Sequence Variations and Haplotypes of theGJB2Gene Revealed by Resequencing of 192 Chromosomes from the General Population in Korea

Abstract

ObjectivesHearing impairment (HI) is the most common sensory deficit in human. The Gap Junction Protein, Beta-2 (GJB2) gene encodes the protein connexin 26, and this gene accounts for up to half of the cases of autosomal recessive nonsyndromic HI. This study was conducted to obtain a set of sequence variations (SVs) of the GJB2 gene among Koreans from the general population for making molecular genetic diagnoses and performing genetic counseling.MethodsWe resequenced the GJB2 gene in 192 chromosomes from 96 adult individuals of Korean descent and who were without a history of hearing difficulty. The data of the SVs was obtained and the haplotypes were reconstructed from the data.ResultsFive SVs were observed, including a novel one (c.558G>A; p.T186T), with the allele frequencies ranging from 0.5% (1/192) to 41% (79/192). The linkage disequilibrium study and haplotype construction showed that some of the SVs are in tight linkage, resulting in a limited number of haplotypes.ConclusionWe observed SVs of the GJB2 gene with different allele frequencies, and a limited number of haplotypes were constructed. The data from this study can be used as reference data for GJB2-related hearing genetic studies, including studies on the founder effect and population genetics, and this data is particularly relevant to people of East Asian decent.

Evidence for Central Asian Origin of the p.Val27Ile Variant in the GJB2 Gene

“…The p.Val27Ile polymorphism seems to be rare or absent in European and African populations [26,32]. The second most frequent polymorphism of GJB2 is p.Glu114Gly; it occurs almost exclusively in the Asian continent (in the same regions as p.Val27Ile) and its highest AFs are found in East Asia: Koreans and Chinese 17% [13,14,18] and Japanese 13% [12] followed by Mongolians and Altaian ethnic group 11% in Central Asia [15,16].…”

“…The most frequent polymorphic variants are c.79G>A (p.Val27Ile) and c.341G>A (p.Glu114Gly); these are most frequent in East Asian populations [12][13][14]18].…”

“…The p.Val27Ile polymorphism has been reported as the most common variant of GJB2 gene in several studies [12][13][14][15][16][18][19][20][21][22][23][24][25]. It occurs in the first transmembrane domain of connexin-26 and it involves the conversion of a valine codon (evolutionarily conserved), to an isoleucine codon (Val27Ile).…”

“…In Asia, the haplotype p. (Val27Ile; p.Glu114Gly) accounts for 30-50% of the cases of p.Val27Ile and almost 100% of the cases of p.Glu114Gly [14][15][16]18]. The p.Val27Ile and p.Glu114Gly polymorphisms seem to be tightly linked, and this has been proposed as haplotype tagging SNPs [18]. In America this haplotype is rare or absent [19-23, 25, 30, 31].…”

“…It occurs in the first transmembrane domain of connexin-26 and it involves the conversion of a valine codon (evolutionarily conserved), to an isoleucine codon (Val27Ile). It is considered a polymorphism because it appears with similar frequency both in people with normal hearing (PNH) and in people with hearing impairment (PHI) [15,16,18,20,23,26].…”