Submission Details

PIGW was first reported in relation to autosomal recessive Glycosylphosphatidylinositol (GPI) biosynthesis defect 11 (MONDO:0014457) in 2014 (Chiyonobu T et al., PMID:24367057). This rare congenital glycosylation disorder is characterized by hypotonia, severe developmental delay, intellectual disability, seizures, increased serum alkaline phosphatase, and dysmorphic facial features. Defects in this gene have been identified as a cause of age-dependent epileptic spasms (West syndrome) as well as a syndrome exhibiting hyperphosphatasia and cognitive disability (HPMRS5) [provided by RefSeq, Jul 2017]. It is caused by mutations in the PIGW gene, which functions in the third step of GPI biosynthesis by acylating the inositol ring of phosphatidylinositol and encodes a 504–amino acid inositol acyltransferase (Murakami et al., 2003, PubMed:14517336). Eight variants (missense) that have been reported in 6 probands in 6 publications (Chiyonobu T et al., 2014, PMID:24367057; Hogrebe M et al., 2016, PMID:27626616; Meier N et al., 2019, PMID:30679815; Fu L et al., 2019, PMID:30813920; Peron A et al., 2020, PMID:32198969; and Foskett GK et al., 2018, PMID: ), are included in this curation. This gene-disease relationship is also supported by a rescue in cell culture model that mimics a specific inherited GPI deficiency and assesses the effectiveness of various synthetic compounds in reestablishing normal GPI biosynthesis. (Guerrero PA et al., 2021, PMID:34618440). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Congenital Disorder of Glycosylation GCEP on the meeting date February 6, 2025 (SOP Version 11).