PIGU

Inheritance Pattern: AR

Disease ID:MONDO:0032824

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0032824

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0032824

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0032824

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0032824

Submitter: ClinGen

*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.

Inheritance Pattern: AD

Disease ID:MONDO:0032824

Submitter: Illumina

The PIGU gene is located on chromosome 20 at 20q11.22 and encodes the phosphatidylinositol glycan anchor biosynthesis class U protein, a ubiquitously expressed protein which is a component of the glycosylphosphatidylinositol (GPI) transamidase complex. The glycosylphosphatidylinositol (GPI) anchor links many types of protein to the cell surface and the GPI transamidase complex couples the GPI anchored proteins (GPI-APs) onto the GPI anchor within the endoplasmic reticulum before transport to the cell surface. GPI-APs mediate a range of cellular processes including cellular signalling, cell adhesion and immune modulation as well as playing key roles in embryogenesis and neurodevelopment. The PIGU gene was first reported in relation to autosomal dominant PIGU-related glycosylphosphatidylinositol biosynthesis deficiency in 2019 (31353022: Knaus et al. 2019). In this report, two missense variants were associated with PIGU-related glycosylphosphatidylinositol biosynthesis deficiency in five individuals from three families. In all cases variants were identified in a homozygous state and caused a reduction in presentation of cell surface GPI anchored proteins, due to decreased GPI transaminase activity (31353022: Knaus et al. 2019). A number of genes associated with biosynthesis of the GPI anchor have been identified, these disorders, collectively known as GPI biosynthesis deficiencies are associated with a clinical spectrum of disease which includes intellectual disability and seizures as the key features (30054924: Bellai-Dussault et al. 2019). Specifically, three further components of the GPI transamidase complex; GPAA1, PIGT and PIGS have all been associated with autosomal recessive glycosylphosphatidylinositol biosynthesis deficiencies (12802054: Hong et al. 2013). 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.