Epilepsy subtype-specific copy number burden observed in a genome-wide study of 17 458 subjects
Lisa‐Marie Niestroj(University of Cologne), Eduardo Pérez‐Palma(Cleveland Clinic Lerner College of Medicine), Daniel P. Howrigan(Broad Institute), Yadi Zhou(Cleveland Clinic Lerner College of Medicine), Feixiong Cheng(Cleveland Clinic Lerner College of Medicine), Elmo Saarentaus(University of Helsinki), Peter Nürnberg(University of Cologne), Remi Stevelink(Utrecht University), Mark J. Daly(Broad Institute), Aarno Palotie(Broad Institute), Dennis Lal(Broad Institute), the Epi25 Collaborative, Yen‐Chen Anne Feng(Broad Institute), Daniel P. Howrigan(Broad Institute), Liam Abbott(Cleveland Clinic Lerner College of Medicine), Katherine Tashman, Felecia Cerrato(Broad Institute), Dennis Lal(Broad Institute), Claire Churchhouse, Namrata Gupta, Benjamin M. Neale, Samuel F. Berkovic, Holger Lerche, David B. Goldstein(Broad Institute), Daniel H. Lowenstein(Cleveland Clinic Lerner College of Medicine), Gianpiero L. Cavalleri(Cleveland Clinic Lerner College of Medicine), Patrick Cossette, Chris Cotsapas(University of Cologne), Peter De Jonghe, Tracy Dixon‐Salazar(Cleveland Clinic Lerner College of Medicine), Renzo Guerrini(Cleveland Clinic Lerner College of Medicine), Håkon Håkonarson, Erin L. Heinzen(Cleveland Clinic Lerner College of Medicine), Ingo Helbig(Cleveland Clinic Lerner College of Medicine), Patrick Kwan(Cleveland Clinic Lerner College of Medicine), Anthony G Marson, Slavé Petrovski, Sitharthan Kamalakaran(Cleveland Clinic Lerner College of Medicine), Sanjay M Sisodiya, Randy Stewart, Sarah Weckhuysen, Chantal Depondt(Cleveland Clinic Lerner College of Medicine), Dennis Dlugos, Ingrid E. Scheffer(Cleveland Clinic Lerner College of Medicine), Pasquale Striano, Catharine Freyer, Roland Krause(Cleveland Clinic Lerner College of Medicine), Patrick May, Kevin E. McKenna, Brigid M. Regan, Susannah T. Bellows, Costin Leu, Brigid M. Regan, Caitlin A. Bennett, Susannah T. Bellows(Cleveland Clinic Lerner College of Medicine), Esther C Johns, Alexandra MacDonald, Hannah Shilling, Rosemary Burgess, Dorien Weckhuysen, Melanie Bahlo, Terence J. O’Brien(Cleveland Clinic Lerner College of Medicine), Patrick Kwan, Slavé Petrovski, Marian Todaro, Sarah Weckhuysen, Hannah Stamberger(University of Cologne), Peter De Jonghe, Chantal Depondt, Danielle M. Andrade, Tara Sadoway(University of Helsinki), Kelly Mo, Heinz Krestel, Sabina Gallati, Savvas Papacostas, Ioanna Kousiappa, George A. Tanteles, Katalin Štěrbová, Markéta Vlčková, Lucie Sedláčková, Petra Laššuthová, Karl Martin Klein, Felix Rosenow, Philipp S. Reif, Susanne Knake, Wolfram S. Kunz, Gábor Zsurka, Christian E. Elger, Jürgen Bauer(Cleveland Clinic Lerner College of Medicine), Michael Rademacher, Manuela Pendziwiat, Hiltrud Muhle, Annika Rademacher, Andreas van Baalen, Sarah von Spiczak, Ulrich Stephani, Zaid Afawi, Amos D. Korczyn, Moien Kanaan, Christina Canavati(Cleveland Clinic Lerner College of Medicine), Gerhard Kurlemann, Karen Müller‐Schlüter(Cleveland Clinic Lerner College of Medicine), Gerhard Kluger(Cleveland Clinic Lerner College of Medicine), Martin Häusler, Ilan Blatt, Johannes R. Lemke, Ilona Krey, Yvonne Weber, Stefan Wolking, Felicitas Becker, Christian Hengsbach, Sarah Rau(Cleveland Clinic Lerner College of Medicine), Ana F. Maisch, Bernhard J. Steinhoff, Andreas Schulze‐Bonhage, Susanne Schubert‐Bast, Herbert Schreiber, Ingo Borggräfe, Christoph J. Schankin(Cleveland Clinic Lerner College of Medicine), Thomas Mayer(Cleveland Clinic Lerner College of Medicine), Rudolf Korinthenberg(Cleveland Clinic Lerner College of Medicine), Knut Brockmann(Cleveland Clinic Lerner College