Abstract

We identified 15q13.3 microdeletions encompassing the CHRNA7 gene in 12 of 1,223 individuals with idiopathic generalized epilepsy (IGE), which were not detected in 3,699 controls (joint P = 5.32 × 10−8). Most deletion carriers showed common IGE syndromes without other features previously associated with 15q13.3 microdeletions, such as intellectual disability, autism or schizophrenia. Our results indicate that 15q13.3 microdeletions constitute the most prevalent risk factor for common epilepsies identified to date.

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Acknowledgements

We thank all the subjects and their families for participating in this study. We are also grateful to H. Bode for referral of subjects and A. Ackerhans and K. Moldenhauer for database management. This study used samples from the NINDS Human Genetics Resource Center DNA and Cell Line Repository (http://ccr.coriell.org/ninds), as well as clinical data. NINDS Repository sample numbers corresponding to the samples used are available upon request. This study was supported by grants from the German Research Foundation (SA434/4-1, T.S., P.N.), the German Federal Ministry of Education and Research (National Genome Research Network, NGFN-2: NeuroNet, NGFNplus: EMINet), the European Community (FP6 Integrated Project EPICURE, LSHM-CT-2006-037315; grant agreement 219250, A.J.S.), the PopGen biobank, the University of Kiel (I.H.), the Danish National Research Foundation (R.S.M.), in part by grants from the NIH (HD043569, E.E.E.), the National Epilepsy Funds (NEF, grant no. 04-08, B.P.C.K., D. Lindhout), the Netherlands Organization for Scientific Research (NOW, grant no. 917.66.315, B.P.C.K., C.d.K.) and the German Research Foundation/German Federal Ministry of Education and Research (DFG/BMBF) excellence cluster “Inflammation at Interfaces” (A.F., M.W., S.S.). E.E.E. is an investigator of the Howard Hughes Medical Institute.

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Affiliations

  1. Participating centers in the EPICURE Integrated Project are as follows: Department of Neuropediatrics, University Medical Center Schleswig-Holstein (Kiel Campus), Schwanenweg 20, 24105 Kiel, Germany (I.H., H.M., S.v.S., K.L.K., I.S., U.S.). Institute for Clinical Molecular Biology, University Medical Center Schleswig-Holstein (Kiel Campus), Arnold-Heller-Strasse 3, 24105 Kiel, Germany (A.F., M.W., S.S.). Institute of Medical Informatics and Statistics, University Medical Center Schleswig-Holstein (Kiel Campus), Brunswiker Strasse 10, 24105 Kiel, Germany (M.N.). Cologne Center for Genomics, University of Cologne, Zülpicher Strasse 47, 50674 Cologne, Germany (T.S., C.L., P.N.). Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany (C.L., V.G., T.S.). Department of Epileptology, University of Bonn, Sigmund Freud Strasse 1, 53105 Bonn, Germany (A.A.K.-L., C.E.E.). Department of Neurology, Charité University Medicine, Campus Virchow Clinic, Humboldt University of Berlin, Augustenburger Platz 1, 13353 Berlin, Germany (V.G., B.S., T.S.). Interdisciplinary Epilepsy-Center, Department of Neurology, Philipps University Marburg, 35033 Marburg, Germany (K.M.K., P.S.R., F.R.). Department of Neurology, University of Ulm, Helmholtzstrasse 8/1, 89081 Ulm, Germany (Y.W., H.L.). Department of Clinical Neurology (F.Z.) and Department of Pediatrics and Neonatology (L.U., M.F.), Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria. Center of Brain Research, Department of Biochemistry and Molecular Biology, Medical University of Vienna, Spitalgasse 4, A-1090 Vienna, Austria (K.F.). Department of Neurology, Danish Epilepsy Centre, Dianalund Kolonivej 1, 4293 Dianalund, Denmark (R.S.M., H.H.). Wilhelm Johannsen Centre for Functional Genome Research, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen N, Denmark (R.S.M.). Netherlands Section Complex Genetics, Department of Medical Genetics, University Medical Center Utrecht, Str. 2.112 Universiteitsweg 100, 3584 CG Utrecht, The Netherlands (B.P.C.K., C.d.K., D. Lindhout). Department of Neurology, Oosterschelde Hospital, P.O. Box 106, 4460 BB Goes, The Netherlands (F.V.). SEIN Epilepsy Institute in The Netherlands, P.O. Box 540, 2130AM Hoofddorp, The Netherlands (G.-J.d.H., D. Lindhout).

