title: Whole-exome sequencing identifies a novel genotype-phenotype correlation in the entactin domain of the known deafness gene TECTA.
abstract: Postlingual progressive hearing loss, affecting primarily the high frequencies, is the clinical finding in most cases of autosomal dominant nonsyndromic hearing loss (ADNSHL). The molecular genetic etiology of ADNSHL is extremely heterogeneous. We applied whole-exome sequencing to reveal the genetic etiology of high-frequency hearing loss in a mid-sized Korean family without any prior linkage data. Whole-exome sequencing of four family members (two affected and two unaffected), together with our filtering strategy based on comprehensive bioinformatics analyses, identified 21 potential pathogenic candidates. Sanger validation of an additional five family members excluded 20 variants, leaving only one novel variant, TECTA c.710C>T (p.T237I), as the strongest candidate. This variant resides in the entactin (ENT) domain and co-segregated perfectly with non-progressive high-frequency hearing loss in the family. It was absent among 700 ethnically matched control chromosomes, and the T237 residue is conserved among species, which supports its pathogenicity. Interestingly, this finding contrasted with a previously proposed genotype-phenotype correlation in which variants of the ENT domain of TECTA were associated with mid-frequency hearing loss. Based upon what we observed, we propose a novel "genotype to phenotype" correlation in the ENT domain of TECTA. Our results shed light on another important application of whole-exome sequencing: the establishment of a novel genotype-phenotype in the molecular genetic diagnosis of autosomal dominant hearing loss.
authors.affiliation: Department of Otorhinolaryngology, Seoul National University Bundang Hospital, Seongnam, South Korea.
authors.forename: Byung Yoon
authors.initials: BY
authors.lastname: Choi
authors.affiliation: Korean Bioinformation center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, South Korea.
authors.forename: Jiwoong
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Otolaryngology, Ajou University School of Medicine, Suwon, South Korea.
authors.forename: Juyong
authors.initials: J
authors.lastname: Chung
authors.affiliation: Department of Otorhinolaryngology, Seoul national University College of Medicine, Seoul, South Korea.
authors.forename: Ah Reum
authors.initials: AR
authors.lastname: Kim
authors.affiliation: Department of Otorhinolaryngology, Seoul national University College of Medicine, Seoul, South Korea.
authors.forename: Sue Jean
authors.initials: SJ
authors.lastname: Mun
authors.affiliation: Department of Otorhinolaryngology, Seoul national University College of Medicine, Seoul, South Korea.
authors.forename: Seong Il
authors.initials: SI
authors.lastname: Kang
authors.affiliation: Korean Bioinformation center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, South Korea; Department of Bioinformatics, University of Science and Technology, Daejeon, South Korea.
authors.forename: Sang-Heon
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Korean Bioinformation center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, South Korea; Department of Bioinformatics, University of Science and Technology, Daejeon, South Korea.
authors.forename: Namshin
authors.initials: N
authors.lastname: Kim
authors.affiliation: Department of Otorhinolaryngology, Seoul national University College of Medicine, Seoul, South Korea.
authors.forename: Seung-Ha
authors.initials: SH
authors.lastname: Oh
mesh_terms: D001483:Base Sequence; D003638:Deafness / Q000235:genetics; D059472:Exome / Q000235:genetics; D016326:Extracellular Matrix Proteins / Q000235:genetics* / Q000502:physiology; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics / Q000502:physiology; D005799:Genes, Dominant / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D008969:Molecular Sequence Data; D010375:Pedigree; D010641:Phenotype; D056910:Republic of Korea; D017422:Sequence Analysis, DNA
chemical_list: D016326:Extracellular Matrix Proteins; D058851:GPI-Linked Proteins; D008562:Membrane Glycoproteins; C491350:TECTA protein, human; C029967:nidogen