Hypertrophic Cardiomyopathy is a Disease of Sarcomere Proteins

Hypertrophic cardiomyopathy (HCM) is a primary disease of cardiac myocytes caused by mutations in genes encoding sarcomere proteins. The ensuing phenotype, however, is multicellular, induced by biological and functional changes in myocytes and non-myocyte cardiac cells, particularly fibroblasts. The molecular genetic basis of HCM has been partially elucidated, and over three dozen genes are implicated as causes of HCM. MYBPC3, which encodes myosin binding protein C3, is the most common causal gene, followed by MYH7, which encodes the β-myosin heavy chain (β-MYH or MYH7) protein. Approximately 35% to 40% of HCM cases are caused by mutations in the MYBPC3 and MYH7 genes. Mutations in genes encoding the thin filament, Z disk, and other sarcomere-associated proteins cause about 10% to 15% of HCM cases. Overall, the genetic discoveries identify HCM as a disease of sarcomere proteins. Nevertheless, the causal genes for a significant fraction of patients with clinically diagnosed HCM remain unknown. This, in part, may reflect the oligogenic nature of HCM in a subset of cases, phenocopy conditions, including overdiagnosis of HCM, and the current approach to genetic screening.

Advances in the molecular genetic basis of HCM have ushered in the applications of genetic discoveries to care for patients with HCM, including genetic testing and the development of specific therapies that target the underpinning mechanism of HCM. Identification of additional causal genes and the development of new therapies, including genetic interventions to target and correct the causal mutation, are expected to further impact the clinical management of patients with HCM.