Extensive identification of genes involved in congenital and structural heart disorders and cardiomyopathy
Nadine Spielmann, Gregor Miller, Tudor I. Oprea, Chih‐Wei Hsu, Gisela Fobo, Goar Frishman, Corinna Montrone, Hamed Haseli Mashhadi, Jeremy Mason, Violeta Muñoz‐Fuentes, Stefanie Leuchtenberger, Andreas Ruepp, Matias Wagner, Dominik S. Westphal, Cordula M. Wolf, Agnes Görlach, Adrián Sanz‐Moreno, Yi-Li Cho, Raffaele Teperino, Stefan Brandmaier, Sapna Sharma, Isabella Galter, Manuela A. Östereicher, Lilly Zapf, Philipp Mayer‐Kuckuk, Jan Rozman, Lydia Teboul, Rosie Bunton-Stasyshyn, Heather Cater, Michelle Stewart, Skevoulla Christou, Henrik Westerberg, Amelia Willett, Janine M. Wotton, Willson Roper, Audrey E. Christiansen, Christopher Ward, Jason D. Heaney, Corey Reynolds, Jan Procházka, Lynette Bower, David Clary, Mohammed Selloum, Ghina Bou About, Olivia Wendling, Hugues Jacobs, Sophie Leblanc, Hamid Méziane, Tania Sorg, Enrique Audain, Arthur Gilly, Nigel W. Rayner, Juan Antonio Aguilar‐Pimentel, Lore Becker, Lillian Garrett, Sabine M. Hölter, Oana V. Amarie, Julia Calzada‐Wack, Tanja Klein‐Rodewald, Patricia da Silva‐Buttkus, Christoph Lengger, Claudia Stoeger, Raffaele Gerlini, Birgit Rathkolb, Daniela Mayr, John R. Seavitt, Angelina Gaspero, Jennie R. Green, Arturo Garza, Ritu Bohat, Leeyean Wong, Melissa L. McElwee, Sowmya Kalaga, Tara L. Rasmussen, Isabel Lorenzo, Denise G. Lanza, Rodney C. Samaco, Surabi Veeraragaven, Juan Gallegos, Petr Kašpárek, Silvia Petrezsélyová, Ruairidh King, Sara Johnson, James Cleak, Zsombor Szkoe-Kovacs, Gemma Codner, Matthew Mackenzie, Adam Caulder, Janet Kenyon, Wendy Gardiner, Hayley Phelps, Rhys Hancock, Claire Norris, Michayla Moore, Audrie Seluke, Rachel Urban, Coleen Kane, Leslie O. Goodwin, Kevin A. Peterson, Matthew Mckay
Abstract
Clinical 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 in Casz1, Dnajc18, Pde4dip, Rnf38 or Tmem161b genes show developmental cardiac structural abnormalities, with their human orthologs being categorized as VUR. Using UK Biobank data, we validate the importance of the DNAJC18 gene 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.