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PIGL – Hyperphosphatasia-Intellectual Disability Syndrome

PIGL encodes a key enzyme in the glycosylphosphatidylinositol (GPI)-anchor biosynthesis pathway. Hyperphosphatasia-intellectual disability syndrome (HPMRS; MONDO:0016596) is characterized by elevated serum alkaline phosphatase and global developmental delay, hypotonia, and seizures. To date, PIGL has not been implicated in multiple unrelated HPMRS families. A single case from the Deciphering Developmental Disorders study reported a child with neurodevelopmental delay and elevated alkaline phosphatase harboring biallelic splice site variant c.336->G (p.Asp113fsTer2) (PMID:28327575). The variant disrupts exon 2 and introduces a frameshift leading to premature termination.

Cellular assays demonstrate that PIGL haploinsufficiency or deletion in TK6 lymphoblastoid cells causes loss of GPI-anchored proteins on the cell surface, confirming a functional deficit in GPI-anchor remodeling (PMID:27100116; PMID:25970100). No animal models or rescue experiments have been reported for PIGL in HPMRS. Based on a single proband and absence of additional unrelated families, the gene–disease association is classified as Limited. Genetic evidence is limited (Tier I) and functional data are Moderate, supporting a loss-of-function mechanism. Further clinical studies are needed to confirm PIGL’s role in HPMRS.

Key Take-home: PIGL currently shows limited clinical validity for HPMRS but functional assays support a pathogenic mechanism, highlighting the need for additional family-based evidence.

References

  • European journal of human genetics • 2017 • Analysis of exome data for 4293 trios suggests GPI-anchor biogenesis defects are a rare cause of developmental disorders. PMID:28327575
  • Archives of toxicology • 2016 • The in vitro PIG-A gene mutation assay: glycosylphosphatidylinositol (GPI)-related genotype-to-phenotype relationship in TK6 cells. PMID:27100116
  • Environmental and molecular mutagenesis • 2015 • Both PIGA and PIGL mutations cause GPI-a deficient isolates in the Tk6 cell line. PMID:25970100

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

No reported unrelated probands meeting HPMRS clinical criteria; only single DDD case and functional data

Genetic Evidence

Limited

Single family with biallelic PIGL splice variant c.336->G (p.Asp113fsTer2) and abnormal alkaline phosphatase ([PMID:28327575])

Functional Evidence

Moderate

Cellular PIGL deletion and heterozygosity assays demonstrate loss of GPI-anchor synthesis consistent with disease mechanism ([PMID:27100116]; [PMID:25970100])