Evidence of genetic heterogeneity in five kindreds with familial hypertrophic cardiomyopathy.

BACKGROUND Recently, two families with hypertrophic cardiomyopathy have been shown to have mutations in the cardiac beta-myosin heavy chain gene (beta-MHC) located on the long arm of chromosome 14. METHODS AND RESULTS We have performed linkage analysis of five newly ascertained pedigrees with more than 50 chromosomal markers detecting polymorphisms. Our findings confirm the linkage to beta-MHC gene locus on chromosome 14 in one family (LOD score, 4.50) and suggest linkage to the same gene in another kindred. Chromosome 14 markers were not linked to the disease gene in the other three kindreds, however, and a test for genetic heterogeneity was statistically significant. Moreover, markers for the beta-MHC gene identified affected individuals who were recombinants with respect to this gene and the disease phenotype in these three kindreds. CONCLUSIONS These results provide conclusive evidence that hypertrophic cardiomyopathy in separate families is caused by mutations in disease genes at two or more locations in the genome.