Evolutionary origin of pathogenic GJB2 alleles in China

Abstract

The frequency of the pathogenic allele of the autosomal recessive deafness gene GJB2 varies among different populations in the world, and accumulates to a sufficiently high frequency in certain population. The purpose of this study is to investigate the origin and evolution of GJB2 pathogenic alleles in Chinese deaf patients.Children with non-syndromic hearing loss, and their parents, from 295 families were recruited. Customized capture probes targeted at 943 single nucleotide polymorphisms (SNPs) related to GJB2 gene were designed for sequencing of genomic DNA in blood samples. Haplotypes carrying pathogenic allele were analyzed through linkage disequilibrium block building, ancestry tracing, and extended haplotype heterozygosity calculation. Two pathogenic GJB2 alleles, c.235delC (18.41%) and c.109G > A (15.57%), were observed in 867 donors. For c.235delC allele, three different core haplotypes with one major haplotype (97.32%) were found, and their core SNPs were 100% conserved. For c.109G > A allele, six different haplotypes with one major haplotype (93.28%) were found and the major c.109G > A allele evolved from a specific ancestral haplotype. Geographical origins of donors carrying GJB2 c.109G > A and c.235delC core haplotypes centered between Qinghai and Neimenggu. GJB2 c.235delC has long-range linkage disequilibrium. No positive selection signature was found for GJB2 c.235delC or c.109G > A in the studied population.In conclusion, we discovered a single origin of GJB2 c.235delC allele and multiple independent origins of GJB2 c.109G > A allele. Alternative to positive selection or multiple independent recurrent mutation event, population bottleneck effect might account for the observed high population frequency of these pathogenic alleles.

Identification of four novel variants in the CDH23 gene from four affected families with hearing loss

“…In addition, the affected child in family four also carried a heterozygous variant c.235delC (p.Leu79Cysfs*3) in GJB2 , which was inherited from his phenotypically normal father. It is worthy to mention that homozygous c.235delC variants in GJB2 were frequently detected in patients with recessive non-syndromic hearing loss due to a founder effect ( Jiang et al, 2022 ).…”

The GJB2 (Cx26) Gene Variants in Patients with Hearing Impairment in the Baikal Lake Region (Russia)

“…The diversity of the c.235delC haplotypes in different geographical regions may indicate an independent origin of this GJB2 pathogenic variant in Eastern and Northern Asians. However, all previous research focusing on the analysis of the haplotypes bearing c.235delC suggested the hypothesis on the single origin of c.235delC [7,20,21,23,43,[58][59][60]. Thus, in the study by Yan et al (2003), seven SNPs flanking c.235delC were analyzed in patients with HI from China, Japan, Korea and Mongolia, and the only one haplotype A G A C (SNP2-V27I-E114G-SNP1) associated with c.235delC was found [7].…”