Redefining the genetic architecture of hypertrophic cardiomyopathy: role of intermediate-effect variants
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...
| Autores: | , , , , , , , , , , , , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Fecha de publicación: | 2025 |
| País: | España |
| Institución: | Universidad de Cantabria (UC) |
| Repositorio: | UCrea Repositorio Abierto de la Universidad de Cantabria |
| Idioma: | inglés |
| OAI Identifier: | oai:repositorio.unican.es:10902/38807 |
| Acceso en línea: | https://hdl.handle.net/10902/38807 |
| Access Level: | acceso abierto |
| Palabra clave: | Cardiomyopathy Hypertrophic Genetic predisposition to disease Genetic testing Genetic variation Inheritance patterns Risk factors Penetrence |
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España |
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| dc.title.none.fl_str_mv |
Redefining the genetic architecture of hypertrophic cardiomyopathy: role of intermediate-effect variants |
| title |
Redefining the genetic architecture of hypertrophic cardiomyopathy: role of intermediate-effect variants |
| spellingShingle |
Redefining the genetic architecture of hypertrophic cardiomyopathy: role of intermediate-effect variants García Hernandez, Soledad Cardiomyopathy Hypertrophic Genetic predisposition to disease Genetic testing Genetic variation Inheritance patterns Risk factors Penetrence |
| title_short |
Redefining the genetic architecture of hypertrophic cardiomyopathy: role of intermediate-effect variants |
| title_full |
Redefining the genetic architecture of hypertrophic cardiomyopathy: role of intermediate-effect variants |
| title_fullStr |
Redefining the genetic architecture of hypertrophic cardiomyopathy: role of intermediate-effect variants |
| title_full_unstemmed |
Redefining the genetic architecture of hypertrophic cardiomyopathy: role of intermediate-effect variants |
| title_sort |
Redefining the genetic architecture of hypertrophic cardiomyopathy: role of intermediate-effect variants |
| dc.creator.none.fl_str_mv |
García Hernandez, Soledad De la Higuera Romero, Luis Fernandez, Adrian Luisa Peña Peña, Maria Mora Ayestaran, Nerea Basurte Elorz, María Teresa Larrañaga Moreira, Jose María Cárdenas Reyes, Ivonne Villacorta, Eduardo Valverde Gómez, Maria Baustista-Paves, Alicia Veira Villanueva, Elena Ortiz Genga, Martín Lipov, Alex Brogger, Noel Sabater Molina, María Moreno Escobar, Eduardo Ruiz Guerrero, Luis Javier Syrris, Petros Piqueras Flores, Jesús |
| author |
García Hernandez, Soledad |
| author_facet |
García Hernandez, Soledad De la Higuera Romero, Luis Fernandez, Adrian Luisa Peña Peña, Maria Mora Ayestaran, Nerea Basurte Elorz, María Teresa Larrañaga Moreira, Jose María Cárdenas Reyes, Ivonne Villacorta, Eduardo Valverde Gómez, Maria Baustista-Paves, Alicia Veira Villanueva, Elena Ortiz Genga, Martín Lipov, Alex Brogger, Noel Sabater Molina, María Moreno Escobar, Eduardo Ruiz Guerrero, Luis Javier Syrris, Petros Piqueras Flores, Jesús |
| author_role |
author |
| author2 |
De la Higuera Romero, Luis Fernandez, Adrian Luisa Peña Peña, Maria Mora Ayestaran, Nerea Basurte Elorz, María Teresa Larrañaga Moreira, Jose María Cárdenas Reyes, Ivonne Villacorta, Eduardo Valverde Gómez, Maria Baustista-Paves, Alicia Veira Villanueva, Elena Ortiz Genga, Martín Lipov, Alex Brogger, Noel Sabater Molina, María Moreno Escobar, Eduardo Ruiz Guerrero, Luis Javier Syrris, Petros Piqueras Flores, Jesús |
| author2_role |
author author author author author author author author author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Universidad de Cantabria |
| dc.subject.none.fl_str_mv |
Cardiomyopathy Hypertrophic Genetic predisposition to disease Genetic testing Genetic variation Inheritance patterns Risk factors Penetrence |
| topic |
Cardiomyopathy Hypertrophic Genetic predisposition to disease Genetic testing Genetic variation Inheritance patterns Risk factors Penetrence |
| description |
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. |
| publishDate |
2025 |
| dc.date.none.fl_str_mv |
2025 2025-01-01 |
| dc.type.none.fl_str_mv |
journal article http://purl.org/coar/resource_type/c_6501 NA http://purl.org/coar/version/c_be7fb7dd8ff6fe43 |
| dc.type.openaire.fl_str_mv |
info:eu-repo/semantics/article |
| format |
article |
| dc.identifier.none.fl_str_mv |
https://hdl.handle.net/10902/38807 |
| url |
https://hdl.handle.net/10902/38807 |
| dc.language.none.fl_str_mv |
Inglés eng |
| language_invalid_str_mv |
Inglés |
| language |
eng |
| dc.rights.none.fl_str_mv |
open access http://purl.org/coar/access_right/c_abf2 Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ |
| dc.rights.openaire.fl_str_mv |
info:eu-repo/semantics/openAccess |
| rights_invalid_str_mv |
open access http://purl.org/coar/access_right/c_abf2 Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ |
| eu_rights_str_mv |
openAccess |
| dc.publisher.none.fl_str_mv |
American Heart Association |
| publisher.none.fl_str_mv |
American Heart Association |
| dc.source.none.fl_str_mv |
Circulation, 2025, 152(15), 1060-1075 reponame:UCrea Repositorio Abierto de la Universidad de Cantabria instname:Universidad de Cantabria (UC) |
| instname_str |
Universidad de Cantabria (UC) |
| reponame_str |
UCrea Repositorio Abierto de la Universidad de Cantabria |
| collection |
UCrea Repositorio Abierto de la Universidad de Cantabria |
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|
| repository.mail.fl_str_mv |
|
| _version_ |
1869421580785811456 |
| spelling |
Redefining the genetic architecture of hypertrophic cardiomyopathy: role of intermediate-effect variantsGarcía Hernandez, SoledadDe la Higuera Romero, LuisFernandez, AdrianLuisa Peña Peña, MariaMora Ayestaran, NereaBasurte Elorz, María TeresaLarrañaga Moreira, Jose MaríaCárdenas Reyes, IvonneVillacorta, EduardoValverde Gómez, MariaBaustista-Paves, AliciaVeira Villanueva, ElenaOrtiz Genga, MartínLipov, AlexBrogger, NoelSabater Molina, MaríaMoreno Escobar, EduardoRuiz Guerrero, Luis JavierSyrris, PetrosPiqueras Flores, JesúsCardiomyopathyHypertrophicGenetic predisposition to diseaseGenetic testingGenetic variationInheritance patternsRisk factorsPenetrenceBackground: 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.This project was funded by Bristol-Myers Squibb. Drs Bezzina and García-Pavía are supported by the Pathfinder Cardiogenomics program of the European Innovation Council of the European Union (DCM-NEXT project).American Heart AssociationUniversidad de Cantabria20252025-01-01journal articlehttp://purl.org/coar/resource_type/c_6501NAhttp://purl.org/coar/version/c_be7fb7dd8ff6fe43info:eu-repo/semantics/articlehttps://hdl.handle.net/10902/38807Circulation, 2025, 152(15), 1060-1075reponame:UCrea Repositorio Abierto de la Universidad de Cantabriainstname:Universidad de Cantabria (UC)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:repositorio.unican.es:10902/388072026-06-02T12:39:31Z |
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15,812429 |