부산대학교 도서관

Introduction: Truncating variants in TTN (TTNtvs) are the largest genetic cause of dilated cardiomyopathies (DCM). In populations, genetic variation in TTN is pervasive and penetrance estimates for DCM are low, even when carriers are limited to those with TTNtvs in exons with “percentage spliced in” index > 90 (hiPSI), a representation of constitutive cardiac expression. Patients with cardiomyopathies (CM) often carry a large number of other cardiac conditions, such as atrial fibrillation (Afib). We sought to confirm this association and determine whether the presence of Afib and a hiPSI TTNtv predicted CM.Results: Leveraging clinicogenomic data from ~450,000 individuals in two health systems, we show support for associations with both CM and Afib at the population level. We perform a sliding window analysis of TTNtvs and confirm the association is specific to hiPSI exons, with no meaningful associations in exons with less cardio expression. The combination of hiPSI TTNtv carrier status and early Afib diagnosis (dx before age 60) finds a subset of TTN carriers at high risk for CM (34% prevalence) - this risk is 3.5 fold higher than that of all hiPSI TTNtv carriers (9% prevalence) and 5-fold higher than non-carriers with early Afib (5% prevalence, p=4.8e-56 after controlling for age and sex). Further, Afib either predates or is concurrently diagnosed with CM in 72% of those with both diagnoses.Conclusion: CM and Afib are linked in hiPSI TTNtv carriers and may represent progressive manifestations of structurally-based heart failure. Our retrospective analysis suggests hiPSI TTNtv screening (~0.5% of cohorts) in conjunction with routine monitoring for arrhythmias may be an effective strategy to improve outcomes and reduce the incidence of severe cardio outcomes in the population.