Title : Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals Language : English Author, co-author : Motelow, Joshua E. [> >] Povysil, Gundula [> >] Dhindsa, Ryan S. [> >] Stanley, Kate E. [> >] Allen, Andrew S. [> >] Feng, Yen-Chen Anne [> >] Howrigan, Daniel P. [> >] Abbott, Liam E. [> >] Tashman, Katherine [> >] Cerrato, Felecia [> >] Cusick, Caroline [> >] Singh, Tarjinder [> >] Heyne, Henrike [> >] Byrnes, Andrea E. [> >] Churchhouse, Claire [> >] Watts, Nick [> >] Solomonson, Matthew [> >] Lal, Dennis [> >] Gupta, Namrata [> >] Neale, Benjamin M. [> >] Cavalleri, Gianpiero L. [> >] Cossette, Patrick [> >] Cotsapas, Chris [> >] Jonghe, Peter De [> >] 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 [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core] May, Patrick [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core] McKenna, Kevin [> >] Regan, Brigid M. [> >] Bennett, Caitlin A. [> >] Leu, Costin [> >] Leech, Stephanie L. [> >] O’Brien, Terence J. [> >] Todaro, Marian [> >] Stamberger, Hannah [> >] Andrade, Danielle M. [> >] Ali, Quratulain Zulfiqar [> >] Sadoway, Tara R. [> >] Krestel, Heinz [> >] Schaller, André [> >] Papacostas, Savvas S. [> >] Kousiappa, Ioanna [> >] Tanteles, George A. [> >] Christou, Yiolanda [> >] Štěrbová, Katalin [> >] Vlčková, Markéta [> >] Sedláčková, Lucie [> >] Laššuthová, Petra [> >] Klein, Karl Martin [> >] Rosenow, Felix [> >] Reif, Philipp S. [> >] Knake, Susanne [> >] Neubauer, Bernd A. [> >] Zimprich, Friedrich [> >] Feucht, Martha [> >] Reinthaler, Eva M. [> >] Kunz, Wolfram S. [> >] Zsurka, Gábor [> >] Surges, Rainer [> >] Baumgartner, Tobias [> >] Wrede, Randi Von [> >] Pendziwiat, Manuela [> >] Muhle, Hiltrud [> >] Rademacher, Annika [> >] Baalen, Andreas Van [> >] Spiczak, Sarah Von [> >] 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 [> >] Lauxmann, Stephan [> >] Boßelmann, Christian [> >] Kegele, Josua [> >] Hengsbach, Christian [> >] Rau, Sarah [> >] Steinhoff, Bernhard J. [> >] Schulze-Bonhage, Andreas [> >] Borggräfe, Ingo [> >] Schankin, Christoph J. [> >] Schubert-Bast, Susanne [> >] Schreiber, Herbert [> >] Mayer, Thomas [> >] Korinthenberg, Rudolf [> >] Brockmann, Knut [> >] Wolff, Markus [> >] Dennig, Dieter [> >] Madeleyn, Rene [> >] Kälviäinen, Reetta [> >] Saarela, Anni [> >] Timonen, Oskari [> >] Linnankivi, Tarja [> >] Lehesjoki, Anna-Elina [> >] Rheims, Sylvain [> >] Lesca, Gaetan [> >] Ryvlin, Philippe [> >] Maillard, Louis [> >] Valton, Luc [> >] Derambure, Philippe [> >] Bartolomei, Fabrice [> >] Hirsch, Edouard [> >] Michel, Véronique [> >] Chassoux, Francine [> >] Rees, Mark I. [> >] Chung, Seo-Kyung [> >] Pickrell, William O. [> >] Powell, Robert [> >] Baker, Mark D. [> >] Fonferko-Shadrach, Beata [> >] Lawthom, Charlotte [> >] Anderson, Joseph [> >] Schneider, Natascha [> >] Balestrini, Simona [> >] Zagaglia, Sara [> >] Braatz, Vera [> >] Johnson, Michael R. [> >] Auce, Pauls [> >] Sills, Graeme J. [> >] Baum, Larry W. [> >] Sham, Pak C. [> >] Cherny, Stacey S. [> >] Lui, Colin H. T. [> >] Delanty, Norman [> >] Doherty, Colin P. [> >] Shukralla, Arif [> >] El-Naggar, Hany [> >] Widdess-Walsh, Peter [> >] Barišić, Nina [> >] Canafoglia, Laura [> >] Franceschetti, Silvana [> >] Castellotti, Barbara [> >] Granata, Tiziana [> >] Ragona, Francesca [> >] Zara, Federico [> >] Iacomino, Michele [> >] Riva, Antonella [> >] Madia, Francesca [> >] Vari, Maria Stella [> >] Salpietro, Vincenzo [> >] Scala, Marcello [> >] Mancardi, Maria Margherita [> >] Nobili, Lino [> >] Amadori, Elisabetta [> >] Giacomini, Thea [> >] Bisulli, Francesca [> >] Pippucci, Tommaso [> >] Licchetta, Laura [> >] Minardi, Raffaella [> >] Tinuper, Paolo [> >] Muccioli, Lorenzo [> >] Mostacci, Barbara [> >] Gambardella, Antonio [> >] Labate, Angelo [> >] Annesi, Grazia [> >] Manna, Lorella [> >] Gagliardi, Monica [> >] Parrini, Elena [> >] Mei, Davide [> >] Vetro, Annalisa [> >] Bianchini, Claudia [> >] Montomoli, Martino [> >] Doccini, Viola [> >] Barba, Carmen [> >] Hirose, Shinichi [> >] Ishii, Atsushi [> >] Suzuki, Toshimitsu [> >] Inoue, Yushi [> >] Yamakawa, Kazuhiro [> >] Beydoun, Ahmad [> >] Nasreddine, Wassim [> >] Zgheib, Nathalie Khoueiry [> >] Tumiene, Birute [> >] Utkus, Algirdas [> >] Sadleir, Lynette G. [> >] King, Chontelle [> >] Caglayan, S. Hande [> >] Arslan, Mutluay [> >] Yapıcı, Zuhal [> >] Topaloglu, Pınar [> >] Kara, Bulent [> >] Yis, Uluc [> >] Turkdogan, Dilsad [> >] Gundogdu-Eken, Aslı [> >] Bebek, Nerses [> >] Tsai, Meng-Han [> >] Ho, Chen-Jui [> >] Lin, Chih-Hsiang [> >] Lin, Kuang-Lin [> >] Chou, I.