TY - JOUR
T1 - Epilepsy subtype-specific copy number burden observed in a genome-wide study of 17458 subjects
AU - the Epi25 Collaborative
AU - Niestroj, Lisa Marie
AU - Perez-Palma, Eduardo
AU - Howrigan, Daniel P.
AU - Zhou, Yadi
AU - Cheng, Feixiong
AU - Saarentaus, Elmo
AU - Nürnberg, Peter
AU - Stevelink, Remi
AU - Daly, Mark J.
AU - Palotie, Aarno
AU - Lal, Dennis
AU - Feng, Yen Chen Anne
AU - Abbott, Liam E.
AU - Tashman, Katherine
AU - Cerrato, Felecia
AU - Churchhouse, Claire
AU - Gupta, Namrata
AU - Neale, Benjamin M.
AU - Berkovic, Samuel F.
AU - Lerche, Holger
AU - Goldstein, David B.
AU - Lowenstein, Daniel H.
AU - Cavalleri, Gianpiero L.
AU - Cossette, Patrick
AU - Cotsapas, Chris
AU - De Jonghe, Peter
AU - Dixon-Salazar, Tracy
AU - Guerrini, Renzo
AU - Hakonarson, Hakon
AU - Heinzen, Erin L.
AU - Helbig, Ingo
AU - Kwan, Patrick
AU - Marson, Anthony G.
AU - Petrovski, Slavé
AU - Kamalakaran, Sitharthan
AU - Sisodiya, Sanjay M.
AU - Stewart, Randy
AU - Weckhuysen, Sarah
AU - Depondt, Chantal
AU - Dlugos, Dennis J.
AU - Scheffer, Ingrid E.
AU - Striano, Pasquale
AU - Freyer, Catharine
AU - Krause, Roland
AU - May, Patrick
AU - McKenna, Kevin
AU - Regan, Brigid M.
AU - Leu, Costin
AU - Buono, Russell J.
AU - Ferraro, Thomas N.
N1 - Publisher Copyright:
© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
PY - 2020/7/1
Y1 - 2020/7/1
N2 - 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.
AB - 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.
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U2 - 10.1093/brain/awaa171
DO - 10.1093/brain/awaa171
M3 - Article
C2 - 32568404
AN - SCOPUS:85088262031
SN - 0006-8950
VL - 143
SP - 2106
EP - 2118
JO - Brain
JF - Brain
IS - 7
ER -