Brain Advance Access published online on October 20, 2009
Brain, doi:10.1093/brain/awp262
Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies
1 Section Complex Genetics, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands 2 Cologne Centre for Genomics, University of Cologne Cologne, Germany 3 Department of Neuropaediatrics, University Medical Centre Schleswig-Holstein (Kiel Campus), Kiel, Germany 4 Department of Paediatrics, University of Washington, Seattle, USA 5 Department of Genome Sciences, University of Washington, Seattle, USA 6 Department of Epileptology, University of Bonn, Bonn, Germany 7 Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany 8 Department of Neurology, Charité University Medicine, Campus Virchow Clinic, Humboldt University of Berlin, Berlin, Germany 9 Department of Neurology, Interdisciplinary Epilepsy-Centre, Philipps University Marburg, Marburg, Germany 10 Neurological Clinic, University of Ulm, Ulm, Germany 11 University Clinic for Neurology, Medical University of Innsbruck, Innsbruck, Austria 12 Department of Clinical Neurology, Medical University of Vienna, Vienna, Austria 13 Department of Paediatrics and Neonatology, Medical University of Vienna, Vienna, Austria 14 Department for Biochemistry and Molecular Biology, Center for Brain Research, Medical University of Vienna, Vienna, Austria 15 Department of Neurology, Danish Epilepsy Centre, Dianalund, Denmark 16 Wilhelm Johannsen Centre for Functional Genome Research, University of Copenhagen, Copenhagen, Denmark 17 Department of Molecular Genetics, University of Antwerp, Antwerpen, Belgium 18 Institute of Epidemiology, Helmholtz Zentrum München, German Research Centre for Environmental Health, Munich/Neuherberg, Germany 19 Chair of Epidemiology, IBE, University of Munich (LMU), Munich, Germany 20 Klinikum Grosshadern, Munich, Germany 21 Institute for Clinical Molecular Biology, University Medical Centre Schleswig-Holstein (Kiel Campus), Kiel, Germany 22 SEIN Epilepsy Institute in the Netherlands, Heemstede, The Netherlands 23 Howard Hughes Medical Institute, University of Washington, Seattle, USA
Correspondence to:
Thomas Sander, MD, Cologne Centre for Genomics, University of Cologne, Zülpicher Str. 47, 50674 Cologne, Germany E-mail: sandert{at}uni-koeln.de
Idiopathic generalized epilepsies account for 30% of all epilepsies. Despite a predominant genetic aetiology, the genetic factors predisposing to idiopathic generalized epilepsies remain elusive. Studies of structural genomic variations have revealed a significant excess of recurrent microdeletions at 1q21.1, 15q11.2, 15q13.3, 16p11.2, 16p13.11 and 22q11.2 in various neuropsychiatric disorders including autism, intellectual disability and schizophrenia. Microdeletions at 15q13.3 have recently been shown to constitute a strong genetic risk factor for common idiopathic generalized epilepsy syndromes, implicating that other recurrent microdeletions may also be involved in epileptogenesis. This study aimed to investigate the impact of five microdeletions at the genomic hotspot regions 1q21.1, 15q11.2, 16p11.2, 16p13.11 and 22q11.2 on the genetic risk to common idiopathic generalized epilepsy syndromes. The candidate microdeletions were assessed by high-density single nucleotide polymorphism arrays in 1234 patients with idiopathic generalized epilepsy from North-western Europe and 3022 controls from the German population. Microdeletions were validated by quantitative polymerase chain reaction and their breakpoints refined by array comparative genomic hybridization. In total, 22 patients with idiopathic generalized epilepsy (1.8%) carried one of the five novel microdeletions compared with nine controls (0.3%) (odds ratio = 6.1; 95% confidence interval 2.8–13.2; 
2 = 26.7; 1 degree of freedom; P = 2.4 x 10–7). Microdeletions were observed at 1q21.1 [Idiopathic generalized epilepsy (IGE)/control: 1/1], 15q11.2 (IGE/control: 12/6), 16p11.2 IGE/control: 1/0, 16p13.11 (IGE/control: 6/2) and 22q11.2 (IGE/control: 2/0). Significant associations with IGEs were found for the microdeletions at 15q11.2 (odds ratio = 4.9; 95% confidence interval 1.8–13.2; P = 4.2 x 10–4) and 16p13.11 (odds ratio = 7.4; 95% confidence interval 1.3–74.7; P = 0.009). Including nine patients with idiopathic generalized epilepsy in this cohort with known 15q13.3 microdeletions (IGE/control: 9/0), parental transmission could be examined in 14 families. While 10 microdeletions were inherited (seven maternal and three paternal transmissions), four microdeletions occurred de novo at 15q13.3 (n = 1), 16p13.11 (n = 2) and 22q11.2 (n = 1). Eight of the transmitting parents were clinically unaffected, suggesting that the microdeletion itself is not sufficient to cause the epilepsy phenotype. Although the microdeletions investigated are individually rare (<1%) in patients with idiopathic generalized epilepsy, they collectively seem to account for a significant fraction of the genetic variance in common idiopathic generalized epilepsy syndromes. The present results indicate an involvement of microdeletions at 15q11.2 and 16p13.11 in epileptogenesis and strengthen the evidence that recurrent microdeletions at 15q11.2, 15q13.3 and 16p13.11 confer a pleiotropic susceptibility effect to a broad range of neuropsychiatric disorders.
Key Words: idiopathic generalized epilepsy; microdeletions; association; genetics
Abbreviations: CNV, copy number variation; IGE, idiopathic generalized epilepsy; SNP, single nucleotide polymorphism
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Received June 24, 2009. Revised August 25, 2009. Accepted August 27, 2009.
*These authors contributed equally to this work.