title: 16p11.2 600 kb Duplications confer risk for typical and atypical Rolandic epilepsy.
abstract: Rolandic epilepsy (RE) is the most common idiopathic focal childhood epilepsy. Its molecular basis is largely unknown and a complex genetic etiology is assumed in the majority of affected individuals. The present study tested whether six large recurrent copy number variants at 1q21, 15q11.2, 15q13.3, 16p11.2, 16p13.11 and 22q11.2 previously associated with neurodevelopmental disorders also increase risk of RE. Our association analyses revealed a significant excess of the 600 kb genomic duplication at the 16p11.2 locus (chr16: 29.5-30.1 Mb) in 393 unrelated patients with typical (n = 339) and atypical (ARE; n = 54) RE compared with the prevalence in 65,046 European population controls (5/393 cases versus 32/65,046 controls; Fisher's exact test P = 2.83 × 10(-6), odds ratio = 26.2, 95% confidence interval: 7.9-68.2). In contrast, the 16p11.2 duplication was not detected in 1738 European epilepsy patients with either temporal lobe epilepsy (n = 330) and genetic generalized epilepsies (n = 1408), suggesting a selective enrichment of the 16p11.2 duplication in idiopathic focal childhood epilepsies (Fisher's exact test P = 2.1 × 10(-4)). In a subsequent screen among children carrying the 16p11.2 600 kb rearrangement we identified three patients with RE-spectrum epilepsies in 117 duplication carriers (2.6%) but none in 202 carriers of the reciprocal deletion. Our results suggest that the 16p11.2 duplication represents a significant genetic risk factor for typical and atypical RE.
authors.affiliation: Department of Neurology.
authors.forename: Eva M
authors.initials: EM
authors.lastname: Reinthaler
authors.affiliation: Cologne Center for Genomics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany, Department of Neuropediatrics, University Medical Faculty Giessen and Marburg, Giessen, Germany.
authors.forename: Dennis
authors.initials: D
authors.lastname: Lal
authors.affiliation: Unit of Pediatric Neurology and Neurorehabilitation, Department of Pediatrics.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Lebon
authors.affiliation: Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Australia.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Hildebrand
authors.affiliation: Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Australia.
authors.forename: Hans-Henrik M
authors.initials: HH
authors.lastname: Dahl
authors.affiliation: Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Australia.
authors.forename: Brigid M
authors.initials: BM
authors.lastname: Regan
authors.affiliation: Department of Pediatrics, Medical University of Vienna, Vienna, Austria.
authors.forename: Martha
authors.initials: M
authors.lastname: Feucht
authors.affiliation: Private Practice for Pediatrics, Vienna, Austria.
authors.forename: Hannelore
authors.initials: H
authors.lastname: Steinböck
authors.affiliation: Department of Neuropediatrics, St. Anna Children's Hospital, Vienna, Austria.
authors.forename: Birgit
authors.initials: B
authors.lastname: Neophytou
authors.affiliation: Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Gabriel M
authors.initials: GM
authors.lastname: Ronen
authors.affiliation: Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Laurian
authors.initials: L
authors.lastname: Roche
authors.affiliation: Department of Pediatrics, Medical University of Graz, Graz, Austria.
authors.forename: Ursula
authors.initials: U
authors.lastname: Gruber-Sedlmayr
authors.affiliation: Department of Pediatrics, Hospital SMZ Süd Kaiser-Franz-Josef Spital, Vienna, Austria.
authors.forename: Julia
authors.initials: J
authors.lastname: Geldner
authors.affiliation: Department of Pediatrics, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Edda
authors.initials: E
authors.lastname: Haberlandt
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany, Division of Medical Genetics, University Hospital and Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Per
authors.initials: P
authors.lastname: Hoffmann
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany, Division of Medical Genetics, University Hospital and Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Herms
authors.affiliation: Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Institute of Genetic Epidemiology, Neuherberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Gieger
authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Waldenberger
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 Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Wittig
authors.affiliation: Department of Neuropathology, University of Bonn Medical Center, Bonn, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Schoch
authors.affiliation: Department of Neuropathology, University of Bonn Medical Center, Bonn, Germany.
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Becker
authors.affiliation: Department of Neuropediatrics, University Medical Faculty Giessen and Marburg, Giessen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Hahn
authors.affiliation: Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland, Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
authors.forename: Katrin
authors.initials: K
authors.lastname: Männik
authors.affiliation: Cologne Center for Genomics.
authors.forename: Mohammad R
authors.initials: MR
authors.lastname: Toliat
authors.affiliation: Experimental and Clinical Research Center (ECRC) Charité, University Medicine Berlin, Berlin, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Winterer
authors.affiliation: 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: Cologne Center for Genomics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.affiliation: Division of Genetic Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Mefford
authors.affiliation: Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Australia, Florey Institute and Department of Pediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, Australia.
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Scheffer
authors.affiliation: Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Australia.
authors.forename: Samuel F
authors.initials: SF
authors.lastname: Berkovic
authors.affiliation: Service of Medical Genetics, Lausanne University Hospital, Lausanne, Switzerland, Swiss Institute of Bioinformatics, Lausanne, Switzerland and.
authors.forename: Jacques S
authors.initials: JS
authors.lastname: Beckmann
authors.affiliation: Cologne Center for Genomics.
authors.forename: Thomas
authors.initials: T
authors.lastname: Sander
authors.affiliation: Service of Medical Genetics, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Jacquemont
authors.affiliation: Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Reymond
authors.affiliation: Department of Neurology, friedrich.zimprich@meduniwien.ac.at.
authors.forename: Fritz
authors.initials: F
authors.lastname: Zimprich
authors.affiliation: Department of Neuropediatrics, University Medical Faculty Giessen and Marburg, Giessen, Germany.
authors.forename: Bernd A
authors.initials: BA
authors.lastname: Neubauer
mesh_terms: D002648:Child; D002675:Child, Preschool; D058674:Chromosome Duplication; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics*; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics; D056915:DNA Copy Number Variations; D019305:Epilepsy, Rolandic / Q000235:genetics*; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D020641:Polymorphism, Single Nucleotide