TTN truncating variants in hiPSI exons show high penetrance for cardiomyopathy in carriers with atrial fibrillation

BackgroundTruncating variants in TTN (TTNtvs) represent the largest known genetic cause of dilated cardiomyopathies (DCM). At the population level, even when limited to TTNtvs in cardiac-specific exons (hiPSI TTNtvs) penetrance estimates for DCM are low. Recent work shows that individuals harboring TTNtvs have a high prevalence of other cardiac conditions aside from heart failure, in particular, atrial fibrillation (Afib). ObjectivesPinpoint the genetic footprint TTN-related diagnoses aside from DCM, such as Afib, and determine if vetting additional significantly-associated phenotypes better stratifies cardiomyopathy risk across TTN carriers. MethodsWe leverage longitudinal EHR and exome sequencing data from two cohorts to determine the penetrance of TTNtvs using multiple gene expression models against Afib, CM, and other cardiac diagnoses. ResultsControlling for CM and Afib, related cardio phenotypes retain only nominal association with TTNtvs. An unbiased sliding window analysis of TTNtvs across the locus confirms the association is specific to hiPSI exons for both CM and Afib, with no meaningful associations in lowPSI exons nor improvements from LOFTEE designations. We find 34% of hiPSI TTNtv carriers with early Afib have a CM diagnosis - a 5-fold increase in risk over non-carriers with early Afib and 47-fold increase over population controls. ConclusionCM and Afib are often coincident in hiPSI TTNtv carriers, which represent varying and progressive manifestations of structurally-based heart failure. We provide statistical support for a hiPSI variant interpretation model for TTNtvs and evidence for the first population-level screening method with clinical utility for cardiomyopathies, especially in relation to an Afib finding.