Sporadic hypertrophic cardiomyopathy due to the novo myosin mutations

Hypertrophic cardiomyopathy occurs as an autosomal domi-nant familial disorder or as a sporadic disease without familial involvement. While missense mutations in the ft cardiac myosin heavy chain (MHC) gene account for approximately half of all cases of familial hypertrophic cardiomyopathy, the molecular causes of sporadic hypertrophic cardiomyopathy are unknown. To determine whether ft cardiacMHC mutations are also asso-ciated with sporadic disease, we screened this gene in seven individuals with sporadic hypertrophic cardiomyopathy. Muta-tions in the ft cardiac MHC genes were identified in two pro-bands with sporadic disease. In that their parents were neither clinically nor genetically affected, we conclude that mutations in each proband arose de novo. Transmission of the mutation and disease to an offspring occurred in one pedigree, predicting that these are germline mutations. The demonstration ofhyper-trophic cardiomyopathy arising within a pedigree coincident with the appearance of a de novo mutation provides compelling genetic evidence that ft cardiac MHC mutations cause this dis-ease. We suggest that de novo mutations account for some in-stances of sporadic hypertrophic cardiomyopathy and that these mutations can be transmitted to children. The clinical benefits of defining mutations responsible for familial hyper-trophic cardiomyopathy should also be available to some pa-tients with sporadic disease. (J. Clin. Invest. 1992. 90:1666-1671.) Key words: cardiac hypertrophy * myosin heavy chain gene- RNase protectio