Submission Details

PIGU (phosphatidylinositol glycan anchor biosynthesis class u protein) is located on chromosome 20 at 20q11.22. It is part of the PIG protein family, which is key in glycosylphosphatidylinositol synthesis. PIGU was first reported in relation to autosomal recessive glycosylphosphatidylinositol biosynthesis defect 21 (GPIBD21) in 2019 (Knaus et al., PMID: 31353022). This condition is characterized by development delay, intellectual disability, facial anomalies (such as malar flattening, thin upper lip, epicanthus, and depressed nose), vision issues (including hyperopia), seizures, muscular hypotonia, and brain anomalies (like corpus callosum hypoplasia). 2 variants (missense) that have been reported in 5 probands from 3 families in 1 publication (PMIDs: 31353022) are included in this curation. The mechanism of pathogenicity appears to be loss-of-function. This gene-disease relationship is also supported by experimental evidence (protein interaction, biochemical functional evidence; PMID: 30054924). Protein interaction and biochemical functional evidence shows that this protein is part of the phosphatidylinositol glycan (PIG) pathway, which is key in synthesis of glycosylphosphatidylinositol. PIGU is shown in this evidence to directly interact with specific proteins in the family that are associated with related neurodevelopmental disorders. 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 gene-disease pair was originally evaluated by the Syndromic Disorders GCEP on 5/20/2022. It was reevaluated on 6/23/2025 (SOP version 11). There was no new evidence. As a result of this reevaluation, the classification did not change.