Damaging Variants in Proangiogenic Genes Impair Growth in Fetuses with Cardiac Defects

J Pediatr. 2019 Oct;213:103-109. doi: 10.1016/j.jpeds.2019.05.013. Epub 2019 Jun 18.


Objective: To determine the impact of damaging genetic variation in proangiogenic pathways on placental function, complications of pregnancy, fetal growth, and clinical outcomes in pregnancies with fetal congenital heart defect.

Study design: Families delivering a baby with a congenital heart defect requiring surgical repair in infancy were recruited. The placenta and neonate were weighed and measured. Hemodynamic variables were recorded from a third trimester (36.4 ± 1.7 weeks) fetal echocardiogram. Exome sequencing was performed on the probands (N = 133) and consented parents (114 parent-child trios, and 15 parent-child duos) and the GeneVetter analysis tool used to identify damaging coding sequence variants in 163 genes associated with the positive regulation of angiogenesis (PRA) (GO:0045766).

Results: In total, 117 damaging variants were identified in PRA genes in 133 congenital heart defect probands with 73 subjects having at least 1 variant. Presence of a damaging PRA variant was associated with increased umbilical artery pulsatility index (mean 1.11 with variant vs 1.00 without; P = .01). The presence of a damaging PRA variant was also associated with lower neonatal length and head circumference for age z score at birth (mean -0.44 and -0.47 with variant vs 0.23 and -0.05 without; P = .01 and .04, respectively). During median 3.1 years (IQR 2.0-4.1 years) of follow-up, deaths occurred in 2 of 60 (3.3%) subjects with no PRA variant and in 9 of 73 (12.3%) subjects with 1 or more PRA variants (P = .06).

Conclusions: Damaging variants in proangiogenic genes may impact placental function and are associated with impaired fetal growth in pregnancies involving a fetus with congenital heart defect.

Keywords: angiogenesis; congenital heart disease; fetus; genetic modifiers; placenta.

Publication types

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

MeSH terms

  • Angiogenic Proteins / genetics*
  • Case-Control Studies
  • Female
  • Fetal Development / genetics*
  • Genetic Variation / genetics*
  • Heart Defects, Congenital / diagnosis
  • Heart Defects, Congenital / genetics*
  • Heart Defects, Congenital / surgery
  • Humans
  • Infant, Newborn
  • Male
  • Pregnancy
  • Pregnancy Complications / etiology*


  • Angiogenic Proteins