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

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2018-11-13
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Ochoa, Juan Pablo ; García Pinilla, José Manuel ; Mogensen, Jens ; Restrepo Córdoba, Alejandra ; Palomino Doza, Julian ; Villacorta, Eduardo ; Martínez Moreno, Marina ; Ramos Maqueda, Javier ; Zorio, Esther ; Peña Peña, María L. ; García Granja, Pablo E. ; Rodríguez Palomares, José F. ; Cárdenas Reyes, Ivonne J. ; Torre Carpente, María M. de la ; Bautista Pavés, Alicia ; Akhtar, Mohammed M. ; Cicerchia, Marcos N. ; Mogollón Jiménez, María Victoria ; Salazar Mendiguchía, Joel ; Mesa Latorre, José M. ; Arnáez, Blanca ; Olavarri Miguel, Iván ; Fuentes Cañamero, María E. ; Lamounier, Arsonval ; Pérez Ruiz, José María ; Climent Payá, Vicente ; Pérez Sánchez, Inmaculada ; Trujillo Quintero, Juan P. ; Lopes, Luis R. ; Repáraz Andrade, Alfredo ; Marín Iglesias, Rosario ; Rodríguez Vilela, Alejandro ; Sandín Fuentes, María ; Garrote, José A. ; Cortel Fuster, Alejandro ; López Garrido, Miguel ; Fontalba Romero, Ana ; Ripoll Vera, Tomás ; Llano Rivas, Isabel ; Fernandez Fernandez, Xusto ; Isidoro García, María ; García Giustiniani, Diego ; Barriales Villa, Roberto ; Ortiz Genga, Martín ; García Pavía, Pablo ; Elliott, Perry M. ; Gimeno, Juan R. ; Monserrat, Lorenzo ; Bilbao Quesada, Raquel ; Sabater Molina, María
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Publisher
Elsevier [Commercial Publisher]
American College of Cardiology [University Publisher]
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Ciencias Sociosanitarias
DOI
https://doi.org/10.1016/j.jacc.2018.10.001
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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
Abstract
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 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.
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Citation
Journal of the American College of Cardiology 72(20) 2018: 2457-2467
URI
http://hdl.handle.net/10201/139284
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