Titin (TTN) is a giant sarcomeric protein that serves as the myofibrillar backbone for contractile machinery components 1. In striated muscle, titin provides critical structural connections between microfilaments and is a major determinant of sarcomere extensibility and cardiomyocyte stiffness 2. Beyond its structural role, titin functions as a strain sensor and regulates myocardial stiffness, cardiac filling, and contractility through isoform diversity and post-translational modifications including phosphorylation, acetylation, and oxidation 2. TTN truncating mutations are the most common genetic cause of dilated cardiomyopathy (DCM), occurring in approximately 25% of familial cases and 18% of sporadic cases 3. Pathogenic TTN-truncating variants demonstrate a length-dependent mechanism of disease, with mutations overrepresented in the titin A-band region 4. Male mutation carriers experience adverse cardiac events earlier than females 3. Beyond DCM, recessive TTN mutations cause centronuclear myopathy and congenital myopathy with increased titin degradation and truncated proteins in affected muscles 5. The penetrance of TTN-truncating variants exceeds 95% after age 40 years in DCM patients 3. Discriminating pathogenic from benign TTN variants requires integrated analysis of variant position, TTN isoform expression patterns, and cardiac phenotyping 4.