPSI deficiency. Approximately 15% of carrier females develop hyperammonemia during their lifetime and many require chronic medical management. A three-generation family history with attention to other relatives (particularly children) with neurologic signs and symptoms suggestive of UCD should be obtained. Documentation of relevant findings in relatives can be accomplished either through direct examination of those individuals or review of their medical records including the results of biochemical testing, molecular genetic testing and autopsy examination. A family history consistent with Xlinked inheritance suggests OTC deficiency. VOLVER/RETURN OTOPALATODIGITAL, Sndrome GEN:FLNA LOCALIZACIN CROMOSMICA: Xq28 El Sndrome otopalatodigital se caracteriza principalmente por una displasia esqueltica e incluye el sndrome otopalatodigital tipo I (OPD1), el sndrome otopalatodigital tipo II (OPD2), frontometaphyseal displasia (FA), y el sndrome de Melnick-Needles (MNS). En hombres, los sntomas ms leves se presentan en OPD1 y, los ms graves, en FMD y OPD2; la letalidad prenatal es ms comn en hombres con el SNM. Las mujeres muestran expresividad variable. En OPD1, la mayora de las manifestaciones estn presentes en el momento del nacimiento y las mujeres pueden presentar una gravedad similar a los varones afectados, pero algunos slo tienen leves manifestaciones. Hay menos mujeres afectadas por OPD2 y FMD que hombres. La mayora de los hombres con OPD2 mueren durante el primer ao de vida, por lo general la hipoplasia torcica se traduce en insuficiencia pulmonar. Los hombres que sobreviven al primer ao de vida presentan, por lo general, retrasos de desarrollo y necesitan ayuda para alimentarse y asistencia respiratoria. En FMD los hombres no experimentan progresin de la displasia esqueltica, pero pueden tener contracturas articulares y malformaciones en pies y manos. Se observa escoliosis progresiva tanto en hombres como mujeres. En MNS, se observa una amplia variabilidad fenotpica, algunos individuos son diagnosticados en la edad adulta, mientras que otros requieren asistencia respiratoria y ven reducida su longevidad. PERIVENTRICULAR NODULAR HETEROTROPIA, FRONTOMETA PHYSEAL DYSPLASIA, OTOPALATODIGITAL SYNDROME GENE: FLNA CHROMOSOMAL LOCATION: Xq28 The otopalatodigital spectrum disorders, characterized primarily by skeletal dysplasia, include otopalatodigital syndrome
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type I (OPD1), otopalatodigital syndrome type II (OPD2), frontometaphyseal dysplasia (FMD), and Melnick-Needles syndrome (MNS). In males, severity ranges from mild manifestations in OPD1 to more severe presentations in FMD and OPD2; prenatal lethality is most common in males with MNS. Females exhibit variable expressivity. In OPD1, most manifestations are present at birth and females can present with severity similar to affected males, but some have only mild manifestations. In OPD2 and FMD, females are less severely affected than related affected males. Most males with OPD2 die during the first year of life, usually from thoracic hypoplasia that results in pulmonary insufficiency. Males who live beyond the first year of life are usually developmentally delayed and require assistance with feeding and respiratory support. In FMD, males do not experience progression of skeletal dysplasia but may have joint contractures and hand and feet malformations. Progressive scoliosis is observed in both males and females. In MNS, wide phenotypic variability is observed; some individuals are diagnosed in adulthood, while others require respiratory support and have reduced longevity. VOLVER/RETURN PAI 1 GEN: PAI-1 LOCALIZACIN CROMOSMICA: 7q21.3-q22 PAI-1 inhibe el plasmingeno tisular. El polimorfismo 4G/5G est relacionado con variaciones en la concentracin en plasma de PAI-1. El alelo 4G est asociado con un nivel significativamente ms alto de concentraciones de PAI-1 que el alelo 5G, especialmente en presencia de valores elevados de triglicridos. Varios estudios en poblacin masculina sueca han asociado este alelo a un incremento en el riesgo de infarto de miocardio. Sin embargo, otros estudios no han ratificado esta asociacin. PLASMINOGEN ACTIVATOR INHIBITOR 1 (PAI-1) GENE POLYMORPHISM GENE: PAI-1 CHROMOSOMAL LOCATION: 7q21.3-q22 PAI-1 inhibits tissue plasminogen, increased concentrations of which have been shown to be independently associated with myocardial infarction. The 4G/5G polymorphism has been linked with plasma concentrations of PAI-1. The 4G allele is associated with significantly higher concentrations of PAI-1 than the 5G allele, especially in the presence of raised triglyceride values. The 4G allele has been linked to an increased risk of myocardial infarction in a small group of young Swedish men. However, other studies have failed to reveal an association of the 4G allele with myocardial infarction. VOLVER/RETURN Pancreatitis crnica idoptica GEN: SPINK1 LOCALIZACIN CROMOSMICA: 5q32 HERENCIA: Autosmica dominante Algunas familias con una alta tasa de pancreatitis no tienen mutaciones el gen PRSS1 y aproximadamente un tercio de los pacientes presentan una pancreatitis crnica idioptica con mutaciones en el gen SPINK1. La mutacin ms frecuentemente encontrada en pacientes con ICP es la N34S. IDIOPATHIC CHRONIC PANCREATITIS GENE: SPINK1 (Serine protease inhibitor) CHROMOSOMAL LOCATION: 5 MODE OF INHERITANCE: Autosomal dominant Many families with a high frequency of pancreatitis, consistent with an autosomal mode of inheritance, carry no mutation in PRSS1. Approximately one third of all patients have no aetiological factor contributing to the development of chronic
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pancreatitis and are said to have idiopathic chronic pancreatitis (ICP). Recently it has been reported a strong association between mutations in a gene encoding the serine protease inhibitor, Kazal type 1 (SPINK1) and ICP. The human gene has four exons and is located on chromosome 5. The N34S mutation is present in a high percent of patients who do not carry any of the PRSS1 mutations. VOLVER/RETURN Pancreatitis hereditaria GEN: PRSS1 LOCALIZACIN CROMOSMICA: 7q PENETRANCIA: 80% HERENCIA: Autosmica dominante La pancreatitis hereditaria se caracteriza por frecuentes ataques de pancreatitis aguda que eventualmente resulta en una pancreatitis aguda con prdida de funcin exocrina y endocrina del pncreas. Se ha encontrado que las mutaciones causantes de la enfermedad se dan en el gen PRSS1, dos de las mutaciones ms frecuentes son N29I y R122H, otras que tambin aparecen pero con menor frecuencia son A16V y K23R. Nuestro laboratorio estudia de rutina la mutacin R122H aunque el resto de mutaciones tambin pueden ser solicitadas. HEREDITARY PANCREATITIS GENE: PRSS1 (Cationic Tripsinogen) CHROMOSOMAL LOCATION: 7q PENETRANCE: 80% MODE OF INHERITANCE: Autosomal dominant Hereditary pancreatitis (HP) is characterised by recurrent attacks of painful acute pancreatitis from an early age eventually resulting in chronic pancreatitis, with loss of pancreatic exocrine and endocrine function. HP is an autosomal dominant condition with a penetrance of approximately 80%. Causative mutations have been identified in the PRSS1 (PRoteaSe Serine 1) gene which encodes cationic trypsinogen. The two mutations most frequently identified are the N29I mutation, which may indirectly increase the frequency of autoactivation, and the R122H mutation, which is thought to alter a trypsin sensitive hydrolysis site and so stabilise trypsin once activated. A third less common mutation (A16V) with a lower penetrance lies just beyond the signal peptide and may affect trypsinogen transportation. Other rare PRSS1 mutations include R122C, N29T, D22G, and K23R, all of which are associated with HP. Genetaq offers R122H mutation as HP screening test. Others mutations are tested upon request. VOLVER/RETURN PANK2 GEN: PANK2 LOCALIZACIN CROMOSMICA: 20p13-p12.3 INCIDENCIA: 1-3: 1,000,000 HERENCIA: autosmica recesiva La neurodegeneracin asociada a pantotenato quinasa es una forma de neurodegeneracin con acumulacin de hierro en el cerebro o tambin llamada sndrome de Hallervorden-Spatz. El PKAN se caracteriza por distona progresiva y depsitos de hierro con aparicin normalmente antes de los 10 aos. Algunos de los sntomas son disartria, rigidez y retinopata pigmentaria. Entorno al 25% de los individuos afectos tienen edad de presentacin superior a los 10 aos, defectos en el habla, episodios psiquitricos y progresin ms gradual de la enfermedad. Un signo tpico de los pacientes de PKAN se presenta en MRI y se conoce como ojos de tigre. PANK2 Rev 36 05/05/2009

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GENE: PANK2 CHROMOSOMAL LOCATION: 20p13-p12.3 PENETRANCE:1-3: 1,000,000 MODE OF INHERITANCE: Autosomal dominant Pantothenate kinase-associated neurodegeneration (PKAN) is a form of neurodegeneration with brain iron accumulation, or NBIA (formerly called Hallervorden-Spatz syndrome). PKAN is characterized by progressive dystonia and basal ganglia iron deposition with onset that usually occurs before age ten years. Commonly associated features include dysarthria, rigidity, and pigmentary retinopathy. About 25% of affected individuals have an 'atypical' presentation with later onset (age >10 years), prominent speech defects, psychiatric disturbances, and more gradual progression of disease. PANK2 is the only gene currently known to be associated with PKAN. Brain magnetic resonance imaging (MRI) reveals the 'eye of the tiger' sign. VOLVER/RETURN Parlisis perodica familiar PARLISIS PERIDICA HIPOCALMICA GEN: CACNA1S y SCN4A LOCALIZACIN CROMOSMICA: 1q32 y 17q23.1-q25.3 INCIDENCIA: 1/100,000 HERENCIA: autosmica dominante La parlisis peridica hipocalmica se caracteriza por dos formas diferentes: paraltica y mioptica. La primera cursa con parlisis y flacidez reversible con hipokalemia. Los intervalos entre crisis pueden variar y ser ms prolongados. Un tratamiento preventivo es la sal de potasio o acetazolamida. La edad de aparicin de los primero ataques est entorno a los 20 aos, siendo la frecuencia mayor entre los 15 y 35 aos. El 55-70% de los casos de parlisis peridica hipocalmica presenta mutaciones en el gen CACNA1S y el 8-10% en SCN4A. PARLISIS PERIDICA HIPERCALMICA GEN: SCN4A LOCALIZACIN CROMOSMICA: 17q23.1-q25.3 INCIDENCIA: 1/100,000 HERENCIA: autosmica dominante La paralisis peridica hipercalmica tipo 1 se caracteriza por ataques de debilidad en los msculos de ojos, garganta y nariz, hipercalemia o incremento del potasio en suero. Estos ataques comienzan en la primera dcada de vida aumentando su severidad hasta los 50 aos. Las dietas ricas en potasio y el descanso despus del ejercicio pueden precipitar los ataques que pueden durar de unos 15 minutos a 1 hora y entonces desaparecer. Son varias las mutaciones asociadas a esta patologa que se detectan en el 55% de los casos, estas mutaciones son: L6891, I693T, T704M, A1156T, M1360V, I1495F, M1592V, F1490L+M1493I. HYPOKALEMIC PERIODIC PARALYSIS GENE: CACNA1S and SCN4A CHROMOSOMAL LOCATION: 1q32 and 17q23.1-q25.3 INCIDENCE: 1/100,000 MODE OF INHERITANCE: autosomal dominant Hypokalemic periodic paralysis (HOKPP) is characterized by two different forms: a paralytic form and a myopathic form. The paralytic form is characterized by attacks of reversible flaccid paralysis with concomitant hypokalemia, usually leading to paraparesis or tetraparesis but sparing the respiratory muscles and heart. Acute paralytic crises usually last at least several hours and sometimes days. Some individuals have only one episode in a lifetime; more commonly, crises occur repeatedly: daily, weekly, monthly, or less often. The major triggering factors are carbohydrate-rich meals and rest after exercise; rarely, cold-induced hypokalemic paralysis has been reported. The interval between crises may vary and may be prolonged by preventive treatment with potassium salts or acetazolamide. The age of onset of the first attack ranges from age one to 20 years; the frequency of attacks is highest between ages 15 and 35 and then Rev 36 05/05/2009

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decreases with age. Molecular genetic testing identifies disease-causing mutations in CACNA1S or SCN4A in 80% of individuals meeting clinical diagnostic criteria. Of all individuals with HOKPP, about 55-70% have mutations in CACNA1S and about 8-10% in SCN4A. HYPERKALEMIC PERIODIC PARALYSIS GENE: SCN4A CHROMOSOMAL LOCATION: 17q23.1-q25.3 INCIDENCE: 1/100,000 MODE OF INHERITANCE: autosomal dominant Hyperkalemic periodic paralysis type 1 (hyperPP1) is characterized by attacks of flaccid limb weakness (which may also include weakness of the muscles of the eyes, throat, and trunk); hyperkalemia (serum potassium concentration >5 mmol/L) or an increase of serum potassium concentration of at least 1.5 mmol/L during an attack of weakness and/or provoking/worsening of an attack by oral potassium intake; normal serum potassium and muscle strength between attacks; onset before age 20 years; and absence of paramyotonia (muscle stiffness aggravated by cold and exercise). The attacks of flaccid muscle weakness usually begin in the first decade of life. Initially infrequent, the attacks then increase in frequency and severity over time until about the age of 50 years, after which the frequency of attacks declines considerably. Potassium-rich food or rest after exercise may precipitate an attack. A cold environment, emotional stress, glucocorticoids, and pregnancy provoke or worsen the attacks. A spontaneous attack commonly starts in the morning before breakfast, lasts for 15 minutes to one hour, and then disappears. Usually, cardiac arrhythmia or respiratory insufficiency does not occur during the attacks. Between attacks, hyperPP1 is usually associated with mild myotonia (muscle stiffness) that does not impede voluntary movements. Many older affected individuals develop a chronic progressive myopathy. Molecular genetic testing for eight mutations (L6891, I693T, T704M, A1156T, M1360V, I1495F, M1592V, F1490L+M1493I) detects a mutation in approximately 55% of individuals affected with hyperPP1. These mutation and SCN4A sequence analysis of exons 13, 19, and 21-24 can be performed in our laboratory. VOLVER/RETURN Paramiotona congnita (PMC) GEN: SCN4A LOCALIZACIN CROMOSMICA:17q23-q25.3 INCIDENCIA: 1/100,000 HERENCIA: Autosmica dominante La paramiotonia congnita es un trastorno que afecta a los msculos esquelticos. Aparece a partir de la infancia o la primera infancia, las personas afectas experimentan rachas sostenidas de tensin muscular (miotona) lo que impide la relajacin muscular con normalidad. Las miotonas causan rigidez muscular normalmente despus del ejercicio fsico que puede estar inducida por el enfriamiento muscular. Esto provoca principalmente rigidez en los msculos de la cara, el cuello, los brazos y las manos. A diferencia de muchas otras formas de miotona, la rigidez muscular congnita asociada a paramiotonia tiende a empeorar con movimientos repetitivos. Las mutaciones en el gen SCN4A alteran la estructura y la funcin de los canales de sodio en el tejido muscular. Las alteraciones en estos canales impiden la correcta regulacin del flujo de iones sodio en las clulas del msculo esqueltico. El aumento resultante en el flujo de iones interfiere con la contraccin muscular y la relajacin, dando lugar a los episodios de debilidad muscular o miotona. PARAMYOTONIA CONGENITA GENE: SCN4A CHROMOMAL LOCATION: 17q23-q25.3 INCIDENCE: 1/100,000 MODE OF INHERITANCE: Atosomal dominant Paramyotonia congenita is a disorder that affects muscles used for movement (skeletal muscles). Beginning in infancy or early childhood, people with this condition experience bouts of sustained muscle tensing (myotonia) that prevent muscles from relaxing normally. Myotonia causes muscle stiffness that typically appears after exercise and can be induced by muscle cooling. This stiffness chiefly affects muscles in the face, neck, arms, and hands. Unlike many other Rev 36 05/05/2009

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forms of myotonia, the muscle stiffness associated with paramyotonia congenita tends to worsen with repeated movements. Mutations in the SCN4A gene alter the usual structure and function of sodium channels. The altered channels cannot properly regulate the flow of sodium ions into skeletal muscle cells. The resulting increase in ion flow interferes with normal muscle contraction and relaxation, leading to episodes of myotonia or muscle weakness. VOLVER/RETURN Paraplejia espstica familiar La paraplejia espstica hereditaria se caracteriza por debilidad en las extremidades y espasticidad. Encontramos dos formas: pura con discapacidad neurolgica limitada con debilidad espstica,demencia, amiotrofia, neuropata perifrica, alteraciones hipertnicas de la vejiga y ocasionalmente sensacin de quedarse encajado. La forma compleja cuando no es pura. SPG2 GEN: PLP1 LOCALIZACIN CROMOSMICA: Xq22 HERENCIA: Ligada al X. Forma complicada La parapleja espstica ligada a este gen se cononce con el nombre de enfermedad de Pelizaeus-Merzbacher. Los individuos afectados presentan nistagmus, hipotona, discapacidad cognitiva, ataxia y severa espasticidad. En el 50-75% de los hombres afectados presentan duplicacin, triplicacin y quintuplicacin del gen PLP1, el resto de casos cursa con mutaciones puntuales en ese gen. En nuestro laboratorio se estudia el nmero de copias del gen PLP1 mediante la tcnica del MLPA. SPG3, SPG4 GEN: SPG3 y SPG4 LOCALIZACIN CROMOSMICA: 14q11 y 2p22 HERENCIA: Autosmica dominante. Forma pura Los individuos afectos presentan una la clnica de la parapleja espstica pura, la edad de aparicin est en los 26-35 aos. SPG7 GEN: SPG7 LOCALIZACIN CROMOSMICA: 16q24 HERENCIA: Autosmica recesiva. Forma compleja Los sntomas son debilidad progresiva de las extremidades, hiperreflexia, disartria, disfagia, neuropata axonal y evidencias de lesiones vasculares en MRI craneal. La edad de aparicin est en los 25-42 aos. TRASTORNO SIMILAR A LA ENFERMEDAD DE PELIZAEUS-MERZBACHER GEN: GJA12 LOCALIZACIN CROMOSMICA: 1q HERENCIA: Autosmica recesiva. Forma compleja Se caracteriza por nistagmus, ataxia, espasticidad progresiva, apopleja parcial, neuropata perifrica media y leucodistrofia difusa en MRI. HEREDITARY SPASTIC PARAPLEGIA Hereditary spastic paraplegia (HSP) is characterized by insidiously progressive lower extremity weakness and spasticity. HSP is classified as "uncomplicated" or "pure" if neurologic impairment is limited to progressive lower extremity spastic weakness, hypertonic urinary bladder disturbance, mild diminution of lower extremity vibration sensation and, occasionally, joint position sensation. HSP is classified as "complicated" ("complex") if the impairment present in uncomplicated HSP is accompanied by other system involvement or other neurologic findings such as seizures, dementia, amyotrophy, extrapyramidal disturbance, or peripheral neuropathy, in the absence of other disorders such as diabetes mellitus.

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SPG2 GENE: PLP1, Myelin proteolipid protein CHROMOSOMAL LOCATION: Xq22 MODE OF INHERITANCE: X-linked Complicated HSP Mutations in the PLP1 gene encoding myelin proteolipid protein cause phenotypes in males that range from PelizaeusMerzbacher disease (PMD) to SPG2 . PMD typically manifests in infancy or early childhood with nystagmus, hypotonia, and cognitive impairment; the findings progress to severe spasticity and ataxia. Lifespan is shortened. SPG2 manifests as spastic paraparesis that is highly similar to prototypical uncomplicated autosomal dominant HSP; MRI evidence of white matter disturbance may or may not be present. Lifespan is usually normal. Female carriers may manifest mild-tomoderate signs of the disease. A wide range of severity has been observed even among family members who share the same PLP1 gene mutation. The classes of mutations that cause PLP1-related disorders are duplications, point mutations, and deletions. Triplication and quintuplication of the PLP1 gene also occur. Duplications are found in at least 50-75% of males with PLP1-related disorders; they are typically tandem duplications occurring in Xq22, which includes the entire PLP1 gene. Point mutations, which account for approximately 15%-20% of identified PLP1 mutations, can be identified by gene sequencing. PLP1 duplications are studied by MLPA in our laboratory. SPG3, SPG4 GENE: SPG3, Atlastin. SPG4, Spastin CHROMOSOMAL LOCATION: 14q11. 2p22 MODE OF INHERITANCE: Autosomal dominant Uncomplicated HSP Individuals with hereditaryspastic paraplegia, spastin type (SPG4), the most common form of autosomal dominant HSP, exhibit uncomplicated spastic paraplegia with onset from childhood to senescence (average age of onset is 26-35 years). SPG4 cannot be distinguished reliably from other dominantly inherited forms of HSP by clinical findings alone. Cognitive disturbance and dementia have been reported in some kindreds with SPG4. The other genetic types of autosomal dominant, uncomplicated HSP are clinically very similar. This in part reflects the diagnostic criteria for uncomplicated HSP in which symptoms are limited to bilateral lower extremity spastic weakness associated often with urinary bladder disturbance and occasionally with lower extremity paresthesia. In contrast, age of symptom onset and degree of severity are often quite variable within a given kindred, between kindreds linked to the same genetic locus, and between different genetic types of HSP. In general, however, symptoms begin earlier (less than age 11 years, on average) in SPG3, SPG10, and SPG12 than in SPG4, SPG6, SPG8, and SPG13 (after age 20 years, on average). But, at present, it is not possible to distinguish one genetic type of uncomplicated, dominantly inherited HSP from another using clinical findings alone. SPG7 GENE: SPG7, Paraplegin CHROMOSOMAL LOCATION: 16q24 MODE OF INHERITANCE: Autosomal recessive Complicated HSP Progressive lower extremity weakness, spasticity, and hyperreflexia, and neurologic abnormalities including dysarthria, dysphagia, optic disc pallor, axonal neuropathy, and evidence of "vascular lesions" on cranial MRI have been detected in autosomal recessive complicated HSP. Mean age of onset was 25 years with a range of 25-42 years. Individuals in a second kindred had optic atrophy and cortical and cerebellar atrophy . SPG7, encoding the protein paraplegin at the SPG7 locus present disease-specific mutations in affected individuals from two unrelated kindreds. Although the primary function of paraplegin is not well understood, Casari et al showed that paraplegin is a nuclearencoded, mitochondrial protein and that some individuals with SPG7 gene mutations have histologic evidence (ragged red fibers) and histochemical evidence (no reaction to cytochrome C oxidase) of mitochondrial disturbance in skeletal muscle biopsy. Mitochondrial abnormalities do not appear to be common features of all types of hereditary spastic paraplegia. Histologic and histochemical analysis of skeletal muscle biopsies from individuals with SPG3, SPG6, and Rev 36 05/05/2009

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SPG8 show no evidence of ragged red fibers and no histochemical evidence of oxidation-phosphorylation impairment. Pelizaeus-Merzbacher-Like Disease GENE: GJA12, Gap junction protein, alpha CHROMOSOMAL LOCATION: 1q MODE OF INHERITANCE: Autosomal recessive Complicated HSP The characteristic nystagmus and MRI changes should suggest the diagnosis of PMD/SPG2 especially if family history is consistent with X-linked inheritance. An autosomal recessive syndrome characterized by early-onset nystagmus, delayed motor milestones, ataxia, progressive spasticity, partial seizures, mild peripheral neuropathy, and diffuse leukodystrophy on MRI was found to be caused by mutations in the GJA12 gene that encodes connexin 46.6. VOLVER/RETURN Parkinson PARK8 GEN: LRRK2 LOCALIZACIN CROMOSMICA: 12q12 HERENCIA: Autosmica dominante PARK6 GEN: PINK1 LOCALIZACIN CROMOSMICA: 1p36 HERENCIA: Autosmica recesiva La enfermedad de Parkinson se refiere a todos los estados clnicos caracterizados por temblor, rigidez muscular y movimiento ms lento (bradiquinesia). Pueden ser frecuentes manifestaciones psiquitricas, que incluyen la depresin y alucinaciones visuales. La demencia ocurre en el 20% de los casos. Cuando aparece antes de los 20 aos, hablamos de Parkinson juvenil, si aparece antes de los 50 aos, son clasificados como Parkinson de aparicin temprana y, cuando la aparicin es despus de los 50 aos de edad, hablamos de Parkinson de aparicin tarda. PARKINSON DISEASE PARK8 GENE: LRRK2 CHROMOSOMAL LOCATION: 12q12 MODE OF INHERITANCE: Autosomal dominant PARK6 GENE: PINK1 CHROMOSOMAL LOCATION: 1p36 MODE OF INHERITANCE: Autosomal recessive Parkinsonism refers to all clinical states characterized by tremor, muscle rigidity, and slowed movement (bradykinesia). Parkinson disease is the primary and most common form of parkinsonism. Psychiatric manifestations, which include depression and visual hallucinations, are common but not uniformly present. Dementia eventually occurs in at least 20% of cases. Generally, individuals with onset before age 20 years are considered to have juvenile-onset Parkinson disease, those with onset before age 50 years are classified as having early-onset Parkinson disease, and those with onset after age 50 years are considered to have late-onset Parkinson disease. VOLVER/RETURN PARK-1 GEN: SNCA LOCALIZACIN CROMOSMICA: 4q21-q22
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HERENCIA: autosomica dominante Esta forma de la enfermedad del Parkinson esta causada por mutaciones en el gen alfa sinucleina (SNCA) y se hereda de manera autosmica dominante. Las mutaciones Ala30Pro en el exn 3 y Ala53Thr del exn 4 del gen PARK-1 (alfasinuclena) representan dos de los cambios mas frecuentes en PARK-1 en la poblacin caucsica. Las mutaciones a lo largo de los exones 3 y 4 representan ms del 70% de los cambios observados en este gen.

