Epilepsy subtype-specific copy number burden observed in a genome-wide study of 17 458 subjects
Authors: Niestroj Lisa-Marie , Perez-Palma Eduardo , Howrigan Daniel P , Zhou Yadi , Cheng Feixiong , Saarentaus Elmo , Nürnberg Peter , Stevelink Remi , Daly Mark J , Palotie Aarno , Lal Dennis ,   the Epi25 Collaborative, Feng Yen-Chen Anne , Howrigan Daniel P , Abbott Liam E , Tashman Katherine , Cerrato Felecia , Lal Dennis , Churchhouse Claire , Gupta Namrata , Neale Benjamin M , Berkovic Samuel F , Lerche Holger , Goldstein David B , Lowenstein Daniel H , Cavalleri Gianpiero L , Cossette Patrick , Cotsapas Chris , De Jonghe Peter , Dixon-Salazar Tracy , Guerrini Renzo , Hakonarson Hakon , Heinzen Erin L , Helbig Ingo , Kwan Patrick , Marson Anthony G , Petrovski Slavé , Kamalakaran Sitharthan , Sisodiya Sanjay M , Stewart Randy , Weckhuysen Sarah , Depondt Chantal , Dlugos Dennis J , Scheffer Ingrid E , Striano Pasquale , Freyer Catharine , Krause Roland , May Patrick , McKenna Kevin , Regan Brigid M , Bellows Susannah T , Leu Costin , Regan Brigid M , Bennett Caitlin A , Bellows Susannah T , Johns Esther C , Macdonald Alexandra , Shilling Hannah , Burgess Rosemary , Weckhuysen Dorien , Bahlo Melanie , O’Brien Terence J , Kwan Patrick , Petrovski Slavé , Todaro Marian , Weckhuysen Sarah , Stamberger Hannah , De Jonghe Peter , Depondt Chantal , Andrade Danielle M , Sadoway Tara R , Mo Kelly , Krestel Heinz , Gallati Sabina , Papacostas Savvas S , Kousiappa Ioanna , Tanteles George A , Šterbová Katalin , Vlcková Markéta , Sedlácková Lucie , Laššuthová Petra , Klein Karl Martin , Rosenow Felix , Reif Philipp S , Knake Susanne , Kunz Wolfram S , Zsurka Gábor , Elger Christian E , Bauer Jürgen , Rademacher Michael , Pendziwiat Manuela , Muhle Hiltrud , Rademacher Annika , van Baalen Andreas , von Spiczak Sarah , Stephani Ulrich , Afawi Zaid , Korczyn Amos D , Kanaan Moien , Canavati Christina , Kurlemann Gerhard , Müller-Schlüter Karen , Kluger Gerhard , Häusler Martin , Blatt Ilan , Lemke Johannes R , Krey Ilona , Weber Yvonne G , Wolking Stefan , Becker Felicitas , Hengsbach Christian , Rau Sarah , Maisch Ana F , Steinhoff Bernhard J , Schulze-Bonhage Andreas , Schubert-Bast Susanne , Schreiber Herbert , Borggräfe Ingo , Schankin Christoph J , Mayer Thomas , Korinthenberg Rudolf , Brockmann Knut , Kurlemann Gerhard , Dennig Dieter , Madeleyn Rene , Kälviäinen Reetta , Auvinen Pia , Saarela Anni , Linnankivi Tarja , Lehesjoki Anna-Elina , Rees Mark I , Chung Seo-Kyung , Pickrell William O , Powell Robert , Sisodiya Sanjay M , Schneider Natascha , Balestrini Simona , Zagaglia Sara , Braatz Vera , Marson Anthony G , Johnson Michael R , Auce Pauls , Sills Graeme J , Kwan Patrick , Baum Larry W , Sham Pak C , Cherny Stacey S , Lui Colin H T , Barišic Nina , Cavalleri Gianpiero L , Delanty Norman , Doherty Colin P , Shukralla Arif , McCormack Mark , El-Naggar Hany , Canafoglia Laura , Franceschetti Silvana , Castellotti Barbara , Granata Tiziana , Striano Pasquale , Zara Federico , Iacomino Michele , Madia Francesca , Vari Maria Stella , Mancardi Maria Margherita , Salpietro Vincenzo , Bisulli Francesca , Tinuper Paolo , Licchetta Laura , Pippucci Tommaso , Stipa Carlotta , Muccioli Lorenzo , Minardi Raffaella , Gambardella Antonio , Labate Angelo , Annesi Grazia , Manna Lorella , Gagliardi Monica , Parrini Elena , Mei Davide , Vetro Annalisa , Bianchini Claudia , Montomoli Martino , Doccini Viola , Marini Carla , Suzuki Toshimitsu , Inoue Yushi , Yamakawa Kazuhiro , Tumiene Birute , Mameniskiene Ruta , Utkus Algirdas , Praninskiene Ruta , Grikiniene Jurgita , Samaitiene Ruta , Sadleir Lynette G , King Chontelle , Mountier Emily , Caglayan S Hande , Arslan Mutluay , Yapici Zuhal , Yis Uluc , Topaloglu Pinar , Kara Bulent , Turkdogan Dilsad , Gundogdu-Eken Asli , Bebek Nerses , Ugur-Iseri Sibel , Baykan Betül , Salman Baris , Haryanyan Garen , Yücesan Emrah , Kesim Yesim , Özkara Çigdem , Sheidley Beth R , Shain Catherine , Poduri Annapurna , Buono Russell J , Ferraro Thomas N , Sperling Michael R , Dlugos Dennis J , Lo Warren , Privitera Michael , French Jacqueline A , Cossette Patrick , Schachter Steven , Hakonarson Hakon , Kuzniecky Ruben I , Dlugos Dennis J , Devinsky Orrin , Kuzniecky Ruben I , French Jacqueline A , Hegde Manu , Khankhanian Pouya , Helbig Katherine L , Ellis Colin A , Spalletta Gianfranco , Piras Fabrizio , Piras Federica , Gili Tommaso , Ciullo Valentina 
Published: June 2020

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.