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

• Type of Material: Article
• Authors: Xue Gao, PLA General Hospital; Sha-Sha Huang, PLA General Hospital; Yong-Yi Yuan, PLA General Hospital; Guo-Jian Wang, PLA General Hospital; Jin-Cao Xu, Second Artillery General Hospital; Yu-Bin Ji, Second Artillery General Hospital; Ming-Yu Han, PLA General Hospital; Fei Yu, PLA General Hospital; Dong-Yang Kang, PLA General Hospital; Xi Lin, Emory University; Pu Dai, PLA General Hospital
• Language: English
• Date: 2015-10-01
• Publisher: Wiley
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2015 Wiley Periodicals, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1002/ajmg.a.37206
• Title of Journal or Parent Work: American Journal of Medical Genetics Part A
• ISSN: 1552-4825
• Volume: 167
• Issue: 10
• Start Page: 2357
• End Page: 2365
• Grant/Funding Information: This work was supported by grants from the Project of the National Natural Science Foundation of China (Grant Nos. 30801285, 81230020, 81200751, 81000415, 81371098, 81371096, 81400471, 81371352), grants from China Postdoctoral Science Foundation (2012M521878, 2013T60947), a grant from Military Twelfth Five-year Project of China (CWS115034), a grant from Minister of Science and Technology of China (2012BAI09B02), grants from the National Basic Research Program of China (973 Program) (2014CB541706, 2014CB541701) and a grant from Minister of Health of China (201202005).; Work performed in the Lin lab was supported by a grant from NIH (R33 DC010476).
• Keywords: DEAFNESS; massively parallel sequencing; HAIR-CELL-FUNCTION; CHANNEL; Otolaryngology; Science & Technology; DFNA36; targeted gene capture; MECHANOTRANSDUCTION; MOUSE; IMPAIRMENT; INNER-EAR; MUTATIONS; PROTEIN; TMC1; Life Sciences & Biomedicine; Genetics & Heredity; autosomal dominant nonsyndromic hearing loss
• Research Categories: Health Sciences, General; Biology, Genetics

Abstract

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.