Hypertrophic cardiomyopathy (HCM) is one of the most common forms of genetic cardiomyopathy and is characterized by abnormal thickening of the heart muscle. Genetic mutations may affect any portion of the sarcomere, including thick and thin filaments. Mutations in more than a dozen genes encoding the thick and thin filaments of the cardiac sarcomere have been linked to HCM and ultimately lead to cardiac muscle dysfunction. While thick-filament mutations are the most common and best characterized, thin-filament mutations remain clinically relevant. Some evidence suggests thin-filament mutations are associated with more arrhythmias and earlier progression to advanced heart failure.
TNNI3 is a critical component of the thin filament of the sarcomere. TNNI3 variants compose 3-5% of all HCM cases, impacting approximately 25,000 individuals in the United States. Mutations in the TNNI3 gene often result in left ventricular hypertrophy and restrictive cardiomyopathy, leading to arrhythmias, heart failure, and shortened lifespan.