Mutations in VEGFA are associated with congenital left ventricular outflow tract obstruction

Biochem Biophys Res Commun. 2010 May 28;396(2):483-8. doi: 10.1016/j.bbrc.2010.04.124. Epub 2010 Apr 24.


Left ventricular outflow tract obstruction (LVOTO) comprises a spectrum of stenotic lesions. Previous studies have shown that the vascular endothelial growth factor (VEGF) signaling system plays a critical role in cardiac cushion formation, vasculogenesis, and angiogenesis. We hypothesize that VEGFA may be a potential candidate gene associated with the spectrum of LVOTO lesions. However, it remains unclear whether the VEGFA gene is responsible for the development of LVOTO malformations. In this study, we identified three exon mutations in the VEGFA gene in three of 192 nonsyndromic LVOTO patients, and the overall mutation frequency was 1.6% (3/192). The c.454C>T (p.Arg152X) nonsense mutation and c.19_22dupGACA (p.Thr8ArgfsX78) internal tandem duplication mutation each introduced a premature stop codon and are predicted to produce a truncated VEGFA protein. The c.998G>A missense mutation changes a highly conserved arginine to a glutamine at residue 333 (p.Arg333Gln). These mutations were carried by some family members, and average penetrance was 33.3%. The present study suggests, for the first time to our knowledge, that VEGFA mutations may be associated with congenital LVOTO malformations. We provide evidence that LVOTO is likely oligogenic.

MeSH terms

  • Adolescent
  • Amino Acid Sequence
  • Child
  • Child, Preschool
  • Codon, Nonsense / genetics
  • Exons / genetics
  • Female
  • Genetic Predisposition to Disease*
  • Heart Defects, Congenital / genetics*
  • Humans
  • Infant
  • Male
  • Molecular Sequence Data
  • Mutation, Missense
  • Pedigree
  • Penetrance
  • Vascular Endothelial Growth Factor A / genetics*
  • Ventricular Outflow Obstruction / congenital*
  • Ventricular Outflow Obstruction / genetics*


  • Codon, Nonsense
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A