Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies

被引：344

作者：

de Kovel, Carolien G. F. ^{[2
]}

Trucks, Holger ^{[1
]}

Helbig, Ingo ^{[3
]}

Mefford, Heather C. ^{[4
,5
]}

Baker, Carl ^{[5
]}

Leu, Costin ^{[1
]}

Kluck, Christian ^{[1
]}

Muhle, Hiltrud ^{[3
]}

von Spiczak, Sarah ^{[3
]}

Ostertag, Philipp ^{[3
]}

Obermeier, Tanja ^{[3
]}

Kleefuss-Lie, Ailing A. ^{[6
]}

Hallmann, Kerstin ^{[6
]}

Steffens, Michael ^{[7
]}

Gaus, Verena ^{[8
]}

Klein, Karl M. ^{[9
]}

Hamer, Hajo M. ^{[9
]}

Rosenow, Felix ^{[9
]}

Brilstra, Eva H. ^{[2
]}

Trenite, Dorothee Kasteleijn-Nolst ^{[2
]}

Swinkels, Marielle E. M. ^{[2
]}

Weber, Yvonne G. ^{[10
]}

Unterberger, Iris ^{[11
]}

Zimprich, Fritz ^{[12
]}

Urak, Lydia ^{[13
]}

Feucht, Martha ^{[13
]}

Fuchs, Karoline ^{[14
]}

Moller, Rikke S. ^{[15
,16
]}

Hjalgrim, Helle ^{[15
]}

De Jonghe, Peter ^{[17
]}

Suls, Arvid ^{[17
]}

Rueckert, Ina-Maria ^{[18
]}

Wichmann, Heinz-Erich ^{[18
,19
,20
]}

Franke, Andre ^{[21
]}

Schreiber, Stefan ^{[21
]}

Nuernberg, Peter ^{[1
]}

Elger, Christian E. ^{[6
]}

Lerche, Holger ^{[10
]}

Stephani, Ulrich ^{[3
]}

Koeleman, Bobby P. C. ^{[2
]}

Lindhout, Dick ^{[2
,22
]}

Eichler, Evan E. ^{[5
,23
]}

Sander, Thomas ^{[1
,8
]}

机构：

[1] Univ Cologne, Cologne Ctr Genom, D-50674 Cologne, Germany

[2] Univ Med Ctr Utrecht, Dept Med Genet, Sect Complex Genet, Utrecht, Netherlands

[3] Univ Med Ctr Schleswig Holstein, Dept Neuropaediat, Kiel, Germany

[4] Univ Washington, Dept Paediat, Seattle, WA 98195 USA

[5] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA

[6] Univ Bonn, Dept Epileptol, D-5300 Bonn, Germany

[7] Univ Bonn, Inst Med Biometry Informat & Epidemiol, D-5300 Bonn, Germany

[8] Humboldt Univ, Dept Neurol, Charite Univ Med, Campus Virchow Clin, Berlin, Germany

[9] Univ Marburg, Dept Neurol, Interdisciplinary Epilepsy Ctr, Marburg, Germany

[10] Univ Ulm, Neurol Clin, Ulm, Germany

[11] Med Univ Innsbruck, Univ Clin Neurol, Innsbruck, Austria

[12] Med Univ Vienna, Dept Clin Neurol, Vienna, Austria

[13] Med Univ Vienna, Dept Paediat & Neonatol, Vienna, Austria

[14] Med Univ Vienna, Dept Biochem & Mol Biol, Ctr Brain Res, Vienna, Austria

[15] Danish Epilepsy Ctr, Dept Neurol, Dianalund, Denmark

[16] Univ Copenhagen, Wilhelm Johannsen Ctr Funct Genome Res, Copenhagen, Denmark

[17] Univ Antwerp, Dept Mol Genet, B-2020 Antwerp, Belgium

[18] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol, Munich, Germany

[19] Univ Munich LMU, IBE, Chair Epidemiol, Munich, Germany

[20] Univ Munich, Klinikum Grosshadern, D-8000 Munich, Germany

[21] Univ Med Ctr Schleswig Holstein, Inst Clin Mol Biol, Kiel, Germany

[22] SEIN Epilepsy Inst Netherlands, Heemstede, Netherlands

[23] Univ Washington, Howard Hughes Med Inst, Seattle, WA 98195 USA

来源：

BRAIN | 2010年 / 133卷

基金：

美国国家卫生研究院;

关键词：

idiopathic generalized epilepsy; microdeletions; association; genetics; COPY-NUMBER VARIATIONS; 15Q13.3; MICRODELETIONS; STRUCTURAL VARIATION; MECHANISMS; SPECTRUM; DUPLICATIONS; DELETIONS; GENETICS; 16P11.2; 1Q21.1;

D O I：

10.1093/brain/awp262

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

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; chi(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.

引用

页码：23 / 32

页数：10

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