-Jun [> >] Poduri, Annapurna [> >] Shiedley, Beth R. [> >] Shain, Catherine [> >] Noebels, Jeffrey L. [> >] Goldman, Alicia [> >] Busch, Robyn M. [> >] Jehi, Lara [> >] Najm, Imad M. [> >] Ferguson, Lisa [> >] Khoury, Jean [> >] Glauser, Tracy A. [> >] Clark, Peggy O. [> >] Buono, Russell J. [> >] Ferraro, Thomas N. [> >] Sperling, Michael R. [> >] Lo, Warren [> >] Privitera, Michael [> >] French, Jacqueline A. [> >] Schachter, Steven [> >] Kuzniecky, Ruben I. [> >] Devinsky, Orrin [> >] Hegde, Manu [> >] Greenberg, David A. [> >] Ellis, Colin A. [> >] Goldberg, Ethan [> >] Helbig, Katherine L. [> >] Cosico, Mahgenn [> >] Vaidiswaran, Priya [> >] Fitch, Eryn [> >] Berkovic, Samuel F. [> >] Lerche, Holger [> >] Lowenstein, Daniel H. [> >] Goldstein, David B. [> >] Publication date : 30-Apr-2021 Journal title : The American Journal of Human Genetics Peer reviewed : Yes Audience : International ISSN : 0002-9297 Keywords : [en] epilepsy ; epileptic encephalopathy ; seizures ; whole-exome sequencing ; focal epilepsy ; generalized epilepsy ; intolerance ; ClinVar ; Epi25 ; LouvainAbstract : [en] Summary Both mild and severe epilepsies are influenced by variants in the same genes, yet an explanation for the resulting phenotypic variation is unknown. As part of the ongoing Epi25 Collaboration, we performed a whole-exome sequencing analysis of 13,487 epilepsy-affected individuals and 15,678 control individuals. While prior Epi25 studies focused on gene-based collapsing analyses, we asked how the pattern of variation within genes differs by epilepsy type. Specifically, we compared the genetic architectures of severe developmental and epileptic encephalopathies (DEEs) and two generally less severe epilepsies, genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). Our gene-based rare variant collapsing analysis used geographic ancestry-based clustering that included broader ancestries than previously possible and revealed novel associations. Using the missense intolerance ratio (MTR), we found that variants in DEE-affected individuals are in significantly more intolerant genic sub-regions than those in NAFE-affected individuals. Only previously reported pathogenic variants absent in available genomic datasets showed a significant burden in epilepsy-affected individuals compared with control individuals, and the ultra-rare pathogenic variants associated with DEE were located in more intolerant genic sub-regions than variants associated with non-DEE epilepsies. MTR filtering improved the yield of ultra-rare pathogenic variants in affected individuals compared with control individuals. Finally, analysis of variants in genes without a disease association revealed a significant burden of loss-of-function variants in the genes most intolerant to such variation, indicating additional epilepsy-risk genes yet to be discovered. Taken together, our study suggests that genic and sub-genic intolerance are critical characteristics for interpreting the effects of variation in genes that influence epilepsy.Research centres : Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) Target : Researchers Permalink : http://hdl.handle.net/10993/46990 DOI : 10.1016/j.ajhg.2021.04.009 Other URL : https://www.sciencedirect.com/science/article/pii/S0002929721001403 FnR project : FnR ; FNR11583046 > Roland Krause > MechEPI > Epileptogenesis Of Genetic Epilepsies > 01/04/2018 > 31/03/2021 > 2017 
[University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core]
