Abstract 12595: Individuals Identified Genome-First With Truncating Variants in Titin Have Increased Prevalence and Distinct Etiology of Heart Failure

IntroductionTruncating variants in the TTN gene (TTNtv) are a major contributor to heritable forms of dilated cardiomyopathy (DCM); however, high prevalence in the general population presents a challenge to clinical interpretation. We have found that—when ascertained genome-first—individuals with TTNtv have increased odds for heart failure (HF).HypothesisIndividuals with TTNtv also have a distinct etiology of HF compared with controls without TTNtv.MethodsFrom whole exome sequence data of 61,019 individuals in the Geisinger MyCode project, we identified all individuals with TTNtv in constitutively expressed exons and selected age- and sex-matched controls without TTNtv. We then reviewed the inpatient and outpatient charts of the patients diagnosed with HF to determine the underlying causes or comorbidities. Frequencies were statistically compared with Fisher’s Exact test.ResultsOf 310 individuals with TTNtv, 59 (19%) had HF compared with 30 (10%) controls (p=0.001). TTNtv-related HF was more commonly characterized by reduced ejection fraction (HFrEF prevalence69% vs. 43%, p=0.02; Figure), had lower prevalence of ischemic etiology (32% vs. 63%, p=0.007), and had higher prevalence of prior non-ischemic cardiomyopathy diagnoses (53% vs. 17%, p=0.001). Despite recent evidence linking TTNtv with arrhythmia, there was no difference in pre-existing arrhythmia, including atrial fibrillation (61% in TTNtv vs. 63% in controls, p=0.99). Similarly, the prevalence of hypertension was no different (64% vs. 67%, p=0.99).ConclusionsIn a large unselected clinical population, HF in individuals with TTNtv is more prevalent than in age and sex matched controls, and more commonly presents with systolic dysfunction associated with non-ischemic cardiomyopathy. These findings may help to inform the interpretation and clinical response to incidental findings of TTNtv from genomic sequencing.