Molecular epidemiology of Chinese Han deaf patients with bi-allelic and mono-allelic GJB2 mutations

Xiaoyu Yu,Jun Xu,Lin Li,Yun Lin,Tao Yang,Hao Wu,Tuanjie Che

doi:10.1186/s13023-020-1311-2

Abstract

BackgroundRecessive mutations in GJB2 is the most common cause of genetic hearing loss worldwide. The aim of this study is to determine the spectrum and frequency of GJB2 variants in Chinese Han deaf patients and to investigate the underlying causative genes in patients with mono-allelic GJB2 mutations.MethodsWe analyzed the mutation screening results of GJB2 in 1852 Chinese Han probands with apparently autosomal-recessive hearing loss in our laboratory. Targeted next-generation sequencing of 139 known deafness-related genes were performed in 44 probands with mono-allelic GJB2 mutations.ResultsBi-allelic GJB2 mutations was identified in 25.65% of patients, in which the c.235delC (p.L79Cfs*3) mutation is the most frequent cause for both severe-to-profound (84.93%) and mild-to-moderate hearing loss (54.05%), while the c.109G > A (p.V37I) mutation is another frequent cause for mild-to-moderate hearing loss (40.54%). In 3.89% of patients only one mutant allele can be identified in GJB2. Targeted next generation sequencing in 44 such probands revealed digenic heterozygous mutations in GJB2/GJB6 and GJB2/GJB3 as the likely pathogenic mechanism in three probands. In 13 probands, on the other hand, pathogenic mutations in other deafness-associated genes (STRC, EYA1, MITF, PCDH15, USH2A, MYO15A, CDH23, OTOF, SLC26A4, SMPX, and TIMM8A) can be identified as the independent genetic cause, suggesting that the mono-allelic GJB2 mutations in those probands is likely co-incidental.ConclusionsOur results demonstrated that GJB2 should be a primary target for mutation screening in Chinese Han deaf patients, and those with mono-allelic GJB2 mutations should be further screened by next generation sequencing.

Highlights

Hearing loss is a heterogeneous disorder that affects language acquisition and social skill development in children
Spectrum and genotype-phenotype correlation of GJB2 mutations Sanger sequencing of both the coding and noncoding exon and flanking sites of GJB2 in 1852 Chinese Han deaf probands identified a total of 47 different mutations
Additional or alternative causes in patients with monoallelic GJB2 mutations In our cohort, we found 72 (3.89%) deaf probands carrying only a single recessive pathogenic mutation of GJB2 (Additional file 1: Table S1, the heterozygous c.109G > A variant is not included in this group due to its incomplete penetrance and high frequency in the general population of Chinese Hans [13])

Summary

Introduction

Hearing loss is a heterogeneous disorder that affects language acquisition and social skill development in children. There have been over 100 genes identified to cause non-syndromic hearing loss and over 700 genetic syndromes described with features of hearing loss. Mutations in a single gene GJB2 (OMIM 121011) account for a large proportion of nonsyndromic hearing loss in most populations worldwide [2]. A number of missense mutations may lead to autosomal dominant non-syndromic hearing loss DFNA3 and autosomal dominant syndromic hearing loss associated with hyperproliferative epidermal disorders [5, 6]. Recessive mutations in GJB2 is the most common cause of genetic hearing loss worldwide. The aim of this study is to determine the spectrum and frequency of GJB2 variants in Chinese Han deaf patients and to investigate the underlying causative genes in patients with mono-allelic GJB2 mutations

Objectives

Methods

Results

Discussion

Conclusion