Genetics and clinics: together to diagnose cardiomyopathies

The diagnostic paths of hereditary cardiomyopathies (CMPs) include both clinical and molecular genetics. The first step is the clinical diagnosis that guides the decisions about treatments, monitoring, prognostic stratification, and prevention of major events. The type of CMP [hypertrophic cardiomyopathy, dilated cardiomyopathy, restrictive cardiomyopathy, and arrhythmogenic right ventricular cardiomyopathy (ARVC)] is defined by the phenotype, and the genetic testing may identify the precise cause. Furthermore, genetic testing provides a pre-clinical diagnosis in unaffected family members and the basis for prenatal diagnosis. It can contribute to risk stratification (e.g. LMNA) and can be a major diagnostic criterion (e.g. ARVC). The test can be limited to a single gene when the pre-test diagnostic hypothesis is based on proven clinical evidence (e.g. GLA for Fabry disease). Alternatively, it can be expanded from a multigene panel to a whole exome or whole genome sequencing when the pre-test hypothesis is a genetically heterogeneous disease. In the last decade, the study of larger genomic targets led to the identification of numerous gene variants not only pathogenic (clinically actionable) but also of uncertain clinical significance (not actionable). For the latter, the pillar of the genetic diagnosis is the correct interpretation of the pathogenicity of genetic variants, which is evaluated using both bioinformatics and clinical-genetic criteria about the patient and family. In this context, cardiologists play a central role in the interpretation of genetic tests, performing the deep-phenotyping of variant carriers and establishing the co-segregation of the genotype with the phenotype in families.