PARK-1 GENE: SNCA CHROMOSOMAL LOCALITATION: 4q21-q22 MODE OF INHERITANCE: autosomal dominant This form of Parkinson disease is caused by mutations in the alpha-synuclein gene (SNCA). It is inherited in an autosomal dominant manner.Ala30Pro in exon 3 and Ala53Thr in exon 4 of the gene PARK1( alpha-synuclein) are the most common mutations in caucasian population. Mutations in this exons represents approximately 70% of changes detected in this gene. VOLVER/RETURN

ENFERMEDAD DE PARKINSON JUVENIL GEN: PARK-2 LOCALIZACIN CROMSOMICA: 6q25.2-q27 HERENCIA: Autosmica recesiva Mutaciones en el gen PARK2, que codifica para la protena parkina, son uno de los factores predominantes causantes de la enfermedad de Parkinson juvenil autosmica recesiva. El diagnstico de esta enfermedad se considera ante todo en individuos que presenten una aparicin temprana de parkinsonismo (menores de 40 aos), particularmente si se sospecha una herencia autosmica recesiva. La frecuencia de deteccin de mutaciones vara en funcin de la historia familiar y la edad de aparicin de la enfermedad. La ausencia de mutaciones en el gen PARK2 no puede excluir el diagnstico de la enfermedad de parkinson juvenil tipo parkina. En caso de resultado negativo, se recomienda el estudio de mutaciones del gen PINK1 (PARK6), relacionado con la enfermedad de Parkinson de aparicin temprana autosmica recesiva. Si pudiera tratarse de herencia autosmica dominante, se recomienda el estudio de mutaciones de los genes SNCA (PARK1) y LRRK2 (PARK8). PARKIN TYPE OF JUVENILE PARKINSON DISEASE GENE: PARK-2 CHROMOSOMAL LOCATION: 6q25.2-q27 MODE OF INHERITANCE: Autosomal recessive The diagnosis of parkin type of juvenile Parkinson disease is considered primary in individuals with early-onset parkinsonism (age <40 years), particularly if autosomal recessive inheritance is suspected. PARK2, the gene encoding the protein parkin, is the only gene known to be associated with parkin type of juvenile Parkinson disease. Mutation detection frequency varies by family history and age of onset. The absence of a PARK2 mutation in one or both alleles cannot completely exclude the diagnosis of parkin type of juvenile Parkinson disease. In case of a negative result, we recommend the mutation test of PINK1 (PARK6) gene , related to autosomal recessive early-onset Parkinson disease. If autosomal dominant inheritance is suspected, then we propose the mutation analysis of SNCA (PARK1) and LRRK2 (PARK8) genes.

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VOLVER/RETURN PARK-8 GEN: LRRK2 LOCALIZACION CROMOSOMICA: 12q12-q13.1 HERENCIA: autosmica dominante La Enfermedad del Parkinson relacionada con el gen LRRK2 (PARK-8) se caracteriza por una serie de rasgos compatibles con la enfermedad de parkinson idioptica: rasgos motores iniciales que derivan en temblores asimtricos que progresan lentamente y/o bradiquinesia, rigidez muscular, inestabilidad postural y anormalidades en el movimiento incluyendo la festinacin y la congelacin de dichos movimientos. El inicio se produce, tpicamente, despus de los 50 aos. El nico gen asociado con este tipo de Parkinson es el LRRK2, gen codificante de una protena llamada dardarina (con funcin kinasa, rica en leucina y con repeticiones aminoacdicas de serina/treonina). Este gen es muy activo en el cerebro y otros tejidos del cuerpo. Las mutaciones patognicas ms frecuentes se localizan en el exn 31(R1441C, .R1441G),35 (Y1699C) y 41(G2019S, I2020T). Nuestro laboratorio ofrece tanto el screening de estas mutaciones como la secuenciacin completa del gen. PARK-8 GENE: LRRK2 CHROMOSOMAL LOCALITATION: 12q12-q13.1 MODE OF INHERITANCE: autosomal dominant LRRK2-related Parkinson disease (PD) is characterized by features consistent with idiopathic PD: initial motor features of slowly progressive asymmetric tremor at rest and/or bradykinesia, cog-wheel muscle rigidity, postural instability and gait abnormalities including festination and freezing. Onset is typically after 50 years of age. LRRK2, encoding leucine-rich repeat serine/threonine-protein kinase 2 (dardarin), is the only gene associated with LRRK2-related PD. The LRRK2 gene is active in the brain and other tissues throughout the body. At least five mutations are known to be pathogenic (exon 31 (R1441C, .R1441G), 35 ( Y1699C) y 41(G2019S, I2020T )).Targeted mutation analysis is recommended in most cases. VOLVER/RETURN PFEIFFER, SINDROME DE GEN: FGFR1 y FGFR2 LOCALIZACIN CROMOSMICA: 8p11.2 (FGFR1), 10q26 (FGFR2) HERENCIA: autosmica dominante El Sndrome de Pfeiffer es un trastorno gentico caracterizado por la fusin prematura de algunos huesos del crneo (craneosinostosis). Esta fusin prematura impide el normal crecimiento del crneo afectando por tanto a la forma de la cabeza y la cara. Como caractersticas generales los individuos afectos presentan hipertelorismo ocular, proptosis, hipoplasia mediofacial y prognatismo mandibular. Los huesos de las manos y los pies tambin se ven afectados en este sndrome. El sndrome de Pfeiffer se divide en tres subtipos. El Tipo 1, tambin conocido como sndrome de Pfeiffer clsico es la forma menos severa, la mayora de las personas con sndrome de Pfeiffer tipo 1 tienen una inteligencia y una esperanza de vida normales. Los tipos 2 y 3 son las formas ms graves del Sndrome de Pfeiffer, en estos casos s es comn el retraso mental y/o del desarrollo.
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Este sndrome es el resultado de mutaciones en los genes FGFR1 y FGFR2 (codifican los receptores del factor de crecimiento de fibroblastos 1 y 2, respectivamente). El sndrome de Pfeiffer Tipo 1 est causado por mutaciones en FGFR1 (5%) o FGFR2 (95%). Los tipos 2 y 3 estn causados por mutaciones en el gen FGFR2. PFEIFFER SYNDROME GENE: FGFR1 y FGFR2 CHROMOSOMAL LOCALITATION: 8p11.2 (FGFR1), 10q26 (FGFR2) MODE OF INHERITANCE: autosomal dominant Pfeiffer syndrome is a genetic disorder characterized by the premature fusion of certain skull bones (craniosynostosis). This early fusion prevents the skull from growing normally and affects the shape of the head and face. Facial features include ocular hypertelorism, proptosis, midface hypoplasia, small beaked nose, and prognathism. Pfeiffer syndrome also affects bones in the hands and feet. Pfeiffer syndrome is divided into three subtypes. Type 1, also known as classic Pfeiffer syndrome, is the less severe form. Most individuals with type 1 Pfeiffer syndrome have normal intelligence and a normal life span. Types 2 and 3 are more severe forms of Pfeiffer syndrome that often involve developmental delay/mental retardation. Pfeiffer syndrome results from mutations in the FGFR1 or FGFR2 genes which encode the fibroblast growth receptors 1 and 2, respectively. Type 1 Pfeiffer syndrome is caused by mutations in either the FGFR1 (5%) or FGFR2 (95%) gene. Types 2 and 3 are caused by mutations in the FGFR2 gene. VOLVER/RETURN

POMPE, Sndrome de GEN: GAA LOCALIZACION CROMOSOMICA: 17q25.2-q25.3 HERENCIA: autosmica recesiva La Glucogenosis tipo II (GSDII) o sndrome de Pompe es una enfermedad producida por el acmulo de glucgeno, siendo los tejidos ms afectados el msculo cardiaco y el esqueltico. Se clasifica en funcin de la edad de aparicin, los rganos afectados, la severidad y la velocidad de progresin de la enfermedad. Existen dos subtipos generales: el sndrome de Pompe de inicio infantil clsico y el sndrome de Pompe de inicio tardo (formas infantil, juvenil y adulta). Se hereda de una manera autosmica recesiva. El nico gen implicado es el GAA que codifica para la enzima lisosomal alfa glucosidasa cida. Las mutaciones en GAA dan como resultado un ARNm inestable y/o una enzima severamente truncada que da lugar a la ausencia o reduccin de la actividad enzimtica GAA. Se recomienda un screening de las tres mutaciones ms comunes (Asp645Glu, Arg854X, y IVS1-13t> G) antes de proceder al anlisis de la secuencia completa del gen. POMPE DISEASE GENE: GAA CHROMOSOMAL LOCATION: 17q25.2-q25.3 MODE OF INHERITANCE: autosomal recessive Glycogen storage disease type II (GSD II), or Pompe disease, is classified by age of onset, organ involvement, severity, and rate of progression.The two general subtypes of GSD II are: Infantile-onset Pompe disease and Late-onset Pompe disease (childhood, juvenile and adult-onset). GSD II is inherited in an autosomal recessive manner. GAA is the only gene known to be associated with GSD II. GAA
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mutations result in mRNA instability and/or severely truncated acid alpha-glucosidase. An individual could be tested first for one of the three common mutations (Asp645Glu, Arg854X, and IVS1 -13T>G) before proceeding to full sequence analysis. VOLVER/RETURN Prader Willi, sndrome GEN: SNRPN LOCALIZACIN CROMOSMICA: 15q11 INCIDENCIA: 1:25,000 HERENCIA: autosmica dominante El Prader-Willi se caracteriza por hipotona severa, dificultades a la hora de comer en la infancia seguida de un exceso de apetito y desarrollo gradual de una obesidad mrbida, hipogonadismo y corta estatura. Disponemos de un ensayo de metilacin que detecta el cromosoma 15 paterno, la disomia uniparental del cromosoma 15 materno. Aproximadamente el 98% de los casos con sndrome de Prader-Willi se detectan mediante este anlisis. Este anlisis directo del DNA para los enfermos con este sndrome se recomienda para confirmar el diagnstico de pacientes con o sin antecedentes familiares. El cariotipo de unos padres de un hijo afectado y los estudios de metilacin de un feto son vlidos para un diagnstico prenatal. Otros estudios, incluyendo anlisis por deleciones FISH y estudios dismicos uniparentales (requieren muestras de sangre de los padres), se recomiendan despus de un positivo. PRADER-WILLI SYNDROME GENE: SNRPN CHROMOSOMAL LOCATION: 15q11 INCIDENCE: 1 in 25,000 births MODE OF INHERITANCE: deletion; uniparental disomy; imprinting defects; some autosomal dominant rearrangements Prader-Willi syndrome is characterized by severe hypotonia and feeding difficulties in early infancy, followed by excessive eating and gradual development of morbid obesity (unless externally controlled) in later infancy and childhood. All patients have some degree of cognitive impairment. Hypogonadism, short stature, and characteristic behaviors are also common. Prader-Willi syndrome (PWS) is caused by a deletion or disruption of the paternal SNRPN gene region. Our methylation-sensitive assay detects both deletions of the paternal chromosome 15 and uniparental disomy of the maternal chromosome 15. Approximately 98% of PWS cases are detectable using this assay. This direct DNA analysis for PWS is now recommended for the confirmation of a diagnosis in a patient with or without a family history of the condition. Further studies, including uniparental disomy studies (which require parental blood samples), are available and recommended following a positive test result. VOLVER/RETURN PSEUDOACONDROPLASIA GEN: COMP LOCALIZACIN CROMSOMICA: 19p 13.1 HERENCIA: Autosmica dominante

La pseudoacondroplasia se caracteriza por una estatura y caractersticas faciales normales en el nacimiento, cayendo, a la edad de 2 aos, el ndice de crecimiento por debajo de la curva de crecimiento estndar. Este hecho conduce a un crecimiento desproporcionado de los miembros cortos. Un rasgo tpico de estos individuos es la llamada marcha de pato, que aparece cuando comienzan a caminar. Se trata de una enfermedad degenerativa y aproximadamente la mitad de los individuos con pseudoacondroplasia requerirn ciruga de reemplazo de la cadera. Presenta una herencia autosomica dominante y esta producida por mutaciones en el gen COMP (codifica la matriz
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proteica del cartlago) (Briggs et al 1995; Hecht et al 1995; reviewed bey Briggs & Chapman 2002). Todas las mutaciones caracterizadas hasta el momento han sido mutaciones estructurales en los exones 8-14 y en los exones 15-19. Aproximadamente el 30 % de los individuos con pseudoacondroplasia tienen la misma mutacin recurrente, la deleccion de un triplete GAC (cido aspartico) dentro de una secuencia de cinco codones GAC en el exn 13.

PSEUDOACHONDROPLASIA GENE: COMP CHROMOSOMAL LOCATION: 19p 13.1 MODE OF INHERITANCE: autosomal dominant

Pseudoachondroplasia is characterized by normal length at birth and normal facies. Often the presenting feature is a waddling gait, recognized at the onset of walking. Typically, by about age two years, the growth rate falls below the standard growth curve, leading to a moderately severe form of disproportionate short-limb short stature. Degenerative joint disease is progressive and about half of individuals with pseudoachondroplasia eventually require hip replacement surgery. Pseudoachondroplasia is inherited in an autosomal dominant manner. COMP, the gene encoding the cartilage oligomeric matrix protein, is the only gene known to be associated with pseudoachondroplasia (Briggs et al 1995; Hecht et al 1995; reviewed bey Briggs & Chapman 2002). All mutations characterized to date have been structural mutations found in the exons 8-14 and exons 15-19. About 30% of individuals with pseudoachondroplasia have the same recurrent mutation, deletion of a single GAC (aspartic acid) codon within a run of five consecutive GAC codons in exon 13. VOLVER/RETURN Pseudoxantoma elstico GEN: ABCC6 LOCALIZACIN CROMOSMICA: 16p13.1 INCIDENCIA: 1:25,000 a 1:100,000 HERENCIA: autosmica recesiva El Pseudoxantoma elstico afecta a la piel, ojos, sistema cardiovascular y gastrointestinal. La mayor causa de morbilidad y invalidez es debida a la reducida visin producida por una hemorragia macular y un disciforme cicatrizado. La deteccin de mutaciones en el gen ABCC6 se da en el 80% de los casos de PXE. PSEUDOXANTHOMA ELASTICUM GENE: ABCC6 CHROMOSOMAL LOCATION: 16p13.1 INCIDENCE: 1:25,000 to 1:100,000 MODE OF INHERITANCE: autosomal recessive Pseudoxanthoma elasticum (PXE) affects the skin, eye, cardiovascular system, and gastrointestinal system. Individuals most commonly present with papules in the skin and/or with angioid streaks of the retina found on routine eye examination or associated with retinal hemorrhage. Rarely, individuals may present with vascular signs and symptoms: gastrointestinal bleeding or intermittent claudication. The most frequent cause of morbidity and disability in PXE is reduced vision from macular hemorrhage and disciform scarring. Most affected individuals live a normal life span. Sequence analysis detects mutations in about 80% of affected individuals. VOLVER/RETURN

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QT largo, sndrome GEN: KCNQ1 LOCALIZACIN CROMOSMOCA: 11p15.5 INCIDENCIA: Depende de la poblacin estudiada. HERENCIA: Autosmica dominante La prolongacin del intervalo QTc se asocia a arritmias, con taquicardia ventricular y fibrilacin ventricular. Lo que puede terminar en sncope o muerte sbita. Podemos completar la secuenciacin del gen KCNQ1.

LONG QT SYNDROME GENE: KCNQ1 CHROMOSOMAL LOCATION: 11p15.5 INCIDENCE: Prevalence varies depending on the population studied MODE OF INHERITANCE: Autosomal dominant Prolongation of the QTc interval is associated with tachyarrhythmias, including ventricular tachycardia, episodes of torsade de pointes ventricular tachycardia, and ventricular fibrillation, which may culminate in syncope or sudden death. We are testing the completed sequence of KCNQ1 gene. VOLVER/RETURN Retinitis pigmentosa dominante GEN: RHO LOCALIZACIN CROMOSMICA: 3q21.3-q24 INCIDENCIA: 1:4.000 HERENCIA: Autosmica dominante La retinitis pigmentosa es un grupo heterogneo de degeneraciones retinianas progresivas que comparten caractersticas clnicas comunes, que incluyen ceguera nocturna, disminucin del campo visual, depsito de pigmento en la retina externa y electroretinograma (ERG) disminuido o abolido. RHETINITIS PIGMENTOSA WITH RECESIVE HEREDITY GENE: RHO CHROMOSOMAL LOCATION: 3q21.3-q24 INCIDENCE: 1:4.000 MODE OF INHERITANCE:autosomal dominant The retinitis pigmentosa is a heterogeneous group of progressive retinal degeneration that share common clinical features, which include night blindness, decreased visual field, depositing pigment in the retina external electroretinograma (ERG) decreased or abolished. VOLVER/RETURN Retinosquisis GEN: RS1 LOCALIZACIN CROMOSMICA: Xp22.2 INCIDENCIA: 1:28,000 en el norte de Francia y 1:17,000 en Finlandia HERENCIA: Ligada al X recesiva. La retinosquisis juvenil ligada al X est caracterizada por un desdoblamiento de la retina en dos capas. Tiene su aparicin en la primera dcada de vida, aunque en algunos casos es ms temprana, como a los tres meses. Exmenes del fondo de ojo muestran una esquisis en la mcula. Est disponible el anlisis de tres mutaciones ms frecuentes (GLU72LYS, GLY74VAL, GLY109ARG) situadas en el exn 4, junto con el anlisis de la secuencia completa del gen RS1.

