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

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

  • J Am Coll Cardiol. 2018 Nov 13;72(20):2457-2467. doi: 10.1016/j.jacc.2018.10.001.
Juan Pablo Ochoa 1,  María Sabater-Molina 2,  José Manuel García-Pinilla 3,  Jens Mogensen 4,  Alejandra Restrepo-Córdoba 5,  Julián Palomino-Doza 6,  Eduardo Villacorta 7,  Marina Martinez-Moreno 8,  Javier Ramos-Maqueda 9,  Esther Zorio 10,  Maria L Peña-Peña 11,  Pablo E García-Granja 12,  José F Rodríguez-Palomares 13,  Ivonne J Cárdenas-Reyes 14,  María M de la Torre-Carpente 15,  Alicia Bautista-Pavés 16,  Mohammed M Akhtar 17,  Marcos N Cicerchia 14,  Raquel Bilbao-Quesada 18,  Maria Victoria Mogollón-Jimenez 19,  Joel Salazar-Mendiguchía 20,  José M Mesa Latorre 21,  Blanca Arnaez 22,  Ivan Olavarri-Miguel 23,  María E Fuentes-Cañamero 24,  Arsonval Lamounier Jr 25,  José María Pérez Ruiz 26,  Vicente Climent-Payá 27,  Inmaculada Pérez-Sanchez 2,  Juan P Trujillo-Quintero 14,  Luis R Lopes 28,  Alfredo Repáraz-Andrade 29,  Rosario Marín-Iglesias 30,  Alejandro Rodriguez-Vilela 31,  María Sandín-Fuentes 12,  Jose A Garrote 32,  Alejandro Cortel-Fuster 33,  Miguel Lopez-Garrido 2,  Ana Fontalba-Romero 34,  Tomás Ripoll-Vera 35,  Isabel Llano-Rivas 36,  Xusto Fernandez-Fernandez 14,  María Isidoro-García 37,  Diego Garcia-Giustiniani 14,  Roberto Barriales-Villa 38,  Martín Ortiz-Genga 25,  Pablo García-Pavía 5,  Perry M Elliott 39,  Juan R Gimeno 40,  Lorenzo Monserrat 14
Affiliations

Affiliations

  • 1 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.
  • 2 Hospital Clínico Universitario Virgen de la Arrixaca, Inherited Cardiac Diseases Unit, Department of Cardiology, Murcia, Spain.
  • 3 Hospital Universitario Virgen de la Victoria, Cardiology, Heart Failure and Inherited Cardiac Diseases Unit, Málaga, Spain.
  • 4 Odense Universitetshospital, Cardiology, Odense, Denmark.
  • 5 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.
  • 6 Hospital Universitario 12 de Octubre, Cardiology, Madrid, Spain.
  • 7 Hospital Universitario de Salamanca, Cardiology, Salamanca, Spain.
  • 8 Hospital General Universitario de Elche, Cardiology, Elche, Spain.
  • 9 Hospital Universitario Virgen de Valme, Cardiology, Sevilla, Spain.
  • 10 Hospital Universitario La Fe, Valencia, Spain.
  • 11 Universidade da Coruña, GRINCAR (Cardiovascular Research Group), A Coruña, Spain; Hospital Universitario Virgen del Rocío, Cardiology, Sevilla, Spain.
  • 12 Hospital Clínico Universitario de Valladolid, Cardiology, Valladolid, Spain.
  • 13 Hospital Vall d'Hebron, Cardiology, Barcelona, Spain.
  • 14 Health in Code S.L., Scientific Department, A Coruña, Spain.
  • 15 Hospital Universitario Rio Hortega, Cardiology, Valladolid, Spain.
  • 16 Hospital Universitario San Cecilio, Cardiology, Granada, Spain.
  • 17 Saint Bartholomew's Hospital, Barts Heart Centre, London, United Kingdom; European Reference Network on Rare and Complex Diseases of the Heart.
  • 18 Complexo Hospitalario Universitario de Vigo, Cardiology, Vigo, Spain.
  • 19 Hospital San Pedro de Alcántara, Cardiology, Cáceres, Spain.
  • 20 Health in Code S.L., Scientific Department, A Coruña, Spain; Universitat Autónoma de Barcelona, Departament de Genetica i de Microbiologia, Barcelona, Spain.
  • 21 Hospital Universitario Príncipe de Asturias, Clinical Genetics, Alcalá de Henares, Spain.
  • 22 Hospital Sierrallana, Cardiology, Torrelavega, Spain.
  • 23 Hospital Universitario Marqués de Valdecilla, Cardiology, Santander, Spain.
  • 24 Hospital Universitario Infanta Cristina, Cardiology, Badajoz, Spain.
  • 25 Health in Code S.L., Scientific Department, A Coruña, Spain; Universidade da Coruña, GRINCAR (Cardiovascular Research Group), A Coruña, Spain.
  • 26 Hospital Regional Universitario "Carlos Haya," Cardiology, Málaga, Spain.
  • 27 Hospital General Universitario de Alicante, Cardiology, Alicante, Spain; Alicante Institute for Health and Biomedical Research (ISABIAL-FIDABIO Foundation), Alicante, Spain.
  • 28 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.
  • 29 Complexo Hospitalario Universitario de Vigo, Genetics and Molecular Pathology, Vigo, Spain.
  • 30 Hospital Universitario Puerta del Mar, Cádiz, Spain.
  • 31 Complexo Hospitalario Arquitecto Marcide, Cardiology, El Ferrol, Spain.
  • 32 Hospital Universitario Rio Hortega, Molecular Genetics Laboratory, Valladolid, Spain.
  • 33 Hospital Provincial Castellón, Cardiology, Castellon, Spain.
  • 34 Hospital Universitario Marqués de Valdecilla, Genetics, Santander, Spain.
  • 35 Hospital Son Llatzer, Cardiology, Inherited Cardiomyopathies Unit, Palma de Mallorca, Spain.
  • 36 Hospital Universitario Cruces, Clinical Genetics, Barakaldo, Spain.
  • 37 Universidad de Salamanca, Medicine, Salamanca, Spain; Hospital Universitario de Salamanca, Molecular Genetics and Pharmacogenetics, Salamanca, Spain.
  • 38 Instituto de Investigación Biomédica de A Coruña (INIBIC), A Coruña, Spain; Complexo Hospitalario Universitario A Coruña, Cardiology, A Coruña, Spain.
  • 39 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.
  • 40 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.
PMID: 30442288 DOI: 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 = 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.

Keywords

FHOD3; cardiomyopathies; formins; genetics; hypertrophic cardiomyopathy; sudden death.

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