title: Burden analysis of rare microdeletions suggests a strong impact of neurodevelopmental genes in genetic generalised epilepsies.
abstract: Genetic generalised epilepsy (GGE) is the most common form of genetic epilepsy, accounting for 20% of all epilepsies. Genomic copy number variations (CNVs) constitute important genetic risk factors of common GGE syndromes. In our present genome-wide burden analysis, large (≥ 400 kb) and rare (< 1%) autosomal microdeletions with high calling confidence (≥ 200 markers) were assessed by the Affymetrix SNP 6.0 array in European case-control cohorts of 1,366 GGE patients and 5,234 ancestry-matched controls. We aimed to: 1) assess the microdeletion burden in common GGE syndromes, 2) estimate the relative contribution of recurrent microdeletions at genomic rearrangement hotspots and non-recurrent microdeletions, and 3) identify potential candidate genes for GGE. We found a significant excess of microdeletions in 7.3% of GGE patients compared to 4.0% in controls (P = 1.8 x 10-7; OR = 1.9). Recurrent microdeletions at seven known genomic hotspots accounted for 36.9% of all microdeletions identified in the GGE cohort and showed a 7.5-fold increased burden (P = 2.6 x 10-17) relative to controls. Microdeletions affecting either a gene previously implicated in neurodevelopmental disorders (P = 8.0 x 10-18, OR = 4.6) or an evolutionarily conserved brain-expressed gene related to autism spectrum disorder (P = 1.3 x 10-12, OR = 4.1) were significantly enriched in the GGE patients. Microdeletions found only in GGE patients harboured a high proportion of genes previously associated with epilepsy and neuropsychiatric disorders (NRXN1, RBFOX1, PCDH7, KCNA2, EPM2A, RORB, PLCB1). Our results demonstrate that the significantly increased burden of large and rare microdeletions in GGE patients is largely confined to recurrent hotspot microdeletions and microdeletions affecting neurodevelopmental genes, suggesting a strong impact of fundamental neurodevelopmental processes in the pathogenesis of common GGE syndromes.
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany; Department of Neuropediatrics, University Medical Center Giessen and Marburg, Giessen, Germany; EPICURE Consortium.
authors.forename: Dennis
authors.initials: D
authors.lastname: Lal
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany; EPICURE Consortium.
authors.forename: Ann-Kathrin
authors.initials: AK
authors.lastname: Ruppert
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany; EPICURE Consortium.
authors.forename: Holger
authors.initials: H
authors.lastname: Trucks
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany; EPICURE Consortium.
authors.forename: Herbert
authors.initials: H
authors.lastname: Schulz
authors.affiliation: EPICURE Consortium; Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Carolien G
authors.initials: CG
authors.lastname: de Kovel
authors.affiliation: EPICURE Consortium.
authors.forename: Dorothée
authors.initials: D
authors.lastname: Kasteleijn-Nolst Trenité
authors.affiliation: EPICURE Consortium; Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Anja C M
authors.initials: AC
authors.lastname: Sonsma
authors.affiliation: EPICURE Consortium; Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Bobby P
authors.initials: BP
authors.lastname: Koeleman
authors.affiliation: EPICURE Consortium; Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands; SEIN Epilepsy Institute in the Netherlands, Hoofddorp, The Netherlands.
authors.forename: Dick
authors.initials: D
authors.lastname: Lindhout
authors.affiliation: EPICURE Consortium; Department of Neurology and Epileptology, Hertie Institute of Clinical Brain Research, University of Tübingen, Tübingen, Germany.
authors.forename: Yvonne G
authors.initials: YG
authors.lastname: Weber
authors.affiliation: EPICURE Consortium; Department of Neurology and Epileptology, Hertie Institute of Clinical Brain Research, University of Tübingen, Tübingen, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Lerche
authors.affiliation: EPICURE Consortium; Department of Neurology, University of Munich Hospital-Großhadern, Munich, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Kapser
authors.affiliation: EPICURE Consortium; Department of Neurology, University of Munich Hospital-Großhadern, Munich, Germany.
authors.forename: Christoph J
authors.initials: CJ
authors.lastname: Schankin
authors.affiliation: EPICURE Consortium; Department of Epileptology, University Clinics Bonn, Bonn, Germany.
authors.forename: Wolfram S
authors.initials: WS
authors.lastname: Kunz
authors.affiliation: EPICURE Consortium; Department of Epileptology, University Clinics Bonn, Bonn, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Surges
authors.affiliation: EPICURE Consortium; Department of Epileptology, University Clinics Bonn, Bonn, Germany.