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RETINOSCHISIS GENE: RS1 CHROMOSOMAL LOCATION: Xp22.2 INCIDENCE: 1/28,000 in the north of France; 1/17,000 in Finland. MODE OF INHERITANCE: X-linked recessive X-linked juvenile retinoschisis is characterized by symmetrical bilateral macular involvement with onset in the first decade of life, in some cases as early as three months of age. Fundus examination shows areas of schisis (splitting of the nerve fiber layer of the retina) in the macula, sometimes giving the impression of a spoke wheel pattern. Schisis of the peripheral retina, predominantly inferotemporally, occurs in about 50% of individuals. Affected males typically have vision of 20/60 to 20/120. Visual acuity often deteriorates during the first and second decades of life but then remains relatively stable until the fifth or sixth decade. Mutation analysis for these three mutations is available on a clinical basis. Sequence analysis of the RS1 gene is available on a clinical basis. VOLVER/RETURN RETT, sndrome GEN: MECP2 LOCALIZACIN CROMOSMICA: Xp11 INCIDENCIA: 1:10,000-15,000 HERENCIA: Ligada al X dominante El sndrome de Rett es una enfermedad neurolgica progresiva en la cual los pacientes presentan una reduccin del tono muscular, comportamiento similar al autismo, microcefalia, movimientos retorcidos de las manos, prdida del correcto uso de las manos, disminucin de la habilidad para expresar sentimientos, elusin del contacto visual Los sntomas aparecen entre los 6 y 18 meses de edad. La deteccin de mutaciones en el gen MECP2 se da en el 80% de los casos de sndrome de Rett. RETT SYNDROME GENE: MECP2 (methyl-CpG-binding protein 2) CHROMOSOMAL LOCATION: Xp11 INCIDENCE: 1:10,000-15,000 female births MODE OF INHERITANCE: X-linked dominant Rett syndrome is a progressive neurological disorder in which individuals exhibit reduced muscle tone, autistic-like behavior, microcephaly, wringing and flapping hand movements, loss of purposeful use of the hands, diminished ability to express feelings, avoidance of eye contact, a lag in brain and head growth, gait abnormalities, and seizures. Symptoms occur between ages 6 and 18 months. Our laboratory offers DNA sequencing of the MECP2 for the identification of mutations in this gene. Sequencing of exons 2, 3, and 4 will detect approximately 80% of patients with Rett syndrome. Deletion analysis will detect an additional 10-12% of individuals with classic Rett syndrome who have a large deletion, not detectable by routine sequencing analysis. Prenatal diagnosis is available when the MECP2 mutation has been identified in a family. VOLVER/RETURN Retraso mental. Estudio de regiones subtelomricas El retraso mental est presente en un 1-3% de los individuos de la poblacion general pero slo puede ser explicado en la mitad de los casos. Varias lneas de investigacin indican que los factores genticos estn implicados en los casos de retraso mental idioptico, cuyos sntomas son las caractersticas dismrficas, el retraso en el crecimiento y las malformaciones o tener una historia familiar de retraso mental. Las regiones subtelomricas son interesantes en este tipo de patologa. Muchos telmeros pueden sufrir reordenamientos generando un nmero aberrante de copias subtelomricas asocindose al 8% de los casos. Para hacer este anlisis se usa la tcnica de MLPA.
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MENTAL RETARDATION A significant diagnostic challenge exists to identify the new causes of mental retardation. Mental retardation is present in about 1-3% of individuals in the general population, but it can only be explained in about half of the cases, despite thorough clinical and laboratory investigations. Several lines of evidence indicate that genetic factors are involved in many of the idiopathic cases, as they often show prenatal and postnatal signs such as dysmorphic features, growth retardation, and malformations or have a family history of mental retardation. The subtelomeric regions are interesting from a genomic perspective, as they are gene rich and often involved in chromosomal rearrangements. Most telomeres stain lightly with G-banding, and small rearrangements are therefore difficult to detect. Mental retardation is caused by aberrant copy numbers of subtelomeric regions in up to 8 % of al cases. We used MLPA for testing subtelomeric regions. The MLPA kit contains one probe for each subtelomeric region from chromosome 1-22 + the two X/Y pseudoautosomal regions. VOLVER/RETURN Rin poliqustico, sndrome GEN: PKD1-PKD2 LOCALIZACIN CROMOSMICA: 16p13.3 (PKD2 is on chromosome 4q) INCIDENCIA: 1:1,000 HERENCIA: autosmica dominante La poliquistosis renal autosmica dominante se caracteriza por un desarrollo progresivo de quites en el rin. Las manifestaciones renales incluyen disfuncin renal, hipertensin, dolor renal e insuficiencia renal. La edad de aparacin de la enfermedad es tardo y aproximadamente el 85% de los casos muestran mutaciones en los genes PKD1 y PKD2. GEN: PKHD1 LOCALIZACIN CROMOSMICA: 6p12.2 INCIDENCIA: 1:20.000 HERENCIA: autosmica recesiva La poliquistosis renal autosmica recesiva (PQRAR) es una de las nefropatas hereditarias infantiles ms importantes, con una incidencia de 1 de cada 20.000 individuos. Normalmente se manifiesta en la infancia, suele ser de evolucin fatal durante la lactancia o primera infancia, pero hay un amplio espectro de manifestaciones que pueden abarcar hasta la edad adulta. Adems de la presencia de quistes renales, esta enfermedad se asocia con fibrosis heptica, disgnesis biliar y fibrosis portal. Nuestro laboratorio ofrece un primer screening de los exones donde se localizan la mayora de las mutaciones descritas hasta el momento as como un estudio de secuenciacin ms completo en el que se estudian el resto de exones. POLYCYSTIC KIDNEY DISEASE AUTOSOMAL DOMINANT TYPE GENE: PKD1-PKD2 CHROMOSOMAL LOCATION: 16p13.3 (PKD2 is on chromosome 4q) INCIDENCE: 1 in 1,000 MODE OF INHERITANCE: autosomal dominant Autosomal dominant polycystic kidney disease (ADPKD) is generally a late-onset disorder characterized by progressive cyst development and bilaterally enlarged polycystic kidneys. The renal manifestations of ADPKD include renal function abnormalities, hypertension, renal pain, and renal insufficiency. Approximately 50% of patients with ADPKD have endstage renal disease (ESRD) by age 60 years. Mutations in PKD1 account for approximately 85% of cases of ADPKD. Familial cases of ADPKD with mutations in the PKD1 gene tend to each have a unique mutation in this gene. Our laboratory offers sequencing and linkage analysis for the PKD1and PKD2 genes. As long as there are at least two confirmed clinical diagnoses of ADPKD in a family, and those family members are available for testing, this method can Rev 36 05/05/2009

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be used to make predictions about disease status. (Note: There is a second locus (PKD2) which represents most of the remainder of ADPKD cases. Our laboratory does not offer linkage analysis for PKD2). GENE: PKHD1 CHROMOSOMAL LOCATION: 6p12.2 INCIDENCE: 1 in 20.000 MODE OF INHERITANCE: autosomal recessive

The majority of individuals with autosomal recessive polycystic kidney disease (ARPKD) present in the neonatal period with enlarged echogenic kidneys. At initial presentation, approximately 45% of infants have liver abnormalities, including hepatomegaly, dilated intrahepatic biliary ducts, and increased echogenicity. Pulmonary hypoplasia resulting from oligohydramnios occurs in a number of affected infants. Approximately 30% of affected neonates die, primarily of respiratory insufficiency. More than 50% of affected children progress to end-stage renal disease (ESRD), usually in the first decade of life. With neonatal respiratory support and renal replacement therapies, the ten-year survival of those who live beyond the first year of life has improved to 82%. Fifteen-year survival is estimated to be 67%-79%. A minority of individuals present as older children, usually with hepatosplenomegaly as the presenting feature.Sequence analysis of PKHD1, the only gene known to be associated with ARPKD, is clinically available.

VOLVER/RETURN SNDROME DE ROBINOW GEN: ROR2 LOCALIZACION CROMOSMICA: 9q22 HERENCIA: autosmica recesiva El sndrome de Robinow relacionado con ROR2 es un sndrome de malformacin esqueltica severa que tambin afecta a otros rganos y tiene caractersticas faciales distintivas, estatura baja, defectos en las extremidades y anormalidades genitales. Este desorden es reconocible desde el nacimiento o la niez temprana. ROR2 (receptor tyrosine kinase-like orphan receptor 2) es el gen responsable del sndrome de Robinow autosmico recesivo. El anlisis de la secuencia del gen ROR2 detecta entorno al 65-100% de los individuos afectados. Est causado por mutaciones missense, nonsense y frameshift a lo largo del gen ROR2 que afectan tanto a los dominios extracelulares como intracelulares de la protena. Debido a que la frecuencia de este sndrome es ms alta en poblaciones consanguneas tales como la oman y la turca, la mayora de los individuos afectados que se conocen son homocigotos para las mutaciones causantes de la enfermedad pero los heterocigotos compuestos tambin existen. ROR2-RELATED ROBINOW SYNDROME GENE:ROR2 CHROMOSOMAL LOCALITATION: 9q22 MODE OF INHERITANCE: autosomal recessive ROR2-related Robinow syndrome is a severe skeletal malformation syndrome that also affects other organs and has characteristic facial features, short stature, limb defects, and genital abnormalities. The disorder is recognizable at birth or early childhood. ROR2 (receptor tyrosine kinase-like orphan receptor 2) is the gene responsible for autosomal recessive ROR2-related Robinow syndrome. Sequence analysis of the ROR2 gene detects 65-100% of affected individuals. ROR2-related Robinow syndrome is caused by missense, nonsense, and frameshift mutations throughout the ROR2 gene affecting both extracellular and intracellular domains of the protein. Because the frequency of ROR2-related Robinow syndrome
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is higher in consanguineous populations such as the Omani and Turks, most known affected individuals are homozygous for the disease-causing mutation, but compound heterozygotes also exist.

VOLVER/RETURN

SNDROME DE RUSSELL SILVER GEN: H19 LOCALIZACION CROMOSMICA: 11p15.5 HERENCIA: autosmica dominante o autosmica recesiva. El sndrome de Russell-Silver (RSS) se caracteriza por un retardo del crecimiento intrauterino que viene acompaado de una deficiencia en el crecimiento postnatal. Los individuos afectos tpicamente presentan una estatura baja proporcionada, una circunferencia de la cabeza normal, clinodactilia del dedo meique, caractersticas faciales tpicas y asimetra en la longitud de las extremidades que puede ser el resultado de una hemihipotrofia con crecimiento disminudo del lado afectado. La velocidad de crecimiento es normal en los nios con RSS. Existen evidencias de que los nios con RSS poseen un riesgo significativo de retraso del desarrollo (tanto motor como cognitivo) y problemas en el aprendizaje. El RSS es una condicin genticamente heterognea y para la mayora de los individuos afectos representa ms un fenotipo que un desorden especfico. El diagnstico, por tanto, se basa principalmente en la identificacin de caractersticas clnicas consistentes, especialmente el retardo del crecimiento prenatal y postnatal, con una circunferencia de la cabeza normal. El RSS tiene mltiples etiologas, incluyendo: disoma uniparental materna para el cromosoma 7 (en cerca del 10% de los individuos con RSS); posibles mutaciones o cambios epigenticos que modifican la expresin de genes en la regin improntada del cromosoma 11p15.5, en esta regin estn includos los genes IGF2 y KCNQ1OT1, que se expresan va paterna y son improntados va materna, y tambin los genes CDKNIC y H19 (alteraciones de este ltimo estn presentes en el 35% de los individuos con RSS) que son expresados va materna e improntados va paterna; y herencia autosmica dominante o autosmica recesiva. RUSSELL SILVER SYNDROME GENE:H19 CHROMOSOMAL LOCALITATION: 11p15.5 MODE OF INHERITANCE: autosomal dominant or autosomal recessive inheritance Russell-Silver syndrome (RSS) is characterized by intrauterine growth retardation accompanied by postnatal growth deficiency. Affected individuals typically have proportionately short stature, normal head circumference, fifth-finger clinodactyly, typical facial features, and limb-length asymmetry that may result from hemihypotrophy with diminished growth of the affected side. Growth velocity is normal in children with RSS. Evidence exists that children with RSS are at significant risk for developmental delay (both motor and cognitive) and learning disabilities. RSS is a genetically heterogeneous condition and for most affected individuals represents a phenotype rather than a specific disorder. The diagnosis is therefore primarily based upon identification of consistent clinical features, especially prenatal and postnatal growth retardation with normal head circumference. RSS has multiple etiologies including: maternal uniparental disomy for chromosome 7 (in about 10% of individuals with RSS), possible mutations or epigenetic changes that modify expression of genes in the imprinted region of chromosome 11p15.5, genes in this cluster include IGF2 and KCNQ1OT1, which are paternally expressed and maternally imprinted, and CDKNIC and H19 (in about 35% of individuals with RSS), which are maternally expressed and paternally imprinted; and autosomal dominant or autosomal recessive inheritance. VOLVER/RETURN

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SAETHRE-CHOTZEN, SINDROME DE GEN:TWIST1 (FGFR2 y FGFR3) LOCALIZACIN CROMOSMICA: 7p21.2 HERENCIA: autosmica dominante El sndrome de Saethre-Chotzen se caracteriza porque los individuos afectos presentan sinostosis coronal (uni o bilaterales), asimetra facial (particularmente en individuos con sinostosis unicoronal) ptosis y sindactilia. La inteligencia generalmente es normal, aunque los individuos con grandes deleciones son ms propensos a tener retrasos en el desarrollo. TWIST1 es el nico gen asociado con el sndrome de Saethre-Chotzen. Las mutaciones en el gen TWIST1 se detectan en cerca del 80% de los individuos afectados mediante una combinacin de anlisis de delecin/duplicacin y anlisis de secuencia. El anlisis de la secuencia del exn 1 del gen TWIST1 detecta todas las mutaciones intragnicas en el gen TWIST1. El exn 1 es el nico que se traduce en este gen. Debido a que las caractersticas clnicas de los sndromes de Muenke y Saethre-Chotzen se solapan, debe considerarse el test para la mutacin p.Pro250Arg del gen FGFR3 cuando no se encuentran mutaciones en TWIST1. Adems, ha sido publicado que una familia con las tpicas caractersticas fenotpicas del sndrome de Saethre-Chotzen y sin mutaciones en el gen TWIST1 tena la mutacin p.Gln289Pro en el gen FGFR2. Por lo que tambin debe considerarse el estudio de este gen si no se encuentran mutaciones en TWIST1. SAETHRE-CHOTZEN SYNDROME GENE: TWIST1 (FGFR2 and FGFR3) CHROMOSOMAL LOCALITATION: 7p21.2 MODE OF INHERITANCE: autosomal dominant Classic Saethre-Chotzen syndrome (SCS) is characterized by coronal synostosis (unilateral or bilateral), facial asymmetry (particularly in individuals with unicoronal synostosis), ptosis and syndactyly. Intelligence is usually normal, although those with large deletions are more likely to have developmental delays. TWIST1 is the only gene known to be associated with SCS. TWIST1 mutations are identified in about 80% of affected individuals using a combination of deletion/duplication analysis and sequence analysis. Sequence analysis of exon 1 of the TWIST1 gene detects all intragenic TWIST1 mutations identified to date. Exon 1 is the only translated exon in the gene. Because clinical findings of Muenke syndrome and Saethre-Chotzen syndrome overlap, testing for the FGFR3 p.Pro250Arg mutation should be considered if no TWIST1 mutation is identified in an individual with a presumed diagnosis of Saethre-Chotzen syndrome. Furthermore, a family with phenotypic features of Saethre-Chotzen syndrome and normal TWIST1 sequence analysis had the FGFR2 mutation p.Gln289Pro has been reported. Therefore, FGFR2 sequence analysis is also recommended if no TWIST1 mutation is identified. VOLVER/RETURN Sndrome nefrtico congnito GEN: NPHS1, NPHS2 LOCALIZACIN CROMOSMICA: 9q, 1q Rev 36 05/05/2009

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El sndrome nefrtico congnito es una enfermedad heterognea caracterizada por una fuerte proteinuria y fallo renal. La mayora de las mutaciones implicadas en esta patologa se recogen en los genes NPHS1 y NPHS2. HEREDITARY NEPHROTIC SYNDROME GENE: NPHS1, NPHS2 CHROMOSOMAL LOCATION: 9q, 1q Hereditary nephrotic syndrome is a heterogeneous disease, characterized by heavy proteinuria and renal failure. Mutations of the genes encoding for NPHS1 and NPHS2 lead to early onset of heavy proteinuria and rapid progression to end-stage renal disease. NPHS2 is a stomatin protein family member with a predicted hairpin-like structure localizing to the insertion site of the slit diaphragm of podocytes, the visceral glomerular epithelial cells of the kidney. Genetaq offers codificant DNA sequencing of both genes. VOLVER/RETURN SNDROME VELOCARDIOFACIAL GEN: TBX1 LOCALIZACIN CROMSOMICA: 20q11.21 HERENCIA: Autosmica dominante

Los individuos con el sndrome Velocardiofacial (deleccin 22q11.2) presentan las siguientes caractersticas: problema cardaco congnito (74 % de los individuos), en particular malformaciones conotruncales (tetraloga de Fallot, truncus arterioso); anormalidades palatales (69%), en particular incompetencia velofarngea (VPI) y paladar hendido; rasgos faciales caractersticos y dificultades de aprendizaje (70-90 %). Se hereda de una manera autosmica dominante. Aproximadamente el 93 % de los individuos afectos presentan una deleccin de novo frente a un 7 % que ha heredado la deleccin 22q11.2 de un parental. Es posible realizar un diagnstico prenatal cuando se sospecha, por la exploracin ecogrfica (problema cardaco congnito y/o paladar hendido), de la posibilidad de que el feto presente dicha afeccin. SYNDROME VELOCARDIOFACIAL GENE: TBX1 CHROMOSOMAL LOCATION: 20q11.21 MODE OF INHERITANCE: autosomal dominant Individuals with the 22q11.2 deletion syndrome (del 22q11.2) have a range of findings, including congenital heart disease (74% of individuals), particularly conotruncal malformations (tetralogy of Fallot, truncus arteriosus...); palatal abnormalities (69%), particularly velopharyngeal incompetence (VPI) and cleft palate; characteristic facial features (present in the majority of Caucasian individuals); and learning difficulties (70-90%). The 22q11.2 deletion syndrome is inherited in an autosomal dominant manner. About 93% of probands have a de novo deletion of 22q11.2 and 7% have inherited the 22q11.2 deletion from a parent. Prenatal testing is available for fetuses determined to be at 50% risk by family history and for fetuses not known by family history to be at increased risk for del 22q11.2 who have findings of congenital heart disease and/or cleft palate detected by ultrasound examination. VOLVER/RETURN Smith Lemli Optiz, sndrome GEN: DHCR7 LOCALIZACIN CROMOSMICA: 11q12-q13 FRECUENCIA PORTADORES: 1:100
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HERENCIA: autosmica recesiva El sndrome de SLOS se caracteriza por un fallo en el crecimiento, microcefalia, ptosis, hipospadia, caractersticas dismrficas, sindactilia, niveles bajos de colesterol total y altos de 7-dehidrocolesterol. Las mutaciones ms frecuentes son IVS8-1G>C, T93M, V326L, W151X, R404C, y R352W detectando entorno al 65% de los portadores. SMITH-LEMLI-OPITZ SYNDROME (SLOS) GENE: DHCR7 (7-dehydrocholesterol reductase) CHROMOSOMAL LOCATION: 11q12-q13 CARRIER FREQUENCY: 1 in 100 individuals MODE OF INHERITANCE: autosomal recessive Smith-Lemli-Opitz is characterized by failure to thrive, microcephaly, developmental delay, ptosis, hypospadias, dysmorphic features, syndactyly, low total cholesterol and elevated 7-dehydrocholesterol. Common mutation analysis includes IVS8-1G>C, T93M, V326L, W151X, R404C, and R352W, and detects approximately 65% of carriers. It may be followed by sequence analysis of 7 exons of the SLO gene, which detects up to 90% of all known mutations. Prenatal diagnosis is available when the DHCR7 mutations have been identified in the family. VOLVER/RETURN Sordera hereditaria GEN: GJB2 y ADNmitocondrial LOCALIZACIN CROMOSMICA: 13q12 HERENCIA: autosmica recesiva GEN:GJB6 LOCALIZACIN CROMOSMICA: 13q12.1 GEN:OTOF LOCALIZACIN CROMOSMICA: 2p23-p22 La sordera heredada explica al menos el 50% de todos los casos de sordera y es sobretodo autosmica recesiva y no sintomtica. Las mutaciones del gen conexina-26 (GJB2) explican aproximadamente el 50-80% de los casos no sintomticos recesivos y el 37% de los casos de sordera espordica. Nuestro laboratorio ofrece la posibilidad de analizar la mutacin 35delG (que explica mas del 90% de mutaciones en el gen conexina-26 en individuos de descendencia europea) as como un screening de las mutaciones ms frecuentes en los distintos grupos tnicos: W24X, M34T, V37I, E47X, W77R y E147K en el gen GJB2 junto con los cambios A1555G, C1494T y T1095C en el ADN mitocondrial.Varios estudios estiman que 3-10% de los casos de sordera no sintomticos se deben a la mutacin del gen mitocondrial A1555G. La mutacin del gen mitocondrial se asocia a fototoxicidad a aminoglicsidos. En caso de resultado negativo para este primer algoritmo diagnstico se recomienda un segundo estudio incluyendo las mutaciones N206S e IVS1+1 G>A en el gen GJB2, Q829X en el gen OTOF y del(D13S1854) y del(D13S1854) en el gen GJB6. Tambin est disponible la secuenciacin completa del gen GJB2.

DEAFNESS PANEL: (Connexin 26 and Mitochondrial A1555G Gene Mutation) GENE: GJB2 (CONNEXIN 26) and mtDNA. CHROMOSOMAL LOCATION: 13q12 MODE OF INHERITANCE: autosomal recessive GENE:GJB6 CHROMOSOMAL LOCATION: 13q12.1 GENE:OTOF CHROMOSOMAL LOCATION:2p23-p22
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Inherited deafness accounts for at least 50% of all hearing loss and is mostly autosomal-recessive and non-syndromic. Mutations in the connexin-26 gene account for approximately 50-80% of non-syndromic recessive deafness and 37% of sporadic deafness. Our laboratory offers testing for the 35delG mutation (which accounts for greater than 90% of mutations in the connexin-26 gene in individuals of European descent) and a screening of W24X, M34T, V37I, E47X, W77R y E147K mutations in GJB2 gene and A1555G, C1494T and T1095C in mtDNA.en el ADN. Several studies estimate that 3-10% of non-syndromic hearing loss cases are due to the mitochondrial A1555G gene mutation. The mitochondrial gene mutation is associated with aminoglycoside ototoxicity. Other study for deafness include N206S and IVS1+1 G>A in GJB2 gene, Q829X in OTOF gene and del(D13S1854) / del(D13S1854) in GJB6 gene. VOLVER/RETURN Sotos, sndrome GEN: NSD1 LOCALIZACIN CROMOSMICA: 5q35 HERENCIA: autosmica dominante El sndrome de Sotos se caracteriza por unos rasgos faciales tpicos, discapacidad intelectual y sobrecrecimiento de la circunferencia de la cabeza y un aumento de altura. Se le asocia escoliosis, apopleja, estrabismo, prdida de audicin, defectos cardacos y renales y problemas de comportamiento. En el 80-90% de los casos se ha detectado mutaciones o deleciones en el gen NSD1, ms del 95% de los individuos afectos muestran mutaciones de novo. SOTOS SYNDROME GENE: NSD1 CHROMOSOMAL LOCATION: 5q35 MODE OF INHERITANCE: autosomal dominant Sotos syndrome is characterized by a typical facial appearance, intellectual impairment, and overgrowth (increased height and head circumference). It is associated with neonatal jaundice, scoliosis, seizures, strabismus, conductive hearing loss, congenital cardiac anomalies, renal anomalies, and behavioral problems. The risk of sacrococcygeal teratoma and neuroblastoma is slightly increased. NSD1 is the only gene known to be associated with Sotos syndrome. About 80-90% of individuals with Sotos syndrome have a demonstrable mutation or deletion of NSD1. Among non-Japanese individuals with Sotos syndrome, sequence analysis or mutation scanning detects intragenic mutations in approximately 75-80%. Among those with classic Sotos syndrome, about 10% of individuals of non-Japanese heritage have an NSD1 microdeletion which can be detected by MLPA or FISH. More than 95% of individuals have a de novo mutation. If neither parent of a proband has Sotos syndrome, the risk to sibs of the proband is very low (<1%). The risk to offspring of affected individuals is 50%. Prenatal testing is potentially available for those with identified mutations. VOLVER/RETURN SRY GEN: SRY LOCALIZACIN CROMOSMICA: Yp El desarrollo testicular en cariotipos 46XX se caracteriza por la presencia de genitales masculinos en un individuo 46XX. La estructura Mulleriana es ausente y el 80% de los casos presenta en la pubertad pequeos testculos, ginecomastia y azoospermia. Esta enfermedad se debe a la presencia del gen SRY que codifica la determinacin del sexo en el cromosoma Y.

