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DFNA8/12 caused by TECTA mutations is the most identified subtype of nonsyndromic autosomal dominant hearing loss

Authors

  • Michael S. Hildebrand,

    1. Department of Otolaryngology—Head and Neck Surgery, University of Iowa, Iowa City, Iowa
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    • The first two authors contributed equally to this article.

  • Matías Morín,

    1. Unidad de Genética Molecular, Ramón y Cajal Institute of Health Research (IRYCIS) and Biomedical Network Research Centre on Rare Diseases (CIBERER), Madrid, Spain
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    • The first two authors contributed equally to this article.

  • Nicole C. Meyer,

    1. Department of Otolaryngology—Head and Neck Surgery, University of Iowa, Iowa City, Iowa
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  • Fernando Mayo,

    1. Unidad de Genética Molecular, Ramón y Cajal Institute of Health Research (IRYCIS) and Biomedical Network Research Centre on Rare Diseases (CIBERER), Madrid, Spain
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  • Silvia Modamio-Hoybjor,

    1. Unidad de Genética Molecular, Ramón y Cajal Institute of Health Research (IRYCIS) and Biomedical Network Research Centre on Rare Diseases (CIBERER), Madrid, Spain
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  • Angeles Mencía,

    1. Unidad de Genética Molecular, Ramón y Cajal Institute of Health Research (IRYCIS) and Biomedical Network Research Centre on Rare Diseases (CIBERER), Madrid, Spain
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  • Leticia Olavarrieta,

    1. Unidad de Genética Molecular, Ramón y Cajal Institute of Health Research (IRYCIS) and Biomedical Network Research Centre on Rare Diseases (CIBERER), Madrid, Spain
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  • Carmelo Morales-Angulo,

    1. Servicio de Otorrinolaringología, Hospital Universitario Marqués de Valdecilla, Santander, Spain
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  • Carla J. Nishimura,

    1. Department of Otolaryngology—Head and Neck Surgery, University of Iowa, Iowa City, Iowa
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  • Heather Workman,

    1. Department of Genetics, The Children's Medical Center of Dayton, Dayton, Ohio
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  • Adam P. DeLuca,

    1. Department of Biomedical Engineering, The University of Iowa, Iowa City, Iowa
    2. Center for Bioinformatics and Computational Biology, The University of Iowa, Iowa City, Iowa
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  • Ignacio del Castillo,

    1. Unidad de Genética Molecular, Ramón y Cajal Institute of Health Research (IRYCIS) and Biomedical Network Research Centre on Rare Diseases (CIBERER), Madrid, Spain
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  • Kyle R. Taylor,

    1. Center for Bioinformatics and Computational Biology, The University of Iowa, Iowa City, Iowa
    2. Department of Electrical and Computer Engineering, The University of Iowa, Iowa City, Iowa
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  • Bruce Tompkins,

    1. Center for Bioinformatics and Computational Biology, The University of Iowa, Iowa City, Iowa
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  • Corey W. Goodman,

    1. Center for Bioinformatics and Computational Biology, The University of Iowa, Iowa City, Iowa
    2. Department of Electrical and Computer Engineering, The University of Iowa, Iowa City, Iowa
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  • Isabelle Schrauwen,

    1. Department of Medical Genetics, University of Antwerp, Antwerp, Belgium
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  • Maarten Van Wesemael,

    1. Department of Medical Genetics, University of Antwerp, Antwerp, Belgium
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  • K. Lachlan,

    1. Wessex Clinical Genetics Service, Southampton University Hospitals NHS Trust, Southampton SO16 5YA, United Kingdom
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  • A. Eliot Shearer,

    1. Department of Otolaryngology—Head and Neck Surgery, University of Iowa, Iowa City, Iowa
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  • Terry A. Braun,

    1. Department of Biomedical Engineering, The University of Iowa, Iowa City, Iowa
    2. Center for Bioinformatics and Computational Biology, The University of Iowa, Iowa City, Iowa
    3. Departments of Ophthalmology and Visual Sciences, The University of Iowa, Iowa City, Iowa
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  • Patrick L.M. Huygen,

    1. Department of Otorhinolaryngology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
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  • Hannie Kremer,

    1. Department of Otorhinolaryngology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
    2. Department of Human Genetics and Nijmegen Centre for Molecular Life Sciences and Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
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  • Guy Van Camp,

    1. Department of Medical Genetics, University of Antwerp, Antwerp, Belgium
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  • Felipe Moreno,

    1. Unidad de Genética Molecular, Ramón y Cajal Institute of Health Research (IRYCIS) and Biomedical Network Research Centre on Rare Diseases (CIBERER), Madrid, Spain
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  • Thomas L. Casavant,

    1. Department of Biomedical Engineering, The University of Iowa, Iowa City, Iowa
    2. Center for Bioinformatics and Computational Biology, The University of Iowa, Iowa City, Iowa
    3. Department of Electrical and Computer Engineering, The University of Iowa, Iowa City, Iowa
    4. Departments of Ophthalmology and Visual Sciences, The University of Iowa, Iowa City, Iowa
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  • Richard J.H. Smith,

    Corresponding author
    1. Department of Otolaryngology—Head and Neck Surgery, University of Iowa, Iowa City, Iowa
    2. Interdepartmental PhD Program in Genetics, Department of Otolaryngology, University of Iowa, Iowa City, Iowa City, Iowa
    • Department of Otolaryngology—Head and Neck Surgery, University of Iowa, 5270 CBRB Building, Iowa City, IA 52242
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  • Miguel A. Moreno-Pelayo

    Corresponding author
    1. Unidad de Genética Molecular, Ramón y Cajal Institute of Health Research (IRYCIS) and Biomedical Network Research Centre on Rare Diseases (CIBERER), Madrid, Spain
    • Unidad Genética Molecular Hospital Ramón y Cajal, Ctra. Colmenar Km 9, 28034 Madrid, Spain
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  • Communicated by Ravi Savarirayan

Abstract

The prevalence of DFNA8/DFNA12 (DFNA8/12), a type of autosomal dominant nonsyndromic hearing loss (ADNSHL), is unknown as comprehensive population-based genetic screening has not been conducted. We therefore completed unbiased screening for TECTA mutations in a Spanish cohort of 372 probands from ADNSHL families. Three additional families (Spanish, Belgian, and English) known to be linked to DFNA8/12 were also included in the screening. In an additional cohort of 835 American ADNSHL families, we preselected 73 probands for TECTA screening based on audiometric data. In aggregate, we identified 23 TECTA mutations in this process. Remarkably, 20 of these mutations are novel, more than doubling the number of reported TECTA ADNSHL mutations from 13 to 33. Mutations lie in all domains of the α-tectorin protein, including those for the first time identified in the entactin domain, as well as the vWFD1, vWFD2, and vWFD3 repeats, and the D1–D2 and TIL2 connectors. Although the majority are private mutations, four of them—p.Cys1036Tyr, p.Cys1837Gly, p.Thr1866Met, and p.Arg1890Cys—were observed in more than one unrelated family. For two of these mutations founder effects were also confirmed. Our data validate previously observed genotype–phenotype correlations in DFNA8/12 and introduce new correlations. Specifically, mutations in the N-terminal region of α-tectorin (entactin domain, vWFD1, and vWFD2) lead to mid-frequency NSHL, a phenotype previously associated only with mutations in the ZP domain. Collectively, our results indicate that DFNA8/12 hearing loss is a frequent type of ADNSHL. Hum Mutat 32:1–10, 2011. © 2011 Wiley-Liss, Inc.

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