Rare deletions at 16p13.11 predispose to a diverse spectrum of sporadic epilepsy syndromes
| Autor: | Claudia B. Catarino, Erin L. Heinzen, Mohamad A. Mikati, Paul M. Matthews, Heinz Gregor Wieser, Patrick G. Buckley, Jörg Hansen, Chantal Depondt, Josemir W. Sander, David Goldstein, Colin P. Doherty, Günter Krämer, Sanjay M. Sisodiya, Nicholas W. Wood, Kevin V. Shianna, Dalia Kasperaviciūte, Dominik Zumsteg, Sarah K. Tate, Anna C. Need, Norman Delanty, Gianpiero L. Cavalleri, Massimo Pandolfo, Julie Huxley-Jones, Reetta Kälviäinen, Marcos Ortega, Curtis Gumbs, Thomas Dorn, William Gallentine, John S. Duncan, Aatif M. Husain, Anne-Mari Kantanen, Marvin Johnson, Kai Eriksson, Rachel A. Gibson, Rodney A. Radtke, Kristen N. Linney, David Leppert, Raymond L. Stallings, Nicole M. Walley, Lefkos T. Middleton, Bernhard J. Steinhoff, Lisa M. S. Clayton, Kenneth D. Cronin, Mihai V. Podgoreanu, David A. Hosford, Paola Nicoletti, Thomas J. Urban, Jessica M. Maia, Dongliang Ge, Jason Smith, Luis O. Caboclo |
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| Přispěvatelé: | University of Zurich, Sisodiya, S M |
| Rok vydání: | 2010 |
| Předmět: |
2716 Genetics (clinical)
610 Medicine & health Biology medicine.disease_cause Bioinformatics Article Idiopathic generalized epilepsy Structural variation 03 medical and health sciences Epilepsy 0302 clinical medicine Childhood absence epilepsy 1311 Genetics mental disorders Genetics medicine Humans Genetics(clinical) Copy-number variation Genetics (clinical) 030304 developmental biology Sequence Deletion 0303 health sciences Mutation Nucleic Acid Hybridization Syndrome Sciences bio-médicales et agricoles medicine.disease 10040 Clinic for Neurology Epilepsy syndromes Disease Susceptibility Haploinsufficiency 030217 neurology & neurosurgery Chromosomes Human Pair 16 |
| Zdroj: | American journal of human genetics, 86 (5 |
| ISSN: | 1537-6605 |
| Popis: | Deletions at 16p13.11 are associated with schizophrenia, mental retardation, and most recently idiopathic generalized epilepsy. To evaluate the role of 16p13.11 deletions, as well as other structural variation, in epilepsy disorders, we used genome-wide screens to identify copy number variation in 3812 patients with a diverse spectrum of epilepsy syndromes and in 1299 neurologically-normal controls. Large deletions (> 100 kb) at 16p13.11 were observed in 23 patients, whereas no control had a deletion greater than 16 kb. Patients, even those with identically sized 16p13.11 deletions, presented with highly variable epilepsy phenotypes. For a subset of patients with a 16p13.11 deletion, we show a consistent reduction of expression for included genes, suggesting that haploinsufficiency might contribute to pathogenicity. We also investigated another possible mechanism of pathogenicity by using hybridization-based capture and next-generation sequencing of the homologous chromosome for ten 16p13.11-deletion patients to look for unmasked recessive mutations. Follow-up genotyping of suggestive polymorphisms failed to identify any convincing recessive-acting mutations in the homologous interval corresponding to the deletion. The observation that two of the 16p13.11 deletions were larger than 2 Mb in size led us to screen for other large deletions. We found 12 additional genomic regions harboring deletions > 2 Mb in epilepsy patients, and none in controls. Additional evaluation is needed to characterize the role of these exceedingly large, non-locus-specific deletions in epilepsy. Collectively, these data implicate 16p13.11 and possibly other large deletions as risk factors for a wide range of epilepsy disorders, and they appear to point toward haploinsufficiency as a contributor to the pathogenicity of deletions. Journal Article Research Support, Non-U.S. Gov't SCOPUS: ar.j info:eu-repo/semantics/published |
| Databáze: | OpenAIRE |
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