Homozygotes for a R869G mutation in the beta-myosin heavy chain gene have a severe form of familial hypertrophic cardiomyopathy

Familial Hypertrophic Cardiomyopathy (FHC) is an autosomal dominant disease characterised by ventricular hypertrophy, with predominant involvement of the interventricular septum. It is a monogenic disease with a high level of genetic heterogeneity (nine genes and more than 110 mutations reported so far). We describe a family with a new R869G mutation in the beta-myosin hea vy chain gene (MYH7). This mutation was found in the heterozygous status in both parents and in the homozygous status in the two children. A haplotype analysis on the MYH7 locus with microsatellite markers showed that the sam e haplotype is transmitted within the family, suggesting a founder effect. Clinically, the father was asymptomatic with mild left ventricular hypertro phy on echocardiography. The mother had a mild form of hypertrophic cardiom yopathy and remained asymptomatic until 60 years old when an atrial fibrill ation occurred. For the two children, clinical diagnosis was performed at 1 2 and 8 years and atrial fibrillation occurred at 17 years. For both childr en, the evolution was characterized by left ventricle (LV) systolic dysfunc tion and a severe dilatation of the left atrium before 40 years of age. Con clusions: In this family, a new R869G mutation in the MYH7 gene was found. Interestingly, a mutation was found at the homozygous status for the first time in FHC. This finding suggests that this particular mutation is compati ble with life, but for homozygous subjects, age at onset of symptoms was ea rlier and the disease much more severe than in the heterozygous subjects, s uggesting a gene-dose effect. (C) 2000 Academic Press.