Abstract
Hereditary hearing loss is a monogenic disease with high genetic heterogeneity. Variants in more than 100 deafness genes underlie the basis of its pathogenesis. The aim of this study was to assess the ratio of SNVs in known deafness genes contributing to the etiology of both sporadic and familial sensorineural hearing loss patients from China. DNA samples from 1127 individuals, including normal hearing controls (n = 616), sporadic SNHL patients (n = 433), and deaf individuals (n = 78) from 30 hearing loss pedigrees were collected. The NGS tests included analysis of sequence alterations in 129 genes. The variants were interpreted according to the ACMG/AMP guidelines for genetic hearing loss combined with NGS data from 616 ethnically matched normal hearing adult controls. We identified a positive molecular diagnosis in 226 patients with sporadic SNHL (52.19%) and in patients from 17 deafness pedigrees (56.67%). Ethnically matched MAF filtering reduced the variants of unknown significance by 8.7%, from 6216 to 5675. Some complexities that may restrict causative variant identification are discussed. This report highlight the clinical utility of NGS panels identifying disease-causing variants for the diagnosis of hearing loss and underlines the importance of a broad data of control and ACMG/AMP standards for accurate clinical delineation of VUS variants.
Highlights
Hearing impairment is one of the most common human disabilities
Genetic factors are estimated to be responsible for >60% of the cases [2, 3], and most of these cases are caused by a single nucleotide variants (SNVs), a small fraction by a small insertion–deletion variant or copy number variants (CNVs) [4, 5]
The comprehensive testing resulted in the identification of gene sequence alterations associated with the underlying genetic cause for hearing loss in 226 patients (52.19%), higher than the 41% identified among cases with multiethnic background [15] and ~40% among Japanese patients [31]
Summary
Hearing impairment is one of the most common human disabilities. 5% of the world’s population (~360 million people) suffer from disabling hearing. More people are affected by severe hearing loss than by epilepsy, multiple sclerosis, spinal injury, stroke, Huntington’s disease, and Parkinson’s disease combined [1]. Sensorineural hearing loss (SNHL) accounts for ~90% of all human hearing loss cases. Among these patients, genetic factors are estimated to be responsible for >60% of the cases [2, 3], and most of these cases are caused by a single nucleotide variants (SNVs), a small fraction by a small insertion–deletion (indel) variant or copy number variants (CNVs) [4, 5].
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