of Medicine), Gerhard Kurlemann(Cleveland Clinic Lerner College of Medicine), Dieter Dennig(Cleveland Clinic Lerner College of Medicine), Rene Madeleyn(Cleveland Clinic Lerner College of Medicine), Reetta Kälviäinen(Cleveland Clinic Lerner College of Medicine), Pia Auvinen(Cleveland Clinic Lerner College of Medicine), Anni Saarela(Cleveland Clinic Lerner College of Medicine), Tarja Linnankivi(Cleveland Clinic Lerner College of Medicine), Anna‐Elina Lehesjoki(Cleveland Clinic Lerner College of Medicine), Mark I. Rees(Cleveland Clinic Lerner College of Medicine), Seo‐Kyung Chung(Cleveland Clinic Lerner College of Medicine), William Owen Pickrell(Cleveland Clinic Lerner College of Medicine), Robert Powell(Cleveland Clinic Lerner College of Medicine), Sanjay M Sisodiya(Cleveland Clinic Lerner College of Medicine), Natascha Schneider(Cleveland Clinic Lerner College of Medicine), Simona Balestrini(Cleveland Clinic Lerner College of Medicine), Sara Zagaglia(Cleveland Clinic Lerner College of Medicine), Vera Braatz(Cleveland Clinic Lerner College of Medicine), Anthony G Marson(Cleveland Clinic Lerner College of Medicine), Michael R. Johnson(Cleveland Clinic Lerner College of Medicine), Pauls Auce(Cleveland Clinic Lerner College of Medicine), Graeme J. Sills(Cleveland Clinic Lerner College of Medicine), Patrick Kwan(Cleveland Clinic Lerner College of Medicine), Larry Baum(Cleveland Clinic Lerner College of Medicine), Pak C. Sham(Cleveland Clinic Lerner College of Medicine), Stacey S. Cherny(Cleveland Clinic Lerner College of Medicine), Colin Hiu Tung Lui(Cleveland Clinic Lerner College of Medicine), Nina Barišić(Cleveland Clinic Lerner College of Medicine), Gianpiero L. Cavalleri(Cleveland Clinic Lerner College of Medicine), Norman Delanty(Cleveland Clinic Lerner College of Medicine), Colin P. Doherty(Cleveland Clinic Lerner College of Medicine), Arif Shukralla(Broad Institute), Mark McCormack(Cleveland Clinic Lerner College of Medicine), Hany El-Naggar(Cleveland Clinic Lerner College of Medicine), Laura Canafoglia(Cleveland Clinic Lerner College of Medicine), Silvana Franceschetti(Cleveland Clinic Lerner College of Medicine), Barbara Castellotti(Cleveland Clinic Lerner College of Medicine), Tiziana Granata(Cleveland Clinic Lerner College of Medicine), Pasquale Striano(Cleveland Clinic Lerner College of Medicine), Federico Zara(Cleveland Clinic Lerner College of Medicine), Michele Iacomino(Cleveland Clinic Lerner College of Medicine), Francesca Madia(Cleveland Clinic Lerner College of Medicine), Maria Stella Vari(Cleveland Clinic Lerner College of Medicine), Maria Margherita Mancardi(Cleveland Clinic Lerner College of Medicine), Vincenzo Salpietro(Cleveland Clinic Lerner College of Medicine), Francesca Bisulli(Cleveland Clinic Lerner College of Medicine), Paolo Tinuper(Cleveland Clinic Lerner College of Medicine), Laura Licchetta(Cleveland Clinic Lerner College of Medicine), Tommaso Pippucci(Cleveland Clinic Lerner College of Medicine), Carlotta Stipa(Cleveland Clinic Lerner College of Medicine), Lorenzo Muccioli(Cleveland Clinic Lerner College of Medicine), Raffaella Minardi(Cleveland Clinic Lerner College of Medicine), Antonio Gambardella(Cleveland Clinic Lerner College of Medicine), Angelo Labate(Cleveland Clinic Lerner College of Medicine), Grazia Annesi(Cleveland Clinic Lerner College of Medicine), Lorella Manna(Cleveland Clinic Lerner College of Medicine), Monica Gagliardi(Cleveland Clinic Lerner College of Medicine), Elena Parrini(Cleveland Clinic Lerner College of Medicine), Davide Mei(Cleveland Clinic Lerner College of Medicine), Annalisa Vetro(Cleveland Clinic Lerner College of Medicine), Claudia Bianchini(Cleveland