Highlight
– Intermediate-effect variants (IEVs) contribute to nearly 5% of hypertrophic cardiomyopathy (HCM) genetic burden.
– Both sarcomeric and non-sarcomeric genes harbor IEVs impacting disease penetrance and severity.
– Presence of IEVs correlates with earlier disease onset, increased left ventricular hypertrophy, and worse major adverse cardiac events.
– IEVs exacerbate phenotype severity when combined with monogenic pathogenic variants, highlighting a modulatory genetic role.
Study Background and Disease Burden
Hypertrophic cardiomyopathy (HCM) is a prevalent inherited cardiac disorder marked by unexplained left ventricular hypertrophy (LVH), predisposing affected individuals to heart failure, arrhythmias, and sudden cardiac death. Genetically, HCM is heterogeneous, principally attributed to rare, highly penetrant variants in sarcomere genes encoding myocardial contractile proteins. However, recent advances recognize the involvement of non-sarcomeric genes and the spectrum of genetic variants underlying the disease has expanded beyond classical Mendelian genetics. Notably, variants with intermediate allele frequencies and moderate effect sizes—termed intermediate effect variants (IEVs)—have been implicated in influencing disease manifestation but remain underexplored. Clarifying the contribution of IEVs is vital to refine the genetic architecture of HCM, improve diagnostic yield, and tailor personalized risk stratification.
Study Design
This comprehensive study undertook an ancestry-based enrichment analysis involving 14 validated HCM-associated genes, including nine core sarcomere genes and five non-sarcomere genes (ALPK3, CSRP3, FHOD3, FLNC, TRIM63). The cohort comprised 10,981 HCM patients of European ancestry compared against 4,030 internal controls and an external dataset of 590,000 non-Finnish Europeans from the gnomAD database. The primary focus was the detection and evaluation of intermediate-frequency missense variants within these genes. The Population-Attributable Fraction (PAF) metric quantified the proportional contribution of IEVs to overall HCM genetics. Furthermore, phenotypic analyses assessed age-related penetrance, left ventricular maximal wall thickness (LVMWT) as a surrogate of disease severity, and major adverse cardiac events (MACE). Patients were stratified into five genetic groups: genotype-negative, isolated IEV carriers, monogenic variant carriers, carriers of both monogenic variants and IEVs, and double monogenic variant carriers.
Key Findings
The study identified 14 pathogenic intermediate effect missense variants scattered across eight genes, cumulatively present in 6.1% of the HCM cohort (731 individuals). Of these, 570 patients (4.8%) harbored IEVs in isolation, with a predominance localized in non-sarcomeric genes (65.3%) over sarcomeric genes (34.7%). The Population-Attributable Fraction ascribed to IEVs was 4.9% (95% CI: 3.2%-6.7%), emphasizing their meaningful genetic contribution.
A progressive gradient was observed for disease penetrance, hypertrophic extent, and clinical outcomes across genetic subgroups. Compared to genotype-negative individuals, isolated IEV carriers exhibited a statistically significant younger median age at diagnosis (59 years vs. 61 years; p=0.0073) and greater mean LVMWT (19.0 mm vs. 18.1 mm; p=0.0043). Importantly, in those carrying monogenic variants, concomitant IEV presence significantly modified disease expression, with earlier onset, more pronounced LVH, and worse MACE-free survival (69.3% vs. 93.3% at age 70; p<0.0001). These findings highlight the additive or synergistic effect of IEVs in modulating the clinical phenotype.
The severity gradient also underscores the biological relevance of non-sarcomeric genes as modulatory elements in HCM pathogenesis, moving beyond the traditional sarcomeric-centric model. Furthermore, the stratification approach revealed that double monogenic variant carriers experience the severest disease phenotype.
Expert Commentary
This seminal work redefines the genetic landscape of HCM by integrating intermediate-frequency variants that possess moderate effect sizes and incomplete penetrance, thereby challenging the strict Mendelian paradigm historically dominant in HCM genetics. The integration of extensive case-control genomic datasets and meticulous phenotypic correlation underscores the robustness of these findings. Clinicians and geneticists should recognize that not all deleterious variants exert large effects independently; some contribute through cumulative or epistatic interactions.
From a mechanistic standpoint, IEVs may impact sarcomere function or myocardial signalling pathways subtly, such that their effects manifest only under specific genetic or environmental contexts. This necessitates refined interpretation algorithms in clinical genetic testing, which currently prioritize rare high-penetrance variants. The study’s limitation includes its focus on European-ancestry populations, warranting validation across diverse ethnicities to ensure generalizability.
Current international guidelines for HCM genetic testing may need revision to incorporate IEV evaluation, facilitating improved prognostication and management strategies. Additionally, further functional studies are essential to elucidate the molecular mechanisms by which IEVs influence phenotype severity.
Conclusion
Intermediate effect variants represent a substantial and previously underappreciated component of HCM’s genetic architecture. Found in approximately 6% of cases, these variants contribute nearly 5% to the genetic burden and significantly affect clinical severity and outcomes, particularly when combined with monogenic pathogenic variants. This nuanced understanding fosters a more comprehensive genetic evaluation framework in HCM, emphasizing the need to include IEV screening during genetic testing. Ultimately, recognizing the multifactorial genetic influences in HCM will enhance risk stratification, guide personalized therapy, and inform family counseling.
References
1. García Hernandez S, de la Higuera Romero L, Fernández A, et al. Redefining the Genetic Architecture of Hypertrophic Cardiomyopathy: Role of Intermediate Effect Variants. Circulation. 2025 Aug 29. doi:10.1161/CIRCULATIONAHA.125.074529
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3. Semsarian C, Ingles J, Maron MS, Maron BJ. New perspectives on the prevalence of hypertrophic cardiomyopathy. J Am Coll Cardiol. 2015;65(12):1249-1254. doi:10.1016/j.jacc.2015.01.019
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