Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies - PubMed (original) (raw)

Comparative Study

. 2010 Jan;133(Pt 1):23-32.

doi: 10.1093/brain/awp262. Epub 2009 Oct 20.

Holger Trucks, Ingo Helbig, Heather C Mefford, Carl Baker, Costin Leu, Christian Kluck, Hiltrud Muhle, Sarah von Spiczak, Philipp Ostertag, Tanja Obermeier, Ailing A Kleefuss-Lie, Kerstin Hallmann, Michael Steffens, Verena Gaus, Karl M Klein, Hajo M Hamer, Felix Rosenow, Eva H Brilstra, Dorothée Kasteleijn-Nolst Trenité, Marielle E M Swinkels, Yvonne G Weber, Iris Unterberger, Fritz Zimprich, Lydia Urak, Martha Feucht, Karoline Fuchs, Rikke S Møller, Helle Hjalgrim, Peter De Jonghe, Arvid Suls, Ina-Maria Rückert, Heinz-Erich Wichmann, Andre Franke, Stefan Schreiber, Peter Nürnberg, Christian E Elger, Holger Lerche, Ulrich Stephani, Bobby P C Koeleman, Dick Lindhout, Evan E Eichler, Thomas Sander

Affiliations

Comparative Study

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

Carolien G F de Kovel et al. Brain. 2010 Jan.

Abstract

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.

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Figures

Figure 1

Figure 1

Genomic position of the microdeletions at the genomic hot spot regions 1q21.1, 15q11.2, 16p11.2, 16p13.11, 22q11.2 and 15q13.3. Red = IGE patients; blue = controls. The positions of genes are also shown. Produced with the University of California, Santa Cruz Genome Browser (

http://www.genome.ucsc.edu

).

Figure 1

Figure 1

Genomic position of the microdeletions at the genomic hot spot regions 1q21.1, 15q11.2, 16p11.2, 16p13.11, 22q11.2 and 15q13.3. Red = IGE patients; blue = controls. The positions of genes are also shown. Produced with the University of California, Santa Cruz Genome Browser (

http://www.genome.ucsc.edu

).

Figure 2

Figure 2

Familial segregation of the microdeletions at 15q11.2, 16p13.11, 22q11.2 and 15q13.3. Arrows denote the index-IGE patient typed by the Affymetrix SNP 6.0 array. Black symbols = individuals affected by IGE. FS = febrile seizure; CAE = childhood absence epilepsy; JAE = juvenile absence epilepsy; JME = juvenile myoclonic epilepsy; EGTCS = epilepsy with generalized tonic–clonic seizures alone; EGMA = epilepsy with generalized tonic–clonic seizures on awakening; TLE = temporal lobe epilepsy; copy number state: n = normal/two copies; filled star indicates deletion carrier. #Families of IGE patients with 15q13.3 deletions reported previously (Helbig et al., 2009).

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