Extensive identification of genes involved in congenital and structural heart disorders and cardiomyopathy

著者: 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, Jenn J. Cook, Jacob P. Lowy, Michael McFarland, Joshua A. Wood, Brandon Willis, Heather Tolentino, Todd Tolentino, Michael Schuchbauer, Jason Salazar, Jennifer Johnson, Rebecca Munson, Abdel Ayadi, Guillaume Pavlovic, Marie‐Christine Birling, Sylvie Jacquot, Dalila Ali-Hadji, Philippe Charles, Philippe André, Marie‐France Champy, Fabrice Riet, Igor Vukobradovic, Zorana Berberovic, Dawei Qu, Ruolin Guo, Abigail D’Souza, Ziyue Huang, Susan Camilleri, Milan Ganguly, Hibret A. Adissu, Mohammed Eskandarian, Xueyuan Shang, Kyle Duffin, Catherine K. Xu, Kyle Roberton, Valerie Laurin, Qing Lan, Gillian Sleep, Amie Creighton, Lauri G. Lintott, Marina Gertsenstein, Monica Pereira, Sandra Tondat, Amit Patel, Maribelle Cruz, Alex Bezginov, D. Craig Miller, Wang Hy, Atsushi Yoshiki, Nobuhiko Tanaka, Masaru Tamura, Zhiwei Liu, Olga Ermakova, Anna Ferrara, Paolo Fruscoloni, Claudia Seisenberger, Antje Bürger, Florian Giesert, John C. Ambrose, P. Arumu gam, R. Bevers, Marta Bleda, F. Boardman-Pretty, C. R. Boustred, Helen Brittain, Mark J. Caulfield, Gcf Chan, Tom Fowler, Adam Giess, Angela Hamblin, Shirley Henderson, Tim Hubbard, Robert W. Jackson, J. Louise Jones, Dalia Kasperavičiūtė, Melis Kayikci, Athanasios Kousathanas, L. Lahnstein, S. E. A. Leigh, I. U. S. Leong, F. J. Lopez, F. Maleady-Crowe, Meriel McEntagart, Federico Minneci, Loukas Moutsianas, M. Mueller, Nirupa Murugaesu, Anna C. Need, Peter O’Donovan, Chris A. Odhams, Christine Patch, D. Perez-Gil, Monica Pereira, J. Pullinger, T. Rahim, Augusto Rendon, T. Rogers, K. Savage, K. Sawant, Richard H. Scott, Afshan Siddiq, A. Sieghart, S. C. Smith, Alona Sosinsky, Alexander Stuckey, M. Tanguy, A. L. Taylor-Tavares, Ellen Thomas, Simon R. Thompson, Arianna Tucci, M. J. Welland, Eleanor Williams, Katarzyna Witkowska, S. M. Wood, Marc‐Phillip Hitz, Eleftheria Zeggini, Eckhard Wolf, Radislav Sedláček, Steven A. Murray, Karen L. Svenson, Robert E. Braun, Jaqueline K. White, Lois Kelsey, Xiang Gao, Toshihiko Shiroishi, Ying Xu, Je Kyung Seong, Fabio Mammano, Glauco P. Tocchini‐Valentini, Arthur L. Beaudet, Terrence F. Meehan, Helen Parkinson, Damian Smedley, Ann‐Marie Mallon, Sara Wells, Harald Grallert, Wolfgang Wurst, Susan Marschall, Helmut Fuchs, Steve D. M. Brown, Ann M. Flenniken, Lauryl M. J. Nutter, Colin McKerlie, Yann Hérault, K. C. Kent Lloyd, Mary E. Dickinson, Valérie Gailus‐Durner, Martin Hrabě de Angelis - Nature Cardiovascular Research 2022 被引用: 68

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.