Loss of the maternal effect gene <i>NLRP2</i> impairs embryonic and extra-embryonic development, revealing a novel genetic cause of congenital anomalies

Maternal-effect genes (MEGs) play a crucial role in early mammalian development, and their dysfunction can lead to severe embryonic and extra-embryonic abnormalities. NLRP2, a MEG that encodes a subcortical maternal complex (SCMC) protein, has been implicated in preimplantation development, but its role after implantation remains underexplored. In this study, we investigated the developmental consequences of maternal Nlrp2 loss-of-function in a maternal knockout (KO) mouse model at embryonic day 11.5. Embryos derived from Nlrp2-KO females have abnormal yolk sac vasculature, increased embryonic resorption, craniofacial abnormalities, neural tube defects, and congenital heart defects. Placental architecture is disrupted with an altered junctional zone and labyrinth structure. Transcriptome profiling of maternal decidua and placenta demonstrated dysregulation of genes involved in trophoblast differentiation and extra-embryonic development. Bisulfite sequencing of these tissues revealed persistence at E11.5 of previously observed locus-specific disruption in DNA methylation at four imprinted loci following maternal Nlrp2 loss. We further describe pregnancy outcomes and offspring phenotypes for two unrelated women with bi-allelic maternal NLRP2 variants. The first carried homozygous NLRP2 nonsense variants and experienced recurrent pregnancy loss and fetuses with multiple structural anomalies, including omphalocele, craniofacial dysmorphism, and cardiac defects. The second carried compound heterozygous frameshift and missense NLRP2 variants and had a child with neurodevelopmental impairment of uncertain etiology. These findings indicate a conserved role for maternal NLRP2 in embryonic viability and placental development, and support further studies in humans into the contribution of NLRP2 and other similar MEGs to offspring congenital anomalies and adverse pregnancy outcomes.