Genetics and clinics: Current applications, limitations, and future developments

Genetic cardiovascular (CV) diseases encompass major groups of Mendelian (>90%) and non-Mendelian, (matrilinear) familial (F) disorders including cardiomyopathies (CMP), aneurysmal diseases, ventricular and supraventricular arrhythmogenic disorders, and pulmonary hypertension (PH). In F-cardiomyopathies (F-CMP), a pathologic mutation provides specific vs. phenotype-based descriptive diagnosis, early, pre-clinical diagnosis in families. Subsets of dilated cardiomyopathies (DCM) (e.g. cardiolaminopathies) include genotype in indications for primary prevention of sudden cardiac death (SCD). Pathologic mutations are one of the major diagnostic criteria for arrhythmogenic CMP. For F-aneurysms, syndromic and non-syndromic, genetics plays a diagnostic role. Syndromes are recognized on phenotypes, while non-syndromic aneurysms are diagnosed on imaging and genetic testing. Risk of events varies, according to the genetic cause. In F-Arrhythmogenic disorders, genetics offers diagnostic, therapeutic, and prognostic benefits, in particular Long QT Syndrome (LQTS), Short QT Syndrome (SQTS), Brugada Syndrome (BS), and Catecholaminergic Polymorfic Ventricular Tachycardia (CPVT); medications may vary according to genotypes. Fatrial arrhythmias, typically atrial fibrillation (AF), are still poorly investigated. F-pulmonary hypertension may have genetic basis (Groups I and V, last classification). Early diagnosis is mandatory given the new available drugs that influence the natural history of the disease. In the future, clinical family screening, genetic counselling, and testing should become systematic; treatments are going to be driven by genetic cause.