Molecular genetics of hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is genetically and phenotypically a heterogeneous disease. Genes identified include the beta myosin heavy chain gene (beta MHC) on chromosome 14q1, the troponin T gene on chromosome 1q, and the alpha tropomyosin gene on chromosome 15q. In addition, a fourth locus is present on chromosome 11q11, but the gene remains to be identified. More than 35 missense mutations in the beta MHC, 3 mutations in troponin T, and 2 mutations in alpha tropomyosin gene in HCM patients have been identified. Functional studies have shown that the mutant beta MHC protein has impaired actomyosin interaction and that expression of the mutant myosin disrupts the assembly of sarcomere in feline cardiocytes. Genotype-phenotype correlations of beta MHC mutations have shown that mutations such as Arg403Gln, Arg453Cys, and Arg719Trp are associated with a high incidence of sudden cardiac death and a significantly decreased life expectancy, whereas mutations Gly256Glu and Leu908Val have a near-normal life span. Preclinical genetic diagnosis should help in genetic counseling and therapeutic stratification.