Pablo Ochoa, JuanSabater-Molina, MariaManuel Garcia-Pinilla, JoseMogensen, JensRestrepo-Cordoba, AlejandraPalomino-Doza, JulianVillacorta, EduardoMartinez-Moreno, MarinaRamos-Maqueda, JavierZorio, EstherPena-Pena, Maria LGarcía-Granja, Pablo ElpidioRodriguez-Palomares, Jose FCardenas-Reyes, Ivonne Jde la Torre-Carpente, Maria MBautista-Paves, AliciaAkhtar, Mohammed MCicerchia, Marcos NBilbao-Quesada, RaquelVictoria Mogollon-Jimenez, MariaSalazar-Mendiguchia, JoelMesa Latorre, Jose MArnaez, BlancaOlavarri-Miguel, IvanFuentes-Canamero, Maria ELamounier, Arsonval, JrPerez Ruiz, Jose MariaCliment-Paya, VicentePerez-Sanchez, InmaculadaTrujillo-Quintero, Juan PLopes, Luis RReparaz-Andrade, AlfredoMarin-Iglesias, RosarioRodriguez-Vilela, AlejandroSandin-Fuentes, MariaGarrote, Jose ACortel-Fuster, AlejandroLopez-Garrido, MiguelFontalba-Romero, AnaRipoll-Vera, TomásLlano-Rivas, IsabelFernandez-Fernandez, XustoIsidoro-Garcia, MariaGarcia-Giustiniani, DiegoBarriales-Villa, RobertoOrtiz-Genga, MartinGarcia-Pavia, PabloElliott, Perry MGimeno, Juan RMonserrat, Lorenzo2024-09-062024-09-062018-11-13Ochoa JP, Sabater-Molina M, Garcia-Pinilla JM, Mogensen J, Restrepo-Cordoba A, Palomino-Doza J, et al. Formin Homology 2 Domain Containing 3 (FHOD3) Is a Genetic Basis for Hypertrophic Cardiomyopathy. J Am Coll Cardiol. 2018 Nov 13;72(20):2457-67.0735-1097http://hdl.handle.net/20.500.13003/17273https://hdl.handle.net/20.500.12105/22517BACKGROUND: 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 = 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.enghttp://creativecommons.org/licenses/by-nc-nd/4.0/CardiomyopathiesFHOD3ForminsgeneticsHypertrophic cardiomyopathySudden deathChildresearch articleAttribution-NonCommercial-NoDerivatives 4.0 International3044228872202457-246710.1016/j.jacc.2018.10.0011558-3597Journal of the American College of Cardiologyopen accessEstudios de CohortesForminasVariación GenéticaFemeninoProteínas de MicrofilamentosMutaciónAdolescenteMasculinoEstudios de SeguimientoCardiomiopatía HipertróficaHumanosPersona de Mediana EdadAdulto JovenAncianoAnciano de 80 o más AñosNiñoLinaje2-s2.0-85056172947450290400007L2001246391