title: The diagnostic yield of whole-exome sequencing targeting a gene panel for hearing impairment in The Netherlands.
abstract: Hearing impairment (HI) is genetically heterogeneous which hampers genetic counseling and molecular diagnosis. Testing of several single HI-related genes is laborious and expensive. In this study, we evaluate the diagnostic utility of whole-exome sequencing (WES) targeting a panel of HI-related genes. Two hundred index patients, mostly of Dutch origin, with presumed hereditary HI underwent WES followed by targeted analysis of an HI gene panel of 120 genes. We found causative variants underlying the HI in 67 of 200 patients (33.5%). Eight of these patients have a large homozygous deletion involving STRC, OTOA or USH2A, which could only be identified by copy number variation detection. Variants of uncertain significance were found in 10 patients (5.0%). In the remaining 123 cases, no potentially causative variants were detected (61.5%). In our patient cohort, causative variants in GJB2, USH2A, MYO15A and STRC, and in MYO6 were the leading causes for autosomal recessive and dominant HI, respectively. Segregation analysis and functional analyses of variants of uncertain significance will probably further increase the diagnostic yield of WES.
authors.affiliation: Department of Otorhinolaryngology, Hearing and Genes, Radboud University Medical Center, Nijmegen, The Netherlands.|The Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Celia
authors.initials: C
authors.lastname: Zazo Seco
authors.affiliation: Department of Otorhinolaryngology, Hearing and Genes, Radboud University Medical Center, Nijmegen, The Netherlands.|The Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Mieke
authors.initials: M
authors.lastname: Wesdorp
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Ilse
authors.initials: I
authors.lastname: Feenstra
authors.affiliation: The Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.|Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Rolph
authors.initials: R
authors.lastname: Pfundt
authors.affiliation: The Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.|Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Jayne Y
authors.initials: JY
authors.lastname: Hehir-Kwa
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Stefan H
authors.initials: SH
authors.lastname: Lelieveld
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Steven
authors.initials: S
authors.lastname: Castelein
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Christian
authors.identifier: 0000-0003-1693-9699
authors.initials: C
authors.lastname: Gilissen
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Ilse J
authors.initials: IJ
authors.lastname: de Wijs
authors.affiliation: Department of Otorhinolaryngology, Hearing and Genes, Radboud University Medical Center, Nijmegen, The Netherlands.|The Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Ronald Jc
authors.initials: RJ
authors.lastname: Admiraal
authors.affiliation: Department of Otorhinolaryngology, Hearing and Genes, Radboud University Medical Center, Nijmegen, The Netherlands.|Radboud Institute for Health Sciences, Nijmegen, The Netherlands.
authors.forename: Ronald Je
authors.initials: RJ
authors.lastname: Pennings
authors.affiliation: Department of Otorhinolaryngology, Hearing and Genes, Radboud University Medical Center, Nijmegen, The Netherlands.|Radboud Institute for Health Sciences, Nijmegen, The Netherlands.
authors.forename: Henricus Pm
authors.initials: HP
authors.lastname: Kunst
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Jiddeke M
authors.initials: JM
authors.lastname: van de Kamp
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Saskia
authors.initials: S
authors.lastname: Tamminga
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Arjan C
authors.initials: AC
authors.lastname: Houweling
authors.affiliation: Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Astrid S
authors.initials: AS
authors.lastname: Plomp
authors.affiliation: Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Department of Pediatrics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Saskia M
authors.initials: SM
authors.lastname: Maas
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Pia Am
authors.initials: PA
authors.lastname: de Koning Gans
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Sarina G
authors.initials: SG
authors.lastname: Kant
authors.affiliation: Department of Genetics, University Medical Centre Groningen, Groningen, The Netherlands.
authors.forename: Christa M
authors.initials: CM
authors.lastname: de Geus
authors.affiliation: Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: Suzanna Gm
authors.initials: SG
authors.lastname: Frints
authors.affiliation: Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: Els K
authors.initials: EK
authors.lastname: Vanhoutte
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: Marieke F
authors.initials: MF
authors.lastname: van Dooren
authors.affiliation: Department of Clinical Genetics, Utrecht Medical Center/Wilhelmina Children's Hospital, Utrecht, The Netherlands.
authors.forename: Marie-José H
authors.initials: MH
authors.lastname: van den Boogaard
authors.affiliation: The Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.|Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Scheffer
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Marcel
authors.initials: M
authors.lastname: Nelen
authors.affiliation: Department of Otorhinolaryngology, Hearing and Genes, Radboud University Medical Center, Nijmegen, The Netherlands.|The Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.|Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Hannie
authors.initials: H
authors.lastname: Kremer
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.|Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: Lies
authors.initials: L
authors.lastname: Hoefsloot
authors.affiliation: Department of Otorhinolaryngology, Hearing and Genes, Radboud University Medical Center, Nijmegen, The Netherlands.|The Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Margit
authors.initials: M
authors.lastname: Schraders
authors.affiliation: The Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.|Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Helger G
authors.initials: HG
authors.lastname: Yntema
mesh_terms: D000072259:Connexin 26; D017630:Connexins / Q000235:genetics; D056915:DNA Copy Number Variations; D059472:Exome; D016326:Extracellular Matrix Proteins / Q000235:genetics; D058851:GPI-Linked Proteins / Q000235:genetics; D005820:Genetic Testing / Q000592:standards / Q000706:statistics & numerical data*; D034381:Hearing Loss / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000235:genetics; D009154:Mutation; D018995:Myosin Heavy Chains / Q000235:genetics; D009218:Myosins / Q000235:genetics; D009426:Netherlands; D017422:Sequence Analysis, DNA / Q000592:standards / Q000706:statistics & numerical data*
chemical_list: D017630:Connexins; D016326:Extracellular Matrix Proteins; C000607042:GJB2 protein, human; D058851:GPI-Linked Proteins; D036341:Intercellular Signaling Peptides and Proteins; C485245:MYO15A protein, human; D008565:Membrane Proteins; C456027:OTOA protein, human; C499079:STRC protein, human; C112735:USH2A protein, human; C089785:myosin VI; D000072259:Connexin 26; D018995:Myosin Heavy Chains; D009218:Myosins