Submission Details

PIGP was first reported in relation to “developmental and epileptic encephalopathy, 55” an autosomal recessive condition, in 2017 (Johnstone et al, PMID: 28334793). This is the only condition associated with PIGP in OMIM.

Four variants (one C-terminal frameshift, one missense, one initiator codon, and one multi-gene deletion) that have been reported in 5 probands in 5 publications (Johnstone et al, 2017, PMID: 28334793; Krenn et al, 2019, PMID: 31139695; Vetro et al, 2020, PMID: 32042915; Kahn et al, 2022, PMID: 36002593; Martín-Grau et al, 2023, PMID: 37125481) are included in this curation. Two of the variants, c.2C>T and c.384del, have been reported in more than one unrelated individual. (Total score for genetic evidence = points). The mechanism of pathogenicity appears to be loss of function based on reduction of surface localization of GPI-anchored proteins in granulocytes from affected individuals, and in invitro functional studies.

This gene-disease relationship is also supported by the biochemical function of the gene product, and interaction with the products of other genes which have been associated with the same condition. PIGP is part of a multi-subunit complex involved in the first step of synthesis of the GPI anchor (Watanabe et al, 2000, PMID: 10944123). In that complex, it interacts with various proteins including PIGA, which has been definitively associated with “complex neurological disorder” by the Epilepsy Gene Curation Expert Panel (Watanabe et al, 2000, PMID: 10944123). (Score for experimental evidence = )

In summary, there is moderate evidence supporting the relationship between PIGP and the autosomal recessive disorder “developmental and epileptic encephalopathy, 55”. This classification was approved by the ClinGen Congenital Disorders of Glycosylation Gene Curation Expert Panel on December 5, 2024 (SOP version #11).