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Hum Mol Genet. 2014 Nov 15;23(22):6069-80. doi: 10.1093/hmg/ddu306. Epub 2014 Jun 16.

16p11.2 600 kb Duplications confer risk for typical and atypical Rolandic epilepsy.

Author information

1
Department of Neurology.
2
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.
3
Unit of Pediatric Neurology and Neurorehabilitation, Department of Pediatrics.
4
Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Australia.
5
Department of Pediatrics, Medical University of Vienna, Vienna, Austria.
6
Private Practice for Pediatrics, Vienna, Austria.
7
Department of Neuropediatrics, St. Anna Children's Hospital, Vienna, Austria.
8
Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada.
9
Department of Pediatrics, Medical University of Graz, Graz, Austria.
10
Department of Pediatrics, Hospital SMZ Süd Kaiser-Franz-Josef Spital, Vienna, Austria.
11
Department of Pediatrics, Medical University of Innsbruck, Innsbruck, Austria.
12
Institute of Human Genetics, University of Bonn, Bonn, Germany, Division of Medical Genetics, University Hospital and Department of Biomedicine, University of Basel, Basel, Switzerland.
13
Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Institute of Genetic Epidemiology, Neuherberg, Germany.
14
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
15
Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
16
Department of Neuropathology, University of Bonn Medical Center, Bonn, Germany.
17
Department of Neuropediatrics, University Medical Faculty Giessen and Marburg, Giessen, Germany.
18
Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland, Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
19
Cologne Center for Genomics.
20
Experimental and Clinical Research Center (ECRC) Charité, University Medicine Berlin, Berlin, Germany.
21
Department of Neurology and Epileptology, Hertie Institute of Clinical Brain Research, University of Tübingen, Tübingen, Germany.
22
Cologne Center for Genomics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
23
Division of Genetic Medicine, University of Washington, Seattle, Washington, USA.
24
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.
25
Service of Medical Genetics, Lausanne University Hospital, Lausanne, Switzerland, Swiss Institute of Bioinformatics, Lausanne, Switzerland and.
26
Service of Medical Genetics, Lausanne University Hospital, Lausanne, Switzerland.
27
Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
28
Department of Neurology, friedrich.zimprich@meduniwien.ac.at.

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.

PMID:
24939913
DOI:
10.1093/hmg/ddu306
[Indexed for MEDLINE]

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