Extensive identification of genes involved in congenital and structural heart disorders and cardiomyopathy
Authors: Spielmann Nadine , Miller Gregor , Oprea Tudor I. , Hsu Chih-Wei , Fobo Gisela , Frishman Goar , Montrone Corinna , Haseli Mashhadi Hamed , Mason Jeremy , Munoz Fuentes Violeta , Leuchtenberger Stefanie , Ruepp Andreas , Wagner Matias , Westphal Dominik S. , Wolf Cordula , Görlach Agnes , Sanz-Moreno Adrián , Cho Yi-Li , Teperino Raffaele , Brandmaier Stefan , Sharma Sapna , Galter Isabella Rikarda , Östereicher Manuela A. , Zapf Lilly , Mayer-Kuckuk Philipp , Rozman Jan , Teboul Lydia , Bunton-Stasyshyn Rosie K. A. , Cater Heather , Stewart Michelle , Christou Skevoulla , Westerberg Henrik , Willett Amelia M. , Wotton Janine M. , Roper Willson B. , Christiansen Audrey E. , Ward Christopher S. , Heaney Jason D. , Reynolds Corey L. , Prochazka Jan , Bower Lynette , Clary David , Selloum Mohammed , Bou About Ghina , Wendling Olivia , Jacobs Hugues , Leblanc Sophie , Meziane Hamid , Sorg Tania , Audain Enrique , Gilly Arthur , Rayner Nigel W. ,   IMPC consortium, Aguilar-Pimentel Juan A. , Becker Lore , Garrett Lillian , Hölter Sabine M. , Amarie Oana V. , Calzada-Wack Julia , Klein-Rodewald Tanja , da Silva-Buttkus Patricia , Lengger Christoph , Stoeger Claudia , Gerlini Raffaele , Rathkolb Birgit , Mayr Daniela , Seavitt John , Gaspero Angelina , Green Jennie R. , Garza Arturo , Bohat Ritu , Wong Leeyean , McElwee Melissa L. , Kalaga Sowmya , Rasmussen Tara L. , Lorenzo Isabel , Lanza Denise G. , Samaco Rodney C. , Veeraragaven Surabi , Gallegos Juan J. , Kašpárek Petr , Petrezsélyová Silvia , King Ruairidh , Johnson Sara , Cleak James , Szkoe-Kovacs Zsombor , Codner Gemma , Mackenzie Matthew , Caulder Adam , Kenyon Janet , Gardiner Wendy , Phelps Hayley , Hancock Rhys , Norris Claire , Moore Michayla A. , Seluke Audrie M. , Urban Rachel , Kane Coleen , Goodwin Leslie O. , Peterson Kevin A. , Mckay Matthew , Cook Jenn J. , Lowy Jacob P. , McFarland Michael , Wood Joshua A. , Willis Brandon J. , Tolentino Heather , Tolentino Todd , Schuchbauer Michael , Salazar Jason , Johnson Jennifer , Munson Rebecca , Ayadi Abdel , Pavlovic Guillaume , Birling Marie-Christine , Jacquot Sylvie , Ali-Hadji Dalila , Charles Philippe , Andre Philippe , Champy Marie-France , Riet Fabrice , Vukobradovic Igor , Berberovic Zorana , Qu Dawei , Guo Ruolin , D’Souza Abigail , Huang Ziyue , Camilleri Susan , Ganguly Milan , Adissu Hibret , Eskandarian Mohammed , Shang Xueyuan , Duffin Kyle , Xu Catherine , Roberton Kyle , Laurin Valerie , Lan Qing , Sleep Gillian , Creighton Amie , Lintott Lauri , Gertsenstein Marina , Pereira Monica , Tondat Sandra , Patel Amit , Cruz Maribelle , Bezginov Alex , Miller David , Hy Wang , Yoshiki Atsushi , Tanaka Nobuhiko , Tamura Masaru , Liu Zhiwei , Ermakova Olga , Ferrara Anna , Fruscoloni Paolo , Seisenberger Claudia , Bürger Antje , Giesert Florian ,   Genomics England Research Consortium, Ambrose J. C. , Arumu gam P. , Bevers R. , Bleda M. , Boardman-Pretty F. , Boustred C. R. , Brittain H. , Caulfield M. J. , Chan G. C. , Fowler T. , Giess A. , Hamblin A. , Henderson S. , Hubbard T. J. P. , Jackson R. , Jones L. J. , Kasperaviciute D. , Kayikci M. , Kousathanas A. , Lahnstein L. , Leigh S. E. A. , Leong I. U. S. , Lopez F. J. , Maleady-Crowe F. , McEntagart M. , Minneci F. , Moutsianas L. , Mueller M. , Murugaesu N. , Need A. C. , O‘Donovan P. , Odhams C. A. , Patch C. , Perez-Gil D. , Pereira M. B. , Pullinger J. , Rahim T. , Rendon A. , Rogers T. , Savage K. , Sawant K. , Scott R. H. , Siddiq A. , Sieghart A. , Smith S. C. , Sosinsky A. , Stuckey A. , Tanguy M. , Taylor-Tavares A. L. , Thomas E. R. A. , Thompson S. R. , Tucci A. , Welland M. J. , Williams E. , Witkowska K. , Wood S. M. , Hitz Marc-Phillip , Zeggini Eleftheria , Wolf Eckhard , Sedlacek Radislav , Murray Steven A. , Svenson Karen L. , Braun Robert E. , White Jaqueline K. , Kelsey Lois , Gao Xiang , Shiroishi Toshihiko , Xu Ying , Seong Je Kyung , Mammano Fabio , Tocchini-Valentini Glauco P. , Beaudet Arthur L. , Meehan Terrence F. , Parkinson Helen , Smedley Damian , Mallon Ann-Marie , Wells Sara E. , Grallert Harald , Wurst Wolfgang , Marschall Susan , Fuchs Helmut , Brown Steve D. M. , Flenniken Ann M. , Nutter Lauryl M. J. , McKerlie Colin , Herault Yann , Lloyd K. C. Kent , Dickinson Mary E. , Gailus-Durner Valerie , Hrabe de Angelis Martin 
Published: February 2022

AbstractClinical presentation of congenital heart disease is heterogeneous, making identification of the disease-causing genes and their genetic pathways and mechanisms of action challenging. By using in vivo electrocardiography, transthoracic echocardiography and microcomputed tomography imaging to screen 3,894 single-gene-null mouse lines for structural and functional cardiac abnormalities, here we identify 705 lines with cardiac arrhythmia, myocardial hypertrophy and/or ventricular dilation. Among these 705 genes, 486 have not been previously associated with cardiac dysfunction in humans, and some of them represent variants of unknown relevance (VUR). Mice with mutations inCasz1,Dnajc18,Pde4dip,Rnf38orTmem161bgenes show developmental cardiac structural abnormalities, with their human orthologs being categorized as VUR. Using UK Biobank data, we validate the importance of theDNAJC18gene for cardiac homeostasis by showing that its loss of function is associated with altered left ventricular systolic function. Our results identify hundreds of previously unappreciated genes with potential function in congenital heart disease and suggest causal function of five VUR in congenital heart disease.