PIGQ (formerly known as GPI1) was first reported in relation to “developmental and epileptic encephalopathy, 77” an autosomal recessive condition, in 2014 (Martin et al, PMID: 24463883). This is the only condition associated with PIGQ in OMIM.
Twelve variants (5 frameshift variants, 4 of which are in the 3’ end of the gene and predicted to escape NMD; 2 canonical splice site variants; 2 missense variants; 2 inframe deletions, one of which was identified in 3 unrelated patients; and one nonsense variant) that have been reported in 9 probands in 4 publications (Martin et al, 2014, PMID: 24463883; Alazami et al, 2015, PMID: 25558065; Starr et al, 2019, PMID: 31148362; Johnstone et al, 2020, PMID: 32588908) are included in this curation. Additional reports are available in the literature (e.g. PMID: 34089469) but the maximum score for genetic evidence (12 points) has already been reached. The mechanism of pathogenicity appears to be loss of function based on lack of PIGQ protein on Western blot in cells from a patient (Martin et al, 2014, PMID: 24463883) and reduction of surface localization of GPI-anchored proteins as well as FLAER labeling in granulocytes and fibroblasts from affected individuals (Martin et al, 2014, PMID: 24463883; Johnstone et al, 2020, PMID: 32588908).
This gene-disease relationship is also supported by the biochemical function of the gene product, which appears to stabilize the enzyme complex involved in the first step of GPI biosynthesis, GPI-N-acetylglucosaminyl-transferase (Watanabe et al, 1998, PMID: 9463366; Tiede et al, 1998, PMID: 9729469; Hong et al, 1999, PMID: 10373468), and interaction with the products of other genes, such as PIGA, which have been associated with a similar condition (Watanabe et al, 1998, PMID: 9463366). PIGA has been definitively associated with “complex neurological disorder” by the Epilepsy Gene Curation Expert Panel. (Score for experimental evidence = 2 points)
In summary, there is definitive evidence supporting the relationship between PIGQ and the autosomal recessive disorder “developmental and epileptic encephalopathy, 77”. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Congenital Disorders of Glycosylation Gene Curation Expert Panel on February 19, 2025 (SOP version 11).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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