The purpose of this project is to determine the chromosomal location of the genes responsible for hypertrophic cardiomyopathy (HCM). This type of heart disease is diagnosed by echocardiography. Its clinical manifestations are highly variable including anatomical abnormalities only, cardiac failure, left ventricular outflow obstruction and/or sudden death. Fifty percent of cases appear to be sporadic whereas the remainder are familial. We have identified five large families in which the disease is clearly transmitted as an autosomal dominant characteristic. For this study, the disease status has been ascertained by echocardiography and DNA was collected from all relevant members of each family. Using DNA probes that detect polymorphic differences among individuals, we have tested for linkage of individual polymorphisms to the HCM gene. Approximately 40 percent of the human genome has been excluded from containing the HCM locus. Recent results have shown that the two largest and most informative families are genetically heterogenous, that is, the genes responsible for the disease in each family localize to two different chromosomes. In one family the gene responsible for HCM maps to the long arm of chromosome 14, corroborating a previous finding in a French Canadian family by another group. In the other family the gene responsible for HCM maps to chromosome 2p. Our clinical studies have verified that many sporadic cases are likely to have a genetic basis. For example, we have identified a pair of identical twins, one of whom has inherited severe HCM, while the other has normal cardiac function and anatomy. Two other families demonstrate obligate carriers of the HCM gene without ventricular hypertrophy but with electrical abnormality. These individuals underscore the importance of a genetic marker for HCM to detect the variable forms of the disease. The ultimate goal is to identify the actual genes that cause the disorder.
