Exon-disrupting deletions of NRXN1 in idiopathic generalized epilepsy

Authors

  • Rikke S. Møller,

    Corresponding author
    • Danish Epilepsy Center, Dianalund, Denmark
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    • These authors contributed equally to this study.
    • EPICURE Consortium, participating groups are listed in the Appendix.
  • Yvonne G. Weber,

    1. Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University Hospital Tübingen, Tübingen, Germany
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    • These authors contributed equally to this study.
    • EPICURE Consortium, participating groups are listed in the Appendix.
  • Laura L. Klitten,

    1. Danish Epilepsy Center, Dianalund, Denmark
    2. Wilhelm Johannsen Center for Functional Genome Research, University of Copenhagen, Copenhagen, Denmark
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    • These authors contributed equally to this study.
  • Holger Trucks,

    1. Cologne Center for Genomics, University of Cologne, Cologne, Germany
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    • EPICURE Consortium, participating groups are listed in the Appendix.
  • Hiltrud Muhle,

    1. Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Christian-Albrechts University, Kiel, Germany
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    • EPICURE Consortium, participating groups are listed in the Appendix.
  • Wolfram S. Kunz,

    1. Department of Epileptology, University of Bonn, Bonn, Germany
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    • EPICURE Consortium, participating groups are listed in the Appendix.
  • Heather C. Mefford,

    1. Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, U.S.A
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  • Andre Franke,

    1. Institute for Clinical Molecular Biology, University Hospital Schleswig-Holstein, Kiel, Germany
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  • Monika Kautza,

    1. Praxis of Human Genetics, Kiel, Germany
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  • Peter Wolf,

    1. Danish Epilepsy Center, Dianalund, Denmark
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  • Dieter Dennig,

    1. Neurological Practice “Am Seelberg”, Stuttgart, Germany
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  • Stefan Schreiber,

    1. Institute for Clinical Molecular Biology, University Hospital Schleswig-Holstein, Kiel, Germany
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  • Ina-Maria Rückert,

    1. Institute of Epidemiology II, Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany
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  • H.-Erich Wichmann,

    1. Institute of Epidemiology II, Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany
    2. Institute of Medical Informatics, Biometry and Epidemiology, Chair of Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany
    3. Klinikum Grosshadern, Munich, Germany
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  • Jan P. Ernst,

    1. Pediatric Practice Oggersheim, Ludwigshafer, Germany
    2. Epilepsy Centre Kork, Kehl, Germany
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  • Claudia Schurmann,

    1. Interfaculty Institute for Genetics and Functional Genomics, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany
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  • Hans J. Grabe,

    1. Department of Psychiatry and Psychotherapy, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany
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  • Niels Tommerup,

    1. Wilhelm Johannsen Center for Functional Genome Research, University of Copenhagen, Copenhagen, Denmark
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  • Ulrich Stephani,

    1. Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Christian-Albrechts University, Kiel, Germany
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    • EPICURE Consortium, participating groups are listed in the Appendix.
  • Holger Lerche,

    1. Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University Hospital Tübingen, Tübingen, Germany
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    • EPICURE Consortium, participating groups are listed in the Appendix.
  • Helle Hjalgrim,

    1. Danish Epilepsy Center, Dianalund, Denmark
    2. Institute of Regional Health Services Research, University of Southern Denmark, Odense, Denmark
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    • EPICURE Consortium, participating groups are listed in the Appendix.
  • Ingo Helbig,

    1. Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Christian-Albrechts University, Kiel, Germany
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    • EPICURE Consortium, participating groups are listed in the Appendix.
  • Thomas Sander,

    1. Cologne Center for Genomics, University of Cologne, Cologne, Germany
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    • EPICURE Consortium, participating groups are listed in the Appendix.
  • EPICURE Consortium

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    • EPICURE Consortium, participating groups are listed in the Appendix.

Errata

This article is corrected by:

  1. Errata: Erratum Volume 54, Issue 12, 2232, Article first published online: 4 December 2013

Address correspondence to Rikke S. Møller, Danish Epilepsy Centre, Kolonivej 7, 4293 Dianalund, Denmark. E-mail: rimo@filadelfia.dk

Summary

Purpose

Neurexins are neuronal adhesion molecules located in the presynaptic terminal, where they interact with postsynaptic neuroligins to form a transsynaptic complex required for efficient neurotransmission in the brain. Recently, deletions and point mutations of the neurexin 1 (NRXN1) gene have been associated with a broad spectrum of neuropsychiatric disorders. This study aimed to investigate if NRXN1 deletions also increase the risk of idiopathic generalized epilepsies (IGEs).

Methods

We screened for deletions involving the NRXN1 gene in 1,569 patients with IGE and 6,201 controls using high-density oligonucleotide microarrays.

Key Findings

We identified exon-disrupting deletions of NRXN1 in 5 of 1,569 patients with IGE and 2 of 6,201 control individuals (p = 0.0049; odds ratio (OR) 9.91, 95% confidence interval (CI) 1.92–51.12). A complex familial segregation pattern in the IGE families was observed, suggesting that heterozygous NRXN1 deletions are susceptibility variants. Intriguingly, we identified a second large copy number variant in three of five index patients, supporting an involvement of heterogeneous susceptibility alleles in the etiology of IGE.

Significance

We conclude that exon-disrupting deletions of NRXN1 represent a genetic risk factor in the genetically complex predisposition of common IGE syndromes.

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