Formin Homology 2 Domain Containing 3 (FHOD3) Is a Genetic Basis for Hypertrophic Cardiomyopathy
Authors: Juan Pablo Ochoa, María Sabater-Molina, José Manuel García-Pinilla, Jens Mogensen, Alejandra Restrepo-Córdoba, Julián Palomino-Doza, Eduardo Villacorta, Marina Martinez-Moreno, Javier Ramos-Maqueda, Esther Zorio, Maria L. Peña-Peña, Pablo E. García-Granja, José F. Rodríguez-Palomares, Ivonne J. Cárdenas-Reyes, María M. de la Torre-Carpente, Alicia Bautista-Pavés, Mohammed M. Akhtar, Marcos N. Cicerchia, Raquel Bilbao-Quesada, Maria Victoria Mogollón-Jimenez, Joel Salazar-Mendiguchía, José M. Mesa Latorre, Blanca Arnaez, Ivan Olavarri-Miguel, María E. Fuentes-Cañamero, Arsonval Lamounier, José María Pérez Ruiz, Vicente Climent-Payá, Inmaculada Pérez-Sanchez, Juan P. Trujillo-Quintero, Luis R. Lopes, Alfredo Repáraz-Andrade, Rosario Marín-Iglesias, Alejandro Rodriguez-Vilela, María Sandín-Fuentes, Jose A. Garrote, Alejandro Cortel-Fuster, Miguel Lopez-Garrido, Ana Fontalba-Romero, Tomás Ripoll-Vera, Isabel Llano-Rivas, Xusto Fernandez-Fernandez, María Isidoro-García, Diego Garcia-Giustiniani, Roberto Barriales-Villa, Martín Ortiz-Genga, Pablo García-Pavía, Perry M. Elliott, Juan R. Gimeno, Lorenzo Monserrat
Journal: Journal of the American College of Cardiology (2018)

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. This study sought to investigate the relation between FHOD3 mutations and the development of hypertrophic cardiomyopathy. 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. 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. 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.