An OGT Missense Variant With Impaired Enzyme Activity in a Child With Severe Developmental Delay and Hepatoblastoma

ABSTRACT O‐GlcNAc transferase (OGT) and its antagonist O‐GlcNAcase (OGA) regulate protein O‐GlcNAcylation, a highly conserved post‐translational modification involved in metabolic sensing. Pathogenic variants in the OGT gene cause an X‐linked congenital disorder of glycosylation (OGT‐CDG) presenting developmental delay, hypotonia, intellectual disability, and dysmorphic features. Here, we report on a child with developmental delay, hypotonia, and dysmorphic features who was found to carry a hemizygous novel OGT variant. This child also developed hepatoblastoma by the age of 17 months. OGT‐CDG was diagnosed by exome sequencing that identified a de novo missense variant in the OGT gene. Functional validation by Western blot on patient‐derived fibroblasts showed reduced O‐GlcNAcylation and OGA expression, while significantly reduced enzyme activity in vitro confirmed the pathogenicity of the variant. To date, no patients with OGT‐CDGs have been reported with hepatoblastoma or other malignancies. Although the occurrence of hepatoblastoma in the proband might be coincidental, the role of O‐GlcNAcylation in cancer suggests that the deficiency of OGT activity might be associated with increased cancer risk.