Redefining the Genetic Architecture of Hypertrophic Cardiomyopathy: Role of Intermediate-Effect Variants
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.
Article Details
Authors (29)
Soledad García Hernandez
Health in Code S.L, A Coruña, Spain (S.G.H.).
Luis de la Higuera Romero
Health in Code S.L, A Coruña, Spain (L.d.l.H.R.).
Adrian Fernandez
Maria Luisa Peña Peña
Department of Cardiology, Hospital Universitario Virgen del Rocío, Sevilla, Spain (M.L.P.P.).
Nerea Mora-Ayestarán
Department of Cardiology, Hospital Universitario Puerta de Hierro, Instituto de Investigación Sanitaria Puerta de Hierro Majadahonda (IDIPHIM), Madrid, Spain (N.M.-A., N.R.-L., J.G.M., P.G.-P.).
María Teresa Basurte-Elorz
Department of Cardiology, Área del Corazón, Hospital Universitario de Navarra, Pamplona, Spain (A.Y.I., M.S., G.L.-L., M.T.B.-E.).
Jose María Larrañaga-Moreira
Unidad de Cardiopatías Familiares, Servicio de Cardiología, Complexo Hospitalario Universitario A Coruña, Instituto de Investigación Biomédica de A Coruña, Spain (J.M.L.-M., R.B.-V.).
Ivonne Cárdenas Reyes
Health in Code S.L., A Coruña, Spain (I.C.R., M.V.-G., M.O.-G., N.B., X.F., A.A.S., J.P.O.).
Eduardo Villacorta
CIBER Cardiovascular, Instituto de Salud Carlos III, Madrid, Spain (C.G.-G., M.G.-D., G.C.-M., M.N.-P., J.M.G.-P., G.C.-V., A.B.-G., R.S.-B., A.G.-Á., M.B., E.Z., E.R.G., E.V., J.L.-F., M.S.-M., R.B.-V., A.D., M.A.E.-C., J.F.R.-P., J.G.M., P.G.-P.).
Maria Valverde-Gómez
Health in Code S.L., A Coruña, Spain (I.C.R., M.V.-G., M.O.-G., N.B., X.F., A.A.S., J.P.O.).
Alicia Baustista-Paves
Inherited Cardiac Diseases Unit, San Cecilio Hospital. Granada, Spain (A.B.-P.).
Elena Veira Villanueva
Complexo Hospitalario Universitario A Coruña, Spain (E.V.V.).
Martín Ortiz-Genga
Health in Code S.L., A Coruña, Spain (I.C.R., M.V.-G., M.O.-G., N.B., X.F., A.A.S., J.P.O.).
Alex Lipov
Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
Noel Brogger
Health in Code S.L., A Coruña, Spain (I.C.R., M.V.-G., M.O.-G., N.B., X.F., A.A.S., J.P.O.).
María Sabater Molina
Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Virgen de la Arrixaca, El Palmar (Murcia), Spain (M.S.M.).
Eduardo Moreno-Escobar
Cardiology Service, San Cecilio Clinical University Hospital, Granada, Spain (E.M.-E.).
Luis Ruiz-Guerrero
Servicio de Cardiología, Hospital Universitario Marqués de Valdecilla, Santander, Cantabria, Spain (L.R.-G.).
Petros Syrris
Institute of Cardiovascular Science, University College London, United Kingdom (A.P., I.H., P.S., P.M.E.).
Xusto Fernández
Jesús Piqueras-Flores
Inherited Heart Disease and Heart Failure Unit, Cardiology Department, General University Hospital of Ciudad Real Faculty of Medicine, University of Castilla La Mancha IDISCAM, Biomedical Research Institute of Castilla La Manch, Spain (J.P.-F.).
Almudena Amor Salamanca
Health in Code S.L., A Coruña, Spain (I.C.R., M.V.-G., M.O.-G., N.B., X.F., A.A.S., J.P.O.).
Connie R. Bezzina
Perry M. Elliott
Institute of Cardiovascular Science, University College London, United Kingdom (A.P., I.H., P.S., P.M.E.).
Roberto Barriales-Villa
Complexo Hospitalario Universitario A Coruña, Instituto de Investigación Biomédica de A Coruña, CIBERCV–Instituto de Salud Carlos III, A Coruña, Spain
Juan Ramón Gimeno-Blanes
Pablo Garcia-Pavia
Department of Cardiology, Hospital Universitario Puerta de Hierro, Instituto de Investigación Sanitaria Puerta de Hierro–Segovia de Arana, Centro de Investigación Biomédica en Red Enfermedades Cardiovaculares, and Centro Nacional de Investigaciones Cardiovasculares, Madrid
Roddy Walsh
Cardiovascular and Genomics Research Institute, City St. George’s, University of London, London, UK (R.W.).
Juan Pablo Ochoa
Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain (N.R.-L., J.P.O., A.G.-Á., P.G.-P.).