Founder Mutations in Myosin-Binding Protein C: Maybe Not So Benign After All.

Abstract

Linkage studies and genetic sequencing in families with hypertrophic cardiomyopathy (HCM) in the 1980s and 1990s established the sarcomere as the genetic basis for HCM.1 In contemporary cohorts, a pathogenic mutation is found in about half of patients with HCM, with ≈50% of these mutations in MYBPC3 (myosin-binding protein C).2,3 Many mutations are unique or seen in a limited number of families. However, in some geographically or culturally isolated populations, founder mutations have arisen from common ancestors many generations ago. The reported frequency of founder mutations for HCM ranges considerably among different countries, with the highest reported prevalence being in Iceland, where almost 90% of all sarcomere gene mutation carriers harbor a single founder mutation in MYBPC3 , comprising 67% of the entire HCM population.4 The vast majority of founder mutations in HCM across all reported studies are found in MYBPC3 , with fewer reported in MYH7 (myosin), TNNT2 (troponin T), and TPM1 (tropomyosin).5 Because of the need for founder mutations to withstand negative selection pressure to perpetuate through multiple generations, there is a general perception that founder mutations confer a more benign phenotype and disease course.4,6,7 This view has been supported by a previous study in France, which found that carriers of a founder mutation identified in 8% of their HCM population were diagnosed 15 years later and experienced a delayed onset of disease complications compared with carriers of other sarcomere gene mutations.8 However, other studies have observed relative equivalence between carriers of founder and nonfounder mutations.5,9 All of the previously reported studies are limited by relatively small numbers and some by incomplete genotyping in comparator HCM cohorts, which could confound results. Most studies have also not distinguished between probands and relatives of probands …