Expanding the Genotypic and Phenotypic Spectrum of PGAP1 Deficiency: Clinical and Functional Insights from 15 Patients

Glycosylphosphatidylinositol-anchored proteins (GPI-APs) play essential roles in neuronal development, synaptic organisation, and signal transduction. Defects in GPI-anchor biosynthesis and remodelling cause rare multisystem neurodevelopmental disorders, among which post-GPI attachment to proteins 1 (PGAP1) deficiency is particularly uncommon. PGAP1 encodes an inositol deacylase that removes an acyl chain from the inositol ring of the GPI anchor, an early remodelling step required for proper trafficking and membrane localisation of GPI-APs. Loss of PGAP1 function leads to structurally abnormal GPI-APs and impaired cellular processes. Fewer than 40 affected individuals have been described, limiting understanding of the clinical spectrum. We systematically characterised 15 individuals with PGAP1 deficiency from 11 unrelated families across 11 countries using standardised phenotyping, molecular analysis, and functional assays. Eight previously unreported pathogenic variants were identified across six exons, including splice-site, truncating, and missense variants, with exon 2 containing the largest cluster. Individuals ranged from 8 months to 23 years. Intellectual disability and global motor delay were the most common features (93.3%), and only 40.0% achieved independent ambulation. Seizures occurred in 66.7% of cases. Scoliosis was observed in 40.0%, and peripheral neuropathy in 33.3%, the latter representing an under-recognised aspect of the disorder. Functional studies showed resistance to phosphatidylinositol-specific phospholipase C cleavage of GPI-APs, confirming impaired GPI-anchor remodelling. These findings expand the genotypic and phenotypic landscape of PGAP1 deficiency, highlight neuropathy as part of the disease spectrum, and emphasise the need for genetic testing and functional validation for accurate diagnosis and management.