Mutations in 12 deubiquitylating enzymes (DUBs) are known to cause neurodevelopmental disorders (NDDs). We generated and assembled genetic evidence that supports the involvement of 26 additional DUBs. USP9X is one of the most frequently mutated DUBs in NDDs. We discovered and studied >50 pathogenic DNA variants in USP9X that cause NDDs. Consistent with human phenotypes, we discovered that brain specific Usp9x knockout in mice caused abnormal learning, memory and communication. At a cellular level, we resolved defects in neural stem cell function, and neuronal cell migration and connectivity. USP9X acts primarily to antagonise the proteasomal degradation of its substrates, and these cellular phenotypes were underpinned by loss of abundance of key regulatory proteins controlling the mTOR, WNT, NOTCH and TGFβ signalling pathways. These substrates and pathways were likewise disrupted in patient-derived primary skin fibroblast cell lines. Intriguingly, these substrates are themselves encoded by genes which cause NDDs through haploinsufficiency culminating in loss of protein abundance. An extended interrogation of all USP9X interactors showed its interactome is enriched in proteins encoded by NDD genes. Similar results were obtained for the interactomes of other DUBs known to cause NDDs including USP7, USP15, USP27X, USP45, OTUD5, OTUD6B, OTUD7A, and ATXN3. The aggregate data implicate a convergent mechanism of pathology in DUB related NDDs involving destabilisation of proteins which themselves cause NDDs through loss of abundance. By extension, these data suggest that NDDs caused by haploinsufficiency can be potentially overcome by antagonising the ubiquitin dependent proteolysis of NDD proteins.