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Y-CHROMOSOME DETECTION (SRY) GENE: SRY (sex-determining region of Y) CHROMOSOMAL LOCATION: Yp Direct DNA analysis of the SRY gene is available for the rapid determination of the genetic factor responsible for maleness. Potential indications include: rapid gender determination of a fetus when the mother is a carrier of an Xlinked recessive condition, determining risk for gonadal dysgenesis, or clarifying a discrepancy between karyotype and ultrasound imaging results. VOLVER/RETURN HIPEREKPLEXIA. STARTLE, SINDROME DE GEN: GLRA1 LOCALIZACION CROMOSOMICA: 5q32 HERENCIA: autosomica dominante o recesiva. La hiperekplexia hereditaria (HPX) se caracteriza por una rigidez muscular generalizada inmediatamente despus del nacimiento que se normaliza durante los primeros aos de vida; un reflejo de startle o de sobresalto (parpadeo y espasmo flexor del tronco) exagerado ante estmulos inesperados, particularmente auditivos; y un periodo corto de rigidez generalizada, despus de la respuesta de startle, durante el cual son imposibles los movimientos voluntarios. Se han asociado cinco genes con la HPX. El 80% de los casos de HPX son debidos a mutaciones en el gen GLRA1, el cual codifica la subunidad 1 del receptor de la glicina. Los otros genes causantes son: SCL6A5, GLRB, GPHN y ARHGEF9. La HPX se hereda de manera autosmica dominante o recesiva. La mayora de los individuos diagnosticados con HPX autosmica dominante tiene un padre afecto; las mutaciones de novo son raras. Los padres de un individuo con HPX autosmica recesiva son heterocigotos obligados y, por tanto, portan un alelo mutado. HYPEREKPLEXIA. STARTLE DISEASE GENE: GLRA1 CHROMOSOMAL LOCATION: 5q32 MODE OF INHERITANCE: autosomal dominant or autosomal recessive Hereditary hyperekplexia (HPX) is characterized by generalized stiffness immediately after birth that normalizes during the first years of life; excessive startle reflex to unexpected (particularly auditory) stimuli; and a short period of generalized stiffness following the startle response during which voluntary movements are impossible. Five genes are known to be associated with HPX. GLRA1, encoding glycine receptor subunit 1, is the major genetic cause of HPX (80%). The other causative genes are: SLC6A5, GLRB, GPHN and ARHGEF9. HPX is inherited in an autosomal dominant or autosomal recessive manner. Most individuals diagnosed with autosomal dominant HPX have an affected parent; de novo mutations are rare. The parents of a child with autosomal recessive HPX are obligate heterozygotes and therefore carry one mutant allele. VOLVER/RETURN Talasemia -TALASEMIA GEN: HBA1 y HBA2 LOCALIZACIN CROMOSMICA: 16pter-p13.3 HERENCIA: autosmica recesiva La talasemia tiene dos formas clnicas: el sndrome Hb Bart, caracterizado por edema generalizado, efusiones pleurales y pericardiales, ms severidad y edad de comienzo fetal, y la enfermedad de la hemoglobina H que se caracteriza por anemia microctica hipocrmica hemoltica y hepatoesplenomegalia. La condicin de portador son
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talasemia caracterizada por microcitosis e hipocromia se produce por la ausencia de dos alelos del gen globulina y la +talasemia por un fenotipo hematolgico silente producida por la ausencia de un alelo. La hemoglobina H est causada por la ausencia de 3 de los 4 alelos del gen. -TALASEMIA GEN: hemoglobin beta LOCALIZACIN CROMOSMICA: 11p15.1 HERENCIA: autosmica recesiva La -talasemia se caracteriza por una reducida sntesis de hemoglobina de cadena beta que resulta en anemia microctica hipocrmica, sangre perifrica anormal con clulas rojas nucleadas y reduccin de la cantidad de hemoglobina A. La edad de aparicin se sita en los 2 aos con severa anemia y hepatoesplenomegalia. La secuenciacin de la regin codificante del gen HBB detecta mutaciones en el 99% de los individuos con talasemia.Deleciones de extensin variable del gen o del cluster HBB que dan como resultado talasemia- o talasemias- complejas denominadas talasemia- y talasemia- son causa muy poco comn de talasemia- y su estudio est disponible clnicamente y se realiza mediante MLPA.

-THALASSEMIA GENE: HBA1 and HBA2 CHROMOSOMAL LOCATION: 16pter-p13.3 MODE OF INHERITANCE: autosomal recessive Alpha-thalassemia (-thalassemia) has two clinically significant forms: Hb Bart hydrops fetalis (Hb Bart) syndrome and hemoglobin H (HbH) disease. Hb Bart syndrome is the most severe form and is characterized by fetal onset of generalized edema, pleural and pericardial effusions, and severe hypochromic anemia. Death usually occurs in the neonatal period. HbH disease is characterized by microcytic hypochromic hemolytic anemia, hepatosplenomegaly, mild jaundice, and sometimes thalassemia-like bone changes. The two carrier states are -thalassemia (-thalassemia trait) characterized by microcytosis (low MCV), hypochromia (low MCH), and normal percentages of HbA2 and F and thalassemia (-thalassemia silent carrier) characterized by either a silent hematologic phenotype or a moderate thalassemia-like hematologic picture. HB Bart results from deletion or dysfunction of all four -globin alleles. HbH results from deletion or dysfunction of three of four -globin alleles. -thalassemia results from deletion or dysfunction of two -globin alleles, and -thalassemia results from deletion or dysfunction of one -globin allele. HBA1, the gene encoding 1-globin, and HBA2, the gene encoding 2-globin, are the two genes associated with -thalassemia. Molecular genetic testing of HBA1 and HBA2 detects about 90% of deletions and about 10% of point mutations in these genes. -THALASSEMIA GENE: hemoglobin beta (HBB) CHROMOSOMAL LOCATION: 11p15.1 MODE OF INHERITANCE: autosomal recessive Beta-thalassemia is characterized by reduced synthesis of the hemoglobin beta chain that results in microcytic hypochromic anemia, an abnormal peripheral blood smear with nucleated red blood cells, and reduced amounts of hemoglobin A (HbA) on hemoglobin analysis. Patients with thalassemia major usually present within the first two years of life with severe anemia and hepatosplenomegaly. Sequencing of the HBB coding region detects 99% of individuals with thalassemia. Deletions of variable extent of the gene or of the HBB cluster that result in -thalassemia or in the complex -thalassemias called -thalassemia and -thalassemia are rare causes of -thalassemia and testing that detects deletions is also available clinically by MLPA.

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Telangiectasia hemorrgica hereditaria GEN: ENG (HHT 1) y ACVRL1/ALK1 (HHT2) LOCALIZACIN CROMOSMICA: 9q34.1 y 12q11-q14 INCIDENCIA: 1:10,000 en norte America HERENCIA: autosmica dominante

VOLVER/RETURN

La telangiectasia hemorrgica hereditaria se caracteriza por la presencia de mltiples malformaciones arteriovenosas que resultan en la unin de venas y arterias. En algunos casos aparecen de pequeo tamao en la piel y la membrana mucosa produciendo traumas y sangrados. La edad de aparicin se sita en los 12 aos de edad y en el 60-80% de los individuos afectados se han detectado mutaciones en los genes ENG y ACVRL1. HEREDITARY HEMORRHAGIC TELANGIECTASIA TYPE1 and TYPE2 GENE: ENG (HHT 1) and ACVRL1/ALK1 (HHT2) CHROMOSOMAL LOCATION: 9q34.1 and 12q11-q14 INCIDENCE: 1:10,000 in North America MODE OF INHERITANCE: autosomal dominant Hereditary hemorrhagic telangiectasia (HHT) is characterized by the presence of multiple arteriovenous malformations (AVMs) that lack intervening capillaries and result in direct connections between arteries and veins. Small AVMs (or telangiectases) close to the surface of skin and to mucous membranes often rupture and bleed after slight trauma. The most common clinical manifestation is spontaneous and recurrent nosebleeding beginning at approximately 12 years of age. Sequence analysis of these genes detects mutations in 60-80% of individuals with HHT. VOLVER/RETURN Tirosinemia tipo 1 GEN: FAH LOCALIZACIN CROMOSMICA: 15q23-q25 INCIDENCIA: 1/ 100,000 a 120,000 HERENCIA: autosmica recesiva La tirosinemia tipo 1 presenta implicaciones severas del hgado y disfuncin tubulorenal asociadas a un problema de crecimiento. Los nios sin tratamiento mueren antes de los 10 aos con fallo heptico, crisis neurolgicas o carcinoma hepatocelular. La combinacin de nitisinona y baja ingesta en las comidas de alimentos que contengan tirosina aumenta la supervivencia en el 90% de los casos. En el 60% de los casos se han detectado mutacione en el gen FAH. TYROSINEMIA TYPE 1 GENE: FAH CHROMOSOMAL LOCATION: 15q23-q25 INCIDENCE: 1/ 100,000 to 120,000 MODE OF INHERITANCE: autosomal recessive Untreated tyrosinemia type I usually presents either in young infants with severe liver involvement or later in the first year with liver dysfunction and renal tubular dysfunction associated with growth failure and rickets. Untreated children may have repeated, often unrecognized, neurologic crises lasting one to seven days that can include change in mental status, abdominal pain, peripheral neuropathy, and/or respiratory failure, requiring mechanical ventilation. Death in the untreated child usually occurs before the age of ten years, typically from liver failure, neurologic crisis, or hepatocellular carcinoma. Combined treatment with nitisinone and a low-tyrosine diet has resulted in a greater than 90% survival rate, normal growth, improved liver function, prevention of cirrhosis, correction of renal tubular acidosis, and improvement in secondary rickets. Tyrosinemia type I results from deficiency of the enzyme fumarylacetoacetate hydrolase (FAH) Targeted mutation analysis for the four common FAH mutations can detect in more than 60% of affected individuals. Rev 36 05/05/2009

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VOLVER/RETURN Thomsen, miotona GEN: CLCN1 LOCALIZACIN CROMOSMICA: 7q35 INCIDENCIA: 1:23,000 HERENCIA: autosmica dominante La miotona congnita se caracteriza por rigidez muscular presente en la juventud estando implicados todos los msculos estriados como los faciales, de la lengua Los msculos son normalmente hipertrofiados y los hombres presentan mayor severidad que las mujeres. La tasa de deteccin de mutacin est en el 95% al secuenciar el gen CLCN1. THOMSEN DISEASE (AUTOSOMAL DOMINANT MYOTONIA CONGENITA AUTOSOMICA) GENE: CLCN1 CHROMOSOMAL LOCATION: 7q35 INCIDENCE: 1:23,000 MODE OF INHERITANCE: autosomal dominant Myotonia congenita is characterized by muscle stiffness present from childhood; all striated muscle groups including the extrinsic eye muscles, the facial muscles, and the tongue may be involved. Stiffness is relieved by repeated contractions of the muscle (the "warm-up" phenomenon). Muscles are usually hypertrophic and men are more severely affected than women. Onset of symptoms is usually in infancy or early childhood. Our laboratory offers sequencing of the entire coding region for CLCN1, which yields a detection rate >95%. BECKER, ENFERMEDAD DE (MIOTONA CONGENITA AUTOSMICA RECESIVA) GEN: CLCN1 LOCALIZACIN CROMOSMICA: 7q35 INCIDENCIA: 1:50,000 HERENCIA: autosmica recesiva La miotona congnita se caracteriza por rigidez muscular presente en la juventud estando implicados todos los msculos estriados como los faciales, de la lengua Los msculos estn normalmente hipertrofiados y los hombres presentan mayor severidad que las mujeres. La tasa de deteccin de mutacin est en el 95% al secuenciar el gen CLCN1. Esta forma est asociada a una mayor rigidez muscular que en el caso de la forma autosmica. Los individuos con la forma recesiva quiz muestren una progresin menor de la debilidad distal. La tasa de deteccin de mutacin est en el 95% al secuenciar el gen CLCN1. BECKER DISEASE (AUTOSOMAL RECESSIVE MYOTONIA CONGENITA) GENE: CLCN1 CHROMOSOMAL LOCATION: 7q35 INCIDENCE: 1:50,000 MODE OF INHERITANCE: autosomal recessive Myotonia congenita is characterized by muscle stiffness present from childhood; all striated muscle groups including the extrinsic eye muscles, the facial muscles, and the tongue may be involved. Stiffness is relieved by repeated contractions of the muscle (the "warm-up" phenomenon). Muscles are usually hypertrophic and men are more severely affected than women. This form is often associated with a more severe stiffness of muscles than that seen in the dominant form. Individuals with the autosomal recessive form may have progressive minor distal weakness and attacks of transient weakness brought on by movement after rest. The average age of onset is slightly older. Our laboratory offers sequencing of the entire coding region for CLCN1, which yields a detection rate >95%.

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VOLVER/RETURN TREACHER COLLINS, SINDROME GEN: TCOF1 LOCALIZACION CROMOSOMICA: 5q32-q33.1 HERENCIA: Autosmica dominante El sndrome de Treacher Collins (TCS) es un raro desorden congnito del desarrollo craneofacial. Se caracteriza por hipoplasia de los huesos zigomticos y la mandbula, anormalidades del odo externo, coloboma del parpado inferior y crecimiento de pelo en la zona preauricular. Alrededor del 40-50% de los individuos sufren la prdida de audicin conductiva, atribuida normalmente a la malformacin (incluyendo anquilosis, hipoplasia o la ausencia) de los huesos del odo e hipoplasia de las cavidades del odo medio. TCOF1 que codifica para una fosfoprotena nucleolar conocida como treacle es el nico gen asociado con el TCS. La secuenciacin directa de la regin codificante y la regin intrnica flanqueante del gen TCOF1 permite detectar mutaciones en aproximadamente el 90-95 % de los individuos afectos. Se hereda de una manera autosmica dominante. Alrededor del 60% de los individuos con TCS presentan este desorden por una mutacin de novo. TREACHER COLLINS, SYNDROME GENE: TCOF1 CHROMOSOMAL LOCATION: 5q32-q33.1 MODE OF INHERITANCE: autosomal dominant Treacher Collins syndrome (TCS) is characterized by hypoplasia of the zygomatic bones and mandible, external ear abnormalities, coloboma of the lower eyelid, and preauricular hair displacement. About 40%-50% of individuals have conductive hearing loss attributed most commonly to malformation (including ankylosis, hypoplasia, or absence) of the ossicles and hypoplasia of the middle ear cavities. TCOF1 is the only gene currently known to be associated with TCS. Direct sequencing of the coding and flanking intronic regions of TCOF1 detects mutations in about 90%-95% of individuals. TCS is inherited in an autosomal dominant manner. About 60% of probands with TCS have the disorder as the result of a de novo gene mutation. VOLVER/RETURN

UMOD GEN: UMOD LOCALIZACIN CROMOSMICA: 16p12.3 INCIDENCIA: rara HERENCIA: Autosomica dominante La clnica incluye excrecin fraccional y reducida de cido rico resultando en hiperuricemia y gota, enfermedad renal intersticial con aparicin entre los 15 y 40 aos de edad. UMOD-Related Kidney Disease GENE: UMOD CHROMOSOMAL LOCATION: 16p12.3 INCIDENCE: UMOD-related kidney disease is rare, being responsible for fewer than 1% of cases of end-stage kidney disease MODE OF INHERITANCE: autosomal dominant Clinical findings typically include reduced fractional excretion of uric acid resulting in hyperuricemia and gout (or precocious gout); interstitial kidney disease usually appearing between ages 15 and 40 years and leading to end-stage renal disease (ESRD) ten to 20 years later; and normal or small-sized kidneys VOLVER/RETURN Rev 36 05/05/2009

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UA-RTULA, SNDROME GEN: LMX1B LOCALIZACIN CROMOSOMICA: 9q34.1 HERENCIA: autosmica dominante El sndrome ua-rotula (NPS) implica cambios en las uas, rodillas y codos, y la presencia de cuernos ilacos. Las uas pueden ser hipoplsticas, distrficas o estar ausentes; surcadas longitudinal u horizontalmente; decoloradas y separadas en dos mitades por una hendidura longitudinal o canto de piel. La rotula puede ser pequea, formada irregularmente o encontrarse ausente. Las anormalidades del codo incluyen la limitacin de extensin, pronacin, y supinacin; cubitus valgus; y pterigia antecubital. La implicacin renal, se pone de manifiesto con proteinuria con o sin hematuria y ocurre en el 30-50 % de los individuos afectados; la insuficiencia renal ocurre en aproximadamente el 5 % de individuos afectados. LMX1B es el nico gene asociado con el sndrome ua-rotula. Analizando la secuencia del exn 2 al 6 del gen LMX1B se detectan cerca del 85 % de las mutaciones. El otro 15% de las mutaciones presumiblemente se encuentran en la parte intrnica o implican una deleccin total o parcial del gen. Se hereda de una manera autosmica dominante. El 88% de los individuos diagnosticados con NPS tienen un pariente afecto. Sin embargo un 20% presenta una mutacin de novo.

NAIL-PATELLA, SNDROME GENE: LMX1B CHROMOSOMAL LOCATION: 9q34.1 MODE OF INHERITANCE: autosomal dominant Nail-patella syndrome (NPS) involves a classic clinical tetrad of changes in the nails, knees, and elbows, and the presence of iliac horns. Nails may be absent, hypoplastic, or dystrophic; ridged longitudinally or horizontally; pitted; discolored and separated into two halves by a longitudinal cleft or ridge of skin. The patellae may be small, irregularly shaped or absent. Elbow abnormalities may include limitation of extension, pronation, and supination; cubitus valgus; and antecubital pterygia. Renal involvement, first manifest as proteinuria with or without hematuria, occurs in 30-50% of affected individuals; renal failure occurs in about 5% of affected individuals. LMX1B is the only gene known to be associated with NPS. Sequence analysis of exons 2 through 6 of the LMX1B gene detects 85% of mutations. The other 15% of mutations presumably lie deep in introns or involve deletion of all or part of the geneNail-patella syndrome is inherited in an autosomal dominant manner. Eighty-eight percent of individuals diagnosed with NPS have an affected parent. Twelve percent of affected individuals have a de novo mutation. VOLVER/RETURN VAN DER WOUDE, Sndrome de GEN: LOCALIZACIN CROMOSMICA: 1q32 HERENCIA: autosmica dominante El sndrome de Van der Woude es una condicin que afecta al desarrollo de la cara (labio y paladar hendidos, depresiones en el centro del labio inferior con glndulas salivares y mucosas) lo que deriva en dificultades de aprendizaje, del desarrollo del habla y otros problemas cognitivos. Est causado por mutaciones en el gen IRF6, el cual codifica un factor de transcripcin. Una escasez de la protena IRF6 afecta al desarrollo y la maduracin de los tejidos de la cara y la cabeza, causando los signos y los sntomas de Sndrome de Van der Woude. El anlisis de secuencia de la regin codificante del gen IRF6 (exones 1-9) detecta las mutaciones en
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aproximadamente un 70% de los individuos con el Sndrome de Van de Woude. VAN DER WOUDE, SYNDROME GENE: IRF6 CHROMOSOMAL LOCALITATION: 1q32 MODE OF INHERITANCE: autosomal dominant Van der Woude syndrome is a condition that affects the development of the face (cleft lip, cleft palate, depressions near the center of the lower lip with salivary and mucous glands). People with van der Woude syndrome who have cleft lip and/or palate, like other individuals with these facial conditions, have an increased risk of delayed language development, learning disabilities, or other mild cognitive problems. Mutations in the IRF6 gene cause van der Woude syndrome. The IRF6 gene codifies a transcription factor. A shortage of the IRF6 protein affects the development and maturation of tissues in the face and in the head, resulting in the signs and symptoms of van der Woude syndrome.This condition is inherited in an autosomal dominant manner. Sequence analysis of the IRF6 coding region (exons 1-9) detects mutations in approximately 70% of individuals with the Van der Woude syndrome. VOLVER/RETURN VITREORETINOPATA EXUDATIVA FAMILIAR GEN: FZD4 LOCALIZACIN CROMOSMICA: 11q14.2 (FZD4) HERENCIA: autosomica dominante La vitreoretinopata exudativa familiar autosmica dominante (adFEVR) se caracteriza por el falloen la vascularizacin retiniana perifrica. Los problemas visuales y el fenotipo variable asociado a adFEVR son el resultado de complicaciones secundarias causadas por la isquemia retiniana. Dos genes se han asociado con la adFEVR: El gen FZD4, que codifica la protena frizzled-4, y el gen LRP5, que codifica para una protena relacionada con el receptor de las lipoprotenas de baja densidad. Cada uno de estos genes es responsable de aproximadamente el 20 % de los casos de adFEVR. Hasta un 90% de los individuos con adFEVR pueden ser asintomticos debido a la baja penetrencia. FAMILIAL EXUDATIVE VITREORETINOPATHY GENE: FZD4 CHROMOSOMAL LOCALITATION: 11q14.2 (FZD4) MODE OF INHERITANCE: autosomal dominant Autosomal dominant familial exudative vitreoretinopathy (adFEVR) is characterized by failure of peripheral retinal vascularization. The visual problems and variable phenotype associated with adFEVR result from secondary complications caused by retinal ischemia. Two genes are known to be associated with adFEVR: FZD4, which encodes the protein frizzled-4, and LRP5, which encodes low-density lipoprotein receptor-related protein 5. Each of these genes is responsible for about 20% of adFEVR cases. adFEVR is inherited in an autosomal dominant manner, but up to 90% of individuals with adFEVR can be asymptomatic because of reduced penetrance. VOLVER/RETURN
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Von Hippel Lindau, sndrome GEN: VHL LOCALIZACIN CROMOSMICA: 3p25-26 INCIDENCIA: 1:36,000 HERENCIA: autosmica dominante El sndrome de von Hippel Lindau se caracteriza por hemangioblastomas en el cerebro, mdula sea y retina, quistes renales, feocromocitoma y tumores en el saco endolinftico. Se estima que el 97% de los casos presentan mutaciones o deleciones en el gen VHL.

