Genetics of familiar hypertrophic cardiomyopathy

Familial hypertrophic cardiomyopathy (FHC) is characterized by left and/or right ventricular hypertrophy, preferentially affecting the interventricular septum, in the absence of other known causes that induce hypertrophy. Typical morphological changes include myocyte hypertrophy and disarray surrounding areas of loose connective tissue. Arrhythmias and premature sudden deaths are common. The clinical manifestations of FHC are numerous, ranging from benign asymptomatic course to severe heart failure and sudden death. FHC is inherited in an autosomal dominant pattern. The results of molecular genetic studies have shown that all mutations found so far concern genes that encode sarcomeric proteins: three contractile proteins, the beta-myosin heavy chain, the ventricular myosin essential light chain 1 and the ventricular myosin regulatory light chain 2; three associated proteins, cardiac troponin T, cardiac troponin I, and alpha-tropomyosin; and finally one myosin-binding protein, the cardiac myosin binding protein C. These genes certainly do not represent the whole spectrum of FHC disease genes since an additional locus was reported and one might reasonably hypothesize that disease genes yet to be identified include additional components of the sarcomere. One of the next challenges is to decipher the mechanisms through which the disease results from sarcomeric gene defects. The focus of the present article is to review the current state of knowledge on (1) the organization and mutations of FHC disease genes and proteins and (2) the in vitro and in vivo functional consequences of these mutations.