Prevalence of GJB2 (Connexin-26) and GJB6 (Connexin-30) Mutations in a Cohort of 300 Brazilian Hearing-Impaired Individuals: Implications for Diagnosis and Genetic Counseling


Autoria(s): BATISSOCO, Ana Carla; ABREU-SILVA, Ronaldo Serafim; BRAGA, Maria Cristina Celia; OTTO, Paulo Alberto; LEZIROVITZ, Karina; DELLA-ROSA, Valter; ALFREDO JR., Tabith; OTTO, Paulo Alberto; MINGRONI-NETTO, Regina Celia
Contribuinte(s)

UNIVERSIDADE DE SÃO PAULO

Data(s)

20/10/2012

20/10/2012

2009

Resumo

Objective: Hereditary nonsyndromic deafness is an autosomal recessive condition in about 80% of cases, and point mutations in the GJB2 gene (connexin 26) and two deletions in the GJB6 gene (connexin 30), del(GJB6-D13S1830) and del(GJB6-D13S1854), are reported to account for 50% of recessive deafness, Aiming at establishing the frequencies of GJB2 mutations and GJB6 deletions in the Brazilian population, we screened 300 unrelated individuals with hearing impairment, who were not affected by known deafness related syndromes. Methods: We firstly screened the most frequently reported mutations, c.35delG and c.167delT in the GJB2 gene, and del(GJB6-D13S1830) and del(GJB6-D13S1854) in the GJB6 gene, through specific techniques. The detected c.35delG and c.167delT mutations were validated by sequencing. Other mutations in the GJB2 gene were screened by single-strand conformation polymorphism and the coding region was sequenced when abnormal patterns were found. Results: Pathogenic mutations in GJB2 and GJB6 genes were detected in 41 individuals (13.7%), and 80.5% (33/41) presented these mutations in homozygosis or compound heterozygosis, thus explaining their hearing defect. The c.35delG in the GJB2 gene was the most frequent mutation (37/300; 12.4%), detected in 23% familial and 6.2% the sporadic cases. The second most frequent mutation (1%; 3/300) was the del(GJB6- D13S1830), always found associated with the c.35delG mutation. Nineteen different sequence variations were found in the GJB2 gene. In addition to the c.35delG mutation, nine known pathogenic alterations were detected 0 67delT, p.Trp24X, p.Val37lle, c.176_191del16, c.235delC, p.Leu90Pro, p.Arg127His, c.509insA, and p.Arg184Pro, Five substitutions had been previously considered benign polymorphisms: c.-15C>T, p.Val27lle, p.Met34hr, p.Ala40Ala, and p.Gly160Ser. Two previously reported Mutations of unknown pathogenicity were found (p.Lys168Arg, and c.684C>A), and two novel substitutions, p.Leu81Val (c.G241C) and p.Met195Val (c.A583G), both in heterozygosis without an accompanying mutation in the other allele. None of these latter four variants of undefined status was present in a sample of 100 hearing controls. Conclusions: The present study demonstrates that Mutations in the GJB2 gene and del(GJB6 D13S1830) are important causes of hearing impairment in Brazil, thus justifying their screening in a routine basis. The diversity of variants in our sample reflects the ethnic heterogeneity of the Brazilian population.

CEPID

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

FAPESP

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

CNPq

Identificador

EAR AND HEARING, v.30, n.1, p.1-7, 2009

0196-0202

http://producao.usp.br/handle/BDPI/27661

http://apps.isiknowledge.com/InboundService.do?Func=Frame&product=WOS&action=retrieve&SrcApp=EndNote&UT=000262312000001&Init=Yes&SrcAuth=ResearchSoft&mode=FullRecord

Idioma(s)

eng

Publicador

LIPPINCOTT WILLIAMS & WILKINS

Relação

Ear and Hearing

Direitos

restrictedAccess

Copyright LIPPINCOTT WILLIAMS & WILKINS

Palavras-Chave #AUTOSOMAL-RECESSIVE DEAFNESS #DEL(GJB6-D13S1830) MUTATION #MOLECULAR-GENETICS #LARGE DELETION #POPULATION #EXPRESSION #FREQUENCY #AMERICAN #ORIGINS #Otorhinolaryngology
Tipo

article

original article

publishedVersion