BackgroundCross-sectional studies of various forms of dilated cardiomyopathy have noted a truncating mutation in the gene encoding titin ( TTNtv) in 7-30% of patients, but the clinical importance of identifying a TTNtv in an asymptomatic adult is largely unknown. In contrast to cross-sectional studies, prospective cohort studies allow for unbiased estimates of the disease risks associated with a genotype exposure. ObjectivesTo determine the prevalence of cardiac imaging abnormalities and risk of incident disease among middle-aged TTNtv carriers without known congestive heart failure. MethodsWe analyze exome sequencing data of 45,747 participants of the UK Biobank without known congestive heart failure to identify TTNtv carriers. Among 10,552 with cardiac magnetic resonance imaging (MRI), we determine the relationship between TTNtv carrier status and left ventricular ejection fraction. In this prospective cohort, we quantify the absolute and relative risks of incident disease in TTNtv carriers versus noncarriers. ResultsAmong 45,747 middle-aged participants without known congestive heart failure, 196 (0.43%) harbored a TTNtv. The average ejection fraction was 61% in TTNtv carriers versus 65% in noncarriers (P = 1.8 x 10-8), with a 9.3-fold increase (95% CI 3.9 - 22.2) in odds of subnormal ejection fraction (P = 5.7 x 10-5). Over a median follow-up of 6.9 years, a composite endpoint of incident dilated cardiomyopathy, congestive heart failure, or all-cause mortality was observed in 6.6% of TTNtv carriers versus 2.9% of non-carriers (adjusted hazard ratio 2.5; 95% CI 1.4 - 4.3; p = 1.1 x 10-3). ConclusionsApproximately 1 in 230 middle-aged adults without known congestive heart failure harbored a TTNtv. These carriers had a substantially increased relative risk--but modest absolute risk--of having a subnormal ejection fraction or manifesting clinical disease during prospective follow-up. Condensed AbstractCross-sectional studies of dilated cardiomyopathy have noted a truncating mutation in the gene encoding titin ( TTNtv) in up to 30% of patients--but the clinical importance of TTNtv in asymptomatic adults is largely unknown. Here, we observe a TTNtv in 0.43% of 45,747 middle-aged adults. Average ejection fraction was 61% in TTNtv carriers versus 65% in non-carriers (p<0.001). Over a median follow-up of 7 years, incident congestive heart failure or mortality was observed in 6.6% of TTTtv carriers versus 2.9% of non-carriers (hazard ratio 2.5; p = 0.001).

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