Here, we describe two patients with intellectual disability, bearing hemizygous mutations in OGT. By combining characterization of the O-GlcNAcylation machinery in patient cells and characterization of the effects of OGT XLID mutations on OGT dual activity in vitro, we provide preliminary evidence suggesting that effects on the O-GlcNAc proteome and proteolytic processing of HCF1 may underpin the observed XLID phenotypes. This evidence concerns the gene OGT and Intellectual disability.