Rare exonic deletions of the RBFOX1 gene increase risk of idiopathic generalized epilepsy

Authors

  • Dennis Lal,

    1. Cologne Center for Genomics, University of Cologne, Cologne, Germany
    2. Department of Neuropediatrics, University Medical Clinic Giessen, Giessen, Germany
    3. Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
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    • Members of the EMINet Consortium are in Appendix 1.
    • Members of the EPICURE Consortium are Appendix 2.
  • Holger Trucks,

    1. Cologne Center for Genomics, University of Cologne, Cologne, Germany
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    • Members of the EMINet Consortium are in Appendix 1.
    • Members of the EPICURE Consortium are Appendix 2.
  • Rikke S. Møller,

    1. Danish Epilepsy Center, Dianalund, Denmark
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    • Members of the EMINet Consortium are in Appendix 1.
    • Members of the EPICURE Consortium are Appendix 2.
  • Helle Hjalgrim,

    1. Danish Epilepsy Center, Dianalund, Denmark
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    • Members of the EMINet Consortium are in Appendix 1.
    • Members of the EPICURE Consortium are Appendix 2.
  • Bobby P. C. Koeleman,

    1. Section Complex Genetics, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
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    • Members of the EPICURE Consortium are Appendix 2.
  • Carolien G. F. de Kovel,

    1. Section Complex Genetics, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
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    • Members of the EPICURE Consortium are Appendix 2.
  • Frank Visscher,

    1. Department of Neurology, Admiraal De Ruyter Hospital, Goes, The Netherlands
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  • Yvonne G. Weber,

    1. Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University Hospital Tübingen, Tübingen, Germany
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    • Members of the EMINet Consortium are in Appendix 1.
    • Members of the EPICURE Consortium are Appendix 2.
  • Holger Lerche,

    1. Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University Hospital Tübingen, Tübingen, Germany
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    • Members of the EMINet Consortium are in Appendix 1.
    • Members of the EPICURE Consortium are Appendix 2.
  • Felicitas Becker,

    1. Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University Hospital Tübingen, Tübingen, Germany
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    • Members of the EMINet Consortium are in Appendix 1.
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  • Christoph J. Schankin,

    1. Department of Neurology, University of Munich Hospital – Großhadern, Munich, Germany
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  • Bernd A. Neubauer,

    1. Department of Neuropediatrics, University Medical Clinic Giessen, Giessen, Germany
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  • Rainer Surges,

    1. Department of Epileptology, University of Bonn, Bonn, Germany
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    • Members of the EMINet Consortium are in Appendix 1.
    • Members of the EPICURE Consortium are Appendix 2.
  • Wolfram S. Kunz,

    1. Department of Epileptology, University of Bonn, Bonn, Germany
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    • Members of the EMINet Consortium are in Appendix 1.
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  • Fritz Zimprich,

    1. Department of Clinical Neurology, Medical University of Vienna, Vienna, Austria
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    • Members of the EPICURE Consortium are Appendix 2.
  • Andre Franke,

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

    1. Hannover Unified Biobank, Hannover Medical School, Hannover, Germany
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  • Janina S. Ried,

    1. Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
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  • Costin Leu,

    1. Cologne Center for Genomics, University of Cologne, Cologne, Germany
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    • Members of the EMINet Consortium are in Appendix 1.
    • Members of the EPICURE Consortium are Appendix 2.
  • Peter Nürnberg,

    1. Cologne Center for Genomics, University of Cologne, Cologne, Germany
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    • Members of the EMINet Consortium are in Appendix 1.
    • Members of the EPICURE Consortium are Appendix 2.
  • Thomas Sander,

    Corresponding author
    • Cologne Center for Genomics, University of Cologne, Cologne, Germany
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    • Members of the EMINet Consortium are in Appendix 1.
    • Members of the EPICURE Consortium are Appendix 2.
  • EMINet Consortium,

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    • Members of the EMINet Consortium are in Appendix 1.
  • EPICURE Consortium

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    • Members of the EPICURE Consortium are Appendix 2.

Address correspondence to Thomas Sander, Cologne Center for Genomics, University of Cologne, Weyertal 115b, 50931 Cologne, Germany. E-mail: thomas.sander@uni-koeln.de

Summary

Purpose

Structural variations disrupting the gene encoding the neuron-specific splicing regulator RBFOX1 have been reported in three patients exhibiting epilepsy in comorbidity with other neuropsychiatric disorders. Consistently, the Rbfox1 knockout mouse model showed an increased susceptibility of seizures. The present candidate gene study tested whether exon-disrupting deletions of RBFOX1 increase the risk of idiopathic generalized epilepsies (IGEs), representing the largest group of genetically determined epilepsies.

Methods

Screening of microdeletions (size: >40 kb, coverage >20 markers) affecting the genomic sequence of the RBFOX1 gene was carried out by high-resolution single-nucleotide polymorphism (SNP) arrays in 1,408 European patients with idiopathic generalized epilepsy (IGE) and 2,256 population controls. Validation of RBFOX1 deletions and familial segregation analysis were performed by quantitative polymerase chain reaction (qPCR).

Key Findings

We detected five exon-disrupting RBFOX1 deletions in the IGE patients, whereas none was observed in the controls (p = 0.008, Fisher's exact test). The size of the exonic deletions ranged from 68 to 896 kb and affected the untranslated 5′-terminal RBFOX1 exons. Segregation analysis in four families indicated that the deletions were inherited, display incomplete penetrance, and heterogeneous cosegregation patterns with IGE.

Significance

Rare deletions affecting the untranslated 5′-terminal RBFOX1 exons increase risk of common IGE syndromes. Variable expressivity, incomplete penetrance, and heterogeneous cosegregation patterns suggest that RBFOX1 deletions act as susceptibility factor in a genetically complex etiology, where heterogeneous combinations of genetic factors determine the disease phenotype.

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