GJB2 Mutations and Degree of Hearing Loss: A Multicenter Study

Abstract

Hearing impairment (HI) affects 1 in 650 newborns, which makes it the most common congenital sensory impairment. Despite extraordinary genetic heterogeneity, mutations in one gene, GJB2, which encodes the connexin 26 protein and is involved in inner ear homeostasis, are found in up to 50% of patients with autosomal recessive nonsyndromic hearing loss. Because of the high frequency of GJB2 mutations, mutation analysis of this gene is widely available as a diagnostic test. In this study, we assessed the association between genotype and degree of hearing loss in persons with HI and biallelic GJB2 mutations. We performed cross-sectional analyses of GJB2 genotype and audiometric data from 1,531 persons, from 16 different countries, with autosomal recessive, mildto-profound nonsyndromic HI. The median age of all participants was 8 years; 90% of persons were within the age range of 0-26 years. Of the 83 different mutations identified, 47 were classified as nontruncating, and 36 as truncating. A total of 153 different genotypes were found, of which 56 were homozygous truncating (T/T), 30 were homozygous nontruncating (NT/NT), and 67 were compound heterozygous truncating/nontruncating (T/ NT). The degree of HI associated with biallelic truncating mutations was significantly more severe than the HI associated with biallelic nontruncating mutations (). The HI of 48 different genotypes was less severe P ! .0001 than that of 35delG homozygotes. Several common mutations (M34T, V37I, and L90P) were associated with mildto-moderate HI (median 25-40 dB). Two genotypes-35delG/R143W (median 105 dB) and 35delG/dela(GJB6-D13S1830) (median 108 dB)-had significantly more-severe HI than that of 35delG homozygotes.

Coordinated control of connexin 26 and connexin 30 at the regulatory and functional level in the inner ear

“…Deafness is a major cause of sensory deficit in humans, and mutations in the DFNB1 locus are almost as frequent as those causing cystic fibrosis (19,20). Several studies have been carried out to understand the molecular mechanisms underlying DFNB1 pathogenesis, either by resorting to creation of murine models (21,22) or by analyzing mutant Cx26 variants in heterologous expression systems (23).…”

Diagnostic pitfalls for GJB2‐related hearing loss: A novel deletion detected by Array‐CGH analysis in a Japanese patient with congenital profound hearing loss

“…Not limited to Africa, it is also commonly found in congenital HL patients among various populations 5, 15. Biallelic‐mutated individuals with R143W and GJB2 truncating mutations display profound HL 5, 15. Considering the 8 kb deletion to be equivalent to a truncating mutation, there appears to be no contradiction in the fact that this patient shows a profound hearing impairment phenotype.…”

“…The p.R143W variant shows an extraordinarily high prevalence among congenital HL patients in Ghana, West Africa 4. Not limited to Africa, it is also commonly found in congenital HL patients among various populations 5, 15. Biallelic‐mutated individuals with R143W and GJB2 truncating mutations display profound HL 5, 15.…”

“…Considering the 8 kb deletion to be equivalent to a truncating mutation, there appears to be no contradiction in the fact that this patient shows a profound hearing impairment phenotype. According to several studies on the carrier frequency of GJB2 mutations, the p.R143W allele frequency is 0.42%(13/3062 alleles) ~0.67% (18/2686 alleles) in congenital HL patients among different ethnic groups,5, 15 and a frequency of up to 0.1% (1/1018 alleles) was observed in the general Japanese population 16. The p.R143W mutation is mostly found in a compound heterozygous form, except for in Ghana.…”

“…The overall incidence is estimated to be one in approximately 1000 newborns 1, 2. The GJB2 gene (MIM# 121011), which encodes the gap junction protein connexin 26 (Cx26), is the most common genetic etiology associated with congenital HL worldwide, with the mutation spectrums known to vary among different ethnic groups 3, 4, 5. The GJB2 gene is a small gene composed of two exons, one of which possesses a 678‐bp coding sequence.…”