title: The homozygous p.V37I variant of GJB2 is associated with diverse hearing phenotypes.
abstract: The homozygous p.V37I variant of GJB2 is frequent in East Asians and has been reported to have a pathogenic role in mild-to-moderate hearing impairment (HI). In this study, we investigated the prevalence and phenotypic spectrum of homozygous p.V37I in three Chinese Han cohorts with severe-to-profound HI (n = 857, Cohort S), mild-to-moderate HI (n = 88, Cohort M) and normal hearing (n = 1550, Cohort N). Sequencing of GJB2 showed that homozygous p.V37I was detected in 1.63% (14/857), 12.5% (11/88) and 0.32% (5/1550) of subjects in Cohorts S, M and N, respectively. It was strongly associated with both mild-to-moderate (p = 2.0 × 10(-11) ) and severe-to-profound (p = 0.001) HI, but was estimated to have a rather low penetrance (17%). Among the hearing impaired subjects with homozygous p.V37I, the onset of HI was congenital in 65% (11/17) and delayed in 35% (6/17). By targeted next-generation sequencing of 79 known deafness genes, we identified an additional homozygous pathogenic mutation of CDH23 in 1 of 14 p.V37I homozygous subjects from Cohort S. Our study suggested that homozygous p.V37I is associated with a broader spectrum of hearing phenotypes than previously revealed. Data presented in this study can be effectively applied to clinical evaluation and genetic counseling of people carrying this variant.
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, Xinhua Hospital; Ear Institute, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Chai
authors.forename: D
authors.initials: D
authors.lastname: Chen
authors.forename: L
authors.initials: L
authors.lastname: Sun
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.forename: X
authors.initials: X
authors.lastname: Pang
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.forename: H
authors.initials: H
authors.lastname: Wu
authors.forename: T
authors.initials: T
authors.lastname: Yang
mesh_terms: D044466:Asian People / Q000235:genetics; D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000235:genetics; D002681:China / Q000453:epidemiology; D015331:Cohort Studies; D000072259:Connexin 26; D017630:Connexins / Q000235:genetics*; D005820:Genetic Testing; D006311:Hearing Disorders / Q000453:epidemiology* / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D020125:Mutation, Missense / Q000235:genetics*; D015995:Prevalence
chemical_list: C442480:CDH23 protein, human; D000070585:Cadherin Related Proteins; D015820:Cadherins; D017630:Connexins; C000607042:GJB2 protein, human; D000072259:Connexin 26
keywords: GJB2; diverse phenotype; hearing impairment; homozygous p.V37I; target next-generation sequencing