Prevalence of the 35delG mutation in the GJB2 gene in two samples of non-syndromic deaf subjects from Chile

Hearing loss is the most common inherited sensorial deficiency in humans; about 1 in 1000 children suffer from severe or profound hearing loss at birth. Mutations in the GJB2 gene are the most common cause of prelingual, non-syndromic autosomal recessive deafness in many populations; the c.35delG mutation is the most common in Caucasian populations. The frequency of the c.35delG mutation was estimated in two samples of deaf patients from Santiago, Chile. Unrelated non-syndromic sensorioneural deaf patients were examined: Group 1 consisted of 47 unrelated individuals with neurosensory deafness referred to the Chilean Cochlear Implant Program; Group 2 included 66 school children with prelingual deafness attending special education institutions for deaf people. Individuals with profound to moderate isolated neurosensory hearing loss with unknown etiology were included. The presence of the c.35delG mutation was evaluated by the allele-specific polymerase chain reaction method (PCR), and in some cases it was confirmed by direct DNA sequencing of the coding region of the GJB2 gene. Deaf relatives were present in 20.3% of the cases. We found 19.5% (22/113) patients with the c.35delG mutation, 6 of them homozygous; these rates are similar to frequencies found in other Latin American countries.

Frecuencia de la mutación 35delG del gen GJB2 (conexina 26) en una muestra de escolares sordos de Santiago / Frequency of the 35delG mutation of GJB2 (connexin 26) in a sample of deafschool children in Santiago

Introducción: Se estima que 1 de cada 1.000 niños presenta hipoacusia severa al nacimiento o en los primeros meses de vida y el 50 por ciento de las hipoacusias congénitas se relacionan con el gen de la conexina 26 (GJB2). En poblaciones caucásicas la variante patogénica 35delG del gen GJB2, que es la más frecuente, se encuentra en 30 por ciento de los pacientes con hipoacusia congénita no sindrómica. En Chile, la frecuencia de esta variante en escolares sordos no está descrita. Objetivos: Estimar la frecuencia de la mutación 35delG del gen GJB2 en niños con sordera congénita no sindrómica y no atribuible a causas ambientales conocidas, de colegios especiales de Santiago. Correlacionar la presencia de 35delG con los antecedentes clínicos de estos niños. Material y método: Se determinó la presencia de la mutación 35delG mediante PCR alelo específico y secuenciación automatizada en 81 escolares. Se buscó asociar la presencia de 35delG y los antecedentes clínicos de los niños mediante la prueba exacta de Fisher. Resultados: En el grupo estudiado, el 11,25 por ciento de los casos presentaron la variante 35delG, siendo ésta más frecuente en los casos en que había antecedentes familiares de sordera. En 8 casos se encontró una variante considerada no patogénica V27I. Conclusión: La frecuencia de la mutación 35delG fue inferior a lo esperado, probablemente debido al método de selección de los niños a estudiar (aquellos cuyos padres no referían causa conocida de sordera, lo cual no fue refrendado por exámenes de laboratorio que permitieran descartar enfermedades infecciosas u otras condiciones causantes de sordera).

Introduction: Congenital hearing loss occurs in 1 in 1000 live births and 50 percent of these cases are related with mutations in the connexin26 gene (GJB2). The 35delG variant is the most common of the known pathogenic alleles in Caucasian populations, reaching a frequency of 30 percent among the non syndromic congenital deaf people. The frequency of this variant has not been described in Chilean deaf children. Aim: To estimate the frequency of the 35delG GJB2 gene mutation in children with non syndromic congenital hearing loss of unknown etiology from deaf schools in Santiago, and to evaluate the association between clinical features of these children and the presence of the 35delG allele. Material and method: The presence of the 35delG mutation was studied by allele specific PCR and automatical sequencing in 81 children. The association between clinical issues and genotypes was explored by Fisher exact test. Results: We found the 35delG variant in 11,25 percent of the children, this mutation was more frequent in familial cases than sporadic cases of deafness. We also found the V27I non pathogenic variant in 8 cases. Conclusion: The frequency of the 35delG mutation was lower than the expected, probably due to the criterion used to select the school children to be studied.

Correlação entre dados audiométricos e mutação 35delG em dez pacientes / Correlation between audiometric data and the 35delG mutation in ten patients

Mutações no gene da conexina 26 parecem ser extremamente comuns na gênese da surdez hereditária não-sindrômica, especialmente, a mutação 35delG, mas ainda há poucos estudos que descrevem as características audiométricas dos pacientes portadores dessas mutações. OBJETIVO: Analisar as características audiométricas em pacientes com mutações no gene da conexina 26 para se delinear uma correlação genótipo-fenótipo. CASUÍSTICA E MÉTODO: Foram avaliadas audiometrias tonal de 33 casos-índice com surdez sensorioneural não-sindrômica e de 8 familiares afetados. Testes moleculares específicos foram realizados para analisar mutações no gene da conexina 26. FORMA DE ESTUDO: Estudo de casos, retrospectivo, em corte transversal. RESULTADOS: Foram encontradas as prevalências de 27,3 por cento da mutação 35delG nos casos-índice e de 12,5 por cento nos familiares afetados. Em relação aos graus de perda, foram encontrados, 41,5 por cento dos pacientes com grau profundo, 39,0 por cento com grau grave e 19,5 por cento com grau moderado com, os pacientes homozigotos e heterozigotos para 35delG, predominando nos graus moderado-grave. CONCLUSÃO: Estes resultados sugerem que os dados audiométricos, associados ao diagnóstico molecular para a surdez, permitiram delinear uma correlação genótipo-fenótipo em dez pacientes com a mutação 35delG. Mas é necessário estudo multicêntrico para se verificar a real expressão fenotípica na população brasileira relacionada à mutação 35delG.

Mutations in the connexin 26 gene seem to be extremely common in non-syndromic hereditary deafness genesis, especially the 35delG, but there are still only a few studies that describe the audiometric characteristics of patients with these mutations. AIM: to analyze the audiometric characteristics of patients with mutations in the connexin 26 gene in order to outline genotype-phenotype correlation. MATERIALS AND METHODS: Tonal audiometries of 33 index cases of non-syndromic sensorineural hearing loss were evaluated and eight affected relatives. Specific molecular tests were carried out to analyze mutations in the connexin 26 gene. EXPERIMENT DESING: Retrospective, cross-sectional study. RESULTS: A 27.3 percent prevalence of mutation 35delG was found in the index cases and 12.5 percent among the relatives affected. In relation to hearing loss degree, 41.5 percent of the patients were found with profound hearing loss, 39 percent with severe HL and 19.5 percent with moderate HL with homozygote and heterozygote patients for the 35delG predominating in the severe-moderate hearing losses. CONCLUSION: Our results suggest that the audiometric data associated with the molecular diagnose of hearing loss helped us to outline a genotype-phenotype correlation in ten patients with 35delG mutation. However, it is still necessary to run multicentric studies to verify the real phenotypic expression in the Brazilian population, as far as the 35delG mutation is concerned.