Abstract 4143019: Fetuses with Congenital Heart Disease and Placental Malperfusion Have Adverse Outcomes and <i>De Novo</i> Variants in Key Placental Developmental Pathways

Background: Placental malperfusion (PMP), and perturbation of shared developmental pathways between the fetal heart and placenta, may play a role in the development and outcomes of congenital heart disease (CHD). We hypothesize that genomic variation in pathways involved in vascular or placental development underlie PMP in CHD, which in turn impacts outcomes. Methods: Fetuses were diagnosed prenatally with structural CHD in our Fetal Heart Program. Maternal characteristics, neonatal biometrics, genomic diagnoses, and outcomes data were reviewed. Placentas with PMP met pathological criteria according to the Amsterdam Placental Workshop classification for maternal or fetal vascular malperfusion, or placental weight &lt;10% for gestational age. All probands (and available parents) underwent genome sequencing and rare, predicted deleterious exonic or putative splicing single nucleotide variants and small insertion deletions were identified from whole genome sequencing data. De novo variants were identified from trios (n = 252) and pathway enrichment analysis was performed. T-tests/Mann-Whitney or Chi-squared/Fishers exact tests were performed with p-value &lt; 0.05 considered significant. Results: Of 299 fetuses with CHD, 51% had evidence of PMP (n=153). There were no significant differences in baseline characteristics or CHD subtype of those with or without PMP. Non-syndromic fetuses with PMP (n=118) had decreased birth weight (3335g vs 3000g; p&lt;0.001), length (49cm vs 48cm; p&lt;0.001), head circumference (34cm vs 33cm; p&lt;0.001), longer index hospitalization (15d vs 21d; p=0.02), and a trend towards increased mortality (6% vs 12.7%; p=0.08). The burden of vascular developmental pathway or de novo variants (34% vs 39%) was similar between groups and not associated with adverse outcomes. Genes with de novo variants were significantly enriched in cardiac developmental pathways in all CHD fetuses, however those with PMP demonstrated distinct enrichment in Notch signaling ( NOTCH1, NOTCH3, DLL4, SMAD6, VIM, TIE1 ) and collagen/extracellular matrix biosynthesis ( COL4A4, FN1, MMP2 ), genes critical for trophoblast and placental vascular development. Conclusion: CHD fetuses with PMP have impaired fetal growth, longer hospital length of stay, and a trend towards increased mortality. In CHD fetuses with PMP, rare, deleterious de novo variants were significantly enriched in several key placental developmental pathways, which may represent key mechanisms underlying PMP in CHD.