Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies
| Autor: | Dick Lindhout, Sarah von Spiczak, Heather C Mefford, Ina Maria Rückert, Martha Feucht, Lydia Urak, Christian Kluck, Peter De Jonghe, Hajo M. Hamer, Fritz Zimprich, Tanja Obermeier, Marielle E M Swinkels, Arvid Suls, Evan E. Eichler, Ingo Helbig, Ailing A. Kleefuß-Lie, Felix Rosenow, Carolien G.F. de Kovel, Ulrich Stephani, Heinz Erich Wichmann, Michael Steffens, Kerstin Hallmann, Stefan Schreiber, Thomas Sander, Helle Hjalgrim, Karoline Fuchs, Bobby P. C. Koeleman, Christian E. Elger, Holger Trucks, Karl Martin Klein, Eva H. Brilstra, Andre Franke, Dorothée G.A. Kasteleijn-Nolst Trenité, Yvonne G. Weber, Costin Leu, Hiltrud Muhle, Verena Gaus, Iris Unterberger, Rikke S. Møller, Peter Nürnberg, Carl Baker, Holger Lerche, Philipp Ostertag |
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| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Male
medicine.medical_specialty Adolescent Parenteral transmission Single-nucleotide polymorphism Biology Epileptogenesis Idiopathic generalized epilepsy Cohort Studies Epilepsy Young Adult Internal medicine medicine Humans Genetic Predisposition to Disease Child Genetics Chromosomes Human Pair 15 Odds ratio medicine.disease Pedigree Child Preschool Etiology Epilepsy Generalized Female Neurology (clinical) Human medicine Chromosome Deletion Chromosomes Human Pair 16 Comparative genomic hybridization |
| Zdroj: | Brain de Kovel, C G F, Trucks, H, Helbig, I, Mefford, H C, Baker, C, Leu, C, Kluck, C, Muhle, H, von Spiczak, S, Ostertag, P, Obermeier, T, Kleefuss-Lie, A A, Hallmann, K, Steffens, M, Gaus, V, Klein, K M, Hamer, H M, Rosenow, F, Brilstra, E H, Trenité, D K-N, Swinkels, M E M, Weber, Y G, Unterberger, I, Zimprich, F, Urak, L, Feucht, M, Fuchs, K, Møller, R S, Hjalgrim, H, De Jonghe, P, Suls, A, Rückert, I-M, Wichmann, H-E, Franke, A, Schreiber, S, Nürnberg, P, Elger, C E, Lerche, H, Stephani, U, Koeleman, B P C, Lindhout, D, Eichler, E E & Sander, T 2010, ' Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies ', Brain, vol. 133, no. 1, pp. 23-32 . https://doi.org/10.1093/brain/awp262 |
| ISSN: | 0006-8950 |
| DOI: | 10.1093/brain/awp262 |
| Popis: | 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 ( |
| Databáze: | OpenAIRE |
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