Genetic and non-genetic determinants of clinical variability in a familial case of hypertrophic cardiomyopathy with heterozygous pathogenic mypbc3 mutation

Abstract Mutations in the MYBPC3 gene, which encodes myosin C–binding protein C (cMyBP–C) are among the main causes of hypertrophic cardiomyopathy (HCM). Truncating mutations are recognized as causative in many HCM patients and recently, even missense mutations (e.g E258K mutation) appear to be clinically related to the disease. E258K is one of the most common MYBPC3 mutations, with a prevalence of 15% in Italians. We report a family case, with father and son affected by HCM in which where this mutation was identified thanks to the NGS. HCM in the father was diagnosed at the age of 70 after several episodes of atrial fibrillation and after a myocardial infarction. The son, a sportsman, had a very early and severe presentation of HCM in the absence of manifest clinical signs. The same E258K mutation was also found in the proband son, in the absence of clinical signs of HCM. Given the diversity of the carrier phenotypes, the molecular analysis of the proband was extended beyond rare variants and we found a common substitution in the DES gene, (encoding desmin) which, acting as an unfavourable modifier, could partly explain the different clinical presentation of HCM. Probably also the intense physical activity carried out by the proband contributed to the phenotype severity. The father, asymptomatic for a much longer period and with a lower hypertrophy grade compared to the proband, may have benefited from a less intense physical activity and from the absence of the DES polymorphism. To date, the role of physical exercise is widely debated: on the one hand, a regular intense physical training could worsen hypertrophy, fibrosis and trigger arrhythmias, on the other hand however, a sedentary lifestyle predisposes to obesity and other cardiovascular risk factors which induce diseases with a worse prognosis than HCM itself. Nowadays 70% of patients with HCM are overweight, and more than 50% are below the minimum recommended exercise threshold. In addition, there is growing evidence that competitive sports are safe and could have beneficial effects in asymptomatic low–risk HCM patients. This case study suggests that the decision–making process must include both genotypic and phenotypic characterization of patients, as well as the evaluation of the causative mutation pathogenicity and of co–existing genetic modifiers.