Haploinsufficiency of vascular endothelial growth factor related signaling genes is associated with tetralogy of Fallot.
Genet Med
; 21(4): 1001-1007, 2019 04.
Article
em En
| MEDLINE
| ID: mdl-30232381
ABSTRACT
PURPOSE:
To determine disease-associated single-gene variants in conotruncal defects, particularly tetralogy of Fallot (TOF).METHODS:
We analyzed for rare loss-of-function and deleterious variants in FLT4 (VEGFR3) and other genes in the vascular endothelial growth factor (VEGF) pathway, as part of a genome sequencing study involving 175 adults with TOF from a single site.RESULTS:
We identified nine (5.1%) probands with novel FLT4 variants seven loss-of-function, including an 8-kb deletion, and two predicted damaging. In ten other probands we found likely disruptive variants in VEGF-related genes KDR (VEGFR2; two stopgain and two nonsynonymous variants), VEGFA, FGD5, BCAR1, IQGAP1, FOXO1, and PRDM1. Detection of VEGF-related variants (19/175, 10.9%) was associated with an increased prevalence of absent pulmonary valve (26.3% vs. 3.4%, p < 0.0001) and right aortic arch (52.6% vs. 29.1%, p = 0.029). Extracardiac anomalies were rare. In an attempt to replicate findings, we identified three loss-of-function or damaging variants in FLT4, KDR, and IQGAP1 in ten independent families with TOF.CONCLUSION:
Loss-of-function variants in FLT4 and KDR contribute substantially to the genetic basis of TOF. The findings support dysregulated VEGF signaling as a novel mechanism contributing to the pathogenesis of TOF.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Tetralogia de Fallot
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Predisposição Genética para Doença
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Receptor 2 de Fatores de Crescimento do Endotélio Vascular
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Receptor 3 de Fatores de Crescimento do Endotélio Vascular
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Adult
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Aged
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Female
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Humans
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Male
/
Middle aged
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article