Sensorineural Hearing Loss: Study of GJB2 and GJB6 Genes Mutations in 275 Unrelated Patients from Semnan Province

Background and Aim : Mutations in the DFNB1 locus, including GJB2 and GJB6 genes, are the most common cause of autosomal recessive non-syndromic sensori-neural hearing loss worldwide. The spectrum and frequency of such mutations are population based. The aim of this study was to investigate the spectrum and prevalence of GJB2 mutations as well as screening of two common large deletions del(D13S1830) and del(D13S1854) of GJB6 gene in 275 unrelated consanguineous families from Semnan (Northeastern Iran).Methods : Pure tone audiometry at 250–8000 Hz was performed for patients and all had severe to profound hearing impairment. All DNA samples were screened for c.35delG mutation by allele specific polymerase chain reaction (AS-PCR) assay. Then, all patients who were negative or heterozygote for 35delG, were screened for large deletions del(GJB6- D13S1830) and del(GJB6-D13S1854) by multiplex PCR. Finally, the samples that remained unresolved after screening were further analyzed by direct sequencing of two exonic and flanking intronic regions of the GJB2 gene.Results : The results revealed 21 allelic variants of the GJB2 gene, 19 of which were recessive pathogenic variants. GJB2 mutations were detected in 15.82% of the alleles, and c.35delG was the most frequent pathogenic allele (43.68%) followed by splice site mutation c.IVS1+1G> A (12.64%). Thirteen genotypes with biallelic recessive pathogenic variants in the GJB2 gene (as homozygous or compound heterozygous state) were found in 32 out of 275 moderate to profound deaf patients (11.64%). None of del(GJB6- D13S1830) and del(GJB6-D13S1854) mutations were detected in the population studied.Conclusion : Our findings indicate that the c.35delG and c.IVS1+1G> A are the most frequent mutations of GJB2 gene in deaf population studied. However, low frequency of GJB2 mutations and lack of common GJB6 deleterious mutations clearly shows the involvement of other genes causing autosomal recessive non-syndromic sensori-neural hearing loss in Semnan population.

Keywords:

Hearing loss , Sensorineural , GJB2 , GJB6 , Semnan population