Intrafamilial Phenotypic Variability in a Rare PGAP2-Associated Neurodevelopmental Disorder: Clinical and Molecular Findings from a Pakistani Family

Hyperphosphatasia with mental retardation syndrome 3 (HPMRS3) is a rare autosomal recessive disorder caused by mutations in the PGAP2 gene , characterized by neurodevelopmental disorders, elevated alkaline phosphatase levels, and variable dysmorphic features. However, genotype-phenotype correlation and the phenotypic spectrum remain incompletely understood. This study aims to expand the genotypic and phenotypic spectrum of PGAP2-related disorders by reporting a rare homozygous missense and likely pathogenic variant associated with HPMRS3. Whole-exome sequencing followed by segregation analysis was performed in a consanguineous Pakistani family presenting with neurodevelopmental abnormalities. Detailed clinical, neurological and biochemical evaluation of affected individuals was conducted to assess developmental, neurological, and dysmorphic features. A homozygous missense variant, c.713G > C; p.(Arg238Pro), was identified in the PGAP2 gene. Affected individuals exhibited developmental delay, epilepsy, hearing impairment, and subtle facial dysmorphic features. The proband showed a severe phenotype with refractory epilepsy and early death, while older affected siblings demonstrated comparatively milder manifestations, indicating intrafamilial phenotypic variability. The identified variant affects a highly conserved arginine residue previously associated with severe HPMRS3 phenotypes, supporting its pathogenic significance. This report strengthens the critical functional importance of conserved arginine residues in PGAP2 and supports a strong genotype–phenotype correlation for p.(Arg238Pro) in the Pakistani population. Our findings highlight the potential severity of homozygous PGAP2 variants in consanguineous families and expand the clinical spectrum of HPMRS3. These findings emphasize the importance of genetic counseling and functional validation studies for improved disease understanding and future therapeutic strategies.