Association between the p.V37I variant of GJB2 and hearing loss: a pedigree and meta-analysis.

Na Shen,Yaowu Zhu,Aiguo Liu,Xiong Wang,Yanjun Lu,Jing Peng,Weiyong Liu

doi:10.18632/oncotarget.17325

Abstract

Pathogenic variants in the gap junction protein beta-2 (GJB2) gene are the most common cause of hearing loss. Of these, the p.V37I variant of GJB2 has a high allele frequency (up to 10%) in East Asians. Characterization of the phenotypic spectrum associated with p.V37I, as well as the role of this variant in the onset of hearing loss could have a remarkable effect on future diagnostic strategies. Here, we performed a pedigree analysis of unrelated families exhibiting various hearing phenotypes, and then conducted a meta-analysis to comprehensively assess the association between the p.V37I and the risk of hearing loss. Pedigree analyses showed that both homozygous p.V37I variants, as well as compound heterozygous p.V37I with other GJB2 pathogenic variants, contributed to various phenotypes of hearing loss. Meanwhile, meta-analysis demonstrated that, compared with those in the wild type group, both p.V37I homozygotes and compound heterozygous p.V37I variants were at significantly higher risk of developing hearing loss (odds ratios = 7.14 and 3.63; 95% confidence intervals = 3.01-16.95 and 1.38–9.54, respectively). Conversely, heterozygous p.V37I variants alone did not increase the risk of hearing loss. Given the high allele carriage rate of p.V37I (up to 10%) within the general population, our work not only provides information that might influence future genetic screening policies, but also offers insight into clinical risk evaluation and genetic counseling regarding hearing loss.

Highlights

Hearing loss (HL) is the most sensory defect that affects 1-3 in every 1,000 newborns worldwide, and half of these cases are attributed to genetic factors [1]
The identification of increasing numbers of HL patients that are homozygous for p.V37I, or compound heterozygous www.impactjournals.com/oncotarget for p.V37I and other gap junction protein beta-2 (GJB2) pathogenic variants, indicates that p.V37I likely increases the risk of HL, for mild-to-moderate cases [6, 12,13,14,15]
Compound heterozygous p.V37I variants were defined as the p.V37I allele in a trans configuration with another pathogenic mutant allele of GJB2 gene

Summary

Introduction

Hearing loss (HL) is the most sensory defect that affects 1-3 in every 1,000 newborns worldwide, and half of these cases are attributed to genetic factors [1]. The p.V37I (c.109G>A) variant of GJB2 has a high allele frequency (up to 10%) among East Asian populations [4,5,6]. This variant, harboring a missense substitution from valine to isoleucine at codon 37, was first identified by Kelley et al in 1998 [7]. The identification of increasing numbers of HL patients that are homozygous for p.V37I, or compound heterozygous www.impactjournals.com/oncotarget for p.V37I and other GJB2 pathogenic variants, indicates that p.V37I likely increases the risk of HL, for mild-to-moderate cases [6, 12,13,14,15]. A recent meta-analysis reported an insignificant association between the carriage rates of p.V37I and HL, which aroused wide concern regarding the pathogenicity of this variant [16]

Methods

Results

Conclusion