Novel compound heterozygous mutations in the MYO15A gene in autosomal recessive hearing loss identified by whole-exome sequencing

Xue Gao,Ming-Yu Han,Dong-Yang Kang,Qing-Yan Zhu,Sha-Sha Huang,Pu Dai,Feng Xin,Li-Ping Guan,Jian-Guo Zhang,Yue-Shuai Song,Yong-Yi Yuan,Guo-Jian Wang

doi:10.1186/1479-5876-11-284

Abstract

BackgroundInherited genetic defects play an important role in congenital hearing loss, contributing to about 60% of deafness occurring in infants. Hereditary nonsyndromic hearing loss is highly heterogeneous, and most patients with a presumed genetic etiology lack a specific molecular diagnosis.MethodsBy whole exome sequencing, we identified responsible gene of family 4794 with autosomal recessively nonsyndromic hearing loss (ARNSHL). We also used DNA from 56 Chinese familial patients with ARNSHL (autosomal recessive nonsyndromic hearing loss) and 108 ethnicity-matched negative samples to perform extended variants analysis.ResultsWe identified MYO15A c.IVS25 + 3G > A and c.8375 T > C (p.V2792A) as the disease-causing mutations. Both mutations co-segregated with hearing loss in family 4794, but were absent in the 56 index patients and 108 ethnicity-matched controls.ConclusionsOur results demonstrated that the hearing loss of family 4794 was caused by novel compound heterozygous mutations in MYO15A.

Highlights

Hearing loss is a common sensory defect that can significantly impact quality of life
Audiograms of the affected siblings showed that the hearing loss was bilateral and severe to profound (Figure 1B)
We focused only on non-synonymous variants, splice acceptor and donor site mutations, and frameshift coding indels, which were more likely to be pathogenic than others, especially those in homozygous or compound heterozygous mode (Additional file 2: Table S2)

Summary

Introduction

Hearing loss is a common sensory defect that can significantly impact quality of life. Nonsyndromic hereditary forms, in which the hearing loss is the only clinical sign, are genetically heterogeneous. Whole-exome sequencing (WES) has become a highly efficient strategy for identifying novel causative genes and mutations involved in heritable disease [2]. Both simple nonsyndromic and complex syndromic forms of hearing loss can be resolved efficiently using WES, especially in small families with distinct and interesting phenotypes that were once too small to map [3]. Inherited genetic defects play an important role in congenital hearing loss, contributing to about 60% of deafness occurring in infants. Hereditary nonsyndromic hearing loss is highly heterogeneous, and most patients with a presumed genetic etiology lack a specific molecular diagnosis

Methods

Results

Conclusion