GJB2 Mutation Spectrum and Genotype-Phenotype Correlation in 1067 Han Chinese Subjects with Non-Syndromic Hearing Loss

Abstract

Mutations in Gap Junction Beta 2 (GJB2) have been reported to be a major cause of non-syndromic hearing loss in many populations worldwide. The spectrums and frequencies of GJB2 variants vary substantially among different ethnic groups, and the genotypes among these populations remain poorly understood. In the present study, we carried out a systematic and extended mutational screening of GJB2 gene in 1067 Han Chinese subjects with non-syndromic hearing loss, and the resultant GJB2 variants were evaluated by phylogenetic, structural and bioinformatic analysis. A total of 25 (23 known and 2 novel) GJB2 variants were identified, including 6 frameshift mutations, 1 nonsense mutation, 16 missense mutations and 2 silent mutations. In this cohort, c.235delC is the most frequently observed pathogenic mutation. The phylogenetic, structural and bioinformatic analysis showed that 2 novel variants c.127G>T (p.V43L), c.293G>C (p.R98P) and 2 known variants c. 107T>C (p.L36P) and c.187G>T (p.V63L) are localized at highly conserved amino acids. In addition, these 4 mutations are absent in 203 healthy individuals, therefore, they are probably the most likely candidate pathogenic mutations. In addition, 66 (24 novel and 42 known) genotypes were identified, including 6 homozygotes, 20 compound heterozygotes, 18 single heterozygotes, 21 genotypes harboring only polymorphism(s) and the wild type genotype. Among these, 153 (14.34%) subjects were homozygous for pathogenic mutations, 63 (5.91%) were compound heterozygotes, and 157 (14.71%) carried single heterozygous mutation. Furthermore, 65.28% (141/216) of these cases with two pathogenic mutations exhibited profound hearing loss. These data suggested that mutations in GJB2 gene are responsible for approximately 34.96% of non-syndromic hearing loss in Han Chinese population from Zhejiang Province in eastern China. In addition, our results also strongly supported the idea that other factors such as alterations in regulatory regions, additional genes, and environmental factors may contribute to the clinical manifestation of deafness.

Effect of GJB2 235delC and 30-35delG genetic polymorphisms on risk of congenital deafness in a Chinese population

“…Increasingly, many genetic studies have been adopted to identify genes involved in the initiation and progression of congenital deafness (Jiang et al, 2014;Dai et al, 2015;Zheng et al, 2015;Xia et al, 2016). We performed the case-control study described here to investigate the role of the GJB2 235delC and 30-35delG polymorphisms in susceptibility to this disease, finding that the GC and CC genotypes of the former were associated with increased risk, but that no such relationship was evident with the latter.…”

“…Previous investigations have reported that approximately 35% of patients with congenital deafness carry GJB2 233-235delC variants (Jiang et al, 2014;Dai et al, 2015;Zheng et al, 2015;Xia et al, 2016). These variations comprise the deletion of a cytosine residue in the GJB2 coding region at positions 233-235, leading to a frameshift mutation.…”

c.464A>G variation in the GJB2 gene is detected in a Han Chinese family

“…Mutations in the GJB2 gene are the most common causes for autosomal recessive nonsyndromic hearing loss (NSHL) [3,4]. In the study by Zheng et al which involved 1067 Han Chinese subjects, mutations in the GJB2 gene are responsible for approximately 34.96% of NSHL, and c.235delC is the most frequently observed pathogenic mutation [5]. In this report, multiple variations in the GJB2 gene have been detected in a Chinese family.…”

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.…”

“…The frequency of 35delG variant is very high in Spain, Italy, and Israel [15]. It accounts for approximately 50% of cases [16] which suggests an evidence for an ancient deletion mutation that had spread in Europe and Middle-East.…”