Spectrum and Frequency of the GJB2 Gene Pathogenic Variants in a Large Cohort of Patients with Hearing Impairment Living in a Subarctic Region of Russia (the Sakha Republic)

Abstract

Pathogenic variants in the GJB2 gene, encoding connexin 26, are known to be a major cause of hearing impairment (HI). More than 300 allelic variants have been identified in the GJB2 gene. Spectrum and allelic frequencies of the GJB2 gene vary significantly among different ethnic groups worldwide. Until now, the spectrum and frequency of the pathogenic variants in exon 1, exon 2 and the flanking intronic regions of the GJB2 gene have not been described thoroughly in the Sakha Republic (Yakutia), which is located in a subarctic region in Russia. The complete sequencing of the non-coding and coding regions of the GJB2 gene was performed in 393 patients with HI (Yakuts—296, Russians—51, mixed and other ethnicities—46) and in 187 normal hearing individuals of Yakut (n = 107) and Russian (n = 80) populations. In the total sample (n = 580), we revealed 12 allelic variants of the GJB2 gene, 8 of which were recessive pathogenic variants. Ten genotypes with biallelic recessive pathogenic variants in the GJB2 gene (in a homozygous or a compound heterozygous state) were found in 192 out of 393 patients (48.85%). We found that the most frequent GJB2 pathogenic variant in the Yakut patients was c.-23+1G>A (51.82%) and that the second most frequent was c.109G>A (2.37%), followed by c.35delG (1.64%). Pathogenic variants с.35delG (22.34%), c.-23+1G>A (5.31%), and c.313_326del14 (2.12%) were found to be the most frequent among the Russian patients. The carrier frequencies of the c.-23+1G>A and с.109G>A pathogenic variants in the Yakut control group were 10.20% and 2.80%, respectively. The carrier frequencies of с.35delG and c.101T>C were identical (2.5%) in the Russian control group. We found that the contribution of the GJB2 gene pathogenic variants in HI in the population of the Sakha Republic (48.85%) was the highest among all of the previously studied regions of Asia. We suggest that extensive accumulation of the c.-23+1G>A pathogenic variant in the indigenous Yakut population (92.20% of all mutant chromosomes in patients) and an extremely high (10.20%) carrier frequency in the control group may indicate a possible selective advantage for the c.-23+1G>A carriers living in subarctic climate.

Molecular epidemiology of Chinese Han deaf patients with bi-allelic and mono-allelic GJB2 mutations

“…It has long been puzzling that mutation screening of GJB2 in a large proportion (6-15%) of patients with autosomal recessive hearing loss would identify only one pathogenic mutant allele [9,29,30]. In our cohort, we also identified 72 (3.89%) subjects carrying only a single recessive pathogenic mutation in GJB2, and that excludes those carrying the incompletely penetrant c.109G > A variant, which has a carrier frequency of 12.2% in Chinese Han normal hearing controls [31].…”

High Rates of Three Common GJB2 Mutations c.516G>C, c.-23+1G>A, c.235delC in Deaf Patients from Southern Siberia Are Due to the Founder Effect

“…The proportion of the splice donor site mutation c.-23+1G>A reaches 27.6% of all mutant GJB2 alleles in Tuvinian deaf patients [ 41 ] and 14.8% in Altaian patients [ 42 ]. Splice donor site GJB2 variant c.-23+1G>A has been detected among deaf patients of different origin around the world [ 14 , 22 , 59 , 62 , 63 , 64 , 65 , 66 , 67 ]. The extremely high prevalence of c.-23+1G>A (up to 92.2% of all mutant GJB2 alleles found in patients and carrier frequency reaching of 10.2%) observed in Yakuts, indigenous Turkic-speaking people living in the subarctic region of Russia (the Sakha Republic, Eastern Siberia), was explained by the founder effect in an isolated population and a probable selective advantage for the c.-23+1G>A heterozygotes in severe subarctic climate [ 22 , 67 , 68 ].…”

Frequency of c.35delG Mutation in GJB2 Gene (Connexin 26) in Syrian Patients with Nonsyndromic Hearing Impairment

“…Same similar DNA variant had already been described in many other Asian countries [16, 17]. с.457G>A p.Val153Ile (rs11033186) in the ClinVar database is classified as a benign/likely benign variant.…”