VON-HIPPEL-LINDAU GENE: VHL CHROMOSOMAL LOCATION: 3p25-26 INCIDENCE: 1 in 36,000 MODE OF INHERITANCE: autosomal dominant Von Hippel-Lindau syndrome (VHL syndrome) is characterized by hemangioblastomas of the brain, spinal cord, and retina; renal cysts and clear cell renal cell carcinoma; pheochromocytoma; and endolymphatic sac tumors. Early recognition of VHL syndrome may allow for timely intervention and improved outcome. Our laboratory offers DNA sequencing of the VHL gene for the identification of mutations in this gene as well as deletion analysis for the detection of full gene deletions. An estimated 97% of cases can be detected using a combination of these methods. Prenatal diagnosis is available when the VHL mutation has been identified in a family. VOLVER/RETURN Waardenburg, sndrome GEN: PAX3 - WS1 y WS3, MITF - WS2A LOCALIZACIN CROMOSMICA: 2q35 (WS1 y WS3) y 3p14 (WS2A) INCIDENCIA: 1:20,000 a 1:40,000 HERENCIA: autosmica dominante El sndrome de Waardenburg se caracteriza por la prdida de audicin y cambios en la pigmentacin del iris, pelo y piel. Las mutaciones en el gen PAX3 son responsables del WS3 con defectos en los miembros y WS1 con desplazamiento lateral de la cantal interna. El gen MITF presenta mutaciones en el 10-15% de los casos de WS2 con ndice W dentro de la normalidad. WAARDENBURG SYNDROME (TYPE 1, 2A, and 3) GENE: PAX3 (paired box gene 3) - WS1 and WS3, MITF (micropthalmia-associated transcription factor) - WS2A CHROMOSOMAL LOCATION: 2q35 (WS1 and WS3) and 3p14 (WS2A) INCIDENCE: 1:20,000 to 1:40,000 MODE OF INHERITANCE: autosomal dominant Waardenburg syndrome (WS) is typically characterized by hearing loss and pigmentary changes of the iris, hair, and skin. The clinical phenotypes of WS type 1 and WS type 2 often overlap. The W-index can be calculated to delineate the more likely diagnosis. Our laboratory offers sequencing of both the PAX3 and MITF genes. Mutations in the PAX3 gene have been identified in greater than 90% of patients with the clinical diagnosis of WS1 (with lateral displacement of the inner canthi). Mutation in PAX3 are also responsible for WS3 (with limb defects). Mutations in the MITF gene have been identified in 10-15% of patients with the clinical diagnosis of WS2 (W-index is within normal limits). Prenatal diagnosis is
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available when the specific WS mutation has been identified in the family. VOLVER/RETURN Walker-Warburg, Sndrome de GEN: POMT1 LOCALIZACIN CROMOSMICA:9q34.1 INCIDENCIA: 7:1.000.000 HERENCIA:Autosmica recesiva Enfermedad que forma parte de la lisencefalia Tipo II y se cataloga dentro de las distrofias musculares congnitas y sus caractersticas son: hidrocefalia congnita, alteraciones de la cmara anterior del ojo (cataratas congnitas bilaterales), adems de alteraciones retinarias y atrofia del nervio ptico. Se puede presentar crisis convulsivas, hipotona al nacimiento de predominio proximal, cambios distrficos en la biopsia muscular con fibrosis, endo y perimisial en ausencia de necrosis, cambios electromiogrficos, con potenciales de bajo voltaje y elevacin de las enzimas musculares. Puede haber tambin malformaciones de Dandy-Walker con hipoplasia de vrmis y prdida de la morfologa del mesencfalo. WALKER-WARBURG SYNDROME GENE: POMT1 CHROMOSOMAL LOCATION: 9q34.1 INCIDENCE: 7:1.000.000 MODE OF INHERITANCE: Autosomal recessive Disease included within the lissencephaly Type II and catalogs within congenital muscular dystrophies and its features are: congenital hydrocephalus, alterations in the anterior chamber of the eye (bilateral congenital cataracts), in addition to alterations retinarias and atrophy of the optic nerve. It can occur seizures, hypotonia birth predominantly proximal, dystrophic changes in the muscle biopsy fibrosis, endo perimisial and in the absence of necrosis, changes Electromyographic with potential low voltage and elevation of muscle enzymes. There may also Dandy-Walker malformation with hypoplasia of vermis and loss of the morphology of the mesencephalon VOLVER/RETURN Williams, Sndrome de GEN: ELN, LIMK1 y el locus D7S613 LOCALIZACIN CROMOSMICA: 7q11 INCIDENCIA: 1:20.000 HERENCIA: Autosmica dominante El sndrome de Williams se caracteriza por una enfermedad cardiovascular que engloba arteriopata elstica, estenosis pulmonar perifrica, estenosis artica supravalvular e hipertensin, fenotipo facial caracterstico, defectos en el tejido conectivo y retraso mental. En el 99% de los casos se produce la delecin del gen implicado en WS. WILLIAMS SYNDROME GENE: Williams-Beuren syndrome critical region (WBSCR) including ELN, LIMK1, and the D7S613 locus CHROMOSOMAL LOCATION: 7q11 INCIDENCE: 1 in 20.000 MODE OF INHERITANCE: Autosomal dominant Williams syndrome (WS) is characterized by cardiovascular disease (elastin arteriopathy, peripheral pulmonary stenosis, supravalvular aortic stenosis, hypertension), distinctive facies, connective tissue abnormalities, mental retardation (usually mild), a specific cognitive profile, unique personality characteristics, growth abnormalities, and
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endocrine abnormalities (hypercalcemia, hypercalciuria, hypothyroidism, and early puberty). Feeding difficulties often lead to failure to thrive in infancy. Hypotonia and hyperextensible joints can result in delayed attainment of motor milestones. Clinical diagnostic criteria are available for Williams syndrome; however, the mainstay for diagnosis is detection of the contiguous gene deletion of the Williams-Beuren syndrome critical region (WBSCR) that encompasses the elastin (ELN) gene. Over 99% of individuals with the clinical diagnosis of WS have this contiguous gene deletion, which can be detected using targeted mutation analysis. VOLVER/RETURN Wilson, enfermedad GEN: WND / ATP7B LOCALIZACIN CROMOSMICA: 13q14.3 CARRIER FREQUENCY: 1:90 HERENCIA: autosmica recesiva La enfermedad de Wilson es un desorden metablico del cobre que puede presentar problemas hepticos, neurolgicos y psiquitricos en los individuos de 3 a 50 aos. Los casos familiares presentan mutaciones en los exones 2, 14 y 18 del gen ATP7B. Nuestro laboratorio ofrece anlisis de secuenciacin del gen completo o slo de los exones donde se encuentran las mutaciones normalmente, aunque estas varan segn la raza del individuo a estudiar.

WILSON DISEASE GENE: WND / ATP7B CHROMOSOMAL LOCATION: 13q14.3 CARRIER FREQUENCY: 1 in 90 MODE OF INHERITANCE: autosomal recessive Wilson disease is a disorder of copper metabolism that can present with hepatic, neurologic, and/or psychiatric disturbances, in individuals ranging in age 3 to 50 years. Familial cases of Wilson disease tend to each have a unique mutation in the WND gene. Our laboratory offers sequencing analysis for the diagnosis of Wilson disease. The mutation detection rate varies depending on the regions analyzed, the ethnicity of the individual, and the specific method used. We performance sequencing in exons 2, 14, and 18. Account for approximately 60% of alleles in the Europe population. VOLVER/RETURN Wolfram, Sndrome de GEN:WFS1 LOCALIZACIN CROMOSMICA: 4p16 HERENCIA: Autosmica recesiva El sndrome de Wolfram (WS) es una enfermedad neurodegenerativa autosmica recesiva caracterizada principalmente por diabetes mellitus familiar y atrofia ptica. Los pacientes del WS presentan con frecuencia otras caractersticas clnicas tales como diabetes inspida, anormalidades renales, desrdenes psiquitricos, y una variedad de sntomas neurolgicos: sordera, ataxia, neuropata perifrica. El gen responsable del sndrome del Wolfram (WFS1) se ha identificado en el cromosoma 4p16.1. WOLFRAM SYNDROME GEN: WFS1 CHROMOSOMAL LOCATION: 4p16 MODE OF INHERITANCE: autosomal recessive This gene encodes a transmembrane protein. Mutations in this gene are associated with an autosomal recessive
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syndrome characterized by insulin-dependent diabetes mellitus and bilateral progressive optic atrophy, usually presenting in childhood or early adult life. Diverse neurologic symptoms, including a predisposition to psychiatric illness, may also be associated with this disorder. A large number and variety of mutations in this gene can be associated with this syndrome. VOLVER/RETURN X frgil, sndrome GEN: FMR-1 LOCALIZACIN CROMOSMICA: Xq27.3 INCIDENCIA: 1.6-4 cada 10,000 hombres afectados; 0.8-2.2 cada 10,000 mujeres afectadas; 1 cada 250 mujeres portadoras. HERENCIA: recesivo ligado al X con anticipacin El sndrome X Frgil se caracteriza por un moderado retraso mental que afecta a hombres y suave, en mujeres. Los hombres pueden presentar caractersticas corporales (cabeza alargada, cara larga, frente y barbilla prominente). Comportamiento anormal, a veces incluyendo autismo, es comn. Al menos en el 96% de los casos, hay una expansin repetitiva de nucletidos (CGG). En muchos casos, el tamao del alelo de uno o de los dos (si es mujer) del gen FMR-1 se puede demostrar por PCR. De todas maneras, algunos casos requieren un anlisis de Southern Blot y/o TP-PCR para determinar el tamao del alelo y el patrn de metilacin. Estos ensayos se llevarn a cabo automticamente si fuera necesario. Se recomienda el anlisis directo de DNA para la confirmacin del paciente con o sin historial familiar relacionado. Se realiza la prueba para pacientes con antecedentes familiares, como el caso de diagnstico prenatal del feto de una familia con una repeticin trinucleotdica conocida. Se realizan muchos estudios para un nio sintomtico del sndrome de X-frgil que son negativos para esta enfermedad y positivos para anormalidades cromosmicas. Por esta razn, sugerimos el anlisis cromosmico simultneo con el anlisis de DNA para X frgil. Alrededor de 1 de cada 250 mujeres son portadoras de premutados e incrementa el riesgo a desarrollar fallos prematuros en los ovarios. Los portadores hombres y mujeres tienen el riesgo de desarrollar el sndrome X frgil tremor ataxia (FXTAS) . FRAGILE X SYNDROME GENE: FMR-1 CHROMOSOMAL LOCATION: Xq27.3 INCIDENCE: 1.6-4 in 10,000 affected males; 0.8-2.2 in 10,000 affected females; 1 in 250 carrier females MODE OF INHERITANCE: X-linked recessive with anticipation Fragile X syndrome is characterized by moderate mental retardation in affected males and mild mental retardation in affected females. Males may have a characteristic appearance (large head, long face, prominent forehead and chin, protuding ears), connective tissue findings (joint laxity), and large testes (postpubertally). Behavioral abnormalities, sometimes including autism spectrum disorder, are also common. In at least 96% of cases of Fragile-X syndrome there is a trinucleotide repeat expansion (CGG). For most cases, the allele size of one or both (if female) FMR-1 genes is demonstrable by PCR. However, some cases will require a Southern blot analysis and/or TP-PCR to determine allele size and methylation pattern. This assay will be performed automatically if it is necessary. Direct DNA analysis of the FMR-1 gene is recommended for the confirmation of a diagnosis in a patient with or without a family history of the condition. Testing of individuals with a confirmed family history is also possible, as is the prenatal diagnosis of a fetus from a family with a known trinucleotide repeat expansion. Please note that many studies performed for a child who is symptomatic of Fragile-X syndrome have subsequently been found to be negative for Fragile-X and positive for a chromosome abnormality. For this reason we would suggest chromosome analysis concurrently with Fragile-X DNA analysis. About 1 in 250 females are premutation carriers and are at increased risk to develop premature ovarian failure. Male and female premutation carriers are also at risk to develop the Fragile-X Tremor Ataxia Syndrome (FXTAS). VOLVER/RETURN

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XANTOMATOSIS CEREBROTENDINOSA GEN: CYP27A1 LOCALIZACION CROMOSMICA: 2q33-qter HERENCIA: autosmica recesiva La xantomatosis cerebrotendinosa (CTX) es una enfermedad de acumulacin de lpidos caracterizada por diarrea desde la infancia, cataratas en la niez, xantomas tendinosos que aparecen en la adolescencia o en adultos jvenes, y disfuncin neurolgica progresiva en adultos (demencia, alteraciones psiquitricas, y ataques). La CTX est causada por la deficiencia del enzima mitocondrial esterol 27-hidroxilasa lo que da lugar a una acumulacin de colestanol y colesterol en virtualmente todos los tejidos. La CTX es diagnosticada en base a las caractersticas clnicas y los exmenes bioqumicos. El nico gen asociado a la CTX es el CYP27A1, que codifica para la esterol 27-hidroxilasa . El anlisis de la secuencia de este gen detecta mutaciones en el 90-100% de los individuos afectos. CEREBROTENDINOUS XANTHOMATOSIS GENE:CYP27A1 CHROMOSOMAL LOCALITATION: 2q33-qter MODE OF INHERITANCE: autosomal recessive Cerebrotendinous xanthomatosis (CTX) is a lipid storage disease characterized by infantile-onset diarrhea, childhoodonset cataract, adolescent- to young adult-onset tendon xanthomas, and adult-onset progressive neurologic dysfunction (dementia, psychiatric disturbances, pyramidal and/or cerebellar signs, and seizures). CTX is caused by deficiency of the mitochondrial enzyme sterol 27-hydroxylase with resulting cholestanol and cholesterol accumulation in virtually every tissue. CTX is diagnosed by clinical features and biochemical testing. CYP27A1, encoding the sterol 27-hydroxylase, is the only gene known to be associated with cerebrotendinous xanthomatosis. Molecular genetic testing of the CYP27A1 gene is clinically available. Sequence analysis of CYP27A1 detects mutations in 90%-100% of affected individuals. VOLVER/RETURN

Zigosidad Aproximadamente 1 de cada 60 nacidos resultan ser gemelos, pudiendo ser dizigticos o monocigticos (idnticos). Nuestro laboratorio ofrece el anlisis de marcadores genticos distribuidos en los distintos cromosomas para determinar la zigosidad. ZYGOSITY Approximately one in every sixty births results in the delivery of twins. Twins are either dizygotic (fraternal) or monozygotic (identical). Our laboratory offers zygosity testing by comparing a panel of genetic markers between the twins. VOLVER/RETURN

2.- ONCOLOGA MOLECULAR


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BRCA 1 y 2 GEN: BRCA1 LOCALIZACIN CROMOSMICA: 17q21 GEN: BRCA2 LOCALIZACIN CROMOSMICA: 13q12.3 HERENCIA: autosmica dominante Las mutaciones en BRCA1 y BRCA2 predisponen al cncer de mama y ovario as como al de prstata (BRCA1) y otros tipos de cncer (BRCA2). En Genetaq, nuestro laboratorio, se ofrece la secuenciacin completa de ambos genes y el estudio de reordenamientos y deleciones mediante MLPA. CANCER DE MAMA. SCREENING GEN: BRCA1 MUTACIONES ANALIZADAS:185delAG,243delA, 330 A>G,589del CT,5236 G>C,5236 G>A,5242 C>A,5242 G>A , 5197_5199del3,IVS18+5 G>A,IVS18-1 G>C ,IVS18-1 G>A. GEN: BRCA2 MUTACIONES ANALIZADAS:1538_1541del4,1825delA,3036_3039del4,6503delTT,6857_6858delAA, 9254_9258del5,9538delAA,exn18 INCIDENCIA DE ESTAS MUTACIONES: las ms frecuentes en poblacin espaola. HERENCIA: autosmica dominante Estas 20 mutaciones son las ms frecuentes en la poblacin espaola y constituyen el algoritmo de mutaciones a estudiar segn consenso en cncer hereditario de la sociedad espaola de oncologa mdica. No se conoce qu porcentaje de cncer de mama familiar es causado por dichas mutaciones. Nuestro laboratorio ofrece el screening para estas mutaciones ms comunes de BRCA1 y BRCA2. BRCA 1 and BRCA2 GENE: BRCA1 CHROMOSOMAL LOCATION: 17q21 GENE: BRCA2 CHROMOSOMAL LOCATION: 13q12.3 MODE OF INHERITANCE: autosomal dominant Mutations in BRCA1 or BRCA2 predispose to breast cancer and ovarian cancer as well as prostate cancer (BRCA1) and other cancers (BRCA2). Sequence analysis combined with other methods can detect both common and familyspecific BRCA1 and BRCA2 mutations, including more than 28 specific large genomic rearrangements of BRCA1. BREAST CANCER.SCREENING GENE: BRCA1 MUTATIONS ANALYZED: 185delAG,243delA 330 A>G,589del CT,5236 G>C,5236 G>A,5242 C>A,5242 G>A , 5197_5199del3,IVS18+5 G>A,IVS18-1 G>C ,IVS18-1 G>A. GENE: BRCA2 MUTATIONSANALYZED:1538_1541del4,1825delA,3036_3039del4,6503delTT,6857_6858delAA, 9254_9258del5, 9538delAA,exon18. INCIDENCE OF THESE MUTATIONS: most common among the spanish population MODE OF INHERITANCE: autosomal dominant These twenty mutations are the most common among the spanish population. It is unknown at this time what percentage of familial breast cancer cases are caused by these mutations. Our laboratory can offer screening for these common BRCA1 and BRCA2 mutations. Prior to testing, we strongly urge all patients to have genetic counseling to review their risk of breast and/or ovarian cancer, to discuss possible findings from screening, and to discuss the relevance of these findings to the management of their health care. Documentation of cancer reported in the family history is advised. Routine testing of all Jewish women for these mutations is not recommended. VOLVER/RETURN
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Cncer de colon polipsico GEN: APC LOCALIZACIN CROMOSMICA: 5q21-q22 INCIDENCIA: 2.5-3:100,000 HERENCIA: autosmica dominante La poliposis adenomatosa familiar es un sndrome de predisposicin de cncer de colon en el cual cientos de miles de plipos de colon precancerosos se desarrollan, empezando como media a los 16 aos (7-36 aos). A los 35 aos el 95% de los inividuos con poliposis adenomatosa familiar tiene plipos. Sin colectoma, el cncer de colon es inevitable. La edad media del diagntico de cncer de colon en individuos sin tratar est en los 39 aos (34-43 aos). Las manifestaciones son: presentar plipos en el fundus gstrico y duodeno, osteomas, anormalidades dentales, hipertrofia congnita del epitelio de pigmentacin retinal, tumores en otros tejidos y asociacin a otros cnceres. En nuestro laboratorio, se puede hacer el screening de las mutaciones I1307K y E1317Q as como la secuenciacin del exn 15 del gen APC. FAMILIAL ADENOMATOUS POLYPOSIS GENE: APC CHROMOSOMAL LOCATION: 5q21-q22 INCIDENCE: 2.5-3 per 100,000 MODE OF INHERITANCE: autosomal dominant Familial adenomatous polyposis is a colon cancer predisposition syndrome in which hundreds to thousands of precancerous colonic polyps developed, beginning at a mean age of 16 years (range 7-36 years). By age 35 years, 95% of individuals with FAP have polyps; without colectomy, colon cancer is inevitable. The mean age of colon cancer diagnosis in untreated individuals is 39 years (range 34-43 years). Extracolonic manifestations are variably present and include polyps of the gastric fundus and duodenum, osteomas, dental anomalies, congenital hypertrophy of the retinal pigment epithelium (CHRPE), soft tissue tumors, desmoid tumors, and associated cancers. We testing I1307K and E1317Q mutations and sequencing the exon 15 of APC gene. VOLVER/RETURN Cncer de colon no polipsico GEN: MLH1 LOCALIZACIN CROMOSMICA: 3p21.3 GEN: MSH2 LOCALIZACIN CROMOSMICA: 2p22-p21 GEN:MSH6 LOCALIZACIN CROMOSMICA: 2p16 HERENCIA: autosmica dominante El cncer de colon no polipsico HNPCC, causado por mutaciones en la lnea germinal de genes de reparacin o asociado a tumores que se presentan en MSI, se caracteriza por un aumento del riesgo de cncer de colon, endometrio, ovario, estmago... Los individuos con NHPCC tienen aproximadamente el 80% de riesgo de sufrir cncer de colon. Mutaciones en los genes MLH1 y MSH2 se detectan en el 90% de las familias con HNPCC. Mutaciones en MSH6 se han descrito en el 7-10% y en PMS2 en menos del 5%. Nuestro laboratorio ofrece el estudio en 2 pasos, primero el anlisis por DGGE de los genes MLH1 y MSH2 seguido de la secuenciacin de los exones que presenten un patrn anormal en esta tcnica. Adems, tambin realizamos la secuenciacin completa del gen MSH6. HEREDITARY NON-POLYPOSIS COLON CANCER GENE: MLH1 CHROMOSOMAL LOCATION: 3p21.3 GENE: MSH2 CHROMOSOMAL LOCATION: 2p22-p21 GENE:MSH6 Rev 36 05/05/2009

C.B.M. GENETAQ C/Frailes 28, 29012, Mlaga Telf. 952657605 www.genetaq.com

CHROMOSOMAL LOCATION: 2p16 MODE OF INHERITANCE: autosomal dominant Hereditary non-polyposis colon cancer (HNPCC), caused by a germline mutation in a mismatch repair gene or associated with tumors exhibiting MSI, is characterized by an increased risk of colon cancer and other cancers (e.g., of the endometrium, ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, skin). Individuals with HNPCC have an approximately 80% lifetime risk for colon cancer. HNPCC is known to be associated with mutations in four genes involved in the mismatch repair pathway (MLH1, MSH2, MSH6, and PMS2). Germline mutations in MLH1 and MSH2 account for approximately 90% of detected mutations in families with HNPCC. Mutations in MSH6 have been reported in approximately 7%-10% of families with HNPCC. Mutations in PMS2 account for fewer than 5% of mutations in families with HNPCC. Our laboratory offers a 2-step process by which the entire coding region of MLH1 or MSH2 is first analyzed via DGGE to identify sequence alterations followed by sequencing to identify the specific sequence alteration, which yields a detection rate of approximately 90-95% for MLH1 and 50-80% for MSH2. Our laboratory offers too the sequencing of the entire coding region for MSH6. VOLVER/RETURN CNCER GSTRICO FAMILIAR GEN: CDH1 LOCALIZACION CROMOSMICA: 16q22.1 HERENCIA: autosmica dominante El cncer gstrico familiar es tanto clnica como genticamente heterogneo. A pesar de todos los esfuerzos para determinar su base gentica, slo un sndrome ha sido caracterizado: el cncer gstrico difuso hereditario (HDGC). El HDGC es la susceptibilidad autosmica dominante a padecer cncer gstrico difuso, un adenocarcinoma pobremente diferenciado que se infiltra en la pared del estmago dando lugar a un mayor espesor de la pared (linitis plastica) sin formar una masa definida. CDH1, que codifica para la cadherina E, es el nico gen que se conoce asociado a HDGC. Las mutaciones detectadas, principalmente, son mutaciones que dan lugar a una protena truncada (usualmente mutaciones frameshit), mutaciones de splicing, o mutaciones puntuales. El anlisis de la secuencia del gen CDH1 detecta mutaciones en aproximadamente el 30% de los individuos con un diagnstico clnico de HDGC. La mayora de los cnceres en individuos con mutaciones en CDH1 aparecen antes de los 40 aos. La penetrancia es incompleta, el riesgo acumulativo estimado de cncer gstrico a la edad de 80 aos es del 67% para los hombres y del 83% para las mujeres. Las mujeres tambin tienen un 39% de riesgo de cncer de mama lobular. FAMILIAL GASTRIC CANCER GENE:CDH1 CHROMOSOMAL LOCALITATION: 16q22.1 MODE OF INHERITANCE: autosomal dominant Familial gastric cancer is both clinically and genetically heterogenous. Despite all efforts to determine its genetic basis, a single syndrome has been characterized: the hereditary diffuse gastric cancer (HDGC). Hereditary diffuse gastric cancer (HDGC) is the autosomal dominant susceptibility for diffuse gastric cancer, a poorly differentiated adenocarcinoma that infiltrates into the stomach wall causing thickening of the wall (linitis plastica) without forming a distinct mass. CDH1, encoding the protein E-cadherin, is the only gene known to be associated with hereditary diffuse gastric cancer. The mutations have mainly been truncating mutations, usually through frameshift mutations, exon/intron splice site mutations, or point mutations. Sequence analysis of all 16 exons of the CDH1 gene detects mutations in about 30% of individuals with a clinical diagnosis of HDGC. Rev 36 05/05/2009

