The Rapidly Evolving Role of Titin in Cardiac Physiology and Cardiomyopathy

The giant muscle filament protein titin is encoded by a single gene consisting of 364 exons. In the past, because of its enormous size and complexity, only few titin mutations were discovered causing different cardiac and skeletal muscle conditions; however, the overall role for heritable diseases, in particular dilated cardiomyopathy (DCM), has been significantly underestimated. Recently performed systematic studies using next-generation sequencing (NGS) recognized TTN as the major human disease gene for DCM, but at the same time those data sets revealed that unique genetic variations are also more common in the general population than previously expected. Truncating variants in TTN have been reported in about 25% of patients with DCM and in 2%3-% of controls; however, most of the disease-associated truncation