Wrestling the Giant: Experience with TTN Testing for Cardiomyopathies American College of Medical Genetics 

The TTN gene is expressed in striated muscle and encodes the protein titin, which spans half the distance of the sarcomere (from Z-disc to M-band) and is the largest known protein. Mutations in TTN constitute a substantial proportion of genetic risk for DCM, with mutation rates up to 25% in probands with familial dilated cardiomyopathy (DCM) and 18% in sporadic DCM cases. However, there is also a high burden of missense variants of unknown significance (VUS) detected in TTN. This makes the decision to choose a multigene panel (MGP) that includes TTN challenging when patients do not have a clear diagnosis of DCM. We sought to determine the characteristics and phenotypic spectrum associated with TTN pathogenic alterations, and to explore the decision to choose a panel including TTN for probands with cardiomyopathies.