C.B.M. GENETAQ C/Frailes 28, 29012, Mlaga Telf. 952657605 www.genetaq.com

The majority of the cancers in individuals with CDH1 mutations occur before the age of 40 years. The penetrance of HDGC is incomplete, the estimated cumulative risk of gastric cancer by age 80 years is 67% for men and 83% for women. Women also have a 39% risk for lobular breast cancer. VOLVER/RETURN C-Myc GEN: C-MYC LOCALIZACIN CROMOSMICA: 8q24 Limfoma de Burkitt, cncer de mama, cervical, colon as como en carcinoma de clulas escamosas de cabeza y cuello, mieloma, linfoma no-Hodgkin y adenocarcinoma gstrico. En adultos, el sndrome del estrs respiratorio producido por dao alveolar tiene una gran expresin de c-myc y en endometriosis es un importante regulador de la proliferacin celular. c-Myc GENE: C-MYC CHROMOSOMAL LOCATION: 8q24 Implicated in Burkitt's lymphoma. Aplification has been described in many types of tumour, including breast, cervical and colon cancers, as well as in squamous cell carcinomas of the head and neck, myeloma, non-Hodgkin's lymphoma, gastric adenocarcinomas and ovarian cancer. In adult respiratory distress syndrome the degree of diffuse alveolar damage and consequently the prognosis may be related to the intensity of expression of c-myc in the alveolar cells which, if severe, may contribute to deregulation of cellular proliferation and apoptosis. In endometriosis, c-myc expression is a possibly important regulator of cellular proliferation. VOLVER/RETURN MEN1 GEN: MEN1 LOCALIZACIN CROMOSMICA: 11q13 INCIDENCIA: 1:30,000 HERENCIA: autosmica dominante La neoplasia mltiple endocrina tipo 1 incluye una combinacin de ms de 20 tumores endocrinos y no endocrinos. Los tumores endocrinos asociados con MEN1 incluyen tumores paratiroideos, en la pituitaria, endocrinos bien diferenciados de la regin pancretica-entero-gstrica, o tumores adrenocorticales. Los no endocrinos asociados a MEN1 incluyen angiofibroma facial, colagenota, lipoma, meningioma, ependiomas, leiomiomas. El 80-90% de los casos asociados a MEN1 presentan alteraciones en este gen. MULTIPLE ENDOCRINE NEOPLASIA TYPE 1 GENE: MEN1 CHROMOSOMAL LOCATION: 11q13 INCIDENCE: one in 30,000 MODE OF INHERITANCE: autosomal dominant Multiple endocrine neoplasia type 1 (MEN1) syndrome includes a varying combination of more than 20 endocrine and non-endocrine tumors. Endocrine tumors associated with MEN1 syndrome include parathyroid tumors, pituitary tumors, well-differentiated endocrine tumors of the gastro-entero-pancreatic (GEP), carcinoid tumors, or adrenocortical tumors. Non-endocrine tumors associated with MEN1 syndrome include facial angiofibromas, collagenomas, lipomas, meningiomas, ependymonas, and leiomyomas. Sequence analysis of MEN1, the only gene known to be associated with MEN1 syndrome, detects MEN1 mutations in about 80-90% of probands with familial MEN1 syndrome and in about 65% of individuals with a single occurrence of MEN1 syndrome in the family. VOLVER/RETURN

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MEN2 GEN: RET LOCALIZACIN CROMOSMICA: 10q11.2 INCIDENCIA: 1:30,000 HERENCIA: autosmica dominante MEN2 se clasifica en 3 subtipos: MEN2A, FMTC (carcinoma medular de tiroides familiar) y MEN2B. Todos derivan en carcinoma medular de tiroides. MEN2A y MEN2B presentan un alto riesgo de feocromocitoma y los portadores de MEN2A de sufrir adenoma paratiroideo o hiperplasia. En el caso de MEN2B incluye neuromas en la mucosa de lengua y labios, fenotipo facial caracterstico con alargamiento de los labios, ganglioneuromatosis del tracto gastrointestinal y cuerpo Marfoide. La edad de aparicin es en la juventud para MEN2B, en la adolescencia MEN2A y en individuos de mediana edad, FMTC. Aproximadamente el 95% de los casos con MEN2A presenta mutaciones en los exones 10 y 11 del gen RET, el 95% de los MEN2B presentan las mutaciones T918M en el exn 16 y/o A883F en el exn 15 del gen RET y en el 88% de los casos de FMTC hay mutaciones en los exones 13 y 14. Por ello, nuestro laboratorio ofrece la secuenciacin de dichos exones del gen RET. MULTIPLE ENDOCRINE NEOPLASIA TYPE 2 GENE: RET CHROMOSOMAL LOCATION: 10q11.2 INCIDENCE: one in 30,000 MODE OF INHERITANCE: autosomal dominant MEN 2 is classified into three subtypes: MEN 2A, FMTC (familial medullary thyroid carcinoma) and MEN 2B. All three subtypes carry a high risk for development of medullary carcinoma of the thyroid (MTC); MEN 2A and MEN 2B carry an increased risk for pheochromocytoma; MEN 2A carries an increased risk for parathyroid adenoma or hyperplasia. Additional features in MEN 2B include mucosal neuromas of the lips and tongue, distinctive facies with enlarged lips, ganglioneuromatosis of the gastrointestinal tract, and an asthenic "Marfanoid" body habitus. The onset of MTC is typically in early childhood in MEN 2B, early adulthood in MEN 2A, and middle age in FMTC. Approximately 95% of families with MEN 2A have a RET mutation in exon 10 or 11. Approximately 95% of individuals with the MEN 2B phenotype have a single point mutation in the tyrosine kinase domain of the RET gene T918M in exon 16, and A883F in exon 15. Approximately 88% of families with FMTC have an identifiable RET mutation. These mutations occur at one of the five cysteine residues (codons 609, 611, 618, 620, and 634) with mutations of codons 618, 620, and 634 each accounting for 25% to 35% of mutations. Mutations in exons 13 and 14. We offer the mutation scanning and/or sequence analysis of exons 10, 11, 13, 14, 15, and 16. VOLVER/RETURN Mutaciones del gen K-ras GEN: c-K-ras LOCALIZACIN CROMOSMICA: 12p12 IMPLICADO EN: tumor (frecuencia de mutacin en K-RAS): pncreas (80-90%), colon y recto (25-60%), pulmn (25-60%), prostata (0-25%), piel (0-25%), tiroides (0-60%), hgado (10-25%), ovario (0-50%), endometrio (10-40%), rin (0-50%), cerebro (0-15%), seminoma (10-45%), leucemia aguda no limfoctica y mielodisplasia (5-15%), vejiga (5%), cabeza y cuello (10%), mama (10%). K-Ras GENE: c-K-ras CHROMOSOMAL LOCATION: 12p12 IMPLICATED IN: tumor (frequency of K-RAS mutations): pancreas (80-90%), colon and rectum (25-60%), lung (25-60%), prostate (0-25%), skin (0-25%), thyroid (0-60%), liver (10-25%), ovary (0-50%), endometrium (10-40%), kidney (0-50%), brain (0-15%), testis (seminoma) (10-45%), acute non lymphocytic leukemia and myelodysplasia (5-15%), urinary bladder (5%), head and neck (10%), breast (10%) VOLVER/RETURN

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Mutaciones del gen p16 GEN: CDKN2A (p16) LOCALIZACIN CROMOSMICA: 9p21 El melanoma es un tumor maligno de los melanocitos el cual se encuentra predominantemente en la piel pero que puede aparecer en ojos e intestino. Alrededor de 160000 nuevos casos de melanoma son detectados al ao en el mundo siendo ms frecuente en hombres y en poblacin caucsica que vive en zonas de clima ms soleado que en otras poblaciones. Los estudios epidemiolgicos sugieren que la exposicin a los rayos ultravioleta A y B es una de las mayores causas de desarrollar melanoma. La luz UV causa dao celular y generan mutaciones en distintos genes. La incidencia de melanoma ha aumentado en los ltimos aos y el diagntico slo es posible cuando empieza a ser visible en la piel. Nuestro laboratorio ofrece la secuenciacin completa del gen p16. p16 GENE: CDKN2A (p16) CHROMOSOMAL LOCATION: 9p21 Melanoma is a malignant tumor of melanocytes which are found predominantly in skin but also in the bowel and the eye. It is one of the rarer types of skin cancer but causes the majority of skin cancer related deaths.Despite many years of intensive laboratory and clinical research, the sole effective cure is surgical resection of the primary tumor before it achieves a thickness of greater than 1 mm. Around 160,000 new cases of melanoma are diagnosed worldwide each year, and it is more frequent in males and caucasians. It is more common in caucasian populations living in sunny climates than other groups. Epidemiologic studies suggest that exposure to ultraviolet radiation (UVA and UVB) is one of the major contributors to the development of melanoma. UV radiation causes damage to the DNA of cells, which when unrepaired can create mutations in the cell's genes. The incidence of melanoma has increased in the recent years, but it is not clear to what extent changes in behavior, in the environment, or in early detection are involved.Today, melanomas are diagnosed only after they become visible on the skin. In the future, however, physicians will hopefully be able detect melanomas based on a patients genotype, not just his or her phenotype. We offer sequence analysis of p16 gene. VOLVER/RETURN p53 GEN: TP53 LOCALIZACIN CROMOSMICA: 17p13 IMPLICADO EN: Sndrome de Li-Fraumeni El sndrome de Li-Fraumeni se caracteriza por la aparicin de sarcoma y cncer de primer grado antes de los 45 aos, y se hereda de manera autosmica dominante. Las mutaciones germinales son variadas pero la mayora se localiza en los exones 4 a 10 del gen p53. Enfermedad hematolgica - 20 - 30% de los casos de CML - 5% de los casos MDS y el 15% de ANLL - 2% de ALL - 15% de CLL - 5-10% de mielomas mltiples. - 60-80% de la enfermedad Hodgkin Cncer de piel Mutaciones en TP53 se detectan en el 40% de los carcinomas de clulas basales y escamosas mientras que son infrecuentes en melanoma maligno. Cncer de mama El 25% de los casos de cncer de mama presenta mutaciones en TP53. Cncer de cabeza y cuello El 40-60% de los cnceres de cabeza y cuello presentan mutaciones en TP53. Cancer de pulmon Rev 36 05/05/2009

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El 40% de los cnceres de pulmn presentan mutaciones G>T en codn 157, 158, 245, 248, 249 y 273 en el gen TP53. Cancer de esfago El 45% de los cnceres de esfago presentan mutaciones en codn 175, 176, 248, 273, 282 en el gen TP53. Cancer de hgado En el 20-50% de los casos se da prdida de 1p, 4q, 5p, 5q, 8q, 13q, 16p, 16q, y 17p. Tambin aparece mutacin en el codn 249 relacionado con la aflatoxina B1 en la zona de China y frica. Cancer gstrico El 30% de los cnceres gastricos presentan mutaciones en TP53. Cancer colorectal El 45% de los cnceres colorectales presentan mutaciones C>T en codon en 175, 245, 248, 273 y 282 en el gen TP53. Cancer de vejiga El 30% de los cnceres de vejiga presentan mutaciones G>A en codon en 280 y 285 en el gen TP53. TP53 est mutado en el 30% de los cnceres de vejiga con una transicin predominante G->A en sitios no metilados y 2 puntos calientes en los codones 280 y 285. Cancer cervical La frecuencia de mutacin de TP53 es muy baja en este tipo de cncer. Carcinoma de ovario La frecuencia de mutacin en cncer de ovario de estado temprano es del 20% y en los tardos del 80%. Cancer de prstata Menos del 20% de los cnceres de vejiga presentan mutacin en el codon 273 en el gen TP53. Glioblastoma La frecuencia de mutacin en glioblastoma secundario es del 60% y en los primarios inferior al 10% con puntos calientes en las posiciones 175, 248 y 273. p53 GENE: TP53 CHROMOSOMAL LOCATION: 17p13 IMPLICATED IN: Li-Fraumeni syndrome Autosomal dominant condition, cancer prone disease, Li-Fraumeni syndrome (LFS) is defined by the existence of a proband with early onset sarcoma and a first degree relative with cancer before 45 years, plus another first/second degree relative with cancer at before 45 years or sarcoma at any age. Germinal mutations are variable, but are mostly missense mutations located in exons 4 to 10 Haematological malignancies TP53 gene alterations have been found in: - 20 - 30% of blast crisis CML (mostly in the myeloid type), often associated with i(17q). - 5% of MDS cases and 15% of ANLL often with a visible del(17p). - 2% of ALL (but with high variations according to the ALL type, reaching 50% of L3 ALL (and Burkitt lymphomas). - 15% of CLL (and 40% in the aggressive CLL transformation into the Richter's syndrome) and 30% of adult T-cell leukaemia (only found in the aggressive form). - 5-10% of multiple myelomas. - 60-80% of Hodgkin disease. - 30% of high grade B-cell NHL (rare in low grade NHL), and 50% of HIV-related NHL. TP53 gene alterations in haematological malignancies are associated with a poor prognosis Skin cancers TP53 is mutated in 40% of basal cell carcinomas and squamous cell carcinomas while mutations are infrequent in malignant melanoma. The pattern of TP53 mutation in skin cancer is highly related to UV exposure with a high frequency of CC->TT and C->T transitions and specific hotspots at codons 196 and 278. Melanoma TP53 gene mutations are rare in melanoma Breast cancer TP53 is mutated in 25% of breast cancers with hotspots at codons 175, 220, 245, 248, 273. Geographical variations in mutation patterns have been observed. The prevalence of mutations is higher in large size, high grade and estrogen

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receptor negative tumors. It is also higher in BRCA1-related tumors. TP53 mutation is a factor of poor prognosis independently of tumor stage and hormone receptor content. It is associated with poor response to doxorubicin therapy. Head and neck squamous cell carcinoma TP53 mutation can be found in about 40-60% of HNSCC cancers and is thought to be an early event as it is often detected in precancerous lesions. TP53 mutation is associated with poor prognosis in HNSCC. Lung cancers Is multistep, through C-MYC or N-MYC activation, H-RAS1 or K-RAS2 mutation, P53, RB1, and P16 inactivation, loss of heterozygosity (LOH) at 3p, 13q, 17p. TP53 is mutated in 40% of lung cancers with frequent G->T transversions at codons 157, 158, 245, 248, 249 and 273. These mutations are linked to exposure to tobacco smoke. TP53 gene mutations may be associated with bad prognosis. Oesophagus cancers TP53 is mutated in 45% of oesophageal cancers with hotspots at codons 175, 176, 248, 273, 282. It is thought to be an early event as it is often detected in precancerous lesions. Liver cancer Losses of 1p, 4q, 5p, 5q, 8q, 13q, 16p, 16q, and 17p in 20 to 50% of cases. Specific mutation at codon 249 related to aflatoxin B1 dietary exposure in exposed area (China, Africa); low frequency of mutation in developed countries. Gastric cancer TP53 mutations are found in about 30% of gastric cancer with a spectrum similar to the one of colorectal cancer. The prognostic value of these mutations is unknown. Colorectal cancers A number of genes are known to be implicated in tumour progression in colorectal cancers : APC, P53, KRAS2, mismatch repair genes (MMR genes). TP53 is mutated in 45% of colorectal cancer cases with a majority of C->T transitions at CpG sites and hotspots at codons 175, 245, 248, 273 and 282. TP53 mutation may be associated with poor prognosis in patient treated with chemotherapy. Bladder cancer Highly variable, according to the stage and the grade. TP53 is mutated in 30% of bladder cancers with a majority of G>A transitions at non-CpG sites and 2 hotspots at codons 280 and 285. Cervical cancer The frequency of TP53 mutation in cervical cancer is very low. Ovary carcinoma TP53 mutation is present in 20% in early stage to 80% in late stage ovarian cancers. The prognostic value of TP53 gene mutation is still a matter of debate, although positive IHC staining for p53 protein seems to be associated with poor prognosis. Prostate cancer TP53 mutations are found in less than 20% of prostate cancers with a main hotspot at codon 273. Little is known about the role and prognostic value of these mutations. Glioblastoma TP53 mutation is an early and frequent (over 60%) event in secondary glioblastomas while it is rare in primary glioblastomas (inferior to 10%) with hotspots at codons 175, 248 and 273. TP53 mutation is associated with good prognosis as it is more frequent in secondary glioblastomas which occur in young patients and are of better prognosis. VOLVER/RETURN PTEN GEN: PTEN LOCALIZACIN CROMOSMICA: 10q23.3 HERENCIA: Autosmica dominante El PTEN est relacionado con el sndrome de Cowden (CS), el sndrome de Bannayan-Riley-Ruvalcaba (BRRS) y el sndrome de Proteus (PS). CS es un sndrome de hamartoma mltiple con un alto riesgo de desarrollar tumores benignos y malignos de la tiroides, de mama y endometrio. Los individuos afectados por lo general presentan macrocefalia, trichilemmomas, papilomatosa y ppulas y suele aparecer tras cumplir los 20 aos. El riesgo de desarrollar cncer de mama es de 25-50%, con una edad media de diagnstico entre 38 y 46 aos, el riesgo de cncer de tiroides (por lo general, folicular, pocas veces papilar, pero nunca medular) es de un 10%, y el riesgo de cncer de Rev 36 05/05/2009

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endometrio pueden acercarse a 5-10%. BRRS congnita es un trastorno caracterizado por macrocefalia, poliposis intestinal, lipomas y mculas pigmentadas de la glande. El PS es una patologa compleja, aparecen malformaciones congnitas y plipos hamartomatosos, as como nevus del tejido conectivo, nevus epidrmico, y hyperostoses. PTEN Hamartoma Tumor Syndrome (PHTS) GENE: PTEN CHROMOSOMAL LOCATION: 10q23.3 MODE OF INHERITANCE: Autosomal dominant The PTEN hamartoma tumor syndrome (PHTS) includes Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), Proteus syndrome (PS), and Proteus-like syndrome. CS is a multiple hamartoma syndrome with a high risk of benign and malignant tumors of the thyroid, breast, and endometrium. Affected individuals usually have macrocephaly, trichilemmomas, and papillomatous papules and present by the late 20s. The lifetime risk of developing breast cancer is 25-50%, with an average age of diagnosis between 38 and 46 years; the lifetime risk for thyroid cancer (usually follicular, rarely papillary, but never medullary thyroid cancer) is around 10%, and the risk for endometrial cancer may approach 5-10%. BRRS is a congenital disorder characterized by macrocephaly, intestinal polyposis, lipomas, and pigmented macules of the glans penis. PS is a complex, highly variable disorder involving congenital malformations and hamartomatous overgrowth of multiple tissues, as well as connective tissue nevi, epidermal nevi, and hyperostoses. Proteus-like syndrome is undefined but refers to individuals with significant clinical features of PS who do not meet the diagnostic criteria for PS. VOLVER/RETUR Retinoblastoma GEN: RB1 LOCALIZACIN CROMOSMICA: 13q14.1-q14.2 INCIDENCIA: 1:15,000 - 20,000 HERENCIA: autosmica dominante El retinoblastoma es un tumor maligno que se desarrolla en la retina y ocurre antes de los 5 aos. El retinoblastoma puede ser unifocal o multifocal, sobre el 60% de los afectos lo presentan unilateral con una edad diagnstico de 24 meses y el 40% tienen un retinoblastoma bilateral realizando el diagnstico con 15 meses de edad. La identificacin de mutaciones puntuales se da en el 70% de los casos tras realizar la secuenciacin del gen RB1. RETINOBLASTOMA GENE: RB1 CHROMOSOMAL LOCATION: 13q14.1-q14.2 INCIDENCE: 1:15,000 - 20,000 MODE OF INHERITANCE: autosomal dominant RB is a malignant tumor of the developing retina that occurs in children, usually before age five years. RB occurs in cells that have cancer-predisposing mutations in both copies of the gene RB1. RB may be unifocal or multifocal. About 60% of affected individuals have unilateral RB with a mean age of diagnosis of 24 months; about 40% have bilateral RB with a mean age of diagnosis of 15 months. Individuals heterozygous for a cancer-predisposing mutation in one RB1 allele are said to have a germline mutation and thus have a hereditary predisposition to RB. They also have an increased risk of developing other RB-related (non-ocular) tumors. Identification of point mutations which account for about 70% of oncogenic RB1 mutations can detected by sequence analysis of RB1 gene. VOLVER/RETURN

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3.- HEMATOLOGIA MOLECULAR


Anlisis de la expresin del Gen mdr1 Un gran obstculo en el xito de la quimioterapia es la capacidad de la clula tumoral para sobrevivir a la exposicin de determinados frmacos antitumorales. Existe un tipo de resistencia denominada multidroga (MDR) que es el resultado de una disminucin de la droga acumulada en la clula tumoral debido a un flujo dependiente de energa. La adquisicin del fenotipo MDR es el resultado de la expresin del gen MDR que codifica una protena de membrana de 170 Kda llamada P-glicoprotena, cuya funcin es actuar como bomba de salida de componentes hidrofbicos. La expresin MDR se observa en diferentes tumores y tejidos normales. Algunos tumores como carcinoma renal o colon no responden a la quimioterapia, asociados frecuentemente a altos niveles de expresin de MDR1 previo al tratamiento. ANALYSIS OF THE MULTIDRUG RESISTANCE MDR1 GENE EXPRESSION The ability of tumor cells to survive exposure to various anticancer drugs presents the greatest obstacle to successful cancer chemotherapy. A particularly important type of tumor drug resistance, termed multidrug resistance (MDR), is manifested by cross-resistance to a number of structurally and functionally unrelated lipophilic drugs. This type of resistance has been shown to be the result of decreased drug accumulation in resistant cells due to energy-dependent drug efflux. Acquisition of the MDR phenotype in human cells is the result of expression of the MDR gene, which encodes a 170-kDa membrane glycoprotein, called P-glycoprotein, believed to function as an efflux pump for various hydrophobic compounds. MDR gene expression is frequently observed in different human tumors, both untreated and treated with chemotherapeutic drugs, as well as in some normal tissues. Some tumor types known to be intrinsically unresponsive to chemotherapy, such as renal cell or colon carcinomas, frequently show high levels of MDR1 expression prior to drug treatment. VOLVER/RETURN Bcl-1 Descripcin: el gen codifica para la ciclina D1; 295 aminocidos; 36 kDa. Expresin: no hay una expresin normal en linfocitos; expresin dependiente de ciclo celular: mxima en G1, mnima en S Localizacin: principalmente nuclear. Funcin: Control del ciclo celular: Progresin de G1 a G1/S; forma complejos con CDK4 y 6; fosoforilacin de RB1 por la ciclina D1/CDK4; inhibida por P21, P15 y P16 Entidad: t(11;14)(q13;q32)/B-cell BCL1 IgH. Patologa: t(11;14) se detecta principalmente en el linfoma de clulas del manto; tambin en leucemia Bpromieloctica, linfoma esplnico; raro en leucemia linfoctica crnica, mieloma mltiple. Resultado de la anomala cromosmica: 5' BCL1 translocado en el cromosoma 14 cerca de JH (IgH) y C en 3'. Protena anormal: No existe protena de fusin, sino intercambio de promotor; el enhancer del gen de la inmunoglobulina estimula la expresin de bcl-1. Esta sobreexpresin acelera el trnsito celular en fase G1. Diagnstico: La deteccin se hace mediante PCR. BCL-1 Description: the gene encodes the cyclin D1; 295 amino acids; 36 kDa Expression: no normal expression in lymphocytes; cell cycle dependant expression: maximal expression in G1, minimal in S Localisation: mainly nuclear Function: cell cycle control: G1 progression and G1/S transition; forms complexes with CDK4 and 6, and further with RB1; phosphorylation of RB1 by cyclin D1/CDK4 removes the cell cycle arrestin G1/S start point; inhibited by P21, P15, and P16.
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Entity: t(11;14)(q13;q32)/B-cell malignancies --> BCL1 - IgH Disease: t(11;14) is mainly found in mantle cell lymphoma; also in: B-prolymphocytic leukaemia, plasma cell leukaemia, splenic lymphoma with villous lymphocytes; rarely in: chronic lymphocytic leukaemia, multiple myeloma Hybrid/Mutated Gene: 5' BCL1 translocated on chromosome 14 near JH (junctions genes of IgH) and C in 3'. Abnormal Protein: no fusion protein, but promoter exchange; the immunoglobulin gene enhancer stimulates the expression of BCL1. Oncogenesis: overexpression of BCL1 accelerates the cell transit through the G1 phase. Diagnosis: We used PCR for detection. VOLVER/RETURN Bcl-2 Descripcin: 25 kDa; 205 aminocidos (BCL2b) o 239 aminocidos (BCL2a, que tiene, adems, una cola hidrofbica de anclaje a membrana. Esta cola tiene actividad anti-apopttica; Contiene dominios BH (homo/heterodimerizacin) y NH. Expresin: amplia; en B y T en particular. Localizacin: Principalmente en membrana mitocondrial. Funcin: antiapoptosis, mediante un proceso complejo; dimerizacin con BAX; papel antiapopttico formando complejos con caspasa-9 y APAF1, previniendo la cascada de proteasas (a travs de activacin dependiente de caspasa-3 citocromo C). Entidad: t(14;18)(q32;q21)/B-cell IgH - BCL2 Patologa: B- cell NHL principalmente; se encuentra en el 80 - 90 % de linfomas foliculares, 30% de linfomas de clulas grandes difusas. Resultado de la anomala cromosmica: 5' BCL2 se transloca en el cromosoma 14 cerca de JH (IgH) y C en 3. Protena anormal: No existe protena de fusion, sino intercambio de promotor; el enhancer del gen de la inmunoglobulina estimula la expresin de BCL-2. Como BCL-2 es un inhibidor apopttico, se retrasa la muerte celular y hay una acumulacin celular. Diagnstico: La deteccin se hace mediante nested-PCR. BCL-2 Description: 25 kDa; 205 amino acids (BCL2b) or 239 amino acids (BCL2a, which has, in addition, a hydrophobic tail for membrane anchorage; this tail seems necessary for anti apoptotic ability); contain homo/heterodimerization domains (BH) and NH domains. Expression: wide; in B and T cells in particular Localisation: mainly in the mitochondrial membrane; other membranes Function: antiapoptosis, through a possibly complex process; dimerization, especially with BAX; role of the BCL2 antiapoptosis members in forming complexes with caspase-9 and APAF1 (homolog of the nematode CED-4), which prevent them to initiate the protease cascade (through caspase-3 cytochrome C dependent activation and) leading to apoptosis Entity: t(14;18)(q32;q21)/B-cell malignancies --> IgH - BCL2 Disease: B- cell NHL mainly; found in 80 to 90 % of follicular lymphomas, 30% of diffuse large cell lymphomas Hybrid/Mutated Gene: 5' BCL2 translocated on chromosome 14 near JH (junctions genes of IgH) and C in 3' Abnormal Protein: no fusion protein, but promoter exchange; the immunoglobulin gene enhancer stimulates the expression of BCL2 Oncogenesis: as BCL2 is an apoptosis inhibitor, cell death is delayed, and there is cell accumulation (more than real transformation) Diagnosis: We used nested PCR for detection. VOLVER/RETURN Bcl-6 Descripcin: Protena de 706 aminocidos, 78.8 kDa. Expresin: Expresin en lnea germinal de clulas B y T, otros tejidos linfoides, clulas musculares y keratinocitos. Localizacin: Nuclear. Rev 36 05/05/2009

