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

Placental mesenchymal dysplasia (PMD) is a placental abnormality resembling partial hydatidiform moles without trophoblastic proliferation. Although many PMD cases involve androgenetic/biparental mosaicism or chimerism, we recently reported that approximately 30% of cases retain biparental genomes (BiPMD) and exhibit aberrant methylation at multiple imprinted differentially methylated regions (DMRs). This resembles multilocus imprinting disturbances (MLIDs) and biparental hydatidiform moles (BiHMs), which are associated with pathogenic variants in subcortical maternal complex (SCMC) genes. However, the involvement of SCMC variants in BiPMD pathogenesis remains unclear.

We performed whole-exome sequencing on seven mothers with BiPMD during pregnancy, focusing on SCMC-related and DNA methylation maintenance genes. We identified compound heterozygous frameshift and missense variants in NLRP5 in one mother, and a heterozygous missense variant in NLRP2 in another. In silico predictions suggested that the NLRP5 frameshift variant was pathogenic, whereas the missense variants were deemed likely benign. Methylation specific-multiplex ligation-dependent probe amplification (MS-MLPA) of placental tissues revealed aberrant methylation patterns in multiple imprinted DMRs. The affected DMRs varied between cases and within the same case, with abnormalities also observed in macroscopically normal placental regions.

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.