2018 Volume 93 Issue 5 Pages 171-179
Autosomal dominant non-syndromic hearing loss (ADNSHL) is characterized by postlingual progressive onset. Due to its high genetic heterogeneity, it is difficult to perform a molecular diagnosis for most patients with ADNSHL. In our study, whole-exome sequencing (WES) was used to screen pathogenic gene candidates by analyzing genomic DNA samples from a large Chinese family (JSNY-067), including the proband and her father, who suffered from non-syndromic hearing loss. The pathogenicity of candidate nonsynonymous variants in ADNSHL genes was evaluated by co-segregation analysis in family members by direct PCR and Sanger sequencing. Furthermore, multiple in silico analyses (SIFT, Polyphen2, PROVEAN and MutationTaster) and molecular dynamics simulation were used to assess the potential pathogenicity of the candidate mutations. We identified a novel causative mutation, c.622A>G in MYO6 (DFNA22), that resulted in a p.K208E substitution. This mutation co-segregated with the hearing loss phenotype in extended family members, and was predicted to be pathogenic by SIFT, PolyPhen2, PROVEAN and MutationTaster. Furthermore, molecular dynamics simulation analysis revealed that the p.K208E substitution had a limited influence on the whole protein structure and stability, but that it could affect the locations of the sidechains of nearby hydrophilic residues, which in turn resulted in the sidechains of Asn186 and Glu190 being exposed more frequently at the surface of the protein. WES has thus been shown to be a useful molecular diagnostic tool in screening uncommon gene mutations associated with hereditary hearing loss.