Universität zu Köln

Niestroj, Lisa-Marie, Perez-Palma, Eduardo ORCID: 0000-0003-0546-5141, Howrigan, Daniel P., Zhou, Yadi, Cheng, Feixiong, Saarentaus, Elmo ORCID: 0000-0002-8475-7187, Nuernberg, Peter, Stevelink, Remi, Daly, Mark J., Palotie, Aarno and Lal, Dennis (2020). Epilepsy subtype-specific copy number burden observed in a genome-wide study of 17 458 subjects. Brain, 143. S. 2106 - 2119. OXFORD: OXFORD UNIV PRESS. ISSN 1460-2156

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Abstract

Cytogenic 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Niestroj, Lisa-Marie UNSPECIFIED UNSPECIFIED UNSPECIFIED Perez-Palma, Eduardo UNSPECIFIED orcid.org/0000-0003-0546-5141 UNSPECIFIED Howrigan, Daniel P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Zhou, Yadi UNSPECIFIED UNSPECIFIED UNSPECIFIED Cheng, Feixiong UNSPECIFIED UNSPECIFIED UNSPECIFIED Saarentaus, Elmo UNSPECIFIED orcid.org/0000-0002-8475-7187 UNSPECIFIED Nuernberg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Stevelink, Remi UNSPECIFIED UNSPECIFIED UNSPECIFIED Daly, Mark J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Palotie, Aarno UNSPECIFIED UNSPECIFIED UNSPECIFIED Lal, Dennis UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-327212
DOI:	10.1093/brain/awaa171
Journal or Publication Title:	Brain
Volume:	143
Page Range:	S. 2106 - 2119
Date:	2020
Publisher:	OXFORD UNIV PRESS
Place of Publication:	OXFORD
ISSN:	1460-2156
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language DE-NOVO MUTATIONS; 15Q13.3 MICRODELETIONS; GENERALIZED EPILEPSY; 16P13.11 PREDISPOSE; ILAE COMMISSION; INCREASE RISK; VARIANTS; CLASSIFICATION; DUPLICATIONS; ASSOCIATION Multiple languages Clinical Neurology; Neurosciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/32721