Expanding the genotypic and phenotypic spectrum of PGAP1 deficiency: clinical and functional insights from 15 patients.

PGAP1

Biallelic loss of function of PGAP1, an inositol deacylase required for GPI-anchor remodelling and proper membrane targeting of anchored proteins

GPI-anchored proteins are essential for neuronal development and synaptic organisation, and defects in GPI-anchor biosynthesis or remodelling cause rare neurodevelopmental disorders including PGAP1 deficiency, whose clinical spectrum remained poorly defined because reported cohorts were small. The authors report 15 individuals with biallelic PGAP1 variants from 11 unrelated families, ascertained through international collaboration and phenotyped using a standardised questionnaire supplemented by available records. The most frequently recorded features were developmental delay or intellectual disability, motor delay, speech impairment, facial dysmorphism, hypotonia and seizures; independent walking was clearly documented in only a minority. Because investigations were not uniform across sites, MRI, EEG, electrophysiology and ophthalmology findings are reported descriptively, and confirmed peripheral neuropathy could not be analysed as a cohort-level prevalence. Functional studies in selected patient-derived cells or model systems demonstrated PI-PLC resistance of GPI-anchored proteins, confirming impaired anchor remodelling.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The strength of this series is its restraint: the authors explicitly refuse to turn heterogeneous data into prevalences, which is rare and welcome in international cohorts assembled by genotype matching. In practice, the combination of neonatal hypotonia, seizures and severe motor delay with rarely achieved independent walking remains the most usable signal pointing to a GPI-anchor remodelling defect. The PI-PLC resistance assay deserves to be known to laboratories: it is an accessible functional argument for reclassifying a variant of uncertain significance.

Analysis by Dr Thibaut Benquey