Heart failure & cardiomyopathies
Redefining the Genetic Architecture of Hypertrophic Cardiomyopathy: Role of Intermediate-Effect Variants
Authors' conclusion
IEVs are present in 6.1% of HCM cases and account for 4.8% of HCM genetic burden. IEVs also influence disease severity and outcomes, particularly when combined with monogenic disease-causing variants.
Study context
- Population
- Patients with hypertrophic cardiomyopathy (HCM); controls of European ancestry and gnomAD non-Finnish EuropeansHCM cases, whole cohort
- Participants
- 11,991 patients
- Comparison
- IEV carriers vs genotype-negative HCM patients; monogenic+IEV vs monogenic only
- Isolated IEVn = 570
- Outcome
- IEV prevalence and population-attributable fraction
Methodological detailsancestry-based enrichment analysis
- Ancestry-based enrichment analysis
Main finding
As reported in the abstract
- Individuals with intermediate-effect variants (IEVs) (14 IEVs in 8 genes)
- 731 (6.1% of the cohort)
- Isolated IEV carriers
- 570 (4.8%)
- Isolated IEVs in sarcomeric genes
- 198 (34.7%)
- Isolated IEVs in nonsarcomeric genes
- 372 (65.3%)
- Population-attributable fraction of IEVs
- 4.9% (95% CI, 3.2-6.7)
Observational data: associations, not effects.
Further findings
Median age at diagnosis
P = 0.0073
- LV maximum wall thickness · mean 18.1±3.7 versus 19.0±4.3; higher in IEV carriers
- P = 0.0043
- MACE-free survival at 70 years · 70 years of age — Monogenic+IEV: younger HCM onset and higher LV maximum wall thickness vs monogenic only · Monogenic+IEV vs Monogenic · 93.3% versus 69.3%; significantly lower with monogenic+IEV
- all P<0.0001 · P < 0.0001
MACE-free survival at 70 years · 70 years of age
- Significant gradient in penetrance, phenotypic severity and MACE across genetic groups
Original publication
Redefining the Genetic Architecture of Hypertrophic Cardiomyopathy: Role of Intermediate-Effect Variants. Circulation. Published 29 August 2025. doi:10.
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