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Formin Homology 2 Domain Containing 3 (FHOD3) Is a Genetic Basis for Hypertrophic Cardiomyopathy

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dc.contributor.authorOchoa, Juan Pablo
dc.contributor.authorSabater Molina, María
dc.contributor.authorGarcía Pinilla, José Manuel
dc.contributor.authorMogensen, Jens
dc.contributor.authorRestrepo Córdoba, Alejandra
dc.contributor.authorPalomino Doza, Julian
dc.contributor.authorVillacorta, Eduardo
dc.contributor.authorMartínez Moreno, Marina
dc.contributor.authorRamos Maqueda, Javier
dc.contributor.authorZorio, Esther
dc.contributor.authorPeña Peña, María L.
dc.contributor.authorGarcía Granja, Pablo E.
dc.contributor.authorRodríguez Palomares, José F.
dc.contributor.authorCárdenas Reyes, Ivonne J.
dc.contributor.authorTorre Carpente, María M. de la
dc.contributor.authorBautista Pavés, Alicia
dc.contributor.authorAkhtar, Mohammed M.
dc.contributor.authorCicerchia, Marcos N.
dc.contributor.authorMogollón Jiménez, María Victoria
dc.contributor.authorSalazar Mendiguchía, Joel
dc.contributor.authorMesa Latorre, José M.
dc.contributor.authorArnáez, Blanca
dc.contributor.authorOlavarri Miguel, Iván
dc.contributor.authorFuentes Cañamero, María E.
dc.contributor.authorLamounier, Arsonval
dc.contributor.authorPérez Ruiz, José María
dc.contributor.authorCliment Payá, Vicente
dc.contributor.authorPérez Sánchez, Inmaculada
dc.contributor.authorTrujillo Quintero, Juan P.
dc.contributor.authorLopes, Luis R.
dc.contributor.authorRepáraz Andrade, Alfredo
dc.contributor.authorMarín Iglesias, Rosario
dc.contributor.authorRodríguez Vilela, Alejandro
dc.contributor.authorSandín Fuentes, María
dc.contributor.authorGarrote, José A.
dc.contributor.authorCortel Fuster, Alejandro
dc.contributor.authorLópez Garrido, Miguel
dc.contributor.authorFontalba Romero, Ana
dc.contributor.authorRipoll Vera, Tomás
dc.contributor.authorLlano Rivas, Isabel
dc.contributor.authorFernandez Fernandez, Xusto
dc.contributor.authorIsidoro García, María
dc.contributor.authorGarcía Giustiniani, Diego
dc.contributor.authorBarriales Villa, Roberto
dc.contributor.authorOrtiz Genga, Martín
dc.contributor.authorGarcía Pavía, Pablo
dc.contributor.authorElliott, Perry M.
dc.contributor.authorGimeno, Juan R.
