Prevalence of p.V37I variant of GJB2 in mild or moderate hearing loss in a pediatric population and the interpretation of its pathogenicity.

Sun O Chang,Seung Ha Oh,Kyu-Hee Han,Woong-Yang Park,Ahreum Kim,Byung Yoon Choi,Ja-Won Koo,So Young Kim,Gibeom Park

doi:10.1371/journal.pone.0061592

Abstract

A p.V37I variant of GJB2 has been reported from subjects with moderate or slight hearing loss especially in East Asian populations. This study aimed to estimate the prevalence of the p.V37I variant among such subjects and prove, epidemiologically, its pathogenic potential to cause mild hearing loss. A total of 380 subjects from 201 families with hearing loss were enrolled. From them, 103 families were selected who had autosomal recessive inheritance or sporadic occurrence of hearing loss and who were younger than 15 years old. GJB2 sequencing was carried out for the probands of all 103 families. The prevalence of the p.V37I variant was compared between the subtle, mild or moderate hearing loss (group I) and the severe or profound hearing loss (group II) groups. Where possible, a targeted next generation sequencing of 82 deafness genes was performed from the p.V37I carrier to exclude the existence of other pathogenic genes. Five (4.8%) of 103 probands were found to carry p.V37I. The carrier frequency of p.V37I among group I (18.2%) was significantly higher than that of group II (1.2%) or the reported Korean normal hearing control group (1.0%). Detection of the p.V37I variant of GJB2 in 18.2% of Koreans with mild hearing loss strongly suggests its contribution to the pathogenesis of milder hearing loss, which might justify sequencing of GJB2 from these subjects in the Korean population.

Highlights

Despite significant heterogeneity of genetic deafness, GJB2 causes more than 50% of autosomal recessive nonsyndromic deafness in many populations [1,2]
The variant was detected in a trans configuration with a known pathogenic variant in three subjects and as a monoallelic variant in two subjects
The carrier frequency of the p.V37I allele was calculated as 18.2% among Korean subjects with moderate or slight hearing loss in this study

Summary

Introduction

Despite significant heterogeneity of genetic deafness, GJB2 (encoding Gap junction beta-2 protein, known as connexin 26) causes more than 50% of autosomal recessive nonsyndromic deafness in many populations [1,2]. More than 100 different pathogenic mutations and 24 polymorphisms have been identified within the GJB2 gene (http://davinci.crg.es/deafness/) [3]. The mutational spectra often vary among different ethnic groups. The p.V37I is another GJB2 variant that is frequently found in East Asian populations [10,11,12,13]. The variant resides in transmembrane M1 domain in beta connexins [14]. The p.V37I variant has been frequently observed to be associated with mild to moderate hearing loss [15,16]

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Conclusion