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

Christine Ackerman, Adam E. Locke, Eleanor Feingold, Benjamin Reshey, Karina Espana, Janita Thusberg, Sean Mooney, Lora J.H. Bean, Kenneth J. Dooley, Clifford L. Cua, Roger H. Reeves, Stephanie L. Sherman, Cheryl L. Maslen

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63 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)646-659
Number of pages14
JournalAmerican journal of human genetics
Issue number4
StatePublished - Oct 5 2012

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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