Redefining the Genetic Architecture of Hypertrophic Cardiomyopathy: Role of Intermediate-Effect Variants

Journal article

S. García Hernández, L. de la Higuera Romero, A. Fernández, M. L. Peña-Peña, N. Mora-Ayestarán, M. T. Basurte-Elorz, J. Larrañaga-Moreira, I. C. Cárdenas Reyes, E. Villacorta, Maria Valverde-Gómez, A. Bautista-Pavés, Elena Veira Villanueva, M. Ortiz-Genga, Alex Lipov, Noël Brögger, M. Sabater Molina, E. Moreno-Escobar, Luis Ruiz-Guerrero, P. Syrris, X. Fernández, J. Piqueras-Flores, A. Amor Salamanca, C. Bezzina, P. Elliott, R. Barriales-Villa, J. Gimeno-Blanes, P. García-Pavía, Roddy Walsh, Juan Pablo Ochoa
Circulation, 2025

Semantic Scholar DOI PubMedCentral PubMed

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APA Click to copy
Hernández, S. G., de la Higuera Romero, L., Fernández, A., Peña-Peña, M. L., Mora-Ayestarán, N., Basurte-Elorz, M. T., … Ochoa, J. P. (2025). Redefining the Genetic Architecture of Hypertrophic Cardiomyopathy: Role of Intermediate-Effect Variants. Circulation.

Chicago/Turabian Click to copy
Hernández, S. García, L. de la Higuera Romero, A. Fernández, M. L. Peña-Peña, N. Mora-Ayestarán, M. T. Basurte-Elorz, J. Larrañaga-Moreira, et al. “Redefining the Genetic Architecture of Hypertrophic Cardiomyopathy: Role of Intermediate-Effect Variants.” Circulation (2025).

MLA Click to copy
Hernández, S. García, et al. “Redefining the Genetic Architecture of Hypertrophic Cardiomyopathy: Role of Intermediate-Effect Variants.” Circulation, 2025.

BibTeX Click to copy

@article{s2025a,
  title = {Redefining the Genetic Architecture of Hypertrophic Cardiomyopathy: Role of Intermediate-Effect Variants},
  year = {2025},
  journal = {Circulation},
  author = {Hernández, S. García and de la Higuera Romero, L. and Fernández, A. and Peña-Peña, M. L. and Mora-Ayestarán, N. and Basurte-Elorz, M. T. and Larrañaga-Moreira, J. and Reyes, I. C. Cárdenas and Villacorta, E. and Valverde-Gómez, Maria and Bautista-Pavés, A. and Villanueva, Elena Veira and Ortiz-Genga, M. and Lipov, Alex and Brögger, Noël and Molina, M. Sabater and Moreno-Escobar, E. and Ruiz-Guerrero, Luis and Syrris, P. and Fernández, X. and Piqueras-Flores, J. and Salamanca, A. Amor and Bezzina, C. and Elliott, P. and Barriales-Villa, R. and Gimeno-Blanes, J. and García-Pavía, P. and Walsh, Roddy and Ochoa, Juan Pablo}
}

Abstract

BACKGROUND: Hypertrophic 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. METHODS: We conducted an ancestry-based enrichment analysis of 14 validated HCM genes, including the 9 core sarcomeric and 5 nonsarcomeric genes (ALPK3, CSRP3, FHOD3, FLNC, and TRIM63). Enrichment of intermediate frequency missense variants was evaluated in 10 981 patients with HCM, 4030 internal controls of European-ancestry, and 590 000 external controls from gnomAD non-Finnish Europeans. The population-attributable fraction was calculated to assess contribution of IEVs to HCM. Age-related disease penetrance, phenotypic severity (left ventricular maximum wall thickness), and major adverse cardiac events were analyzed in 11 991 HCM cases of the whole cohort according to 5 genetic groups: genotype negative, isolated IEV, monogenic, monogenic+IEV, and double monogenic. RESULTS: Fourteen 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]; P=0.0073) and a higher mean left ventricular maximum wall thickness (18.1±3.7 versus 19.0±4.3; P=0.0043). IEVs also modified disease expression in individuals with monogenic variants, causing a more aggressive phenotype than in individuals from the monogenic-only group with HCM onset at younger age and a higher left ventricular maximum wall thickness (all P<0.0001), with major adverse cardiac event–free survival being significantly lower (93.3% versus 69.3% at 70 years of age; P<0.0001). CONCLUSIONS: 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. Evaluation of IEVs should be considered when HCM genetic testing is performed.