Clinic Lerner College of Medicine), Martino Montomoli(Cleveland Clinic Lerner College of Medicine), Viola Doccini(Cleveland Clinic Lerner College of Medicine), Carla Marini(Cleveland Clinic Lerner College of Medicine), Toshimitsu Suzuki(Cleveland Clinic Lerner College of Medicine), Yushi Inoue(Cleveland Clinic Lerner College of Medicine), Kazuhiro Yamakawa(Cleveland Clinic Lerner College of Medicine), Biruté Tumiene(Cleveland Clinic Lerner College of Medicine), Rūta Mameniškienė(Cleveland Clinic Lerner College of Medicine), Algirdas Utkus(Cleveland Clinic Lerner College of Medicine), Rūta Praninskienė(Cleveland Clinic Lerner College of Medicine), Jurgita Grikinienė(Cleveland Clinic Lerner College of Medicine), Rūta Samaitienė(Cleveland Clinic Lerner College of Medicine), Lynette G. Sadleir(Cleveland Clinic Lerner College of Medicine), Chontelle King(Cleveland Clinic Lerner College of Medicine), Emily Mountier(Cleveland Clinic Lerner College of Medicine), S. Hande Çağlayan(Cleveland Clinic Lerner College of Medicine), Mutluay Arslan(Cleveland Clinic Lerner College of Medicine), Zühal Yapıcı(Cleveland Clinic Lerner College of Medicine), Uluç Yiş(Cleveland Clinic Lerner College of Medicine), Pınar Topaloğlu(Cleveland Clinic Lerner College of Medicine), Bülent Kara(Cleveland Clinic Lerner College of Medicine), Dilşad Türkdoğan(Cleveland Clinic Lerner College of Medicine), Aslı Gündoğdu-Eken(Cleveland Clinic Lerner College of Medicine), Nerses Bebek(Cleveland Clinic Lerner College of Medicine), Sibel Uğur‐İşeri(Cleveland Clinic Lerner College of Medicine), Betül Baykan(Cleveland Clinic Lerner College of Medicine), Barış Salman(Cleveland Clinic Lerner College of Medicine), Garen Haryanyan(Cleveland Clinic Lerner College of Medicine), Emrah Yücesan(Cleveland Clinic Lerner College of Medicine), Yeşim Kesim(Cleveland Clinic Lerner College of Medicine), Çiğdem Özkara(Cleveland Clinic Lerner College of Medicine), Beth Rosen Sheidley(Cleveland Clinic Lerner College of Medicine), Catherine Shain(Cleveland Clinic Lerner College of Medicine), Annapurna Poduri(Cleveland Clinic Lerner College of Medicine), Russell J. Buono(Cleveland Clinic Lerner College of Medicine), Thomas N. Ferraro(Cleveland Clinic Lerner College of Medicine), Michael R. Sperling(Cleveland Clinic Lerner College of Medicine), Dennis Dlugos(Broad Institute), Warren Lo(Cleveland Clinic Lerner College of Medicine), Michael Privitera(Cleveland Clinic Lerner College of Medicine), Jacqueline A. French(Cleveland Clinic Lerner College of Medicine), Patrick Cossette(Cleveland Clinic Lerner College of Medicine), Steven C. Schachter(Cleveland Clinic Lerner College of Medicine), Håkon Håkonarson(Cleveland Clinic Lerner College of Medicine), Ruben I Kuzniecky(Cleveland Clinic Lerner College of Medicine), Dennis Dlugos(Cleveland Clinic Lerner College of Medicine), Orrin Devinsky(Cleveland Clinic Lerner College of Medicine), Ruben I Kuzniecky(Cleveland Clinic Lerner College of Medicine), Jacqueline A. French(Cleveland Clinic Lerner College of Medicine), Manu Hegde(Cleveland Clinic Lerner College of Medicine), Pouya Khankhanian(Cleveland Clinic Lerner College of Medicine), Katherine L. Helbig(Cleveland Clinic Lerner College of Medicine), Colin A. Ellis(Cleveland Clinic Lerner College of Medicine), Gianfranco Spalletta(Cleveland Clinic Lerner College of Medicine), Fabrizio Piras(Cleveland Clinic Lerner College of Medicine), Federica Piras(Cleveland Clinic Lerner College of Medicine), Tommaso Gili(Cleveland Clinic Lerner College of Medicine), Valentina Ciullo
Cited by 80Open Access
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.
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