Landmark genetic mapping studies beginning in the 1990s defined hypertrophic cardiomyopathy (HCM) as an autosomal dominant inherited disease caused by specific mutations in cardiac sarcomere genes. 1 Certain mutations in large families were initially described as being more deleterious than others, giving hope that genetic testing would enable predictions of disease severity. However, a more complicated story emerged as extreme locus and phenotypic heterogeneity became evident as the rule rather than the exception in less select populations. 2 Indeed, HCM is now recognized as a disease which is primarily caused by a single mutation but then modulated greatly by other factors. In fact, the variability in phenotype attributable to disease modifiers has confounded studies of genotype–phenotype correlations for the primary mutations themselves. Founder mutations offer a distinct advantage in studying disease variability in HCM. Not only is the mutation identical in all subjects, but so also is the surrounding genetic region (haplotype block), which includes the regulatory sequences immediately adjacent to and within the gene. Therefore, differences in disease expression must arise from either other genetic variation or environmental factors. Several previous studies of founder mutations in HCM have shown extreme disease variability, with a range of clinical expression similar to that found in studies of HCM with mixed genotypes. The study by Claes and colleagues adds to this growing evidence in the case of a founder mutation in MYL2. 3 Together, these studies provide robust evidence for the importance of additional genetic and/or environmental factors in the development of HCM.