Abstract
BackgroundHereditary hearing loss is genetically heterogeneous, and hundreds of mutations in than 60 genes are involved in this disease. Therefore, it is difficult to identify the causative gene mutations involved. In this study, we combined targeted genomic capture and massively parallel sequencing (MPS) to address this issue.MethodsUsing targeted genomic capture and MPS, 104 genes and three microRNA regions were selected and simultaneously sequenced in 23 unrelated probands of Chinese families with nonsyndromic hearing loss. The results were validated by Sanger sequencing for all available members of the probands’ families. To analyze the possible pathogenic functional effects of the variants, three types of prediction programs (Mutation Taster, PROVEAN and SIFT) were used. A total of 195 healthy Chinese Han individuals were compared as controls to verify the novel causative mutations.ResultsOf the 23 probands, six had mutations in DFNA genes [WFS1 (n = 2), COCH, ACTG1, TMC1, and POU4F3] known to cause autosomal dominant nonsyndromic hearing loss. These included one novel in-frame indel mutation, three novel missense mutations and two reported missense mutations. Furthermore, one proband from a family with recessive DFNB carried two monoallelic mutations in the GJB2 and USH2A genes. All of these mutations co-segregated with the hearing loss phenotype in 36 affected individuals from 7 families and were predicted to be pathogenic.ConclusionsMutations in uncommon deafness genes contribute to a portion of nonsyndromic deafness cases. In the future, critical gene mutations may be accurately and quickly identified in families with hereditary hearing loss by targeted genomic capture and MPS.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-014-0311-1) contains supplementary material, which is available to authorized users.
Highlights
Hearing loss is an extremely common problem worldwide, and it is one of the most genetically heterogeneous disorders occurring in humans
We found six deleterious non-synonymous mutations: COCH, p.G38D; WFS1, p.R653C; ACTG1, p.E316K; TMC1, p.D572N; POU4F3, p.P164R and USH2A, p.P1684L
Using targeted genomic capture and massively parallel sequencing (MPS), we have successfully identified causative gene mutations in six families with autosomal dominant nonsyndromic hearing loss (NSHL), and in patients from a family with recessive DFNB, we detected two monoallelic mutations in the GJB2 and USH2A genes, respectively
Summary
Hearing loss is an extremely common problem worldwide, and it is one of the most genetically heterogeneous disorders occurring in humans. WES uses next-generation technologies to provide a transformational approach for identifying causative mutations of Mendelian disorders. Different targeted genomic capture methods and MPS have been successfully applied to detect gene mutations in relatively small sets of deafness families [6,7,8,9]. We performed targeted genomic capture and MPS to screen 104 genes and three microRNA regions that are known to be responsible for hereditary hearing loss in 23 unrelated probands of Chinese families with NSHL. Hereditary hearing loss is genetically heterogeneous, and hundreds of mutations in than 60 genes are involved in this disease. We combined targeted genomic capture and massively parallel sequencing (MPS) to address this issue
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have