authors.forename: Christian E
authors.initials: CE
authors.lastname: Elger
authors.affiliation: EPICURE Consortium; Department of Neurology, Charité University Medicine, Campus Virchow Clinic, Berlin, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Gaus
authors.affiliation: EPICURE Consortium; Department of Neurology, Charité University Medicine, Campus Virchow Clinic, Berlin, Germany; Department of Neurology, Vivantes Humboldt-Klinikum, Berlin, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Schmitz
authors.affiliation: EPICURE Consortium; Department of Neuropediatrics, University Medical Center Schleswig-Holstein (Kiel Campus), Kiel, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Helbig
authors.affiliation: EPICURE Consortium; Department of Neuropediatrics, University Medical Center Schleswig-Holstein (Kiel Campus), Kiel, Germany.
authors.forename: Hiltrud
authors.initials: H
authors.lastname: Muhle
authors.affiliation: EPICURE Consortium; Department of Neuropediatrics, University Medical Center Schleswig-Holstein (Kiel Campus), Kiel, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Stephani
authors.affiliation: EPICURE Consortium; Epilepsy-Center Hessen, Department of Neurology, Philipps-University Marburg, Marburg, Germany; Epilepsy Center Frankfurt Rhein-Main, Department of Neurology, Johann Wolfgang Goethe University Frankfurt, Frankfurt, Germany.
authors.forename: Karl M
authors.initials: KM
authors.lastname: Klein
authors.affiliation: EPICURE Consortium; Epilepsy-Center Hessen, Department of Neurology, Philipps-University Marburg, Marburg, Germany; Epilepsy Center Frankfurt Rhein-Main, Department of Neurology, Johann Wolfgang Goethe University Frankfurt, Frankfurt, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Rosenow
authors.affiliation: Department of Neuropediatrics, University Medical Center Giessen and Marburg, Giessen, Germany.
authors.forename: Bernd A
authors.initials: BA
authors.lastname: Neubauer
authors.affiliation: EPICURE Consortium; Department of Neurology, Medical University of Vienna, Vienna, Austria.
authors.forename: Eva M
authors.initials: EM
authors.lastname: Reinthaler
authors.affiliation: EPICURE Consortium; Department of Neurology, Medical University of Vienna, Vienna, Austria.
authors.forename: Fritz
authors.initials: F
authors.lastname: Zimprich
authors.affiliation: EPICURE Consortium; Department of Pediatrics and Neonatology, Medical University of Vienna, Vienna, Austria.
authors.forename: Martha
authors.initials: M
authors.lastname: Feucht
authors.affiliation: EPICURE Consortium; Department of Neurology, Danish Epilepsy Centre, Dianalund, Denmark; Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark.
authors.forename: Rikke S
authors.initials: RS
authors.lastname: Møller
authors.affiliation: EPICURE Consortium; Department of Neurology, Danish Epilepsy Centre, Dianalund, Denmark; Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark.
authors.forename: Helle
authors.initials: H
authors.lastname: Hjalgrim
authors.affiliation: EPICURE Consortium; Neurogenetics Group, VIB Department of Molecular Genetics, University of Antwerp, Antwerp, Belgium; Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: De Jonghe
authors.affiliation: EPICURE Consortium; Neurogenetics Group, VIB Department of Molecular Genetics, University of Antwerp, Antwerp, Belgium; Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Arvid
authors.initials: A
authors.lastname: Suls
authors.affiliation: Institute of Epidemiology and Biobank Popgen, Christian Albrechts University, Kiel, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Lieb
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.affiliation: Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Institute of Medical Informatics, Biometry and Epidemiology, and Chair of Genetic Epidemiology, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Strauch
authors.affiliation: Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Gieger
authors.affiliation: Interfaculty Institute for Genetics and Functional Genomics, Ernst Moritz Arndt University, Greifswald, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Schurmann
authors.affiliation: Department of Neurology, University Medicine Greifswald, Ernst Moritz Arndt University, Greifswald, Germany.
authors.forename: Ulf
authors.initials: U
authors.lastname: Schminke
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany; EPICURE Consortium; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany; EPICURE Consortium.
authors.forename: Thomas
authors.initials: T
authors.lastname: Sander
mesh_terms: D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D002648:Child; D015331:Cohort Studies; D056915:DNA Copy Number Variations; D004829:Epilepsy, Generalized / Q000235:genetics*; D005260:Female; D015321:Gene Rearrangement; D056726:Genetic Association Studies; D015894:Genome, Human; D006801:Humans; D008297:Male; D065886:Neurodevelopmental Disorders / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D054730:Protein Interaction Domains and Motifs; D017384:Sequence Deletion; D055815:Young Adult