Unbalanced chromatin binding of Polycomb complexes drives neurodevelopmental disorders.

The prevalence of neurodevelopmental disorders (NDDs) in children is increasing, yet their underlying causes remain largely unknown. We identified heterozygous mutations in the Polycomb repressive complex 1 (PRC1) E3 ligases RING1 and RNF2 in individuals with NDDs and revealed distinct mechanisms by which they compromise PRC1 activity. We developed cellular and mouse models carrying the Ring1b(R70H) variant, which disrupts PRC1/PRC2 recruitment balance and mis-regulates Polycomb target genes. Allele-specific profiling showed that Ring1b(R70H) preferentially assembles into canonical PRC1 (cPRC1) via the intrinsically disordered region (IDR) of Pcgf2, reducing variant PRC1 (vPRC1) and PRC2.1 binding to chromatin. In Rnf2(WT/R70H) neuroprecursors, Polycomb complexes aberrantly suppress Wnt signaling, diverting neuroprecursors to non-neuronal lineages and halting neurogenesis. Rnf2(R70H/R70H) mice are perinatally lethal, while heterozygotes exhibit altered axonal organization, hippocampal and medial prefrontal cortex (mPFC) neuronal imbalances, reduced sociability, and increased anxiety. Our findings reveal an epigenetic mechanism essential for neurodevelopmental integrity and brain function and demonstrate how mutations in Rnf2 disrupt PRC1 occupancy at chromatin, contributing to NDDs.