Targeted gene capture and massively parallel sequencing identify TMC1 as the causative gene in a six-generation Chinese family with autosomal dominant hearing loss.

Hereditary nonsyndromic hearing loss is extremely heterogeneous. Mutations in the transmembrane channel-like gene1 (TMC1) are known to cause autosomal dominant and recessive forms of nonsyndromic hearing loss linked to the loci of DFNA36 and DFNB7/11, respectively. We characterized a six-generation Chinese family (5315) with progressive, postlingual autosomal dominant nonsyndromic hearing loss (ADNSHL). By combining targeted capture of 82 known deafness genes, next-generation sequencing and bioinformatic analysis, we identified TMC1 c.1714G>A (p. D572N) as the disease-causing mutation. This mutation co-segregated with hearing loss in other family members and was not detected in 308 normal controls. In order to determine the prevalence of TMC1 c.1714G>A in Chinese ADNSHL families, we used DNA samples from 67 ADNSHL families with sloping audiogram and identified two families carry this mutation. To determine whether it arose from a common ancestor, we analyzed nine STR markers. Our results indicated that TMC1 c.1714G>A (p.D572N) account for about 4.4% (3/68) of ADNSHL in the Chinese population.