Genotype-phenotype associations in sarcomeric hypertrophic cardiomyopathy associated with mutations in the MYBPC3...

Hypertrophic cardiomyopathy (HCM) is caused by mutations in sarcomere-related genes, with MYBPC3 being the most common. Documenting potential genotype-phenotype associations may allow for more personalized genetic counselling.

Observational case-control, cohort, and cross-sectional studies reporting genotype-phenotype associations and the occurrence of predefined events were selected from Cochrane and Medline databases. A random- effects meta-analysis was conducted. Twenty-four studies were included, with 3869 patients enrolled. The mean age at diagnosis of HCM associated with mutations in the MYBPC3 gene was 39.8 years (95 % CI 32.96 to 46.55), and the mean maximum left ventricular thickness was 20.4 mm (95 % CI 19.72 to 21.06). Proportion rates were 12.6 % (95 % CI 5.7 to 21.5 %) for septal reduction therapy, 20.4 % (95 % CI 11.9 to 30.2 %) for the development of heart failure New York Heart Association (NYHA) III/IV functional class, 16.1 % (95 % CI 10.3 to 22.6 %) for the occurrence of atrial fibrillation, and 26 % (95 % CI 17.0 to 36.1 %) for ventricular tachycardia. Cardioverter-defibrillators were implanted in 31.4 % (95 % CI 18.6 to 45.6 %) for secondary prevention, and sudden cardiac arrest occurred in 14.7 % (95 % CI 7.8 to 23.0 %) of patients. Cardiovascular death occurred in 8.6 % of patients over a median of 73 months of follow-up.

This is the largest meta-analysis of MYBPC3 HCM patients to date. We were able to obtain data on the proportion rates of events in this population, which allows to answer some questions about the clinical course of HCM disease associated with mutations in the MYBPC3 gene more clearly. We found not only a late disease onset and low mortality risk, but importantly, a non-negligible risk of developing severe heart failure throughout life.