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Article: Epilepsy subtype-specific copy number burden observed in a genome-wide study of 17 458 subjects

TitleEpilepsy subtype-specific copy number burden observed in a genome-wide study of 17 458 subjects
Authors
Keywordscopy number variation
epilepsy
genetic generalized epilepsy
developmental and epileptic encephalopathy
focal epilepsy
Issue Date2020
PublisherOxford University Press. The Journal's web site is located at http://brain.oxfordjournals.org/
Citation
Brain, 2020, v. 143 n. 7, p. 2106-2118 How to Cite?
AbstractCytogenic testing is routinely applied in most neurological centres for severe paediatric epilepsies. However, which characteristics of copy number variants (CNVs) confer most epilepsy risk and which epilepsy subtypes carry the most CNV burden, have not been explored on a genome-wide scale. Here, we present the largest CNV investigation in epilepsy to date with 10 712 European epilepsy cases and 6746 ancestry-matched controls. Patients with genetic generalized epilepsy, lesional focal epilepsy, non-acquired focal epilepsy, and developmental and epileptic encephalopathy were included. All samples were processed with the same technology and analysis pipeline. All investigated epilepsy types, including lesional focal epilepsy patients, showed an increase in CNV burden in at least one tested category compared to controls. However, we observed striking differences in CNV burden across epilepsy types and investigated CNV categories. Genetic generalized epilepsy patients have the highest CNV burden in all categories tested, followed by developmental and epileptic encephalopathy patients. Both epilepsy types also show association for deletions covering genes intolerant for truncating variants. Genome-wide CNV breakpoint association showed not only significant loci for genetic generalized and developmental and epileptic encephalopathy patients but also for lesional focal epilepsy patients. With a 34-fold risk for developing genetic generalized epilepsy, we show for the first time that the established epilepsy-associated 15q13.3 deletion represents the strongest risk CNV for genetic generalized epilepsy across the whole genome. Using the human interactome, we examined the largest connected component of the genes overlapped by CNVs in the four epilepsy types. We observed that genetic generalized epilepsy and non-acquired focal epilepsy formed disease modules. In summary, we show that in all common epilepsy types, 1.5–3% of patients carry epilepsy-associated CNVs. The characteristics of risk CNVs vary tremendously across and within epilepsy types. Thus, we advocate genome-wide genomic testing to identify all disease-associated types of CNVs.
Persistent Identifierhttp://hdl.handle.net/10722/287183
ISSN
2019 Impact Factor: 11.337
2015 SCImago Journal Rankings: 6.097
PubMed Central ID

 

DC FieldValueLanguage
dc.contributor.authorNiestroj, LM-
dc.contributor.authorPerez-Palma, E-
dc.contributor.authorHowrigan, DP-
dc.contributor.authorZhou, Y-
dc.contributor.authorCheng, F-
dc.contributor.authorSaarentaus, E-
dc.contributor.authorNürnberg, P-
dc.contributor.authorStevelink, R-
dc.contributor.authorDaly, MJ-
dc.contributor.authorPalotie, A-
dc.contributor.authorLal, D-
dc.contributor.authorBaum, LW-
dc.contributor.authorSham, PC-
dc.contributor.authorThe Epi25 Collaborative-
dc.date.accessioned2020-09-22T02:57:04Z-
dc.date.available2020-09-22T02:57:04Z-
dc.date.issued2020-
dc.identifier.citationBrain, 2020, v. 143 n. 7, p. 2106-2118-
dc.identifier.issn0006-8950-
dc.identifier.urihttp://hdl.handle.net/10722/287183-
dc.description.abstractCytogenic testing is routinely applied in most neurological centres for severe paediatric epilepsies. However, which characteristics of copy number variants (CNVs) confer most epilepsy risk and which epilepsy subtypes carry the most CNV burden, have not been explored on a genome-wide scale. Here, we present the largest CNV investigation in epilepsy to date with 10 712 European epilepsy cases and 6746 ancestry-matched controls. Patients with genetic generalized epilepsy, lesional focal epilepsy, non-acquired focal epilepsy, and developmental and epileptic encephalopathy were included. All samples were processed with the same technology and analysis pipeline. All investigated epilepsy types, including lesional focal epilepsy patients, showed an increase in CNV burden in at least one tested category compared to controls. However, we observed striking differences in CNV burden across epilepsy types and investigated CNV categories. Genetic generalized epilepsy patients have the highest CNV burden in all categories tested, followed by developmental and epileptic encephalopathy patients. Both epilepsy types also show association for deletions covering genes intolerant for truncating variants. Genome-wide CNV breakpoint association showed not only significant loci for genetic generalized and developmental and epileptic encephalopathy patients but also for lesional focal epilepsy patients. With a 34-fold risk for developing genetic generalized epilepsy, we show for the first time that the established epilepsy-associated 15q13.3 deletion represents the strongest risk CNV for genetic generalized epilepsy across the whole genome. Using the human interactome, we examined the largest connected component of the genes overlapped by CNVs in the four epilepsy types. We observed that genetic generalized epilepsy and non-acquired focal epilepsy formed disease modules. In summary, we show that in all common epilepsy types, 1.5–3% of patients carry epilepsy-associated CNVs. The characteristics of risk CNVs vary tremendously across and within epilepsy types. Thus, we advocate genome-wide genomic testing to identify all disease-associated types of CNVs.-
dc.languageeng-
dc.publisherOxford University Press. The Journal's web site is located at http://brain.oxfordjournals.org/-
dc.relation.ispartofBrain-
dc.rightsPre-print: Journal Title] ©: [year] [owner as specified on the article] Published by Oxford University Press [on behalf of xxxxxx]. All rights reserved. Pre-print (Once an article is published, preprint notice should be amended to): This is an electronic version of an article published in [include the complete citation information for the final version of the Article as published in the print edition of the Journal.] Post-print: This is a pre-copy-editing, author-produced PDF of an article accepted for publication in [insert journal title] following peer review. The definitive publisher-authenticated version [insert complete citation information here] is available online at: xxxxxxx [insert URL that the author will receive upon publication here].-
dc.subjectcopy number variation-
dc.subjectepilepsy-
dc.subjectgenetic generalized epilepsy-
dc.subjectdevelopmental and epileptic encephalopathy-
dc.subjectfocal epilepsy-
dc.titleEpilepsy subtype-specific copy number burden observed in a genome-wide study of 17 458 subjects-
dc.typeArticle-
dc.identifier.emailBaum, LW: lwbaum@hku.hk-
dc.identifier.emailSham, PC: pcsham@hku.hk-
dc.identifier.authoritySham, PC=rp00459-
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1093/brain/awaa171-
dc.identifier.pmid32568404-
dc.identifier.pmcidPMC7364765-
dc.identifier.scopuseid_2-s2.0-85088262031-
dc.identifier.hkuros314622-
dc.identifier.volume143-
dc.identifier.issue7-
dc.identifier.spage2106-
dc.identifier.epage2118-
dc.publisher.placeUnited Kingdom-

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