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Repisalud author Pablo Ochoa, Juan author Sabater-Molina, Maria author Manuel Garcia-Pinilla, Jose author Mogensen, Jens author Restrepo-Cordoba, Alejandra author Palomino-Doza, Julian author Villacorta, Eduardo author Martinez-Moreno, Marina author Ramos-Maqueda, Javier author Zorio, Esther author Pena-Pena, Maria L author García-Granja, Pablo Elpidio author Rodriguez-Palomares, Jose F author Cardenas-Reyes, Ivonne J author de la Torre-Carpente, Maria M author Bautista-Paves, Alicia author Akhtar, Mohammed M author Cicerchia, Marcos N author Bilbao-Quesada, Raquel author Victoria Mogollon-Jimenez, Maria author Salazar-Mendiguchia, Joel author Mesa Latorre, Jose M author Arnaez, Blanca author Olavarri-Miguel, Ivan author Fuentes-Canamero, Maria E author Lamounier, Arsonval, Jr author Perez Ruiz, Jose Maria author Climent-Paya, Vicente author Perez-Sanchez, Inmaculada author Trujillo-Quintero, Juan P author Lopes, Luis R author Reparaz-Andrade, Alfredo author Marin-Iglesias, Rosario author Rodriguez-Vilela, Alejandro author Sandin-Fuentes, Maria author Garrote, Jose A author Cortel-Fuster, Alejandro author Lopez-Garrido, Miguel author Fontalba-Romero, Ana author Ripoll-Vera, Tomás author Llano-Rivas, Isabel author Fernandez-Fernandez, Xusto author Isidoro-Garcia, Maria author Garcia-Giustiniani, Diego author Barriales-Villa, Roberto author Ortiz-Genga, Martin author Garcia-Pavia, Pablo author Elliott, Perry M author Gimeno, Juan R author Monserrat, Lorenzo 2024-09-06T09:53:38Z 2024-09-06T09:53:38Z 2018-11-13 Ochoa 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. 10.1016/j.jacc.2018.10.001 1558-3597 0735-1097 Journal of the American College of Cardiology http://hdl.handle.net/20.500.13003/17273 30442288 L2001246391 2-s2.0-85056172947 https://hdl.handle.net/20.500.12105/22517 450290400007 BACKGROUND: 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. eng Cardiomyopathies FHOD3 Formins genetics Hypertrophic cardiomyopathy Sudden death Formin Homology 2 Domain Containing 3 (FHOD3) Is a Genetic Basis for Hypertrophic Cardiomyopathy research article