CANDIDATE PATHWAYS AND BIOMARKERS IN OGT-CDG - A NOVEL INTELLECTUAL DISABILITY SYNDROME

O-GlcNAc Transferase Congenital Disorder of Glycosylation (OGT-CDG) is a recently discovered intellectual disability (ID) syndrome caused by missense mutations in the OGT gene. OGT catalyses O-GlcNAcylation, a dynamic post-translational modification affecting thousands of proteins. OGT-CDG patients present with extensive phenotypic heterogeneity, including ID, developmental delay, and dysmorphic features. Despite some overlap between patients, the clinical presentation is highly variable, complicating diagnosis and impeding the identification of underlying mechanisms. To address this, we enrolled a large cohort of OGT-CDG patients and family members to systematically map the heterogeneity of OGT-CDG. Standardised clinical data collection and genetic screening of OGT variants were used to cluster and stratify patients based on shared and distinct symptom profiles. Blood samples from patients, healthy family members, and OGT-CDG mouse models carrying patient mutations were analysed for biomarker discovery and validation. Preliminary data from three different OGT-CDG mouse models showed upregulated Ogt mRNA levels and downregulated Oga mRNA levels compared to wild type mice in whole brain samples, in leukocytes, and in whole blood, respectively, suggesting that altered O-GlcNAc homeostasis may contribute to disease pathophysiology. By integrating clinical, genetic, and biomarker data, this study aims to provide a comprehensive characterisation of OGT-CDG. Defining clinical profiles and associated biological signatures will offer novel insights into the aetiological processes underlying this syndrome, paving the way for improved diagnostic tools and potential therapeutic interventions for affected patients and their families.