Submission Details

The OGT gene (OMIM_300255) is located on chromosome Xq13.1 and encodes the O-linked N-acetyleglucosamine (O-GlCNAc) transferase, which is an enzyme that modifies intracellular proteins post-translationally by transferring N-acetylglucosamine (GlcNAc) from UDP-GlcNAc to serine and threonine residues of protein substrates through O-glycosylation. OGT was first reported in relation to intellectual disability, X-linked 106 (MONDO:0030907) in 2017 (Willems et al., 2017, PMID 28584052; Vaidyanathan et al., 2017, PMID 28302723). Ten variants (9 missense, 1 splice region variant) that have been reported in 10 probands in 10 publications (PMIDs:32080367, 28584052, 28302723, 31627256, 31296563, 29769320, 29606577, 37334838, 35970915, 33349918) are included in this curation. These affected individuals have been described with de novo or maternally inherited missense variants presenting with developmental delay, intellectual disability, dysmorphic features of the face and hands, eye abnormalities and hypotonia. Although the exact mechanism of how missense variants in OGT results in a syndromic intellectual disability disorder is unknown, each described variant has a collection of function evidence demonstrating detrimental effects of these missense variants on OGT activity. Additional evidence supporting this gene-disease relationship includes a conditional mouse model, transcriptome analysis on mutant hESC, and protein interaction between OGT and genes linked to syndromes with overlapping features (e.g., Sin3A and HCFC1) (PMIDs:29769320, 32896380, 12150998, 21295698). In summary, the available evidence of this gene-disease relationship is convincing due to the essential role OGT plays in development, the high missense constraint of variation in OGT, and the functional evaluation of variants and phenotypic similarities across the affected individuals described in the literature. Currently there is moderate evidence to support the relationship between OGT and X-linked syndromic intellectual disability.

The gene-disease pair was originally evaluated by the Syndromic Disorders GCEP on February 3, 2021 and was re-evaluated on August 8, 2024. As a result of this re-evaluation, although there were new published case reports included (3 missense variants from PMIDs: 35970915, 33349918, 37334838) and new experimental evidence in the form of biochemical evidence (PMID: 26237509), a mouse model (PMID: 38566589) and a drosophila model (PMID: 35500025), the classification did not change. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date of August 8, 2024 (SOP Version 10).