Cardiomyopathy prevalence exceeds 30% in individuals with TTN variants and early atrial fibrillation

Purpose: TTN truncating variants (TTNtvs) represent the largest known genetic cause of dilated cardiomyopathies (DCMs), however their penetrance for DCM in general populations is low. More broadly, patients with cardiomyopathies (CMs) often exhibit other cardiac conditions, such as atrial fibrillation (Afib), which has also been linked to TTNtvs. This retrospective analysis aims to characterize the relationship between different cardiac conditions in those with TTNtvs and identify individuals with the highest risk of DCM. Methods: In this work we leverage longitudinal electronic health record and exome sequencing data from approximately 450,000 individuals in 2 health systems to statistically confirm and pinpoint the genetic footprint of TTNtv-related diagnoses aside from CM, such as Afib, and determine whether vetting additional significantly associated phenotypes better stratifies CM risk across those with TTNtvs. We focused on TTNtvs in exons with a percentage spliced in >90% (hiPSI TTNtvs), a representation of constitutive cardiac expression. Results: When controlling for CM and Afib, other cardiac conditions retained only nominal association with TTNtvs. A sliding window analysis of TTNtvs across the locus confirms that the association is specific to hiPSI exons for both CM and Afib, with no meaningful associations in percent spliced in <= 90% exons (loPSI TTNtvs). The combination of hiPSI TTNtv status and early Afib diagnosis (before age 60) found a subset of TTNtv individuals at high risk for CM. The prevalence of CM in this subset was 33%, a rate that was 3.5 fold higher than that in in-dividuals with hiPSI TTNtvs (9% prevalence), 5-fold higher than that in individuals without TTNtvs with early Afib (6% prevalence), and 80-fold higher than that in the general population. Conclusion: Our retrospective analyses revealed that those with hiPSI TTNtvs and early Afib (similar to 1/2900) have a high prevalence of CM (33%), far exceeding that in other individuals with TTNtvs and in those without TTNtvs with an early Afib diagnosis. These results show that combining phenotypic information along with genomic population screening can identify pa-tients at higher risk for progressing to symptomatic heart failure. (c) 2023 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).