Analysis of TTN truncating variants (TTNtv) as a common cause of dilated cardiomyopathy (DCM). DCM-Rat-TTNtv-2016

TTN truncating variants (TTNtv) commonly cause dilated cardiomyopathy (DCM). However, we also observe potentially silent truncations in cardiac TTN transcripts in more than 0.5% of the general population, perhaps reflecting position-dependent allelic effects. To better understand TTNtv we integrated TTN allelic series, cardiac imaging and genomic data from humans and studied rat models with disparate TTNtv. In patients, TTNtv throughout the molecule, from the Z-disc to the M-line, were consistently associated with DCM. Ribosomal profiling in rat exposed the translational footprint of premature stop codons in Ttn and revealed TTNtv position-independent triggering of nonsense-mediated degradation of the mutant allele and a perturbation of cardiac metabolism. Changes in cardiac physiology were mild but upon stress the hearts of TTNtv rats failed. In healthy humans, TTNtv were associated with imaging precursors of DCM. TTNtv exhibit penetrant molecular and physiological phenotypes across species, with a continuum of expressivity in health and disease.