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

Fecha de publicación:

Autores de IIS La Fe

Participantes ajenos a IIS La Fe

  • Ochoa, JP
  • Sabater-Molina, M
  • Garcia-Pinilla, JM
  • Mogensen, J
  • Restrepo-Cordoba, A
  • Palomino-Doza, J
  • Villacorta, E
  • Martinez-Moreno, M
  • Ramos-Maqueda, J
  • Peña-Peña ML
  • Garcia-Granja, PE
  • Rodriguez-Palomares, JF
  • Cardenas-Reyes, IJ
  • de la Torre-Carpente, MM
  • Bautista-Paves, A
  • Akhtar, MM
  • Cicerchia, MN
  • Bilbao-Quesada, R
  • Mogollon-Jimenez, MV
  • Salazar-Mendiguchia, J
  • Mesa Latorre JM
  • Arnaez, B
  • Olavarri-Miguel, I
  • Fuentes-Canamero, ME
  • Lamounier, A
  • Pérez Ruiz JM
  • Climent-Paya, V
  • Perez-Sanchez, I
  • Trujillo-Quintero, JP
  • Lopes, LR
  • Reparaz-Andrade, A
  • Marin-Iglesias, R
  • Rodriguez-Vilela, A
  • Sandin-Fuentes, M
  • Garrote, JA
  • Cortel-Fuster, A
  • Lopez-Garrido, M
  • Fontalba-Romero, A
  • Ripoll-Vera, T
  • Llano-Rivas, I
  • Fernandez-Fernandez, X
  • Isidoro-Garcia, M
  • Garcia-Giustiniani, D
  • Barriales-Villa, R
  • Ortiz-Genga, M
  • Garcia-Pavia, P
  • Elliott, PM
  • Gimeno, JR
  • Monserrat, L

Grupos

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. (C) 2018 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Datos de la publicación

ISSN/ISSNe:
0735-1097, 1558-3597

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY  ELSEVIER SCIENCE INC

Tipo:
Article
Páginas:
2457-2467
Factor de Impacto:
9,280 SCImago ℠
Cuartil:
Q1 SCImago ℠

Citas Recibidas en Web of Science: 45

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Keywords

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

Campos de estudio

Proyectos asociados

RED INVESTIGACION (RECAVA)

RD06/0014/0004 . INSTITUTO DE SALUD CARLOS III; FUNDACION PARA LA INV BIOMEDICA- HOSPITAL GREGORIO MARAÑON; FUNDACIÓN PARA LA INVESTIGACIÓN DEL HOSPITAL UNIVERSITARIO LA FE DE LA COMUNIDAD VALENCIANA . 2006

CANALOPATIAS EN LA ATIOPATOGENIA DEL SINDROME DE MUERTE SUBITA DEL LACTANTE

Investigador Principal: ESTHER ZORIO GRIMA

PI07/0831 . INSTITUTO DE SALUD CARLOS III . 2007

RED DE BIOBANCOS (BIOBANCOS)

RD09/0076/00021 . INSTITUTO DE SALUD CARLOS III; FUNDACIÓN PARA LA INVESTIGACIÓN DEL HOSPITAL UNIVERSITARIO LA FE DE LA COMUNIDAD VALENCIANA . 2010

ESTUDIO DE MICRORNAS IMPLICADOS EN LOS SISTEMAS HEMOSTÁTICO, PROTEOLÍTICO Y ANGIOGÉNICO: SU RELACIÓN CON LA TROMBOSIS Y LA PATOLOGÍA ENDOMETRIAL.

PROMETEO/2011/027 . FUNDACIÓN PARA LA INVESTIGACIÓN DEL HOSPITAL UNIVERSITARIO LA FE DE LA COMUNIDAD VALENCIANA; CONSELLERIA DE EDUCACION . 2011

RED CARDIOVASCULAR

Investigador Principal: FRANCISCO ESPAÑA FURIO

RD12/0042/0029 . INSTITUTO DE SALUD CARLOS III; FUNDACIÓN PARA LA INVESTIGACIÓN DEL HOSPITAL UNIVERSITARIO LA FE DE LA COMUNIDAD VALENCIANA . 2013

CARACTERIZACION METABOLOMICA DE LA MIOCARDIOPATIA ARRITMOGENICA

Investigador Principal: ESTHER ZORIO GRIMA

2013_0126_CRC_METABOLOMICA_ZORIO . FUNDACIÓN PARA LA INVESTIGACIÓN DEL HOSPITAL UNIVERSITARIO LA FE DE LA COMUNIDAD VALENCIANA . 2013

CARACTERIZACIÓN DEL PATRÓN DE MICRORNAS EN LA MUERTE SÚBITA CARDIACA DE ORIGEN ISQUÉMICO. ANÁLISIS DE SU RELACIÓN CON LA DISLIPEMIA, LA GRASA EPICÁRDICA, LA ESTEATOSIS NO ALCOHÓLICA Y FACTORES DE COAGULACION Y FIBRINOLISIS.

Investigador Principal: ESTHER ZORIO GRIMA

2013_0454_CRC_ZORIO . ASTRAZENECA FARMACÉUTICA SPAIN, S.A.; FUNDACION ESPAÑOLA DE TROMBOSIS Y HEMOSTASIA . 2014

MECANISMOS DE ENFERMEDAD EN LA MIOCARDIOPATIA ARRITMOGENICA, MEJORAS EN SU DIAGNOSTICO Y BUSQUEDA DE DIANAS TERAPEUTICAS.

Investigador Principal: ESTHER ZORIO GRIMA

PI14/01477 . INSTITUTO DE SALUD CARLOS III . 2015

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