A novel classification system to predict the pathogenic effects of CHD7 missense variants in CHARGE syndrome

Authors

  • Jorieke E.H. Bergman,

    1. Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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    • Both these authors contributed equally to this work.

  • Nicole Janssen,

    1. Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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    • Both these authors contributed equally to this work.

  • Almer M. van der Sloot,

    1. EMBL/CRG Systems Biology Research Unit, Center for Genomic Regulation (CRG), UPF Barcelona, Spain; Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada
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  • Hermien E.K. de Walle,

    1. Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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  • Jeroen Schoots,

    1. Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
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  • Nanna D. Rendtorff,

    1. Wilhelm Johannsen Center for Functional Genome Research, Department of Cellular and Molecular Medicine (ICMM), the Panum Institute, University of Copenhagen, Copenhagen, Denmark
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  • Lisbeth Tranebjærg,

    1. Wilhelm Johannsen Center for Functional Genome Research, Department of Cellular and Molecular Medicine (ICMM), the Panum Institute, University of Copenhagen, Copenhagen, Denmark
    2. Department of Audiology, Bispebjerg Hospital, Copenhagen, Denmark
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  • Lies H. Hoefsloot,

    1. Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
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  • Conny M.A. van Ravenswaaij-Arts,

    1. Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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  • Robert M.W. Hofstra

    Corresponding author
    1. Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands
    • Department of Clinical Genetics, Erasmus Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands.
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  • Communicated by Sean V. Tavtigian

Abstract

CHARGE syndrome is characterized by the variable occurrence of multisensory impairment, congenital anomalies, and developmental delay, and is caused by heterozygous mutations in the CHD7 gene. Correct interpretation of CHD7 variants is essential for genetic counseling. This is particularly difficult for missense variants because most variants in the CHD7 gene are private and a functional assay is not yet available. We have therefore developed a novel classification system to predict the pathogenic effects of CHD7 missense variants that can be used in a diagnostic setting. Our classification system combines the results from two computational algorithms (PolyPhen-2 and Align-GVGD) and the prediction of a newly developed structural model of the chromo- and helicase domains of CHD7 with segregation and phenotypic data. The combination of different variables will lead to a more confident prediction of pathogenicity than was previously possible. We have used our system to classify 145 CHD7 missense variants. Our data show that pathogenic missense mutations are mainly present in the middle of the CHD7 gene, whereas benign variants are mainly clustered in the 5′ and 3′ regions. Finally, we show that CHD7 missense mutations are, in general, associated with a milder phenotype than truncating mutations. Hum Mutat 33:1251–1260, 2012. © 2012 Wiley Periodicals, Inc.

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