The clinical profile and prognosis of patients with hypertrophic cardiomyopathy, a primary cardiac muscle disease caused mostly by mutations in sarcomeric protein-encoding genes, have been linked to particular disease-causing mutations in the past. However, such associations are often based on cross-sectional observations, as longitudinal studies of the progression of the disease in genotypically defined patients are sparse. Most importantly, the relative contribution of age, gender and genetic cause to disease profile and progression has not yet been reported, and the question remains whether one or more of these factors could mask the effect of the other(s).We previously described cross-sectional family studies of two hypertrophic cardiomyopathy (HCM)-causing mutations, R92W(TNNT2) and R403W(MYH7), both associated with minimal hypertrophy, but with widely different life expectancies. We re-investigated 22 and 26 R92W(TNNT2) and R403W(MYH7) mutation carriers in these and additional South African R92W(TNNT2) families after a mean 11.08 +/- 2.79 years, and compared the influence of the two mutations, in the context of age and gender, on disease progression.We demonstrated a positive correlation between age and interventricular septal thickness for both mutations, with more than a third of all mutation carriers developing clinically recognised hypertrophy only after the age of 35 years. This period of hypertrophically silent HCM also coincided with the years in which most sudden cardiac deaths occurred, particularly in male R92W(TNNT2) carriers. Statistical analyses indicated that the particular mutation was the strongest determinant of left ventricular remodelling; particularly, LVESD increased and EF reduction was noted in the majority of R403W(MYH7) carriers, which may require clinical follow-up over the longer term.Statistical modelling of follow-up data suggests that an interplay between unidentified, possibly gender-associated factors, and the causal mutation are the determinants of eventual cardiac function and survival, but not of the extent of hypertrophy, and emphasises the need for long-term follow-up even in individuals with apparently mild disease.