Small selected cohort studies suggest that mutations in the cardiac myosin binding protein-C (MYBPC3) gene cause late-onset, clinically benign hypertrophic cardiomyopathy (HCM). The aim of this study was to test this hypothesis in a large series of families with HCM associated with MYBPC3 mutations.

The initial study population comprised 57 probands with 42 mutations (26 [61.9%] novel) in MYBPC3. Missense mutations (15, 45.6%) were the most frequent, and multiple mutations occurred in 4 (7.0%) probands. Another 110 mutation carriers were identified during familial evaluation; 38 were clinically affected with left ventricular hypertrophy ≥13 mm. Disease penetrance was, therefore, incomplete (56.9% in all mutation carriers, 34.5% in relatives), related to age (38.4% <40 versus 68.6% ≥40 years, P<0.001), and was greater in males than females (65.1% versus 48.1%, P=0.03). In 9 families (25 individuals) with the R502W mutation, there was marked heterogeneity in age at diagnosis (5 to 80 years), pattern of hypertrophy (11 none, 9 asymmetrical, 3 concentric, 1 apical, 1 eccentric), and prognosis (premature sudden death in 2 individuals compared with survival to advanced age in 6 individuals). During follow up of 7.9+/−4.5 years, in 82 clinically affected individuals the annual risk of sudden death and all cause mortality was 0.46% and 0.93% per year, respectively.

Disease expression in families with HCM related to MYBPC3 mutations shows marked heterogeneity with incomplete, age-related, and gender specific penetrance. Importantly, complex genetic status is observed and should be considered when mutation analysis and cascade screening is used in the evaluation of at risk family members.