title: Unraveling of Enigmatic Hearing-Impaired GJB2 Single Heterozygotes by Massive Parallel Sequencing: DFNB1 or Not?
abstract: The molecular etiology of nonsyndromic sensorineural hearing loss (SNHL) in subjects with only one detectable autosomal recessive GJB2 mutation is unclear. Here, we report GJB2 single heterozygotes with various final genetic diagnoses and suggest appropriate diagnostic strategies. A total of 160 subjects with SNHL without phenotypic markers were screened for GJB2 mutations. Single-nucleotide variants or structural variations within the DFNB1 locus or in other deafness genes were examined by Sanger sequencing, breakpoint PCR, and targeted exome sequencing (TES) of 129 deafness genes. We identified 27 subjects with two mutations and 10 subjects with only one detectable mutation in GJB2. The detection rate of the single GJB2 mutation among the 160 SNHL subjects in the present study (6.25%) was higher than 2.58% in normal hearing controls in Korean. The DFNB1 was clearly excluded as a molecular etiology in four (40%) subjects: other recessive deafness genes (N = 3) accounted for SNHL and the causative gene for the other non-DFNB1 subject (N = 1) was not identified. The etiology of additional two subjects was potentially explained by digenic etiology (N = 2) of GJB2 with MITF and GJB3, respectively. The contribution of the single GJB2 mutation in the four remaining subjects is unclear. Comprehensive diagnostic testing including TES is prerequisite for understanding GJB2 single heterozygotes.
authors.affiliation: From the Department of Otorhinolaryngology-Head and Neck Surgery, CHA medical center, CHA university, Seongnam (SYK), Department of Otorhinolaryngology-Head and Neck Surgery (SYK, ARK), Seoul National University Hospital, Seoul National University College of Medicine; Samsung Genome Institue (NKDK, CL), Samsung Medical Center, Seoul, Korea; Department of Health Sciences and Technology (CL), SAIHST, Sungkyunkwan University, Seobu-ro, Jangan-gu, Suwon, Republic of Korea; Department of Otorhinolaryngology-Head and Neck Surgery (MYK, E-HJ, BYC), Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam; Samsung Genome Institute (W-YP), Samsung Medical Center; Department of Molecular Cell Biology, School of Medicine (W-YP), Sungkyunkwan University; Sensory Organ Research Institute (BYC), Seoul National University Medical Research Center, Seoul, Korea; and Wide River Institute of Immunology (BYC), Seoul National University College of Medicine, Hongcheon, Republic of Korea.
authors.forename: So Young
authors.initials: SY
authors.lastname: Kim
authors.forename: Ah Reum
authors.initials: AR
authors.lastname: Kim
authors.forename: Nayoung K D
authors.initials: NKD
authors.lastname: Kim
authors.forename: Chung
authors.initials: C
authors.lastname: Lee
authors.forename: Min Young
authors.initials: MY
authors.lastname: Kim
authors.forename: Eun-Hee
authors.initials: EH
authors.lastname: Jeon
authors.forename: Woong-Yang
authors.initials: WY
authors.lastname: Park
authors.forename: Byung Yoon
authors.initials: BY
authors.lastname: Choi
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D000072259:Connexin 26; D017630:Connexins / Q000235:genetics*; D005260:Female; D006319:Hearing Loss, Sensorineural / Q000235:genetics*; D006579:Heterozygote; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D010375:Pedigree
chemical_list: D017630:Connexins; C000607042:GJB2 protein, human; D000072259:Connexin 26