Variants of NLRP genes encoding subcortical maternal complex components are linked to biparental placental mesenchymal dysplasia

These findings suggest that maternal variants in NLRP genes, which encode components of the SCMC, may contribute to the development of BiPMD with MLIDs. SCMC dysfunction due to SCMC gene mutations may cause aberrant methylation at imprinted DMRs in early embryos with cell-to-cell variation in the affected DMRs among cells, leading to a mosaic pattern of abnormal cells and normal cells. Through differentiation into placental tissues in this mosaic condition, BiPMD with aberrant methylation of multiple DMRs can occur. Taken together, our findings support the hypothesis that MLID in live-born individuals, BiPMD, and BiHMs may collectively represent a continuum within the MLID spectrum. Further studies are needed to elucidate how SCMC dysfunction leads to imprinting errors and to improve the diagnosis and understanding of PMD and related imprinting disorders.