Intermediate-effect variants were identified in 5% of HCM cases and were associated with earlier diagnosis, increased hypertrophy severity, and higher cardiovascular mortality when combined with monog
Does the presence of Intermediate Effect Variants (IEVs) modify disease severity and clinical outcomes in patients with hypertrophic cardiomyopathy?
Intermediate effect variants (IEVs) contribute to about 5% of HCM cases and act as significant disease modifiers, increasing phenotypic severity and cardiovascular mortality when co-occurring with monogenic variants.
Absolute Event Rate: 0% vs 0%
Abstract Background Hypertrophic cardiomyopathy (HCM) is a genetically heterogeneous disorder mainly associated with rare variants in eight core sarcomere genes, though recently validated non-sarcomeric genes have also emerged as important contributors. Non-Mendelian genetic factors, such as polygenic risk scores and intermediate-effect variants (IEVs), can play a crucial role in modulating disease expression. Understanding the clinical impact of IEVs is crucial to unravel HCM's complex genetic architecture. Methods We conducted an ancestry-based enrichment analysis of validated HCM genes, including sarcomere (MYBPC3, MYH7, TNNT2, TNNI3, TNNC1, ACTC1, TPM1, MYL3, MYL2) and non-sarcomere genes (ALPK3, CSRP3, FHOD3, FLNC, TRIM63), by comparing the frequency of intermediate-frequency missense variants (0.01FAF0.00004) across three cohorts:14,113 HCM cases, 8,114 non-cardiomyopathy internal controls, and the gnomAD non-Finnish European population. Significant enrichment was defined by odds ratio (OR)≥2, p0.05, and estimated penetrance (EP)15%. We also estimated their potential global contribution for explaining part of the burden of HCM by calculating the population attributable fraction (PAF). To assess the clinical impact of IEVs, the HCM cohort was stratified into five genetic groups: negative genotype, isolated IEVs, monogenic, monogenic and IEV, and double monogenic. Disease penetrance was assessed by age at diagnosis, phenotypic severity was evaluated based on left ventricular wall thickness (LVMWT) as both continuous and categorical variable (25mm severe; 30mm massive). A combined cardiovascular death endpoint (heart failure-related and sudden-cardiac death) was also analyzed. Results Fourteen IEVs across eight genes were identified (see table), potentially accounting for up to 5% of the genetic background in our HCM cohort. We observed a statistically significant gradient in penetrance, phenotypic severity, and clinical outcomes across genetic groups, correlating with increasing effect sizes (see figure). Carriers of IEVs exhibited a younger median age at diagnosis (58years; IQ95%:57–60) compared to genotype-negative patients (61years; IQ95%:60–61) and a higher proportion of severe hypertrophy (6.5% vs. 2.4%, p0.0001). The presence of an IEV alongside a monogenic variant acted as a significant modifier of these variables. LVMWT was higher in the Monogenic+IEV group vs the Monogenic-only group (22.23±5.23 mm vs. 20.67±4.98 mm). Cardiovascular mortality was also significantly higher in the Monogenic+IEV group compared to the Monogenic group (p0.0001). Conclusions In this study, 14 selected IEVs were identified, contributing to 5% of HCM cases of the cohort, probably representing a necessary genetic component contributing to disease expression. These variants influence disease severity and clinical outcomes, underscoring the importance of integrating IEVs into refined genetic risk stratification models to improve clinical management.Seleced IEV. Relevant Evidence. IEV. Comparative Clinical Impact
Hernandez et al. (Sat,) reported a other. Intermediate-effect variants were identified in 5% of HCM cases and were associated with earlier diagnosis, increased hypertrophy severity, and higher cardiovascular mortality when combined with monog.