    • Ingo Helbig
    • , Andre Franke
    • , Hiltrud Muhle
    • , Carolien de Kovel
    • , Sarah von Spiczak
    • , Katherine L Kron
    • , Ines Steinich
    • , Ailing A Kleefuß-Lie
    • , Costin Leu
    • , Verena Gaus
    • , Bettina Schmitz
    • , Karl M Klein
    • , Philipp S Reif
    • , Felix Rosenow
    • , Yvonne Weber
    • , Holger Lerche
    • , Fritz Zimprich
    • , Lydia Urak
    • , Karoline Fuchs
    • , Martha Feucht
    • , Frank Visscher
    • , Gerrit-Jan de Haan
    • , Rikke S Møller
    • , Helle Hjalgrim
    • , Michael Wittig
    • , Michael Nothnagel
    • , Christian E Elger
    • , Peter Nürnberg
    • , Bobby P C Koeleman
    • , Dick Lindhout
    • , Ulrich Stephani
    • , Stefan Schreiber
    •  & Thomas Sander
  2. Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.

    • Heather C Mefford
    • , Carl Baker
    •  & Evan E Eichler
  3. Department of Genetic Medicine and Development, University of Geneva Medical School and University Hospitals of Geneva, 1211 Geneva, Switzerland.

    • Andrew J Sharp
    • , Michel Guipponi
    •  & Alain Malafosse
  4. IRCCS Associazione Oasi Maria Santissima, 94018 Troina, Italy.

    • Marco Fichera
    • , Daniela Luciano
    •  & Corrado Romano
  5. Centre Saint Paul-Hôpital Henri Gastaut, 13258 Marseilles 09, France.

    • Pierre Genton
  6. Unité Fonctionnelle EEG-Epileptologie, Service de Neurologie, Hôpital Pasteur, 06002 Nice Cedex 01, France.

    • Pierre Thomas
  7. Howard Hughes Medical Institute, University of Washington, Seattle, Washington 98195, USA.

    • Evan E Eichler

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Contributions

T.S. and E.E.E. initiated and designed the study; I.H., H.M., S.v.S., I.S., A.A.K.-L., V.G., B.S., K.M.K., P.S.R., F.R., Y.W., H.L., F.Z., L.U., K.F., M. Feucht, F.V., G.-J.d.H., R.S.M., H.H., D. Luciano, C.R., D. Lindhout, C.E.E., U.S. and T.S. recruited and phenotyped the EPICURE sample; H.C.M., A.J.S., M.G., M. Fichera, C.B., P.G., P.T., A.M. and E.E.E. recruited and phenotyped the mixed IGE sample; A.F., M.W., M.N. and S.S. recruited and phenotyped the PopGen control sample; I.H., A.F., C.L., K.L.K., I.S., M.W., M.N., P.N. and T.S. performed the CNV analysis on SNP arrays; H.C.M., A.J.S., M. Fichera, C.B. and D. Luciano performed the qPCR screening; H.C.M., M. Fichera, C.B. and D. Luciano performed the screening using Illumina Genotyping BeadChips; H.C.M., A.J.S. and C.B. performed the confirmation using NimbleGen arrays; C.d.K., B.P.C.K. and D. Lindhout performed the confirmation using Illumina CNV BeadChips; I.H., H.C.M., A.J.S., M.G., M. Fichera, A.F., C.d.K., K.L.K., C.R., B.P.C.K., D. Lindhout, E.E.E. and T.S. coordinated the work and prepared the manuscript.

Corresponding author

Correspondence to Thomas Sander.

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DOI

https://doi.org/10.1038/ng.292

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