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Funcin: La protena se une a una secuencia especfica de ADN y reprime su transcripcin. La unin a ADN es mediada a travs de la secuencia TTCCT(A/C)GAA mientras las interacciones protena-protena se realizan mediante dominios BTB/POZ interactuando con otras protenas a travs de dedos de zinc (incluyendo Histone Deacetylase 1 (HDAC1) y Silencing Mediator of Retinoid and Thryoid Receptor 1 (SMRT1)). El extremo carboxi-terminal, por otra parte, es responsable de la union especfica al ADN a travs de sus 6 dedos de zinc. Entidad: 3q27 /NHL (non Hodgkin linfomas). Patologa: El mayor nmero de translocaciones que afectan al gen BCL-6 se detectan en los linfomas B no-Hodgkin, detectndose en el 15-40% de los casos de linfomas de clulas B grandes (DLBCL), 6-15% en los linfomas foliculares y en el 50% de los casos de linfomas de Hodgkin nodulares. Citogentica: Los reordenamientos en 3q27 son diversos e incluyen microdeleciones, mutaciones puntuales y hipermutacin. El 50% de estas translocaciones afectan a genes Ig en 14q32 (IgH), 2p12 (IgK) y 22q12 (IgL) (e.g. t(3;14)(q27;q32). Menos de la mitad afectan a otras regiones cromosmicas (1q21, 2q21, 4p11, 5q31, 6p21, 7p12, 8q24, 9p13, 11q13, 11q23, 12q11, 13q14-21, 14q11, 15q21; 16p11...). Adems, hay alteraciones biallicas. Resultado de la anomala cromosmica: La sustitucin de promotor entre BCL-6 y sus diferentes partners dan lugar a transcritos quimricos con un extremo 5del gen participante fusionado al sitio de splice del exn 2 del BCL-6. En algunos casos se pueden encontrar quimeras recprocas con la regin reguladora 5del BCL-6 fusionada con regin codificante del gen partner. Diagnstico: La deteccin se hace mediante multiplex-PCR. BCL-6 Description: The protein product is 706 amino acids with an estimated molecular weight of 78.8 kDa. Expression: Normally expressed in germinal center B and T cells, other lymphoid tissues, in skeletal muscle cells and in keratinocytes. Localisation: Nuclear paraspeckles/dots Function: The protein can bind to sequence specific DNA and repress its transcription in addition to recruiting other protein repressors. The DNA binding is mediated through the consensus sequence: TTCCT(A/C)GAA while the proteinprotein interactions are mediated through the BTB/POZ domain and it has been shown to interact with other zinc finger proteins and corepressors (including Histone Deacetylase 1 (HDAC1)and Silencing Mediator of Retinoid and Thryoid Receptor 1 (SMRT1)). The carboxy terminus, on the other hand, is responsible for sequence specific DNA binding through its 6 zinc fingers. Entity: 3q27 rearrangements /NHL (non Hodgkin lymphomas) Disease: B cell non-Hodgkin Lymphoma (B-NHL) carry the greatest number of translocations involving the BCL6 gene locus. Translocations are most commonly detected within 15-40% of Diffuse Large B-Cell Lymphomas (DLBCL), 6-15% of Follicular Lymphomas (FL), and 50% of nodular lymphocyte predominant Hodgkin Lymphomas. Cytogenetics: 3q27 rearrangements/aberrations are diverse and include: translocations, micro-deletions, point mutations and hypermutation. Approximately 50% of 3q27 translocations involves Ig genes at 14q32 (IgH), 2p12 (IgK) and 22q12 (IgL) (e.g. t(3;14)(q27;q32). Less than half (~40%) include a variety of other chromosomal regions (1q21, 2q21, 4p11, 5q31, 6p21, 7p12, 8q24, 9p13, 11q13, 11q23, 12q11, 13q14-21, 14q11, 15q21; 16p11...). In addition, there are frequent bi-allelic alterations (translocation and deletion or mutation on the non-translocated allele). Hybrid/Mutated Gene: hybrid gene and transcripts are formed following promoter substitution between BCL6 and its different partners. Chimeric transcripts are generally detected containing the 5' part of the gene partner fused to the normal BCL6 exon 2 splice acceptor site. In some cases reciprocal chimeric transcripts driven by the 5' regulatory region of BCL6 fused to the partner gene coding region, have been characterised. Diagnosis: We used multiplex PCR for detection. VOLVER/RETURN Cromosoma Ph (BCR-ABL) GENES: Abelson oncogene (ABL) y Breakpoint Cluster Region (BCR) LOCALIZACIN CROMOSMICA: t(9;22)(q34;q11) INCIDENCIA 90-95% en pacientes con leucemia mieloide crnica (CML) y 11-30% de adultos con leucemia linfoblstica aguda (ALL). Existe un test de ARN directo para identificar pacientes con la translocacin BCR-abl. Rev 36 05/05/2009

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El anlisis cualitativo/cuantitativo del reordenamiento BCR/abl es una herramienta til en el pronstico de pacientes con CML o AML. Diagnstico: La deteccin se hace mediante multiplex-PCR y la cuantificacin, si procede, por real-time PCR. BCR/ABL (PHILADELPHIA CHROMOSOME) GENES: Abelson oncogene (ABL) and Breakpoint Cluster Region (BCR) CHROMOSOMAL LOCATION: t(9;22)(q34;q11) INCIDENCE: 90-95% of chronic myeloid leukemia (CML) patients 11-30% of adult acute lymphoblastic leukemia (ALL) patients MODE OF INHERITANCE: somatic cell genetic disorder A direct RNA test is available to identify patients with a translocation of the ABL oncogene into the BCR gene on chromosome 22. The fused transcript of the two genes has been implicated in the malignant process of both chronic myeloid leukemia patients and acute lymphocytic leukemia patients. Qualitative/Quantitative direct RNA analysis for the BCR/ABL rearrangement is useful for prognostication of patients with CML or AML. Diagnosis: We used multiplex PCR for detection and real time- PCR for quantification. VOLVER/RETURN Estudio del reordenamiento t(11:18) Patologa: Linfoma no Hodgkin de clulas B (NHL), linfoma de clulas B zona marginal de tejido linfoide asociado a mucosa. Epidemiologa: 50% encontrado extranodal MZBCL o tipo MALT, ausente en bazo y nodal MZBCL Genes y protenas: BYRC3 (11q21) Protena miembro de la familia de inhibidores de apoptosis IAP. MALT1 (18q21) Resultado de la anomala cromosmica: Protena de fusin API1-MLTC. Todos los linfomas tipo MALT con translocacin t(11:18) expresan la protena de fusin API1-MLTC con tres dominios BIR de API2 fusionados al dominio p20 de la caspasa y al VDJ4-like de MLT. MARGINAL ZONE B-CELL LYMPHOMA t(11;18) Disease: B-cell non Hodgkin lymphoma (NHL), marginal zone B-cell lymphoma of Mucosa-Associated Lymphoid Tissue ( ) -type Epidemiology: found in extranodal MZBCL or MALT-type (50 %), absent in splenic and nodal MZBCL Genes involved and proteins: BYRC3 (11q21) The protein is a member of the inhibitor of apoptosis' (IAP) protein family. MALT1 (18q21) Result of the chromosomal anomaly: N- term API2-MLT C-term fusion protein; All MALT-type lymphomas reported with a t(11;18) express an in frame' API2-MLT fusion protein with consistently the three BIR domains of API2 fused to the caspace p20 domain and VDJ4 like domain of MLT. VOLVER/RETURN Estudio del reordenamiento AML/ETO Patologa: AML (Leucemia mieloide aguda) Epidemiologa: Incidencia anual 1/106; 10% de AML, 40% de M2 AML; la ms frecuente anomala en AML peditricas. Observada en nios y adultos. Media de edad sobre 30 aos, con aparicin rara en individuos mayores. Genes y protenas: AML1 (21q22) La protena contiene un dominio Runt en el extremo C, un dominio de transactivacin; heterodmera; expresada ampliamente; localizacin nuclear; factor de trancripcin (activados) para varios genes hematopoyticos. ETO (8q22) La protena tiene tres dominios ricos en prolina, en la regin carboxi-terminal, una regin PEST; expresin restringida a Rev 36 05/05/2009

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tejido; localizacin nuclear; posible factor de transcripcin. Descripcin: El dominio Runt N-terminal del AML se fusiona con el residuo 577 de ETO. No se detectan productos recprocos. Esta protena de fusin reconoce el sitio consenso de unin del AML1 (compitiendo con el AML1 normal) y dimerizando con la subunidad cbtb/CBTB. Oncognesis: Alteracin probable de la regulacin transcripcional de los genes diana de AML1. Diagnstico: La deteccin se hace mediante multiplex-PCR y la cuantificacin, si procede, por real-time PCR. TRANSLOCATION t(8;21) (AML/ETO) Disease: AML (acute myeloid leucemia) Epidemiology: annual incidence: 1/106; 10% of AML, 40% of M2 AML; the most frequent anomaly in chilhood AML; seen in children and adults: mean age 30yrs, rare in elderly patients; male excess (4M/3F) is much less than sometimes claimed Genes involved and proteins: AML1 (21q22) The protein contains a Runt domain and, in the C-term, a transactivation domain; forms heterodimers; widely expressed; nuclear localisation; transcription factor (activator) for various hematopoietic-specific genes ETO (8q22) The protein has 3 proline rich domains, 2 Zn fingers, and in C-term, a PEST region; tissue restricted expression; nuclear localisation; putative transcription factor Description: the N-term runt domain from AML1 is fused to the 577 C-term residues from ETO; reciprocal product not detected; probable DNA binding role; the fusion protein retains the ability to recognize the AML1 consensus binding site (--> negative dominant competitor with the normal AML1) and to dimerize with the cbtb/CBTB subunit. Oncogenesis: probable altered transcriptional regulation of normal AML1 target genes. Diagnosis: We used multiplex PCR for detection and real time- PCR for quantification. VOLVER/RETURN Estudio del reordenamiento CBFbeta MYH11 Entidad: inv(16)(p13q22), t(16;16)(p13;q22), y del(16)(q22) en Leucemia aguda no linfoblstica (ANLL) o sndromes mielodisplsicos (MDS) CBFb-MYH11 Patologa: patognomnica de M4eo-ANLL: con eosinofilia; frecuente afectacin del CNS Pronstico: Alta tasa de CR; mejor pronstico que la mayora de las otras ANLL Hbrido/Gen Mutado: 5' CBFb - 3' MYH11 Protena anormal. El extremo N-terminal y la mayora de CBFb se fusiona con el extremo C-terminal de MYH11, con su dominio de multimerizacin Diagnstico: La deteccin se hace mediante multiplex-PCR y la cuantificacin, si procede, por real-time PCR. CBFB - MYH11 Entity. inv(16)(p13q22), t(16;16)(p13;q22), and del(16)(q22) in acute non lymphoblastic leukaemia (ANLL) or myelodysplastic syndromes (MDS) --> CBFb - MYH11 Disease: nearly pathognomonic of M4eo-ANLL: with eosinophilia; frequent CNS involvement Prognosis: high CR rate; better prognosis than most other ANLL Cytogenetics: the 3 chromosome anomalies are variants of each other Hybrid/Mutated Gene: 5' CBFb - 3' MYH11 Abnormal Protein. the N-term and most of CBFb is fused to the MYH11 C-term with its multimerization domain Diagnosis: We used multiplex PCR for detection and real time- PCR for quantification. VOLVER/RETURN Estudio del reordenamiento DEK/CAN Patologa: ANLL y/o MDS Epidemiologa: 1% de ANLL; media de edad (25-30 yrs) pero con amplio rango de afectacin; raro en edad avanzada. Genes y protenas:
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DEK (6p23) La protena contiene dominios acdicos y una seal de localizacin cromosmica; protena de unin al ADN. Regulador transcripcional y transductor de seal. CAN (9q34) La protena contiene dominios de dimerizacin homodmeros: localizacin membrana nuclear; asociada a complejo de poro nuclear. Resultado de la anomala cromosmica La protena de fusin tiene 165 kDa; La mayora del extremo N-terminal con casi toda la protena DEK se fusiona con las dos terceras partes de la protena CAN, en su extremo C-terminal. TRANSLOCATION DEK/CAN: t(6;9)(p23;34) Disease: ANLL and/or MDS Epidemiology: 1% of ANLL; found at any age, but median age (25-30 years) is less than usual in ANLL; rare in the elderly. Genes involved and proteins: DEK (6p23) The protein contains acidic domains and a nuclear localisation signal; DNA binding protein; transcriptional regulation and signal transduction. CAN (9q34) The protein contains dimerization domains -> forms homodimers; nuclear membrane localisation; associated with the nuclear pore complex Result of the chromosomal anomaly The fusion protein has 165 kDa; N-term with almost the entire DEK protein fused to the C-terminal two-thirds of the CAN protein. VOLVER/RETURN Estudio del reordenamiento E2A/PBX Patologa: ALL, tipo L1/L2 ; encontrada de manera excepcional en L3-like ALL, T-ALL, LMNH, o ANLL. Epidemiologa: 5% de ALL, o 20% de pre B ALL; aparicin en nios y jvenes adultos (1-60 aos, media: 10 aos una de las ms frecuentes en ALL en infancia); 3 varones/4 mujeres. Genes y protenas: E2A (19p13) La protena contiene un dominio transcripcional y un sitio de unin al ADN hlice-loop-hlice; unin especfica a potenciador de inmunoglobulinas; localizacin nuclear; factor de transcripcin. PBX1 (1q23) La protena contiene un homeodominio que se une al ADN; localizacin nuclear; regulacin transcripcional. Descripcin: 550 aminocidos; 85 kDa; La regin N terminal de E2A, donde se encuentran los dominios de activacin transcripcional se fusiona con el carboxiterminal de PBX1 en su regin de homeodominio; Potente activador transcripcional. Oncognesis: Actividad pleiotrpica. Diagnstico: La deteccin se hace mediante multiplex-PCR y la cuantificacin, si procede, por real-time PCR. TRANSLOCATION E2A/PBX: t(1;19)(q23;13) Disease: ALL, L1/L2 type; exceptionally found in L3-like ALL, T-ALL, LMNH, or ANLL Epidemiology: 5% of ALL, or 20% of pre B ALL; found in children and young adults (1-60 yrs, median: 10 yrs --> one of the most frequent ALL in childhood); 3 male/4 female patients Genes involved and proteins: E2A (19p13) The protein contains transcriptional activation domains and a basic helix-loop-helix DNA binding site; binds specifically to an immunoglobulin enhancer; nuclear localisation; transcription factor PBX1 (1q23) The protein contains a homeodomain to binds to DNA; nuclear localisation; transcription regulation Rev 36 05/05/2009

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Description: 550 amino acids; 85 kDa; N-term transcriptional activation domains from E2A fused to the Hox cooperative motif and homeodomain of C-term PBX1; potent transcriptional activator. Oncogenesis: pleiotropic transforming activity Diagnosis: We used multiplex PCR for detection and real time- PCR for quantification. VOLVER/RETURN Estudio del reordenamiento MLL/AF4 Patologa: ALL principalmente. Epidemiologa: nios (incluyendo nios de menos de 2 aos, con leucemia congenital) y adultos. Genes y protenas: MLL (11q23) Protena de 431 kDa; contiene dos motivos de unin al ADN (gancho AT y dedos de zinc), un motivo de metiltransferasa, un bromodominio; localizacin nuclear; Factor regulador transcripcional. AF4 (4q21) La protena contiene una secuencia target nuclear; localizacin nuclear; Activador transcripcional. Resultado de la anomala cromosmica: 2319 aminocidos; 240 kDa; La regin N-terminal gancho AT y DNA metiltransferasa de MLL se une a AF4 por la regin C-terminal; L aprotena recproca (AF4-MLL) se puede expresar o no. Es bastante similar a la protena de fusin encontrada en MLL/ENL con t(11;19). Diagnstico: La deteccin se hace mediante multiplex-PCR y la cuantificacin, si procede, por real-time PCR. TRANSLOCATION MLL/AF4: t(4;11)(q21;q23) Disease: ALL mainly Epidemiology: children (including infants: named a congenital leukaemia when before 1 yr or 2 years of age) and adults; half cases are under 4 yrs, 1/3 under 1yr; Genes involved and proteins: MLL (11q23) The protein has 431 kDa; contains two DNA binding motifs (a AT hook, and Zinc fingers), a DNA methyl transferase motif, a bromodomain; transcriptional regulatory factor; nuclear localisation AF4 (4q21) The protein contains a nuclear targeting sequence; nuclear localisation; function: transcription activator Result of the chromosomal anomaly: 2319 amino acids; 240 kDa; N-term AT hook and DNA methyltransferase from MLL fused to AF4 C-term; the reciprocal (AF4-MLL) may or may not be expressed; quite similar to the MLL/ENL fusion protein found with t(11;19) Diagnosis: We used multiplex PCR for detection and real time- PCR for quantification. VOLVER/RETURN Estudio del reordenamiento MYC/IgH Patologa: Descrita tanto en ALL como en Linfoma no-Hodgkin, especialmente en linfoma de Burkitt. Epidemiologa: La translocacin est presente en el linfoma endmico de Burkitt y en tumores no endmicos (Europa, Amrica, Japn). Genes y protenas: C- MYC (8q24) Myc es un factor de transcripcin de la familia hlice-giro-hlice/cremallera de leucina que activa la transcripcin en forma de dmero obligado con la protena Max. IgH (14q32) Resultado de la anomala cromosmica: La protena c-myc resultante de la translacin del segundo y tercer exn, juega un importante papel en la regulacin del crecimiento celular y la diferenciacin. Oncognesis: La expresin constitutiva de c-myc induce proliferacin incluso en ausencia de factores de crecimiento. TRANSLOCATION MYC/IGH: t(8;14)(q24;q32) Rev 36 05/05/2009

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Disease: described both in B-cell acute lymphoblastic leukemia (ALL) and in non-Hodgkin lymphomas (NHL), especially in the Burkitt lymphoma. Epidemiology: the translocation is present in both the endemic African Burkitt lymphoma and in the non endemic tumor type (Europe, America, Japan) Genes involved and proteins: C- MYC (8q24) Myc protein is a transcription factor of the helix-loop-helix/leucine zipper family that activates transcription as obligate heterodimer with a partner protein, Max. IgH (14q32) Result of the chromosomal anomaly: The protein c-myc resulting from the translation of the second and third exons, through DNA- binding properties, plays a role in regulating cell growth and differentiation. Oncogenesis: constitutive expression of c-myc induces proliferation even in the absence of growth factors VOLVER/RETURN Estudio del reordenamiento NPM/ALK Patologa: Se encuentran mas del 50% de casos con linfoma anaplsico de clulas grandes (ALCL), un grado alto de linfoma no-Hodgkin con translocaciones afectando a 2p23. Ellos incluyen ALK, por lo que se denominan ALK+ALCL. La t(2;5) es la ms frecuente de las translocaciones 2p23 en ALK+ALCL Epidemiologa: El 10% de NHL. Se encuentran en nios y jvenes adultos, media de edad 16 aos. Genes y protenas: NPM (5q35) Es una protena de unin a ARN relacionada con el ensablaje preribosomal. Tiene localizacin nuclear. ALK (2p23) Tras su glicosilacin, se produce una glicoprotena asociada a receptor de membrana tirosnkinasa. Descripcin: 80 kDa; 680 aminocidos; Desde el aminocido 116 de la NPM, por su extremo N-terminal, se fusiona con el aminocido 563 del extremo C-terminal de ALK (en el dominio de oligomerizacin y sitio de unin de metal para NPM1 y la regin citoplasmtica completa de ALK). La localizacin caracterstica es tanto en ncleo como citoplasma. La protena normal NPM est confinada al ncleo. Activacin constitutiva del dominio cataltico de ALK. Oncognesis: Va funcin kinasa activada mediante oligomerizacin de NPM-ALK mediada por la parte NPM. TRANSLOCATION NPM/ALK: t(2;5)(p23;q35) Disease: Translocations involving 2p23 are found in more than half cases of anaplasic large cell lymphoma (ALCL), a high grade non Hodgkin lymphoma (NHL). They involve ALK, and are therefore called ALK+ ALCL. The t(2;5) is the far most frequent 2p23 translocation in ALK+ ALCL. Epidemiology: 10% of NHL; found in children and young adults; median around 16 yrs) Genes involved and proteins: NPM (5q35) The protein has nuclear localisation; RNA binding nucleolar phosphoprotein involved in preribosomal assembly. ALK (2p23) The protein after glycosylation, produces a glycoprotein; membrane associated tyrosine kinase receptor. Description: 80 kDa; 680 amino acids; the 116 N-term aminoacids from NPM are fused to the 563 C-term aminoacids of ALK (i.e. composed of the oligomerization domain and the metal binding site of NPM1, and the entire cytoplasmic portion of ALK); no apparent expression of the ALK/NPM1 counterpart. Characteristic localisation both in the cytoplasm and in the nucleus, due to heterooligomerization of NPM-ALK and normal NPM whereas the normal NPM protein is confined to the nucleus; constitutive activation of the catalytic domain of ALK. Oncogenesis: via the kinase function activated by oligomerization of NPM-ALK mediated by the NPM part. VOLVER/RETURN Estudio del reordenamiento PLZF/RAR Patologa: Observada especficamente en leucemia promieloctica aguda (APL), o M3 ANLL; en la mayora de casos Rev 36 05/05/2009