dc.contributor.authorMonserrat, Lorenzo
dc.contributor.authorBilbao Quesada, Raquel
dc.contributor.departmentCiencias Sociosanitarias
dc.date.accessioned2024-02-12T12:01:27Z
dc.date.available2024-02-12T12:01:27Z
dc.date.copyright© 2018 The Authors
dc.date.issued2018-11-13
dc.description©2018. This document is the Published, version of a Published Work that appeared in final form in Journal of the American College of Cardiology (JACC). To access the final edited and published work see https://doi.org/10.1016/j.jacc.2018.10.001
dc.description.abstractBACKGROUND The genetic cause of hypertrophic cardiomyopathy remains unexplained in a substantial proportion of cases. Formin homology 2 domain containing 3 (FHOD3) may have a role in the pathogenesis of cardiac hypertrophy but has not been implicated in hypertrophic cardiomyopathy. OBJECTIVES This study sought to investigate the relation between FHOD3 mutations and the development of hypertrophic cardiomyopathy. METHODS FHOD3 was sequenced by massive parallel sequencing in 3,189 hypertrophic cardiomyopathy unrelated probands and 2,777 patients with no evidence of cardiomyopathy (disease control subjects). The authors evaluated protein-altering candidate variants in FHOD3 for cosegregation, clinical characteristics, and outcomes. RESULTS The authors identified 94 candidate variants in 132 probands. The variants’ frequencies were significantly higher in patients with hypertrophic cardiomyopathy (74 of 3,189 [2.32%]) than in disease control subjects (18 of 2,777 [0.65%]; p < 0.001) or in the gnomAD database (1,049 of 138,606 [0.76%]; p < 0.001). FHOD3 mutations cosegregated with hypertrophic cardiomyopathy in 17 families, with a combined logarithm of the odds score of 7.92, indicative of very strong segregation. One-half of the disease-causing variants were clustered in a small conserved coiled-coil domain (amino acids 622 to 655); odds ratio for hypertrophic cardiomyopathy was 21.8 versus disease control subjects (95% confidence interval: 1.3 to 37.9; p < 0.001) and 14.1 against gnomAD (95% confidence interval: 6.9 to 28.7; p < 0.001). Hypertrophic cardiomyopathy patients carrying (likely) pathogenic mutations in FHOD3 (n ¼ 70) were diagnosed after age 30 years (mean 46.1 18.7 years), and two-thirds (66%) were males. Of the patients, 82% had asymmetric septal hypertrophy (mean 18.8 5 mm); left ventricular ejection fraction <50% was present in 14% and hypertrabeculation in 16%. Events were rare before age 30 years, with an annual cardiovascular death incidence of 1% during follow-up. CONCLUSIONS FHOD3 is a novel disease gene in hypertrophic cardiomyopathy, accounting for approximately 1% to 2% of cases. The phenotype and the rate of cardiovascular events are similar to those reported in unselected cohorts. The FHOD3 gene should be routinely included in hypertrophic cardiomyopathy genetic testing panels.es
dc.formatapplication/pdfes
dc.format.extent11es
dc.identifier.citationJournal of the American College of Cardiology 72(20) 2018: 2457-2467
dc.identifier.doihttps://doi.org/10.1016/j.jacc.2018.10.001
dc.identifier.issnPrint: 0735-1097
dc.identifier.issnElectronic: 1558-3597
dc.identifier.urihttp://hdl.handle.net/10201/139284
dc.languageenges
dc.publisherElsevier [Commercial Publisher]
dc.publisherAmerican College of Cardiology [University Publisher]
dc.relationThis study was supported by grants from the National Institute for Health Research University College London Hospitals Biomedical Research Centre (to Drs. Elliot, Akhtar, and Lopes); Centro de Investigación Biomédica en Red (CIBERCV), “Instituto de Salud Carlos III,” CB16/11/00425 (to Dr. Barriales-Villa) and CB16/11/00432 (to Dr. Garcia-Pavia); “Instituto de Salud Carlos III,” FEDER “Union Europea, Una forma de hacer Europa” (PI14/01477 and La Fe Biobank PT17/0015/0043) (to Dr. Molina) and PI17/01941 (to Dr. Garcia-Pavia). Drs. Ochoa, Cárdenas-Reyes, Salazar-Mendiguchía, Cicerchia, García-Giustiniani, Trujillo, and Ortiz-Genga are employees of Health in Code SL. Dr. Barriales-Villa has received personal fees from Health in Code SL. Dr. Fernandez-Fernandez is an employee of and stakeholder of Health In Code SL. Dr. Monserrat is a stakeholder and CEO of Health in Code SLes
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International
dc.rights.accessRightsinfo:eu-repo/semantics/openAccess
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.titleFormin Homology 2 Domain Containing 3 (FHOD3) Is a Genetic Basis for Hypertrophic Cardiomyopathyes
dc.typeinfo:eu-repo/semantics/articlees
dc.type.versioninfo:eu-repo/semantics/publishedVersion
dspace.entity.typePublicationes
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