Maternal cholesterol deficiency predisposes congenital heart defects risk.

The relationship between maternal cholesterol deficiency and the risk of congenital heart defects (CHDs) in offspring is not fully understood. In a birth cohort study of 5041 family trios, we found that low maternal cholesterol levels were significantly associated with an increased risk of CHD, with RRs of 1.52 in the second trimester and 1.73 in the third trimester. To further investigate this link, we treated pregnant mice with cholesterol-lowering agents, namely, ezetimibe or atorvastatin. Both treatments led to a significant increase in the incidence of CHD in offspring. To identify a pathogenic variant that could provide genetic evidence linking cholesterol synthesis to CHD occurrence and serve as a target for constructing a genetic mouse model, we performed whole-genome sequencing (WGS) on 103 CHD cases from the birth cohort. We identified a recurrent functional variant in the CYP51A1 gene (c.1147 A > G, p.Ile383Val). We then developed a Cyp51I383V knock-in mouse model. This variant disrupted cholesterol synthesis, resulting in CHD through impaired hedgehog (Hh) signaling. Most intriguingly, maternal dietary intervention to increase cholesterol intake effectively reduced the risk of CHD in Cyp51I383V mutant offspring. Our study suggests that low maternal cholesterol during pregnancy increases the risk of CHD in offspring by inhibiting Hh signaling and that maternal cholesterol supplementation during pregnancy may reduce the occurrence of CHD.