Advances in molecular genetics of
hypertrophic cardiomyopathy (HCM) have led to identification of mutations in 11 genes coding for sarcomeric
proteins. In addition, mutations in gene coding for the gamma subunit of
AMP-activated protein kinase and triplet-repeat syndromes, as well as in
mitochondrial DNA have been identified in patients with HCM. Mutations in genes coding for the
beta-myosin heavy chain, myosin binding protein-C, and cardiac
troponin T account for approximately 2/3 of all HCM cases. Accordingly, HCM is considered a disease of contractile sarcomeric
proteins. Genotype-phenotype correlation studies show mutations and the genetic background affect the phenotypic expression of HCM. The final phenotype is the result of interactions between the causal genes, genetic background (modifier genes), and probably the environmental factors. The molecular pathogenesis of HCM is not completely understood. The initial defects caused by the
mutant proteins are diverse. However, despite their diversity, they converge into common final pathway of impaired cardiac myocyte function. The latter leads to an increased myocyte stress and subsequent activation of stress-responsive signaling
kinases and trophic factors, which activate the transcriptional machinery inducing
cardiac hypertrophy, interstitial
fibrosis and myocyte disarray, the pathological characteristics of HCM. Studies in transgenic animal models show that
cardiac hypertrophy, interstitial
fibrosis, and myocyte disarray are potentially reversible. These findings raise the possibility of reversal of evolving phenotype or prevention of phenotypes in human patients with HCM. Elucidation of the molecular genetic basis and the pathogenesis of HCM could provide the opportunity for genetic based diagnosis, risk stratification, and implementation of preventive and therapeutic measures in those who have inherited the causal mutations for HCM.