Burden of Recurrent and Ancestral Mutations in Families With Hypertrophic Cardiomyopathy

Background— Hypertrophic cardiomyopathy is a genetically heterogeneous myocardial disease with >1000 causal variants identified. Nonunique variants account for disease in many families. We sought to characterize nonunique variants in Australian families and determine whether they arise from common ancestral mutations or recurrent mutation events. Methods and Results— Genetic test results of 467 index patients from apparently unrelated families with hypertrophic cardiomyopathy were evaluated. Causal variants were found in 185 of 467 (40%) families. Nonunique variants accounted for 122 of 185 (66%) families. The most common single genetic cause of hypertrophic cardiomyopathy is the recurrent MYBPC3 (myosin-binding protein-C) variant c.1504C>T, p.Arg502Trp, which was found in 13 of 185 (7%) families with a causal variant identified. Thirteen variants in MYBPC3 and MYH7 (myosin heavy chain 7) were each identified >3 times and accounted for 78 of 185 (42%) hypertrophic cardiomyopathy families with a causal variant. Haplotype analysis of these 13 variants was performed on 126 individuals from 70 Australian families, and 11 variants arose through recurrent mutation events. Two variants, MYBPC3 c.1928-2A>G and MYH7 c.2681A>G, p.Glu894Gly, were found on 1 haplotype in 6 families each, supportive of a single mutation event inherited from a common ancestor. Conclusions— The majority of families with a causal variant identified have a nonunique variant. Discovery of the genetic origins of human disease forms a fundamental basis for improved understanding of disease pathogenesis and phenotype development.