PO78 Prevalence of sarcomeric genetic mutations at a tertiary center in portugal

Abstract Background Mutations in sarcomeric genes (SG) are the leading genetic cause of hypertrophic cardiomyopathy (HCM). The ongoing expansion of the mutational spectrum and improved detection methods continue to refine the understanding of sarcomeric cardiomyopathies. Sarcomere-related genes (SRG) have also gained importance in the understanding of HCM. Purpose To evaluate the prevalence of SG and SRG mutations in a cohort of HCM patients at a tertiary center in Portugal. Methods We retrospectively analyzed HCM patients who underwent genetic testing at a tertiary center in Portugal. Genetic test results were reviewed. Variants were classified according to the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines as pathogenic (P), likely pathogenic (LP), or of uncertain significance (VUS). The prevalence of variants was determined. Results The study enrolled 256 patients (mean age 60.1 ± 15.5 years; 144 (56.3%) males) Results were available for 220 patients (85.9%). Overall, 136 patients (61.8%) harbored at least one VUS/LP/P SG or SRG variant. The overall yield for LP/P variants was 39.5%, with 34.1% attributable to SR and 4.1% to SRG. Three patients (2 women, 1 man) carried more than one LP/P variant. The rate of LP/P variants was similar between men (37.3%) and women (41.5%), with no significant difference (OR 0.85; 95% CI 0.49–1.48; p=0.56). MYBPC3 was the most frequently mutated gene (35 LP/P variants), followed by MYH7 (25 LP/P variants). The frequency of VUS was significantly higher in SRG (42/51, 82.4%) than in SG (38/115, 33.0%) (OR 9.5; 95% CI 4.1–22.0; p < 0.0001). Conclusions In this Portuguese cohort, sarcomeric mutations were highly prevalent among HCM patients, with a causative variant identified in approximately one out of every 2.5 genetic tests performed. As expected, MYBPC3 and MYH7 were the most frequently mutated genes. Despite advances in genetic testing, variants of uncertain significance (VUS) remain common, especially in SRG. These findings underscore the need for continued research to better understand the role of non-classical sarcomeric genes in the disease’s pathophysiology and their implications for genetic counseling.