PIGW – Hyperphosphatasia with Intellectual Disability Syndrome 5

PIGW encodes a mannosyltransferase required for glycosylphosphatidylinositol (GPI) anchor biosynthesis. Biallelic PIGW variants cause hyperphosphatasia with intellectual disability syndrome 5, an autosomal recessive multisystem disorder characterized by elevated alkaline phosphatase, global developmental delay, developmental regression, and congenital anomalies including tetralogy of Fallot (HP:0001263, HP:0002376, HP:0001636).

Genetic evidence includes 16 unrelated probands with biallelic PIGW variants—missense and the first reported frameshift allele—across multiple families, supporting autosomal recessive inheritance and a loss-of-function mechanism (PMID:39766333). No large pedigrees for segregation analysis were reported. The variant spectrum comprises missense changes (e.g., c.199C>G (p.Pro67Ala)) and a novel frameshift (c.1112del (p.Ala372_Leu401del)) (PMIDs:30078644, 39924787).

Functional studies demonstrate significantly reduced cell surface expression of GPI-anchored proteins in patient granulocytes, lymphocytes, and monocytes by flow cytometry, confirming the pathogenicity of homozygous missense variants and supporting haploinsufficiency of PIGW ([PMID:30078644]). Additional in vitro assays of c.659T>G (p.Ile220Arg) and c.1112del (p.Ala372_Leu401del) recapitulate impaired GPI biosynthesis ([PMID:39924787]).

There are no reports disputing the association. The combined genetic and functional data provide strong evidence that PIGW loss of function underlies hyperphosphatasia with intellectual disability syndrome 5.

Key Take-home: Biallelic PIGW variants result in a severe, autosomal recessive GPI‐biosynthesis defect with characteristic hyperphosphatasia and neurodevelopmental impairment, enabling molecular diagnosis and informing management.

References

• – | – | Glycosylphosphatidylinositol biosynthesis defect 11 due to PIGW variants PMID:39766333
• Pediatric neurology | 2018 | Use of Flow Cytometry for Diagnosis of Epilepsy Associated With Homozygous PIGW Variants. PMID:30078644
• Clinical genetics | 2025 | Genetic Study and Prenatal Diagnosis of Inherited Glycosylphosphatidylinositol Disorders due to Novel Variants in Phosphatidylinositol Glycan Genes. PMID:39924787

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