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

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.