Genotypic and phenotypic insights into inherited heart diseases at a public hospital in Argentina

Background Inherited heart diseases (IHD) are a diverse group of cardiac disorder. Cardiomyopathies, among the most common, include hypertrophic (HCM), dilated (DCM), arrhythmogenic (ACM), restrictive (RCM), and non-dilated left ventricular cardiomyopathy (NDLVC). HCM (1 in 200–500) is linked to MYBPC3 and MYH7 variants, while DCM (1 in 2500) involves TTN, LMNA, and MYH7. ACM (1 in 2000–5000) is associated with PKP2 and DSP. Channelopathies, such as Long QT Syndrome (LQTS), Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT), and Brugada Syndrome (BrS), are inherited disorders predisposing affected individuals to life-threatening arrhythmias and increasing the risk of sudden cardiac death Objective This study analyzes genotype-phenotype correlations, determines the prevalence of pathogenic variants, and assesses their clinical, prognostic, and therapeutic impact in IHD patients referred to a tertiary healthcare center. Methods A total of 110 patients (85 probands, 25 relatives) were evaluated at the Inherited Heart Disease Clinic at Hospital Fernández (Nov 2021–2024). Genetic testing or analysis was conducted at Hospital SAMIC El Calafate using NGS with targeted panels or whole-exome sequencing. Variants were classified according to the ACMG/AMP guidelines. Clinical assessment included ECG, TTE, CMR, Holter monitoring, and stress testing when indicated. Results The diagnostic yield was 43.5%, enabling a precise diagnosis in over 40% of cases. The mean age was 43 years, while genetically positive patients were younger, averaging 36 years (P<0.0001). HCM was the most prevalent IHD, with 52.4% of probands testing positive. The most frequent variants were MYBPC3 (19%) and MYH7 (11.9%). Among HCM patients, 78.9% were on beta-blockers. Three patients died (two with obstructive HCM, one in terminal phase), resulting in an annual mortality rate of 1.70%. For primary prevention, 15.9% received an ICD. Additionally, 7.1% had atrial fibrillation, and 9.5% developed heart failure. Six patients (7%) had phenocopies, including three with RASopathy-related HCM (RAF1, PTPN11 variants) and three with wild-type ATTR. DCM represented 32% of cases, primarily linked to truncating TTN variants (20%). The mean age was 44 years, with disease onset at 38 years, and 36 years in genetically positive cases. LVEF averaged 32.2%, and LVDD was 63.7 mm. ACM accounted for 2.3% of cases, with pathogenic DSP and SCN5A variants, variable expressivity, ventricular ectopy, and fibrofatty myocardial replacement on CMR. A case with an LMNA variant was confirmed through family segregation analysis at Hospital El Calafate.Channelopathies represented 2.3% of cases, including two LQTS and one BrS case. Conclusion Genetic testing in IHD improves diagnosis, risk stratification, and treatment. Expanding access in public healthcare enhances early detection, improves patient outcomes, and provides crucial family counseling.