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

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.

Hereditary bilateral sudden sensorineural hearing loss

“…However, half of them were observations from deaf families with several affected family members where genetic etiology of hearing loss could be expected. With one exception (19) they also occurred in association with those GJB2 variants which generally cause hearing loss of mild to moderate degree, such as c.269T>C, c.235delC and c.109G>A. Additionally, patients homozygous or compound heterozygous for the variant c.109G>A have often delayed hearing loss onset and rarely they may even have normal hearing, which led to past concerns regarding its pathogenicity (22,23). Moreover, SSNHL episodes in previously published cases did not occur in normal hearing individuals, but as a rapid worsening of previously diagnosed hearing loss.…”

Whole-exome sequencing identifies a novel missense variant within LOXHD1 causing rare hearing loss in a Chinese family

“…To identify the genetic cause of NSHL in this proband, we routinely applied a Sanger sequencing of four common HL-associated genes, including gap junction protein beta-2 ( GJB2 ), gap junction protein beta-3 ( GJB3 ), solute carrier family 26 member 4 ( SLC26A4 ) and mitochondrially encoded 12S RNA ( MT-RNR1 ). DNA preparation, PCR conditions and Sanger sequencing process were described previously [23]. The coding regions of GJB2 and GJB3 , hotspot region (exon7–8 and exon19) of SLC26A4 , and the full-length region of MT-RNR1 were carefully screened, only a homozygous variant, m.827A > G within MT-RNR1 , was identified.…”

Systematic evaluation of gene variants linked to hearing loss based on allele frequency threshold and filtering allele frequency

“…It should be reassuring for clinicians that over 85% of all presumably pathogenic variants were ultra-rare with observed AFs below 0.05% in bottom-up analysis. However, application of the gnomAD and ExAC filtering AF to 74 reported variants with unexpectedly high observed AFs (i.e., over our AF thresholds) allowed us to safely consider 47 variants with still high filtering AFs as not likely NSHL-related, with the notorious exception of one variant ( GJB2 c.109G > A; p.Val37Ile) 23 . Two pathogenic variants identified by the NSHL-specific ACMG guidelines were among those reclassified from “common” to “rare” by application of the filtering AF, suggesting high clinical utility and accuracy of the AF thresholds determined in this study: 0.1% for dominant genes and 0.6% for recessive genes.…”