Genetic Testing

Authors: Rafik Tadros, Sean L. Zheng,  Christopher Grace, Paloma Jordà, Catherine Francis, Sean J. Jurgens, Kate L. Thomson,  Andrew R. Harper, Elizabeth Ormondroyd, Dominique M. West, Xiao Xu, Pantazis Theotokis, Rachel J. Buchan, Kathryn A. McGurk, Francesco Mazzarotto, Beatrice Boschi, Elisabetta Pelo, Michael Lee, Michela Noseda, Amanda Varnava, Alexa Mc Vermeer, Roddy Walsh, Ahmad S. Amin, Marjon A van Slegtenhorst, Nicole Roslin, Lisa J. Strug, Erika Salvi, Chiara Lanzani, Antonio de Marvao, Hypergenes InterOmics Collaborators, Jason D. Roberts, Maxime Tremblay-Gravel, Genevieve Giraldeau, Julia Cadrin-Tourigny, Philippe L’Allier, Patrick Garceau, Mario Talajic, Yigal Pinto, Harry Rakowski, Antonis Pantazis, John Baksi, Brian P. Halliday, Sanjay K. Prasad, Paul Jr Barton, Declan P. O’Regan, Stuart A. Cook, Rudolf A. de Boer, Imke Christiaans, Michelle Michels, Christopher Kramer, Carolyn Y. Ho, Stefan Neubauer, HCMR Investigators, Paul M. Matthews, Arthur A. Wilde, Jean-Claude Tardif, Iacopo Olivotto, Arnon Adler, Anuj Goel, James S. Ware, Connie R. Bezzina, Hugh Watkins

Short Description: Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality with both monogenic and polygenic components. We here report results from the largest HCM genome-wide association study (GWAS) and multi-trait analysis (MTAG) including 5,900 HCM cases, 68,359 controls, and 36,083 UK Biobank (UKB) participants with cardiac magnetic resonance (CMR) imaging. We identified a total of 70 loci (50 novel) associated with HCM, and 62 loci (32 novel) as sociated with relevant left ventricular (LV) structural or functional traits. Amongst the common variant HCM loci, we identify a novel HCM disease gene, SVIL, which encodes the actin-binding protein supervillin, showing that rare truncating SVIL variants cause HCM. Mendelian randomization analyses support a causal role of increased LV contractility in both obstructive and non-obstructive forms of HCM, suggesting common disease mechanisms and anticipating shared response to therapy. Taken together, the findings significantly increase our understanding of the genetic basis and molecular mechanisms of HCM, with potential implications for disease management.

Interest: Cardiac Magnetic Resonance Imaging, Cardiac Imaging, Genetics, Genetic Testing, Hypertrophic Cardiomyopathy

Click Here to Read the Full Publication