• Open Access

Next-generation genetic testing for retinitis pigmentosa

Authors

  • Kornelia Neveling,

    1. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
    2. Institute for Genetic and Metabolic Disease, Nijmegen, The Netherlands
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  • Rob W.J. Collin,

    1. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
    2. Department of Ophthalmology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
    3. Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands
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  • Christian Gilissen,

    1. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
    2. Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands
    3. Institute for Genetic and Metabolic Disease, Nijmegen, The Netherlands
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  • Ramon A.C. van Huet,

    1. Department of Ophthalmology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
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  • Linda Visser,

    1. Rotterdam Eye Hospital, Rotterdam, The Netherlands
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  • Michael P. Kwint,

    1. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
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  • Sabine J. Gijsen,

    1. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
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  • Marijke N. Zonneveld,

    1. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
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  • Nienke Wieskamp,

    1. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
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  • Joep de Ligt,

    1. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
    2. Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands
    3. Institute for Genetic and Metabolic Disease, Nijmegen, The Netherlands
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  • Anna M. Siemiatkowska,

    1. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
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  • Lies H. Hoefsloot,

    1. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
    2. Institute for Genetic and Metabolic Disease, Nijmegen, The Netherlands
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  • Michael F. Buckley,

    1. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
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  • Ulrich Kellner,

    1. Augen Zentrum Siegburg, Siegburg, Germany
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  • Kari E. Branham,

    1. Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan
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  • Anneke I. den Hollander,

    1. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
    2. Department of Ophthalmology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
    3. Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands
    4. Institute for Genetic and Metabolic Disease, Nijmegen, The Netherlands
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  • Alexander Hoischen,

    1. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
    2. Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands
    3. Institute for Genetic and Metabolic Disease, Nijmegen, The Netherlands
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  • Carel Hoyng,

    1. Department of Ophthalmology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
    2. Institute for Genetic and Metabolic Disease, Nijmegen, The Netherlands
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  • B. Jeroen Klevering,

    1. Department of Ophthalmology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
    2. Institute for Genetic and Metabolic Disease, Nijmegen, The Netherlands
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  • L. Ingeborgh van den Born,

    1. Rotterdam Eye Hospital, Rotterdam, The Netherlands
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  • Joris A. Veltman,

    1. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
    2. Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands
    3. Institute for Genetic and Metabolic Disease, Nijmegen, The Netherlands
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    • These authors contributed equally to this work

  • Frans P.M. Cremers,

    1. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
    2. Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands
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    • These authors contributed equally to this work

  • Hans Scheffer

    Corresponding author
    1. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
    2. Institute for Genetic and Metabolic Disease, Nijmegen, The Netherlands
    • Department of Human Genetics, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.
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    • These authors contributed equally to this work

Errata

This article is corrected by:

  1. Errata: Next Generation Genetic Testing for Retinitis Pigmentosa Volume 34, Issue 8, 1181, Article first published online: 12 June 2013

  • Communicated by Paolo M. Fortina

Abstract

Molecular diagnostics for patients with retinitis pigmentosa (RP) has been hampered by extreme genetic and clinical heterogeneity, with 52 causative genes known to date. Here, we developed a comprehensive next-generation sequencing (NGS) approach for the clinical molecular diagnostics of RP. All known inherited retinal disease genes (n = 111) were captured and simultaneously analyzed using NGS in 100 RP patients without a molecular diagnosis. A systematic data analysis pipeline was developed and validated to prioritize and predict the pathogenicity of all genetic variants identified in each patient, which enabled us to reduce the number of potential pathogenic variants from approximately 1,200 to zero to nine per patient. Subsequent segregation analysis and in silico predictions of pathogenicity resulted in a molecular diagnosis in 36 RP patients, comprising 27 recessive, six dominant, and three X-linked cases. Intriguingly, De novo mutations were present in at least three out of 28 isolated cases with causative mutations. This study demonstrates the enormous potential and clinical utility of NGS in molecular diagnosis of genetically heterogeneous diseases such as RP. De novo dominant mutations appear to play a significant role in patients with isolated RP, having major implications for genetic counselling. Hum Mutat 33:963–972, 2012. © 2012 Wiley Periodicals, Inc.

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