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

Autor:	Ochoa JP; Health in Code S.L., Scientific Department, A Coruña, Spain; Universidade da Coruña, GRINCAR (Cardiovascular Research Group), A Coruña, Spain. Electronic address: juanpablo.ochoa@healthincode.com., Sabater-Molina M; Hospital Clínico Universitario Virgen de la Arrixaca, Inherited Cardiac Diseases Unit, Department of Cardiology, Murcia, Spain., García-Pinilla JM; Hospital Universitario Virgen de la Victoria, Cardiology, Heart Failure and Inherited Cardiac Diseases Unit, Málaga, Spain., Mogensen J; Odense Universitetshospital, Cardiology, Odense, Denmark., Restrepo-Córdoba A; Hospital Universitario Puerta de Hierro Majadahonda, Cardiology, Heart Failure and Inherited Cardiac Diseases Unit, Madrid, Spain; European Reference Network on Rare and Complex Diseases of the Heart., Palomino-Doza J; Hospital Universitario 12 de Octubre, Cardiology, Madrid, Spain., Villacorta E; Hospital Universitario de Salamanca, Cardiology, Salamanca, Spain., Martinez-Moreno M; Hospital General Universitario de Elche, Cardiology, Elche, Spain., Ramos-Maqueda J; Hospital Universitario Virgen de Valme, Cardiology, Sevilla, Spain., Zorio E; Hospital Universitario La Fe, Valencia, Spain., Peña-Peña ML; Universidade da Coruña, GRINCAR (Cardiovascular Research Group), A Coruña, Spain; Hospital Universitario Virgen del Rocío, Cardiology, Sevilla, Spain., García-Granja PE; Hospital Clínico Universitario de Valladolid, Cardiology, Valladolid, Spain., Rodríguez-Palomares JF; Hospital Vall d'Hebron, Cardiology, Barcelona, Spain., Cárdenas-Reyes IJ; Health in Code S.L., Scientific Department, A Coruña, Spain., de la Torre-Carpente MM; Hospital Universitario Rio Hortega, Cardiology, Valladolid, Spain., Bautista-Pavés A; Hospital Universitario San Cecilio, Cardiology, Granada, Spain., Akhtar MM; Saint Bartholomew's Hospital, Barts Heart Centre, London, United Kingdom; European Reference Network on Rare and Complex Diseases of the Heart., Cicerchia MN; Health in Code S.L., Scientific Department, A Coruña, Spain., Bilbao-Quesada R; Complexo Hospitalario Universitario de Vigo, Cardiology, Vigo, Spain., Mogollón-Jimenez MV; Hospital San Pedro de Alcántara, Cardiology, Cáceres, Spain., Salazar-Mendiguchía J; Health in Code S.L., Scientific Department, A Coruña, Spain; Universitat Autónoma de Barcelona, Departament de Genetica i de Microbiologia, Barcelona, Spain., Mesa Latorre JM; Hospital Universitario Príncipe de Asturias, Clinical Genetics, Alcalá de Henares, Spain., Arnaez B; Hospital Sierrallana, Cardiology, Torrelavega, Spain., Olavarri-Miguel I; Hospital Universitario Marqués de Valdecilla, Cardiology, Santander, Spain., Fuentes-Cañamero ME; Hospital Universitario Infanta Cristina, Cardiology, Badajoz, Spain., Lamounier A Jr; Health in Code S.L., Scientific Department, A Coruña, Spain; Universidade da Coruña, GRINCAR (Cardiovascular Research Group), A Coruña, Spain., Pérez Ruiz JM; Hospital Regional Universitario 'Carlos Haya,' Cardiology, Málaga, Spain., Climent-Payá V; Hospital General Universitario de Alicante, Cardiology, Alicante, Spain; Alicante Institute for Health and Biomedical Research (ISABIAL-FIDABIO Foundation), Alicante, Spain., Pérez-Sanchez I; Hospital Clínico Universitario Virgen de la Arrixaca, Inherited Cardiac Diseases Unit, Department of Cardiology, Murcia, Spain., Trujillo-Quintero JP; Health in Code S.L., Scientific Department, A Coruña, Spain., Lopes LR; Saint Bartholomew's Hospital, Barts Heart Centre, London, United Kingdom; European Reference Network on Rare and Complex Diseases of the Heart; University College London Institute for Cardiovascular Science, London, United Kingdom., Repáraz-Andrade A; Complexo Hospitalario Universitario de Vigo, Genetics and Molecular Pathology, Vigo, Spain., Marín-Iglesias R; Hospital Universitario Puerta del Mar, Cádiz, Spain., Rodriguez-Vilela A; Complexo Hospitalario Arquitecto Marcide, Cardiology, El Ferrol, Spain., Sandín-Fuentes M; Hospital Clínico Universitario de Valladolid, Cardiology, Valladolid, Spain., Garrote JA; Hospital Universitario Rio Hortega, Molecular Genetics Laboratory, Valladolid, Spain., Cortel-Fuster A; Hospital Provincial Castellón, Cardiology, Castellon, Spain., Lopez-Garrido M; Hospital Clínico Universitario Virgen de la Arrixaca, Inherited Cardiac Diseases Unit, Department of Cardiology, Murcia, Spain., Fontalba-Romero A; Hospital Universitario Marqués de Valdecilla, Genetics, Santander, Spain., Ripoll-Vera T; Hospital Son Llatzer, Cardiology, Inherited Cardiomyopathies Unit, Palma de Mallorca, Spain., Llano-Rivas I; Hospital Universitario Cruces, Clinical Genetics, Barakaldo, Spain., Fernandez-Fernandez X; Health in Code S.L., Scientific Department, A Coruña, Spain., Isidoro-García M; Universidad de Salamanca, Medicine, Salamanca, Spain; Hospital Universitario de Salamanca, Molecular Genetics and Pharmacogenetics, Salamanca, Spain., Garcia-Giustiniani D; Health in Code S.L., Scientific Department, A Coruña, Spain., Barriales-Villa R; Instituto de Investigación Biomédica de A Coruña (INIBIC), A Coruña, Spain; Complexo Hospitalario Universitario A Coruña, Cardiology, A Coruña, Spain., Ortiz-Genga M; Health in Code S.L., Scientific Department, A Coruña, Spain; Universidade da Coruña, GRINCAR (Cardiovascular Research Group), A Coruña, Spain., García-Pavía P; Hospital Universitario Puerta de Hierro Majadahonda, Cardiology, Heart Failure and Inherited Cardiac Diseases Unit, Madrid, Spain; European Reference Network on Rare and Complex Diseases of the Heart., Elliott PM; European Reference Network on Rare and Complex Diseases of the Heart; Saint Bartholomew's Hospital, Barts Heart Centre, London, United Kingdom; University College London Institute for Cardiovascular Science, London, United Kingdom., Gimeno JR; Hospital Clínico Universitario Virgen de la Arrixaca, Inherited Cardiac Diseases Unit, Department of Cardiology, Murcia, Spain; European Reference Network on Rare and Complex Diseases of the Heart., Monserrat L; Health in Code S.L., Scientific Department, A Coruña, Spain.
Jazyk:	angličtina
Zdroj:	Journal of the American College of Cardiology [J Am Coll Cardiol] 2018 Nov 13; Vol. 72 (20), pp. 2457-2467.
DOI:	10.1016/j.jacc.2018.10.001
Abstrakt:	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. (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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