Redefining the Genetic Architecture of Hypertrophic Cardiomyopathy: Role of Intermediate-Effect Variants
Soledad García-Hernández, Luis de la Higuera Romero, Adrián Fernández, María Luisa Peña‐Peña, Nerea Mora Ayestarán, María Teresa Basurte-Elorz, José M. Larrañaga‐Moreira, I Cardenas Reyes, Eduardo Villacorta, María Valverde-Gómez, A Bautista-Paves, Elena Villanueva, Martín Ortiz-Genga, Alex Lipov, Noël Brögger, María Sabater‐Molina, Eduardo Moreno Escobar, Luis Ruiz-Guerrero, Petros Syrris, Xusto Fernández, Jesús Piqueras‐Flores, Almudena Amor Salamanca, Connie R. Bezzina, Perry Elliott, Roberto Barriales‐Villa, Juan R. Gimeno, Pablo García‐Pavía, Roddy Walsh, Juan Pablo Ochoa
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.