Unique Mutational Spectrum of the GJB2 Gene and its Pathogenic Contribution to Deafness in Tuvinians (Southern Siberia, Russia): A High Prevalence of Rare Variant c.516G>C (p.Trp172Cys).

Olga L Posukh,Nikolay A Barashkov,Ekaterina A Maslova,Igor V Morozov,Marina V Zytsar,Vladimir N Maximov,Michael I Voevoda,Alexander A Bondar,Valeria Yu Danilchenko,Marita S Bady-Khoo

doi:10.3390/genes10060429

Abstract

Mutations in the GJB2 gene are the main cause for nonsyndromic autosomal recessive deafness 1A (DFNB1A) in many populations. GJB2 mutational spectrum and pathogenic contribution are widely varying in different populations. Significant efforts have been made worldwide to define DFNB1A molecular epidemiology, but this issue still remains open for some populations. The main aim of study is to estimate the DFNB1A prevalence and GJB2 mutational spectrum in Tuvinians—an indigenous population of the Tyva Republic (Southern Siberia, Russia). Sanger sequencing was applied to analysis of coding (exon 2) and non-coding regions of GJB2 in a cohort of Tuvinian patients with hearing impairments (n = 220) and ethnically matched controls (n = 157). Diagnosis of DFNB1A was established for 22.3% patients (28.8% of familial vs 18.6% of sporadic cases). Our results support that patients with monoallelic GJB2 mutations (8.2%) are coincidental carriers. Recessive mutations p.Trp172Cys, c.-23+1G>A, c.235delC, c.299_300delAT, p.Val37Ile and several benign variants were found in examined patients. A striking finding was a high prevalence of rare variant p.Trp172Cys (c.516G>C) in Tuvinians accounting for 62.9% of all mutant GJB2 alleles and a carrier frequency of 3.8% in controls. All obtained data provide important targeted information for genetic counseling of affected Tuvinian families and enrich current information on variability of GJB2 worldwide.

Highlights

Hearing loss (HL) is one of the most common sensory disorders, affecting one in500–1000 newborns, and approximately half of congenital HL cases have a genetic etiology [1].The genetic causes for HL are extremely heterogeneous: over 400 syndromes are associated with HL [2]Genes 2019, 10, 429; doi:10.3390/genes10060429 www.mdpi.com/journal/genesGenes 2019, 10, 429 and over 100 different genes are causally implicated in nonsyndromic HL [3]
Based on the pedigree data, we found that 20 out of 23 familial DFNB1A-patients were from 11 unrelated families with two and more deaf siblings representing typical autosomal recessive type of HL inheritance, and not all affected individuals in these families were examined by us, untested siblings in these Tuvinian families obviously have the same type of HL
Based on pedigree data, we suggest that contribution of the GJB2 mutations to HL in deaf Tuvinians may be more than 22.3% due to probable DFNB1A-cases in untested affected relatives of examined patients, making our results applicable in genetic testing and counseling for a larger number of deaf patients in the Tyva Republic

Summary

Introduction

Hearing loss (HL) is one of the most common sensory disorders, affecting one in500–1000 newborns, and approximately half of congenital HL cases have a genetic etiology [1].The genetic causes for HL are extremely heterogeneous: over 400 syndromes are associated with HL [2]Genes 2019, 10, 429; doi:10.3390/genes10060429 www.mdpi.com/journal/genesGenes 2019, 10, 429 and over 100 different genes are causally implicated in nonsyndromic HL [3]. The genetic causes for HL are extremely heterogeneous: over 400 syndromes are associated with HL [2]. Despite the extraordinary genetic heterogeneity of nonsyndromic HL, homozygous or compound heterozygous mutations in the GJB2 gene (gap junction protein, β-2, OMIM 121011, 13q12.11) encoding transmembrane protein connexin 26 (Cx26) are the most common cause of nonsyndromic autosomal recessive deafness 1A (DFNB1A, OMIM 220290) in many populations [4]. Six connexin 26 molecules associate to form transmembrane hexameric hemichannels (connexons) which dock with hemichannels of adjacent cells forming gap junctions that are essential for the transport of ions and other low-molecular-weight components between cells. High prevalence of the GJB2-associated HL was demonstrated in most populations [1,6,7] making

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