201. Titin-truncating variants affect heart function in disease cohorts and the general population
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Francesco Mazzarotto, Laura Lihua Chan, Calvin W. L. Chin, Ester Khin, Carlo Biffi, Paul J.R. Barton, Upasana Tayal, Sebastiaan van Heesch, Sebastian Schafer, Roddy Walsh, Miao Kui, Lorna R. Fiedler, Nicole Tee, Norbert Hubner, Daniel Rueckert, Antonio de Marvao, Stuart A. Cook, James S. Ware, Valentin Schneider, David Sim, Teresa Totman, Franziska Kreuchwig, Declan P. O'Regan, Nicole S. J. Ko, Timothy J W Dawes, Chee Jian Pua, Benjamin Ng, Owen J. L. Rackham, Sanjay K Prasad, Allison Faber, Dominique P.V. de Kleijn, Jonathan G. Seidman, Eleonora Adami, Wolfgang A. Linke, Jean-Paul Kovalik, Vera Regitz-Zagrosek, Christine E. Seidman, British Heart Foundation, Imperial College Healthcare NHS Trust- BRC Funding, Commission of the European Communities, Fondation Leducq, National Institute for Health Research, Engineering & Physical Science Research Council (EPSRC), Wellcome Trust, Department of Health, and Medical Research Council
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0301 basic medicine ,Cardiomyopathy, Dilated ,Male ,Population ,Cardiomyopathy ,030204 cardiovascular system & hematology ,Bioinformatics ,Article ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Genetics ,Journal Article ,Animals ,Humans ,Connectin ,Comparative Study ,Allele ,education ,Cardiac imaging ,education.field_of_study ,biology ,Genetic Variation ,High-Throughput Nucleotide Sequencing ,Dilated cardiomyopathy ,Heart ,11 Medical And Health Sciences ,06 Biological Sciences ,medicine.disease ,Stop codon ,Cardiovascular physiology ,Rats ,030104 developmental biology ,Case-Control Studies ,biology.protein ,cardiovascular system ,Titin ,Developmental Biology - Abstract
Titin-truncating variants (TTNtv) commonly cause dilated cardiomyopathy (DCM). TTNtv are also encountered in 1/41% of the general population, where they may be silent, perhaps reflecting allelic factors. To better understand TTNtv, we integrated TTN allelic series, cardiac imaging and genomic data in humans and studied rat models with disparate TTNtv. In patients with DCM, TTNtv throughout titin were significantly associated with DCM. Ribosomal profiling in rat showed the translational footprint of premature stop codons in Ttn, TTNtv-position-independent nonsense-mediated degradation of the mutant allele and a signature of perturbed cardiac metabolism. Heart physiology in rats with TTNtv was unremarkable at baseline but became impaired during cardiac stress. In healthy humans, machine-learning-based analysis of high-resolution cardiac imaging showed TTNtv to be associated with eccentric cardiac remodeling. These data show that TTNtv have molecular and physiological effects on the heart across species, with a continuum of expressivity in health and disease.