Genotype-phenotype relationship in cardiomyopathies: from disease onset to prognostic impact

Cardiomyopathies are disorders whose diagnostic definition is improving with the development of genetic investigations. Indeed, the widespread use of genetic tests in clinical practice has led to the identification of several mutations in cardiac genes that, despite their stereotyped molecular basis, are associated to very heterogeneous clinical phenotypes. In particular, pathogenic mutations in sarcomeric, desmosomal or nuclear genes are known to cause the majority of nonischaemic cardiomyopathies. This research project investigated the relationships between genotype and phenotype in the development and evolution of cardiomyopathies through a multiparametric clinical assessment of patients bearing a pathogenic or likely pathogenic mutation in at least one sarcomeric, desmosomal or nuclear gene. First, we defined the penetrance and the phenotypic expressivity in definite mutation carriers. Therefore, we assessed the prognostic significance of these mutations across different phenotypes. Moreover, we investigated the interactions between genetic background and environment, such as high intensity sports, viral infections or drug exposure. The study population included probands and familial carriers of pathogenic, likely pathogenic mutations or variant uncertain significance in genes known to cause cardiomyopathies (DCM, HCM, ARVC), retrospectively enrolled at the ‘Fondazione Toscana Gabriele Monasterio’. Analysis were carried out in subjects who underwent genetic testing since 2012, in order to collect prognostic data regarding a 12-year follow up. A comprehensive clinical biohumoral, electrocardiographic and imaging evaluation was performed, including both retrospective collection of patients’ data and prospective follow-up examinations.