Molecular genetics of familial hypertrophic cardiomyopathy (FHC)

Abstract

Familial hypertrophic cardiomyopathy is an autosomal dominant disease with a wide range of clinical features from benign to severe, and is the most common cause of sudden death in otherwise healthy individuals. The two prominent clinical features are left ventricular hypertrophy and myocyte/myofibrillar disarray. The former is responsible for clinical symptoms such as breathlessness and angina, whereas the latter may lead to sudden cardiac death. The last decade has seen an enormous improvement in our understanding of the molecular genetics of this disorder. The clinical heterogeneity has been linked to genetic heterogeneity; mutations in nine genes encoding sarcomere proteins have been shown to be the molecular basis for the disorder. However, attempts to establish a genotype-phenotype correlation for each of the more than 100 mutations that have been identified have not been highly successful. Additional genetic loci, as well as nongenetic factors such as lifestyle, sex, and age, have also been shown to play a role in modulating the clinical presentation of the disease. How each mutation results in hypertrophy and/or myofibrillar disarray is unclear. The present review discusses the current status of the molecular genetic characterization of this important disorder.