MOLECULAR GENETICS OF HYPERTROPHIC CARDIOMYOPATHY

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Abstract
▪ Abstract Hypertrophic cardiomyopathy (HCM) is genetically and phenotypically a heterogeneous disease. Genes identified include the β myosin heavy chain gene (βMHC) on chromosome 14q1, the troponin T gene on chromosome 1q, and the α 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 βMHC, 3 mutations in troponin T, and 2 mutations in α tropomyosin gene in HCM patients have been identified. Functional studies have shown that the mutant βMHC protein has impaired acto-myosin interaction and that expression of the mutant myosin disrupts the assembly of sarcomere in feline cardiocytes. Genotype-phenotype correlations of βMHC 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.