The X-chromosome gene USP9X encodes a deubiquitylating enzyme that we associated with neurodevelopmental disorders (NDDs) primarily in females. USP9X escapes X-inactivation, and in females de novo heterozygous copy number loss or truncating mutations cause haploinsufficiency culminating in a recognisable syndrome with intellectual disability (ID), signature brain and congenital abnormalities. In contrast, the involvement of USP9X in male NDDs remained tentative. We discovered and interrogated the pathogenicity of 44 male-ascertained USP9X variants associated with NDDs. Twelve missense variants were classified as pathogenic using clinically recommended guidelines, and in silico and phenotypical features align additional variants of unknown significance with pathogenicity. We define a characteristic phenotype of the CNS (white matter disturbances, thin corpus callosum and widened ventricles), and global delay with significant alteration of speech, language, movement and behaviour. We used patient derived cell lines to show variants disrupted the ability of USP9X to regulate a specific subset of substrates which regulate neurodevelopmental signalling pathways, including TGFβ, mTOR and Wnt. We show these same substrates and pathways are disrupted in Usp9x brain-specific knockout mice, and drive defects in neural stem cell function, and axon growth. Furthermore we resolve the presence of cortical malformations, and learning and memory defects which are hallmarks of the human phenotype. Our data thus align USP9X variants with a distinctive neurodevelopmental syndrome in males and identify plausible mechanisms of pathogenesis centred on disrupted neurodevelopmental signalling and cortical development and function