An excess of deleterious variants in VEGF-A pathway genes in Down-syndrome-associated atrioventricular septal defects

Am J Hum Genet. 2012 Oct 5;91(4):646-59. doi: 10.1016/j.ajhg.2012.08.017.


About half of people with trisomy 21 have a congenital heart defect (CHD), whereas the remainder have a structurally normal heart, demonstrating that trisomy 21 is a significant risk factor but is not causal for abnormal heart development. Atrioventricular septal defects (AVSD) are the most commonly occurring heart defects in Down syndrome (DS), and ∼65% of all AVSD is associated with DS. We used a candidate-gene approach among individuals with DS and complete AVSD (cases = 141) and DS with no CHD (controls = 141) to determine whether rare genetic variants in genes involved in atrioventricular valvuloseptal morphogenesis contribute to AVSD in this sensitized population. We found a significant excess (p < 0.0001) of variants predicted to be deleterious in cases compared to controls. At the most stringent level of filtering, we found potentially damaging variants in nearly 20% of cases but fewer than 3% of controls. The variants with the highest probability of being damaging in cases only were found in six genes: COL6A1, COL6A2, CRELD1, FBLN2, FRZB, and GATA5. Several of the case-specific variants were recurrent in unrelated individuals, occurring in 10% of cases studied. No variants with an equal probability of being damaging were found in controls, demonstrating a highly specific association with AVSD. Of note, all of these genes are in the VEGF-A pathway, even though the candidate genes analyzed in this study represented numerous biochemical and developmental pathways, suggesting that rare variants in the VEGF-A pathway might contribute to the genetic underpinnings of AVSD in humans.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Case-Control Studies
  • Down Syndrome / genetics*
  • Genetic Predisposition to Disease
  • Genetic Variation
  • Heart Septal Defects, Atrial / genetics*
  • Heart Septal Defects, Ventricular / genetics*
  • Humans
  • RNA, Untranslated / genetics
  • Vascular Endothelial Growth Factor A / genetics*


  • RNA, Untranslated
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A