title: Exome sequencing identifies a novel frameshift mutation of MYO6 as the cause of autosomal dominant nonsyndromic hearing loss in a Chinese family.
abstract: Autosomal dominant types of nonsyndromic hearing loss (ADNSHL) are typically postlingual in onset and progressive. High genetic heterogeneity, late onset age, and possible confounding due to nongenetic factors hinder the timely molecular diagnoses for most patients. In this study, exome sequencing was applied to investigate a large Chinese family segregating ADNSHL in which we initially failed to find strong evidence of linkage to any locus by whole-genome linkage analysis. Two affected family members were selected for sequencing. We identified two novel mutations disrupting known ADNSHL genes and shared by the sequenced samples: c.328C>A in COCH (DFNA9) resulting in a p.Q110K substitution and a deletion c. 2814_2815delAA in MYO6 (DFNA22) causing a frameshift alteration p.R939Tfs*2. The pathogenicity of novel coding variants in ADNSHL genes was carefully evaluated by analysis of co-segregation with phenotype in the pedigree and in light of established genotype-phenotype correlations. The frameshift deletion in MYO6 was confirmed as the causative variant for this pedigree, whereas the missense mutation in COCH had no clinical significance. The results allowed us to retrospectively identify the phenocopy in one patient that contributed to the negative finding in the linkage scan. Our clinical data also supported the emerging genotype-phenotype correlation for DFNA22.
authors.affiliation: Institute of Otolaryngology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Cheng
authors.affiliation: MOE Key Laboratory of Bioinformatics, Bioinformatics Division and Center for Synthetic and Systems Biology, TNLIST/Department of Automation, Tsinghua University, Beijing, China.|Department of Psychiatry and Centre for Genomic Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Xueya
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Institute of Otolaryngology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Institute of Otolaryngology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Institute of Otolaryngology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Han
authors.affiliation: Institute of Otolaryngology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: MOE Key Laboratory of Bioinformatics, Bioinformatics Division and Center for Synthetic and Systems Biology, TNLIST/Department of Automation, Tsinghua University, Beijing, China.
authors.forename: Liyang
authors.initials: L
authors.lastname: Liu
authors.affiliation: Li Ka Shing Institute of Health Sciences, Department of Obstetrics and Gynaecology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China.
authors.forename: Kwong-Wai
authors.initials: KW
authors.lastname: Choy
authors.affiliation: Institute of Otolaryngology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Dongyi
authors.initials: D
authors.lastname: Han
authors.affiliation: Department of Psychiatry and Centre for Genomic Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Pak C
authors.initials: PC
authors.lastname: Sham
authors.affiliation: MOE Key Laboratory of Bioinformatics, Bioinformatics Division and Center for Synthetic and Systems Biology, TNLIST/Department of Automation, Tsinghua University, Beijing, China.|MCB, Center for Systems Biology, The University of Texas at Dallas, Richardson, TX, USA.
authors.forename: Michael Q
authors.initials: MQ
authors.lastname: Zhang
authors.affiliation: MOE Key Laboratory of Bioinformatics, Bioinformatics Division and Center for Synthetic and Systems Biology, TNLIST/Department of Automation, Tsinghua University, Beijing, China.
authors.forename: Xuegong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Institute of Otolaryngology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Huijun
authors.initials: H
authors.lastname: Yuan
mesh_terms: D000328:Adult; D044466:Asian People / Q000235:genetics; D002681:China; D019295:Computational Biology; D059472:Exome; D005260:Female; D016368:Frameshift Mutation; D005799:Genes, Dominant; D008040:Genetic Linkage; D005838:Genotype; D006319:Hearing Loss, Sensorineural / Q000235:genetics*; D006801:Humans; D008297:Male; D018995:Myosin Heavy Chains / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D017422:Sequence Analysis, DNA
chemical_list: C089785:myosin VI; D018995:Myosin Heavy Chains
keywords: DFNA22; Hearing loss; MYO6; exome sequencing; molecular diagnosis; mutation