PO57 Retrospective analysis of diagnostic genetic testing for hereditary cardiovascular diseases in a Portuguese center

Abstract Background Hereditary cardiovascular diseases are associated with high morbidity and mortality. Genetic testing can positively impact diagnosis, prognosis, family screening, and reproductive counselling. However, it also raises challenges, mainly linked to uncertainty, such as incomplete penetrance, variable expressivity, and variant reclassification. Purpose To determine the diagnostic yield of genetic testing across different hereditary cardiovascular diseases in our population, characterize the genes most frequently implicated, and assess the impact of family history on diagnostic outcomes. Methods Retrospective analysis of patients who underwent genetic testing for hereditary cardiovascular diseases in a national laboratory between January 2011 and March 2025. Patient’s clinical records were reviewed to assess phenotype, genetic testing results and family history. Positive family history was defined as at least one established first- or second-degree relatives with same diagnosis or sudden cardiac death (younger than 55 years in the absence of a diagnosis, or at any age if a diagnosis was confirmed). Variants reported prior to 2015 were reinterpreted according to ACMG criteria. Results A total of 443 probands were included: 289 tested for cardiomyopathies, 132 tested for arrhythmias, and 22 tested with extended panels. Across the entire cohort, genetic testing identified pathogenic or likely pathogenic variants in 18% of cases, variants of uncertain significance (VUS) in 36%, and was negative in 46%. The diagnostic yield varied by test type, being higher in cardiomyopathy panels compared with arrhythmia panels, while extended panels increased the number of VUS reported. In patients with hypertrophic cardiomyopathy the most frequent finding were deleterious variants in MYH7 and MYBPC3 genes, for dilated cardiomyopathy loss of function TTN variants were the most frequent finding, and PKP2 was the most implicated gene in arrythmogenic cardiomyopathies. All patients with Brugada syndrome who received a molecular diagnosis carried SCN5A variants. The presence of family history was significantly associated with a higher likelihood of a positive genetic diagnosis (χ²=26.80; p0.05). Conclusions Genetic testing provided a molecular diagnosis in nearly one-fifth of probands, with higher yields in cardiomyopathy compared to arrhythmia panels, and identified disease-specific gene distributions consistent with international data. The association between positive family history and diagnostic yield underscores its value in risk assessment, nonetheless its absence should not exclude genetic testing in symptomatic patients. Extended panels increased the number of VUS findings, reinforcing the need for cautious interpretation and continuous variant reclassification.