Juan Pablo Ochoa1, María Sabater-Molina2, José Manuel García-Pinilla3, Jens Mogensen4, Alejandra Restrepo-Córdoba5, Julián Palomino-Doza6, Eduardo Villacorta7, Marina Martinez-Moreno8, Javier Ramos-Maqueda9, Esther Zorio10, Maria L Peña-Peña11, Pablo E García-Granja12, José F Rodríguez-Palomares13, Ivonne J Cárdenas-Reyes14, María M de la Torre-Carpente15, Alicia Bautista-Pavés16, Mohammed M Akhtar17, Marcos N Cicerchia14, Raquel Bilbao-Quesada18, Maria Victoria Mogollón-Jimenez19, Joel Salazar-Mendiguchía20, José M Mesa Latorre21, Blanca Arnaez22, Ivan Olavarri-Miguel23, María E Fuentes-Cañamero24, Arsonval Lamounier25, José María Pérez Ruiz26, Vicente Climent-Payá27, Inmaculada Pérez-Sanchez2, Juan P Trujillo-Quintero14, Luis R Lopes28, Alfredo Repáraz-Andrade29, Rosario Marín-Iglesias30, Alejandro Rodriguez-Vilela31, María Sandín-Fuentes12, Jose A Garrote32, Alejandro Cortel-Fuster33, Miguel Lopez-Garrido2, Ana Fontalba-Romero34, Tomás Ripoll-Vera35, Isabel Llano-Rivas36, Xusto Fernandez-Fernandez14, María Isidoro-García37, Diego Garcia-Giustiniani14, Roberto Barriales-Villa38, Martín Ortiz-Genga25, Pablo García-Pavía5, Perry M Elliott39, Juan R Gimeno40, Lorenzo Monserrat14. 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.
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.
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 cardiomyopathypatients 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.
Authors: Arthur A M Wilde; Christopher Semsarian; Manlio F Márquez; Alireza Sepehri Shamloo; Michael J Ackerman; Euan A Ashley; Back Sternick Eduardo; Héctor Barajas-Martinez; Elijah R Behr; Connie R Bezzina; Jeroen Breckpot; Philippe Charron; Priya Chockalingam; Lia Crotti; Michael H Gollob; Steven Lubitz; Naomasa Makita; Seiko Ohno; Martín Ortiz-Genga; Luciana Sacilotto; Eric Schulze-Bahr; Wataru Shimizu; Nona Sotoodehnia; Rafik Tadros; James S Ware; David S Winlaw; Elizabeth S Kaufman; Takeshi Aiba; Andreas Bollmann; Jong-Il Choi; Aarti Dalal; Francisco Darrieux; John Giudicessi; Mariana Guerchicoff; Kui Hong; Andrew D Krahn; Ciorsti Mac Intyre; Judith A Mackall; Lluís Mont; Carlo Napolitano; Pablo Ochoa Juan; Petr Peichl; Alexandre C Pereira; Peter J Schwartz; Jon Skinner; Christoph Stellbrink; Jacob Tfelt-Hansen; Thomas Deneke Journal: J Arrhythm Date: 2022-05-31
Authors: Luis Ramudo-Cela; Sara Santana-Martínez; Maite García-Ramos; Mariano Bergamino; Diego García-Giustiniani; Paula Vélez-Vieitez; Jose Luis Hernández-Hernández; Carmen García-Ibarbia; Pablo González-Bustos; Patricia Ruíz-Martín; Jaime González-Lozano; Luis Santomé-Collazo; Andrea Grana-Fernandez; Pablo Cabaleiro-Cerviño; Martín Ortíz; Lorenzo Monserrat-Iglesias Journal: Pharmacogenomics J Date: 2022-03-31 Impact factor: 3.245
Authors: Arthur A M Wilde; Christopher Semsarian; Manlio F Márquez; Alireza Sepehri Shamloo; Michael J Ackerman; Euan A Ashley; Eduardo Back Sternick; Héctor Barajas-Martinez; Elijah R Behr; Connie R Bezzina; Jeroen Breckpot; Philippe Charron; Priya Chockalingam; Lia Crotti; Michael H Gollob; Steven Lubitz; Naomasa Makita; Seiko Ohno; Martín Ortiz-Genga; Luciana Sacilotto; Eric Schulze-Bahr; Wataru Shimizu; Nona Sotoodehnia; Rafik Tadros; James S Ware; David S Winlaw; Elizabeth S Kaufman; Takeshi Aiba; Andreas Bollmann; Jong Il Choi; Aarti Dalal; Francisco Darrieux; John Giudicessi; Mariana Guerchicoff; Kui Hong; Andrew D Krahn; Ciorsti MacIntyre; Judith A Mackall; Lluís Mont; Carlo Napolitano; Juan Pablo Ochoa; Petr Peichl; Alexandre C Pereira; Peter J Schwartz; Jon Skinner; Christoph Stellbrink; Jacob Tfelt-Hansen; Thomas Deneke Journal: Europace Date: 2022-09-01 Impact factor: 5.486
Authors: James S Ware; Connie R Bezzina; Martin Farrall; Hugh Watkins; Andrew R Harper; Anuj Goel; Christopher Grace; Kate L Thomson; Steffen E Petersen; Xiao Xu; Adam Waring; Elizabeth Ormondroyd; Christopher M Kramer; Carolyn Y Ho; Stefan Neubauer; Rafik Tadros Journal: Nat Genet Date: 2021-01-25 Impact factor: 38.330
Authors: Roddy Walsh; Francesco Mazzarotto; Nicola Whiffin; Rachel Buchan; William Midwinter; Alicja Wilk; Nicholas Li; Leanne Felkin; Nathan Ingold; Risha Govind; Mian Ahmad; Erica Mazaika; Mona Allouba; Xiaolei Zhang; Antonio de Marvao; Sharlene M Day; Euan Ashley; Steven D Colan; Michelle Michels; Alexandre C Pereira; Daniel Jacoby; Carolyn Y Ho; Kate L Thomson; Hugh Watkins; Paul J R Barton; Iacopo Olivotto; Stuart A Cook; James S Ware Journal: Genome Med Date: 2019-01-29 Impact factor: 11.117