I.02 Titin – The newly-emerged "titan" of the cardiac and skeletal muscle disease world

Abstract

The advent of massively parallel sequencing made the routine analysis of enormous genes like <i>TTN</i> (titin) - the gene that encodes the largest protein in nature - finally feasible. As a direct consequence of the increasing use of this technology in the clinical diagnostic setting, it is now abundantly clear that <i>TTN</i> mutations are responsible several important skeletal muscle and cardiac disorders. Many of these disorders have a devastating lifelong impact on affected individuals and their families and are therefore health system priorities. We now know that heterozygous truncating <i>TTN</i> mutations are the most common genetic cause of dilated cardiomyopathy. In addition, heterozygous mutations in two very specific regions of <i>TTN</i> result in two different adult-onset skeletal muscle disorders: tibial muscular dystrophy and hereditary myopathy with early respiratory failure. Recessive titinopathies caused by mutations in both copies of <i>TTN</i> have recently emerged as one of the most common causes of congenital or early-onset muscle disease. Biallelic <i>TTN</i> mutations have also been identified in a growing number of patients with adolescent- and occasionally adult-onset muscle weakness. There are currently no available titinopathy drug treatments. Management is therefore limited to supportive care. In addition, it is strongly suspected that a significant number of "true" titinopathy patients remain without a genetic diagnosis because their <i>TTN</i> mutations have been missed by standard diagnostic approaches. Our understanding of the transcript- and protein-level impacts of patient mutations and the underlying basis of observed differences in clinical severity is also limited. This presentation will focus on recent clinical and research-based developments in the titinopathy field. We will also examine best practice <i>TTN</i> diagnostic approaches, challenges, and pitfalls. Likely future directions in titinopathy diagnosis, research and treatment development will also be explored.