An a//3 cardiac myosin heavy chain (MHC) hybrid gene is coinherited with familial hypertmphic cardiomyopathy (FHC) in one kindred. FHC is a disease of the heart muscle characterized by a thickening of the left ventricular wail with myocyte and myoflbriilar disarray that is inherlted as an autosomal dominant trait. We demonstrate here and in the accompanying article that the cardiac MHC genes, which encode integral myofibrillar components, are mutated in all affected indlviduais from two unrelated families with FHC. in one kindred, an unequal crossover event during meiosis may have produced the u/S cardiac MHC hybrid gene that is present in affected individuals. We conclude that mutations in the cardiac MHC genes can cause FHC. introduction

Familial hypertrophic cardiomyopathy (FHC) is an autosomai dominant disorder that is characterized by unexplained myocardial hypertrophy, a wide spectrum of ciinicat symptoms, and early mortality (reviewed in Sasson et al., 1988; McKenna, 1989). Sudden death can occur in both symptomatic and asymptomatic individuals. Pathologic findings of the disease include increased myocardial mass, with myocyte and myofibriilar disarray (Davies, 1984). There is significant variability in the anatomical distribution of myocardial hypertrophy and the severity of clinical symptoms present in affected individuals from the same family and among individuals from unrelated families (Maron et al., 1981a, 1981b). Although FHC was first recognized as a clinical entity in 1958 (Teare, 1958) the molecular basis for this disease has not been defined. Recently, we and others began studies to identify the gene responsible for FHC using a molecular genetic approach. These studies demonstrated that a locus (designated FHC-7) that causes disease is located on chromosome 14 band ql (Jarcho et al., 1989) and is closely linked to the cardiac myosin heavy chain (MHC) genes