PGAP2 – Hyperphosphatasia with Impaired Intellectual Development Syndrome 3

PGAP2 encodes Post-GPI Attachment to Proteins 2, a key enzyme in post-glycosylphosphatidylinositol (GPI) remodeling. Biallelic pathogenic variants in PGAP2 cause autosomal recessive hyperphosphatasia with impaired intellectual development syndrome 3 (HPMRS3) (MONDO:0013628), characterized by intellectual disability, seizures, hyperphosphatasia and digital anomalies. Early recognition of this genotype–phenotype correlation informs targeted genetic testing and management.

Multiple unrelated families harbor biallelic missense variants in PGAP2, supporting a strong gene–disease association. Four affected individuals from two families presented with HPMRS3 features and novel compound heterozygous or homozygous PGAP2 missense variants (PMID:40225942). A consanguineous Bedouin kindred with autosomal recessive hyperphosphatasia and intellectual disability segregated a homozygous PGAP2 c.554G>A (p.Arg185Gln) variant in all affected members (PMID:29119105). Exome sequencing in index cases identified a homozygous NM_014489.3:c.881C>T (p.Thr294Met) variant in two siblings and one unrelated patient, further confirming pathogenicity (PMID:31805394).

Inheritance is autosomal recessive with segregation observed in at least four pedigrees and three additional affected relatives beyond probands. A minimum of eight probands across four families have been described, all with concordant biallelic missense variants and no healthy homozygotes in controls.291191053180539440225942

The variant spectrum in HPMRS3 is dominated by missense changes. Key alleles include c.554G>A (p.Arg185Gln) and c.881C>T (p.Thr294Met), each affecting highly conserved residues within functional domains. No LoF or splice variants have been reported to date, and there is no evidence of recurrent founder alleles beyond these families.

Functional studies demonstrate a hypomorphic mechanism. Rescue assays in PGAP2-deficient CHO and CRISPR/Cas9 cell lines showed that c.554G>A and the hypomorphic isoform carrying c.881C>T fail to restore surface GPI-AP expression (CD55, CD59) to wild-type levels (PMID:29119105; PMID:31805394). Protein modeling predicts destabilized folding and impaired protein–protein interactions for the novel PGAP2 substitutions (PMID:40225942). These data align with decreased GPI anchor remodeling activity in patient cells and animal models.

Together, the genetic and experimental evidence fulfills ClinGen criteria for a strong clinical validity classification. PGAP2 sequencing should be incorporated into diagnostic panels for hyperphosphatasia with intellectual disability, and functional assays can corroborate variant pathogenicity. Early molecular diagnosis enables appropriate management and genetic counseling.

References

• Human Mutation • 2024 • Macrocephaly and Digital Anomalies Expand the Phenotypic Spectrum of PGAP2 Variants in Hyperphosphatasia with Impaired Intellectual Development Syndrome 3 (HPMRS3) PMID:40225942
• BioMed Research International • 2017 • A Rare Variant in PGAP2 Causes Autosomal Recessive Hyperphosphatasia with Mental Retardation Syndrome, with a Mild Phenotype in Heterozygous Carriers PMID:29119105
• European Journal of Medical Genetics • 2020 • A post glycosylphosphatidylinositol (GPI) attachment to proteins, type 2 (PGAP2) variant identified in Mabry syndrome index cases: Molecular genetics of the prototypical inherited GPI disorder PMID:31805394

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