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Hypertrophic cardiomyopathy occurs as an autosomal dominant familial disorder or as a sporadic disease without familial involvement. While missense mutations in the beta 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 beta cardiac MHC mutations are also associated with sporadic disease, we screened this gene in seven individuals with sporadic hypertrophic cardiomyopathy. Mutations in the beta cardiac MHC genes were identified in two probands 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 of hypertrophic cardiomyopathy arising within a pedigree coincident with the appearance of a de novo mutation provides compelling genetic evidence that beta cardiac MHC mutations cause this disease. We suggest that de novo mutations account for some instances of sporadic hypertrophic cardiomyopathy and that these mutations can be transmitted to children. The clinical benefits of defining mutations responsible for familial hypertrophic cardiomyopathy should also be available to some patients with sporadic disease.

Original publication

DOI

10.1172/JCI116038

Type

Journal article

Journal

J Clin Invest

Publication Date

11/1992

Volume

90

Pages

1666 - 1671

Keywords

Adult, Aged, Cardiomyopathy, Hypertrophic, Female, Humans, Male, Middle Aged, Mutation, Myosins