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Intermediate-effect size p.Arg637Gln in FHOD3 increases risk of HCM and is associated with an aggressive phenotype in homozygous carriers
  1. Jesús Piqueras-Flores1,2,
  2. Eduardo Villacorta-Argüelles3,4,
  3. Joseph Galvin5,
  4. Vicente Climent-Payá6,7,
  5. Luis Enrique Escobar-López8,9,
  6. Almudena Amor-Salamanca10,
  7. Soledad Garcia-Hernandez10,
  8. Sean Esmonde5,
  9. Jorge Martínez-Del Río1,
  10. Maeve Soto-Pérez1,
  11. Pablo Garcia-Pavia8,9,11,
  12. Juan Pablo Ochoa10,11
  1. 1 Inherited Cardiac Diseases Unit, Cardiology Department, Ciudad Real General University Hospital, Ciudad Real, Spain
  2. 2 Medicine Department, Universidad de Castilla-La Mancha, Ciudad Real, Spain
  3. 3 Inherited Heart Disease Unit, Cardiology Department, University Hospital of Salamanca, Salamanca, Spain
  4. 4 Departamento de Medicina, Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
  5. 5 Department of Cardiology, The Mater Misericordiae University Hospital, The Dublin Neurological Institute, Dublin, Ireland
  6. 6 Heart Failure and Inherited Heart Disease Unit, Department of Cardiology, Hospital General Universitario de Alicante, Alicante, Spain
  7. 7 Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain
  8. 8 Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Puerta de Hierro University Hospital of Majadahonda, Majadahonda, Spain
  9. 9 CIBER Cardiovascular, Instituto de Salud Carlos III, IDIPHISA, Madrid, Spain
  10. 10 Health in Code, A Coruña, Spain
  11. 11 Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
  1. Correspondence to Dr Juan Pablo Ochoa, Cardiovascular Genetics, Health in Code, A Coruña (15008), A Coruña, Spain; juanpablo.ochoa{at}


Formin homology 2 domain-containing 3 (FHOD3) gene has emerged as one of the main non-sarcomeric genes associated with hypertrophic cardiomyopathy (HCM), but no cases of biallelic variants associated with disease have been described to date. From 2014 until 2021, FHOD3 was evaluated in our center by next-generation sequencing in 22 806 consecutive unrelated probands. The p.Arg637Gln variant in FHOD3 was enriched in our HCM cohort (284 of 9668 probands; 2.94%) compared with internal controls (64 of 11 480; 0.59%) and gnomAD controls (373 of 64 409; 0.58%), with ORs of 5.40 (95% CI: 4.11 to 7.09) and 5.19 (95% CI: 4.44 to 6.07). The variant affects a highly conserved residue localised in a supercoiled alpha helix considered a clustering site for HCM variants, and in heterozygosis can act as a predisposing factor (intermediate-effect variant) for HCM, with an estimated penetrance of around 1%. Additionally, seven homozygous carriers of p.Arg637Gln in FHOD3 were identified. All but one (unaffected) showed an early presentation and a severe HCM phenotype. All this information suggest that p.Arg637Gln variant in FHOD3 is a low-penetrant variant, with an intermediate effect, that contributes to the development of HCM in simple heterozygosis, being associated with a more severe phenotype in homozygous carriers.

  • Cardiomyopathies
  • Genetic Research
  • Genetics, Medical
  • Cardiology
  • Cardiovascular Diseases

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  • X @VillacoEduardo, @maevesoto, @jpocardio

  • Contributors JP-F and JPO entered the genetic and clinical data, and also planned, conducted, wrote and reviewed the work. LEE-L, AA-S, SG-H, PG-P, EV-A, VC-P, JG, SE, MS-P and JM-DR incorporated clinical and genetic data, reviewed the manuscript and contributed to the planning of the manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.