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se caracteriza por t(15;17)(q25;q21). La translocacin t(11;17) es una variante rara. Epidemiologa: Menos del 1% con morfologa M3 ANLL. Genes y protenas: PLZF (5q35) Es un factor de transcripcin asociado con maduracin mieloide. RAR (2p23) La protena es un receptor nuclear con propiedades de unin a ADN y transcripcin. Resultado de la anomala cromosmica: PLZF(A)-RARa (735 aminocidos; 81 kDa) posee en su extremo N-terminal el dominio POZ y dos de los 9 dedos zinc de PLZF, que se unen con los dominios de unin al ADN del RARa. PLZF(B)-RARa (858 aminocidos; 93 kDa) difiere de la forma A por la inclusin de un segmento de 132 aminocidos ricos en prolina, de PLZF. PLZF-RARa es un receptor del cido retinico con una reduccin en su actividad transcripcional y de unin al ADN. Tambin se detectan dos formas de RARa-PLZF. Uno de RARa(A1)-PLZF (277 aminocidos; 31 kDa) y RARa(A2)PLZF (274 aminocidos; 31 kDa), compuestos por los dominios de activacin transcripcional A1 o A2 de RARa unidos al los siete dedos de zinc carboxiterminal de PLZF. TRANSLOCATION PLZF/RAR: t(2;5)(p23;q35) Disease: specifically observed in acute promyelocytic leukemia (APL), or M3 ANLL; in the vast majority of cases, M3 ANLL is characterized by a t(15;17)(q25;q21); the t(11;17) represents a rare variant translocation with characteristic clinicopathologic features concerning presentation, response to treatment with all-trans retinoic acid (ATRA) and prognosis. Epidemiology: less than 1% of morphologic M3 ANLL. Genes involved and proteins: PLZF (5q35) The protein is a transcription factor associated with myeloid maturation. RAR (2p23) The protein is a nuclear receptor with DNA binding and transcriptional properties. Fuston protein: 1- as a result of the alternative splicing of PLZF gene, two forms of PLZF-RARa protein can be detected: a) PLZF(A)-RARa (735 amino acids; 81 kDa) composed of the N-term part of PLZF including POZ domain and two of the nine zinc fingers, fused to the DNA and ligand binding domains of RARa b) PLZF(B)-RARa (858 amino acids; 93 kDa) differing from form A by the inclusion of a 123 amino acid proline rich segment of PLZF; PLZF-RARa protein is an abnormal retinoic acid receptor with reduced and modified DNA-binding and transcriptional activities. 2- Two forms of RARa-PLZF protein are also detected, due to involvement of alternative promoters of the RARa gene: RARa(A1)-PLZF (277 amino acids; 31 kDa) and RARa(A2)-PLZF (274 amino acids; 31 kDa), composed of A1 or A2 transcriptional activation domain of RARa linked to the seven C-terminal zinc fingers of PLZF. VOLVER/RETURN Estudio del reordenamiento PML/RAR Patologa: M3 ANLL (de novo); muy pocos casos de t(15;17) Se han reportado casos en leucemia relacionada con terapia (t-ANLL). Epidemiologa: Encontrada en el 10% de adultos con ANLL; incidencia anual: 1/106, similar a la de la t(8;21) ; cualquier edad pero frecuente en jvenes adultos. Ratio sexo: 1M/1F. Genes y protenas: PML (15q22) Protena nuclear; contiene dedos de zinc y cremalleras de leucina. Es un factor de transcripcin. RAR (17q12-21) Protena de amplia expresin; receptor nuclear; se une especficamente a secuencias de ADN: HRE (elemento de respuesta a hormonas); dominio de ligando y dimerizacin; papel en crecimiento y receptor nuclear de diferenciacin con unin al ADN y propiedades transcricionales. Descripcin: Los puntos de ruptura en PML son variables; por ejemplo: 932 aminocidos; 103 kDa; N-term de PML, por su regin de unin a DNA y de dimerizacin se une a la mayora de RARa por las regiones de unin al ADN y al cido retinico. Rev 36 05/05/2009

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Oncognesis: Receptor anormal para el cido retinoico con efecto dominante sobre RARa. Diagnstico: La deteccin se hace mediante multiplex-PCR y la cuantificacin, si procede, por real-time PCR. TRANSLOCATION PML/RAR: t(15;17)(q22;q21) Disease: M3 ANLL (di novo); a very few cases of t(15;17) in therapy-related leukaemia (t-ANLL) have been reported. Epidemiology: found in 10% of adult ANLL; annual incidence: 1/10 6, similar to the incidence of the t(8;21) ; any age, but frequent in the young adult; sex ratio 1M/1F. Genes involved and proteins: PML (15q22) The protein is a nuclear protein; contains zinc fingers and a leucine zipper; transcription factor. RAR (17q12-21) The protein has wide expression; nuclear receptor; binds specific DNA sequences: HRE (hormone response elements); ligand and dimerization domain; role in growth and differentiation a nuclear receptor with DNA binding and transcriptional properties. Description: variable, as breakpoints in PML are variable; e.g.: 932 amino acids; 103 kDa; N-term PML, with the DNA binding and the dimerization domains fused to most of RARa with the DNA and retinoid binding regions. Oncogenesis: abnormal retinoic acid receptor with a dominant effect over RAR, antagonizing differentiation. Diagnosis: We used multiplex PCR for detection and real time- PCR for quantification. VOLVER/RETURN Estudio del reordenamiento TEL/AML1 Patologa: Clulas B ALL Epidemiologa: 15 al 35% de B-linage ALL en pediatra: Es la translocacin mas frecuente en este grupo. Raro o ausente en adultos. Genes y protenas: TEL (ETV6) (12p12) La protena contiene un dominio HLH y otro de unin a EST y ADN; Es un factor de transcripcin ETS-relacionado. AML1 (21q22) La protena contiene un dominio Runt en la regin C-terminal y un dominio de transactivacin; heterodmero de amplia expresin; localizacin nuclear; factor de transcripcin activador de varios genes hematopoyticos. Resultado de la anomala cromosmica: La regin de hlice-loop de TEL se fusiona con casi la totalidad de AML1, incluyendo la regin Runt y el dominio de transactivacin. Diagnstico: La deteccin se hace mediante multiplex-PCR y la cuantificacin, si procede, por real-time PCR. TRANSLOCATION TEL/AML1: t(12;21)(p12;q22) Disease: B cell ALL Epidemiology: 15 to 35% of paediatric B-lineage ALL: so far the most frequent translocation in this group; rare or absent in adults and in infants; age: children; no case >20 years so far; male and female equally represented Genes involved and proteins: TEL (ETV6) (12p12) The protein contains a HLH domain and a ETS-DNA binding domain; ETS-related transcription factor. AML1 (21q22) The protein contains a Runt domain and, in the C-term, a transactivation domain; forms heterodimers; widely expressed; nuclear localisation; transcription factor (activator) for various hematopoietic-specific genes. Fusion protein: Helix loop helix of TEL fused to the nearly entire AML1 protein, comprising the Runt domain and the transactivation domain. Diagnosis: We used multiplex PCR for detection and real time- PCR for quantification. VOLVER/RETURN Hipereosinofilia El Sndrome de hipereosinofilia idioptico (SHE) se ha definido tradicionalmente por eosinofilia persistente de ms de
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1.5 109/L durante ms de 6 meses, en ausencia de causas conocidas de eosinofilia (alergias, parasitosis, etc) y presencia de compromiso de dao orgnico debido a la eosinofilia. Se trata de un desorden muy raro en los nios. La etiologa es desconocida. Mientras un proceso de proliferacin de eosinfilos es la base del sndrome, el signo primario que inicia la superproduccin de eosinfilos en la mdula an no ha sido descubierto. Cualquier mecanismo de eosinofilia en sangre perifrica, la infiltracin de tejidos con eosinfilos es la prxima fase en la patognesis del sndrome y es responsable de las consecuencias clnicas. Recientemente, la reestructuracin del clon FIP1L1PDGFRA se ha identificado en un subconjunto de pacientes adultos con HES secundaria a leucemia eosinoflica crnica. En los nios es un desorden muy raro; se han descrito ciertas diferencias clnicas con los adultos y un solo caso con FIP1L1-PDGFRA. En nuestro laboratorio, se estudia dicho reordenamiento mediante nested-PCR y primers especficos. IDIOPATHIC HYPEREOSINOPHILIC SYNDROME Idiopathic hypereosinophilic syndrome (HES) refers to a group of leukoproliferative disorders characterized by an overproduction of eosinophils that results in organ damage. Peripheral eosinophilia with tissue damage has been noted for approximately 80 years, but Hardy and Anderson first described the specific syndrome in 1968. In 1975, Chusid et al defined the 3 features required for a diagnosis of HES. First, a sustained eosinophil count of greater than >1500 cells/mL should persist for more than 6 months. Second, no other etiologies for eosinophilia are present. Finally, patients must have signs and symptoms of organ involvement. This last requirement excludes benign eosinophilia, which may exist for years with no associated pathology. It has been recently identified the FIP1L1-PDGFRA fusion gene. This is generated by a cryptic interstitial chromosomal deletion, del(4)(q12q12), which indicates that these cases are clonal hematopoietic malignancies and should be reclassified as chronic eosinophilic leukemias. We used nested -PCR for detection of fusion gene. VOLVER/RETURN Linfoma T/Linfoma B Clonalidad Las translocaciones se forman como resultado de errores del complejo recombinasa (RAG1, RAG2, etc) responsables de los reordenamientos de las inmunoglobulinas o del receptor de clulas T. El diagnstico de linfoma no-Hodgkin (NHL), especialmente cuando existen infiltrados de linfocitos de tamao medianopequeo o con clulas muy inmaduras o pleomrficas, es complicado. La caracterizacin de un clon por su tamao molecular y su reordenamiento bien en la cadena pesada de la inmunoglobulina (IgH) o del receptor del linfocito T (TCR) resulta muy til para distinguir la evolucin clonal de un linfoma como evolucin de uno primario. Usando primers especficos, el anlisis de PCR puede aplicarse en la deteccin de enfermedad mnima residual, recurrencia o estados tempranos. El reordenamiento en IgH y TCR ocurre en estados tempranos en el desarrollo de linfocitos B y T, mediante la seleccin de segmentos de la regin V, D y J en el gen de IgH o de V y J en el gen del TCR gamma. Adems se introduce mayor diversidad a travs de deleciones, inserciones al azar y hipermutaciones de la uniones entre segmentos, generando un nico segmento VDJ o VJ especfico de cada clon. El anlisis de southern blot es una tcnica estandar para la determinacin de reordenamientos de IgH y TCR, aunque con una gran cantidad de limitaciones, como el tiempo requerido, gran cantidad de ADN sin degradar, el uso de sondas radiactivas Actualmente el uso de la PCR soluciona todos estos problemas mediante ensayos realizados con primers 3JH consenso diseados para reconocer y amplificar los segmentos VDJ y primers 5que reconocen regiones conservadas tales como FR1, FR2 y FR3, para el caso de las inmunoglobulinas. En el caso de reordenamientos de TCR, la mayora de los protocolos usados para TCR beta o gamma requieren de primers mltiplex regin-especfica. El protocolo para la deteccin de TCR gamma usa primers consenso salvando esta dificultad y es el que usamos actualmente en nuestro laboratorio. Diagnstico: La deteccin se hace mediante nested-PCR. T-LYMPHOMA Molecular DNA analysis has been applied to the diagnosis of non-Hodgkin's lymphoma (NHL), especially when the diffuse infiltrates consist of monomorphic small- to medium-sized lymphocytes, or when the neoplastic cells are very immature or pleomorphic in morphology. Characterization of a clone by its molecular size and its sequence of
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rearranged segments of immunoglobulin heavy chain (IgH) or T cell receptor (TCR) gene is also useful in assessing how a secondary lymphoma occurs as a recurrence with clonal evolution or as another primary. Moreover, using specific primers for the rearranged segments, polymerase chain reaction (PCR) analysis can be applied to the detection of minimal residual lymphoma, recurrence, or earliest stage lymphoma. Rearrangement in the IgH and TCR genes occurs at an early stage of B cell or T cell development. It involves the selection of V (variable), D (diversity) and J (joining) segments in the IgH gene, or V and J in the TCR[gamma] gene. Further diversity is introduced by various deletions, random insertions of nucleotide and hypermutation at the junctions between the segments, thus generating a unique VDJ or VJ segment specific to each clone. Southern blot analysis is a standard technique for the determination of rearrangement in IgH and TCR genes, although it is subject to several limitations, such as the substantial time required, the need for large amounts of undegradated genomic DNA and the use of radioactive probes. Recent studies have proposed several protocols using PCR, which seem to overcome these disadvantages. To detect Ig H gene rearrangement, PCR methods are designed to amplify the VDJ segments using consensus 3'-JH primer and 5'-primers that recognize the conserved regions of VH genes such as FR1, FR2 or FR3. For the TCR gene rearrangement, most of the PCR protocols for TCR[beta] or [gamma] gene rearrangement require multiple region-specific primers, but there is one protocol which uses consensus primers for the TCR[gamma] gene. Diagnosis: We used multiplex PCR for detection. B-LYMPHOMA Translocations which frequently result from errors of the recombinase enzyme complexe (RAG1, RAG2, etc.), responsable of the Immunoglobulin and T cell receptor V-J and V-D-J rearrangements, or from errors of the switch enzyme. IGHV, IGHD or IGHJ recombination signals or isolated heptamer (first case) or switch sequences (second case) are observed at the breakpoints. Diagnosis: We used multiplex PCR for detection. VOLVER/RETURN Policitemia Vera. Jak2 JAK2 (V618F) JAK2 es la kinasa activada predominante en respuesta a factores de crecimiento y citocinas como IL-3, GM-CSF o eritropoyetina. Se encuentra asociada al receptor de prolactina y es necesaria en la respuesta a gamma interferon. Ms del 50% de los pacientes con enfermedades linfoproliferativas (policitemia vera, trombocitemia esencial, mielofibrosis idioptica) tienen una ganancia de funcin en el dominio JH2-like de JAK2 debido a la mutacin V617F, que permite una desregulacin de la actividad kinasa. La incidencia de la mutacin V617F est entre el 65 y el 97% en policitemia vera, de 41 a 57% en pacientes con trombocitemia esencial y del 23 al 95% en pacientes con mielofibrosis idioptica. Diagnstico: La deteccin se hace mediante multiplex-PCR de la mutacin V618F. JAK2 (V618F) JAK2 is the predominant JAK kinase activated in response to several growth factors and cytokines such as IL-3, GMCSF and erythropoietin; it has been found to be constitutively associated with the prolactin receptor and is required for responses to gamma interferon. A high proportion (> 50%) of patients with myeloproliferative disorders (MPD; (polycythemia vera, essential thrombocythemia, idiopathic myelofibrosis - see below) carry a dominant gain-of-function V617F mutation in the JH2 kinase-like domain of JAK2. This mutation leads to deregulation of the kinase activity, and thus to constitutive tyrosine phosphorylation activity. The incidence of the V617F mutation in different studies ranges from 65-97% in polycythemia vera, from 41-57% in patients with essential thrombocythemia, and from 23-95% in patients with idiopathic myelofibrosis. Diagnosis: We used multiplex PCR for detection. VOLVER/RETURN

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4.- ENFERMEDADES MITOCONDRIALES


Enfermedades Mitocondriales Los trastornos mitocondriales son un grupo heterogneo de enfermedades que se deben a fallos en la cadena respiratoria mitocondrial. Las caractersticas clnicas comunes de los fallos mitocondriales, incluyen ptosis, oftalmoplegia externa, miopata proximal y ejercicios de intolerancia, cardiomiopata, sordera, atrofia ptica, retinopata pigmentaria y diabetes. Los hallazgos en el sistema nervioso central generalmente fluctan entre encefalopatas, demencia, migraa, ataxia y espasmos. Los trastornos mitocondriales pueden ser causados por defectos del DNA nuclear o mtDNA. Los defectos genticos nucleares pueden heredarse de una forma tanto autosmica dominante como recesiva. Los defectos del mtDNA se transmiten por herencia materna. Muchos pacientes presentan un conjunto de fallos clnicos que terminan en un sndrome especfico; sin embargo, a menudo hay mucha variabilidad clnica. Nuestro laboratorio ofrece las pruebas por 9 mutaciones comunes, incluso de los genes A3243G y T8993C en leu-tRNA (UUR), que causa la encefalopata mitocondrial (MELAS); A8344G y T8356C en el gen del tRNA-lys, causa epilepsia mioclnica asociada a fibras rojas rasgadas (MERRF); mutaciones en G4560A y G11778A que causan neuropatologa ptica hereditaria (LHON); y T8993C y T8993G en la subunidad 6 del gen ATPasa que causa neuropata, ataxia y retinitis pigmentosa (NARP); que es la responsable de aproximadamente el 10% de los casos de los sntomas de Leigh. A parte, una delecin comn de mtDNA, que causa el sndrome de Kearns-Sayre (KSS), oftalmoplegia crnica externa progresiva (CPEO) o sndrome de Pearson. Todos estos anlisis se pueden realizar de manera individual o como una batera. A parte, podemos realizar los anlisis de los 37 genes mitocondriales. Las pruebas genticas prenatales e interpretacin de resultados de los trastornos de mtDNA son complicados debido a la heteroplasmia del mtDNA. MITOCHONDRIAL DISORDERS Mitochondrial disorders are a heterogeneous group of diseases that are caused by abnormalities in the mitochondrial respiratory chain. Common clinical features of mitochondrial disease include ptosis, external ophthalmoplegia, proximal myopathy and exercise intolerance, cardiomyopathy, sensorineural deafness, optic atrophy, pigmentary retinopathy, and diabetes mellitus. The central nervous system findings are often fluctuating encephalopathy, seizures, dementia, migraine, stroke-like episodes, ataxia, and spasticity. Mitochondrial disorders may be caused by defects of nuclear DNA or mtDNA. Nuclear gene defects may be inherited in an autosomal dominant or autosomal recessive manner. MtDNA defects are transmitted by maternal inheritance. Many patients display a cluster of clinical features that fall into a specific clinical syndrome; however, there is often considerable clinical variability. Our laboratory offers testing for nine common mutations, including A3243G and T3271C in tRNA-leu (UUR) gene, which cause MELAS (Mitochondrial Encephalopathy, lactic acidosis and stroke-like episodes), A8344G and T8356C in tRNA-lys gene, which cause MERRF (myoclonic epilepsy and ragged red fiber), G3460A, and G11778A mutations, which cause LHON (Lebers hereditary optic neuropathy), and T8993C and T8993G in subunit 6 of ATPase gene, which cause NARP (neuropathy, ataxia and retinitis pigmentosa), which are also responsible for approximately 10% of Leigh syndrome cases. In addition, a common deletion of mtDNA, which causes Kearns-Sayre syndrome (KSS), chronic progressive external ophthalmoplegia (CPEO) or Pearson marrow-pancreas syndrome is also examined. These analyses can be ordered separately or as a panel. In addition, analysis of all 37 mitochondrial genes is now available. Prenatal genetic testing and interpretation of test results for mtDNA disorders are difficult because of mtDNA heteroplasmy. VOLVER/RETURN

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5.- FORENSE
Prueba de paternidad En nuestro laboratorio se realiza el anlisis de paternidad. Para este estudio se requiere muestra de sangre y/o saliva del presunto padre y del hijo; la madre es opcional. Tambin es posible realizar el anlisis en muestras fetales como lquido amnitico, vellosidad corial o sangre de cordn umbilical. La probabilidad de paternidad es excluyente al 100% mientras que, en el caso de que el presunto padre sea el padre biolgico, la probabilidad es del 99,99%. Otro de los requisitos es acompaar la muestra con el DNI de los individuos a realizar el anlisis o el libro de familia en caso de menores, as como una fotografa reciente de cada uno de ellos. Los resultados se entregarn en 2-3 semanas. PATERNITY DNA ANALYSIS We offer DNA analysis testing to determine paternity. This test requires a blood sample from the potential father(s) and the child(ren). A blood sample from the mother is optional. Fetuses can be tested by routine fetal sampling procedures (i.e., chorionic villus sampling or amniocentesis), or from cord blood at the time of birth. The accuracy of paternity DNA analysis is 100% if the potential father is excluded as the biological father of the child. If the potential father is included as the biological father of the child the accuracy is greater than 99.9%. This is the required certainty for a court of law. Interested individuals in the Boston area may call for an appointment to have their blood samples drawn at the Center for Human Genetics. Please note that we will require photo identification from adults and photographs will be taken of minors without photo identification. In addition, cheek swabs are available for young children and babies in lieu of a blood sample. The accuracy remains the same. Our laboratory can also accept samples drawn at outside institutions. Please call prior to drawing samples so that we can send you the appropriate legal forms to complete and send with the samples. Results can be expected in 2-3 weeks. VOLVER/RETURN

6.- OTRAS
Estudio de obesidad En las sociedades occidentales desarrolladas el aumento de la incidencia de personas con sobrepeso y obesidad hace que ste sea un problema con verdaderas caractersticas epidmicas. En Europa, los porcentajes de obesidad en adultos oscilan alrededor del 10-15% en hombres y el 15-20% en mujeres. La obesidad se asocia a importantes problemas de salud como la diabetes mellitus no dependiente de insulina, la hipertensin, enfermedades coronarias, diversos tipos de cncer y otras alteraciones, adems de representar un problema desde el punto de vista de los costes econmicos y de las complicaciones de tipo social, esttico y psiquitrico que origina. La obesidad es una patologa de tipo multifactorial en la que la contribucin ambiental es evidente, pero en la que se ha puesto de manifiesto el fuerte componente gentico. En nuestro laboratorio, elaboramos un perfil gentico de obesidad a partir de una muestra de sangre. Para ello, se analizan 40 SNPs (single nucleotide polymorphism), pertenecientes a 28 genes que se relacionan con la obesidad, asociando el genotipo obtenido en cada caso con la predisposicin o no a la obesidad y otras implicaciones de estos genes. Obesity Test
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Obesity is a condition that affects more than one-third of all adults and one in five children. It is considered an important risk factor that can lead to the development of diabetes, hypertension and cardiovascular disease. Obesity also increases one's risk of developing conditions such as high blood pressure, diabetes, heart disease, stroke, gall bladder disease and cancer of the breast, prostate and colon. Some people are more susceptible to obesity than others. Our genetics based obesity test is designed to look for SNPs in several key genes that are associated with obesity. We have created a powerful, proprietary methodology for SNP (single nucleotide polymorphism) based nutragenetic profiling. The nutragenetic profil provide a mean of predicting an individual's inherent genetic capacity to combat oxidative stress and other important selected areas of physiologic health. For that, we use 40 SNPs belonging to 28 genes. The test provides a score that can be used as a guide to determine what level of intervention or therapy would be helpful to combat or prevent the problems. VOLVER/RETURN

C.B.M. GENETAQ C/Frailes 28, 29012, Mlaga Telf. 952657605 www.genetaq.com

Rev 36 05/05/2009