MYBPC3 mutations in hypertrophic cardiomyopathy families showed incomplete penetrance (56.9%) that was higher in males (65.1% vs 48.1%, P=0.03) and older individuals (68.6% ≥40 vs 38.4% <40, P<0.001).
Cohort (n=167)
MYBPC3 mutations in hypertrophic cardiomyopathy exhibit marked clinical heterogeneity and incomplete, age- and gender-dependent penetrance, highlighting the need for careful cascade screening.
BACKGROUND: 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. METHODS AND RESULTS: 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. CONCLUSIONS: 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.
Page et al. (Sat,) conducted a cohort in Hypertrophic Cardiomyopathy (n=167). MYBPC3 mutations was evaluated on Disease penetrance and annual risk of sudden death and all cause mortality. MYBPC3 mutations in hypertrophic cardiomyopathy families showed incomplete penetrance (56.9%) that was higher in males (65.1% vs 48.1%, P=0.03) and older individuals (68.6% ≥40 vs 38.4% <40, P<0.001).