More than 40 different beta-cardiac myosin heavy chain (beta-MHC) missense mutations have been identified that cause familial hypertrophic cardiomyopathy (FHC). Some of these are recognized to have important clinical manifestations, such as an increased incidence of sudden death. We report that the beta-MHC missense mutation Arg663His causes predominant cardiac morphology and atrial fibrillation. Longitudinal clinical evaluations were performed in a kindred with FHC. The nucleotide sequence of the beta-MHC gene was analyzed to define the causal mutation. A missense mutation in the beta-MHC gene, Arg663His, was identified in 24 individuals. Clinical studies demonstrated modest left ventricular hypertrophy in affected individuals, predominantly localized in the proximal segment of the interventricular septum, which increased (average = 40 +/- 8%) during 7 years of follow-up. Results showed that 47% of Arg663His adults (age > 16 years) with ventricular hypertrophy developed atrial fibrillation, significantly more (p <0.001) than observed in ungenotyped FHC populations. Survival of affected individuals remained near normal. The beta-MHC missense mutation Arg663His causes a characteristic pattern of ventricular hypertrophy. Arg663His individuals have a markedly higher prevalence of atrial fibrillation, compared with a population with ungenotyped hypertrophic cardiomyopathy. The demonstration of phenotype as a direct consequence of genotype further extends the utility of molecular data in clinical medicine. Early identification of Arg663His individuals has the potential to minimize the serious sequelae of this arrhythmia in this FHC group.