Abstract
Congenital heart defects (CHDs) occur in 50-75% of patients with 22q11.2 deletion syndrome (22q11.2DS), ranging from mild to severe manifestations. The genetic and environmental factors contributing to variable CHD phenotypes in 22q11.2DS are largely unknown. In this study, we used a mouse model of 22q11.2DS, termed Df1/+, to evaluate the effect of maternal vitamin A (VitA) dietary imbalance (supplementation or deficiency) on the incidence of aortic arch defects (AADs), which is a common type of CHD observed in both 22q11.2DS patients and Df1/+ mouse embryos. While most groups showed a previously observed 30% AAD incidence, two groups exhibited significantly higher rates: (1) Df1/+ embryos from WT mothers on a VitA-Supl diet (51% AADs) and (2) Df1/+ embryos from Df1/+ mothers on a VitA-Def diet (45% AADs). Thus, a low or high maternal VitA diet can increase the frequency of AADs in embryos depending on the maternal genotype. Transcriptomic analysis of the hearts of these high-risk embryos at embryonic day (E)18.5 revealed downregulation of key genes (Hdac3, Ptgds, Sirt5, Pfkm, and Lclat1) associated with energy metabolism pathways, such as oxidative phosphorylation and glycolysis, suggesting impaired cardiac recovery mechanisms. In conclusion, our findings demonstrate that altered VitA exposure can exacerbate AAD incidence in a maternal-genotype-dependent manner, highlighting the complex interplay between embryonic and maternal genetic background and environmental factors in CHDs associated with 22q11.2DS.