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

Background Truncating variants in TTN ( TTN tvs) represent the largest known genetic cause of dilated cardiomyopathies (DCM). At the population level, even when limited to TTN tvs in cardiac-specific exons (hiPSI TTN tvs) penetrance estimates for DCM are low. Recent work shows that individuals harboring TTN tvs have a high prevalence of other cardiac conditions aside from heart failure, in particular, atrial fibrillation (Afib). Objectives Pinpoint 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. Methods We leverage longitudinal EHR and exome sequencing data from two cohorts to determine the penetrance of TTN tvs using multiple gene expression models against Afib, CM, and other cardiac diagnoses. Results Controlling for CM and Afib, related cardio phenotypes retain only nominal association with TTN tvs. An unbiased sliding window analysis of TTN tvs 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 TTN tv 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. Conclusion CM and Afib are often coincident in hiPSI TTN tv carriers, which represent varying and progressive manifestations of structurally-based heart failure. We provide statistical support for a hiPSI variant interpretation model for TTN tvs and evidence for the first population-level screening method with clinical utility for cardiomyopathies, especially in relation to an Afib finding.