ArticleCirculation2025
Redefining the Genetic Architecture of Hypertrophic Cardiomyopathy: Role of Intermediate-Effect Variants.
Article in Circulation, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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13 citing papers in PubMed.
- Whole-genome sequencing implicates rare, low-frequency and structural non-coding variation at themedRxiv : the preprint server for health sciences · 2026Article
- When splicing is not all or none: GT>GC 5' splice-site variants as a model for intermediate effects and challenges in variant classification.HGG advances · 2026Article
- Association of Common Ancestry-Enriched Variants With Cardiomyopathy and Arrhythmias.Circulation · 2026Article
- The Role of Next-Generation Sequencing in Cardiovascular Disease: A New Era of Precision Cardiology.Life (Basel, Switzerland) · 2026Review
- Benchmarking genetic birth prevalence estimates against newborn screening data.American journal of human genetics · 2026Article
- Evaluation of Women With Peripartum or Dilated Cardiomyopathy and Their First-Degree Relatives: The DCM Precision Medicine Study.Circulation. Genomic and precision medicine · 2026Observational
- Epigenetics, Modifiers, and Molecular Noise: Rethinking Pathophysiology in Dilated and Hypertrophic Cardiomyopathies.International journal of molecular sciences · 2026Review
- Leveraging Large and Diverse Biobanks to Evaluate Gene-Disease Associations in Hypertrophic Cardiomyopathy.Journal of personalized medicine · 2026Article
- Hypertrophic Cardiomyopathy in the Era of Precision Medicine: Redefining Diagnosis, Therapeutics and Risk.Cardiac failure review · 2026Article
- Genetics in Hypertrophic Cardiomyopathy: An Evolving Clinical Landscape.Cardiac failure review · 2026Review
- Hypertrophic Cardiomyopathy Genotype-Phenotype Analysis in Lithuanian Single-Center Cohort.International journal of molecular sciences · 2025Article
- Genetic Spectrum, Clinical Characteristics, and Molecular Pathogenesis of Hypertrophic Cardiomyopathy Requiring Heart Transplantation.Journal of cardiovascular development and disease · 2025Article
- Reclassification of VUS Using ACMG/AMP Criteria Adapted for Sarcomeric Genes Related to Hypertrophic Cardiomyopathy: Resolution Rate and Considerations.Human mutation · 2025Article
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Authors and funding
29 authors.
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Abstract
backgroundHypertrophic cardiomyopathy (HCM) is a genetically heterogeneous disorder linked primarily to rare variants in sarcomeric genes, although recently certain nonsarcomeric genes have emerged as important contributors. Nonmendelian genetic variants with reproducible moderate-effect sizes and low penetrance, intermediate-effect variants (IEVs), can play a crucial role in modulating disease expression. Understanding the clinical impact of IEVs is crucial to unravel the complex genetic architecture of HCM.
methodsWe conducted an ancestry-based enrichment analysis of 14 validated HCM genes, including the 9 core sarcomeric and 5 nonsarcomeric genes
resultsFourteen IEVs in 8 genes were identified in 731 individuals (6.1% of the cohort), of whom 570 patients (4.8%) had IEVs in isolation: 198 (34.7%) in sarcomeric genes and 372 (65.3%) in nonsarcomeric genes. The contribution of IEVs to HCM genetics according to population-attributable fraction was estimated to be 4.9% (95% CI, 3.2-6.7). A significant gradient in penetrance, phenotypic severity, and major adverse cardiac events was observed across genetic groups. Compared with genotype-negative patients, IEV carriers displayed a younger median age at diagnosis (59 years of age [95% CI, 46-69] versus 61 years [95% CI, 49-70];
conclusionsIEVs 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. Evaluation of IEVs should be considered when HCM genetic testing is performed.
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