title: 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.
authors.affiliation: Institute of Genetics, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Department of Otolaryngology, Wenling People's Hospital, Wenzhou Medical University, Taizhou, China.
authors.forename: Zhengbiao
authors.initials: Z
authors.lastname: Ying
authors.affiliation: Department of Otolaryngology, Wenling People's Hospital, Wenzhou Medical University, Taizhou, China.
authors.forename: Zhaoyang
authors.initials: Z
authors.lastname: Cai
authors.affiliation: Department of Laboratory Medicine, Jinhua Municipal Central Hospital, Jinhua, China.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Sun
authors.affiliation: Attardi Institute of Mitochondrial Biomedicine, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China.
authors.forename: Zheyun
authors.initials: Z
authors.lastname: He
authors.affiliation: Attardi Institute of Mitochondrial Biomedicine, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China.
authors.forename: Yinglong
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Otolaryngology, Wenling People's Hospital, Wenzhou Medical University, Taizhou, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Otolaryngology, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Institute of Genetics, School of Medicine, Zhejiang University, Hangzhou, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Institute of Genetics, School of Medicine, Zhejiang University, Hangzhou, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China.
authors.forename: Min-Xin
authors.initials: MX
authors.lastname: Guan
mesh_terms: D000293:Adolescent; D000328:Adult; D044466:Asian People / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D000072259:Connexin 26; D017630:Connexins / Q000235:genetics*; D004252:DNA Mutational Analysis; D005006:Ethnicity / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D034381:Hearing Loss / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D055815:Young Adult
chemical_list: D017630:Connexins; C000607042:GJB2 protein, human; D000072259:Connexin 26