A novel PGAP1 splice-site variant expanding the clinical and molecular spectrum of GPI-anchor disorders

Genetic defects affecting the biosynthesis and remodeling of glycosylphosphatidylinositol (GPI) anchors constitute a recently recognized group of autosomal recessive neurodevelopmental disorders with highly variable clinical presentations. Among the genes involved in this pathway, PGAP1 encodes an endoplasmic reticulum-associated inositol deacylase that plays a critical role in the initial step of GPI-anchor remodeling. Pathogenic variants in PGAP1 have been reported in only a limited number of families worldwide and are associated with clinical features such as global developmental delay, intellectual disability, seizures, microcephaly, and variable systemic manifestations.

Here, we describe a patient harboring a novel homozygous splice-site variant (NM_024989.4.1173 + 1G > A) with neurodevelopmental impairment. The potential effect on splicing was assessed using in silico tools (SpliceAI, HSF, and varSEAK), while the potential structural consequences were evaluated using AlphaFold and PyMOL. Segregation analysis was performed to assess the inheritance pattern and provide additional evidence for variant classification. A comprehensive review of previously reported cases was also conducted to broaden the known phenotypic spectrum.

The novel variant, which was absent from all public databases, was classified as likely pathogenic according to ACMG guidelines. Computational analyses consistently predicted significant disruption of splicing, while structural modeling suggested conformational alterations associated with the predicted in-frame deletion.

Our findings expand the phenotypic heterogeneity of PGAP1-related disorders and provide further insight into the molecular basis of GPI-anchor remodeling defects. The findings also highlight the utility of genomic analysis for establishing a molecular diagnosis in patients with unexplained neurodevelopmental abnormalities.