Mendeliome
Gene: PIGU Amber List (moderate evidence)Green List (high evidence)
Comment for classification
ClinGen Syndromic Disorder VCEP classified this gene as Limited on 30/06/2025 however reports the same 5 probands as below.
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.Created: 4 Jul 2025, 9:53 p.m. | Last Modified: 4 Jul 2025, 9:53 p.m.
Panel Version: 1.2693
Phenotypes
glycosylphosphatidylinositol biosynthesis defect 21 MONDO:0032824
Publications
I don't know
Downgrade to Amber in light of ClinGen assessment. Only 2 variants reported.Created: 5 Jul 2025, 3:36 p.m. | Last Modified: 5 Jul 2025, 3:36 p.m.
Panel Version: 1.2696
5 patients from 3 unrelated families, with homozygous missense mutations in the PIGU gene. All individuals presented with global DD, severe-to-profound ID, muscular hypotonia, seizures, brain anomalies, scoliosis, and mild facial dysmorphism. Flow cytometric analysis of patient granulocytes showed a characteristic pattern, with reduced cell surface expression of CD16 and CD24. In addition, patient B cells showed increased expression of free GPI anchors determined by a specific antibody, T5. The findings suggested that PIGU mutations reduce the function of the GPI transamidase complex, leading to accumulation of free GPI anchors on the cell surface.Created: 13 Dec 2019, 5:19 a.m. | Last Modified: 13 Dec 2019, 5:19 a.m.
Panel Version: 0.308
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Glycosylphosphatidylinositol biosynthesis defect 21; OMIM #618590
Publications
Gene: pigu has been classified as Amber List (Moderate Evidence).
Gene: pigu has been classified as Green List (High Evidence).
Phenotypes for gene: PIGU were changed from to Glycosylphosphatidylinositol biosynthesis defect 21; OMIM #618590
Publications for gene: PIGU were set to
Mode of inheritance for gene: PIGU was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
gene: PIGU was added gene: PIGU was added to Mendeliome_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services Mode of inheritance for gene: PIGU was set to Unknown
If promoting or demoting a gene, please provide comments to justify a decision to move it.
Genes included in a Genomics England gene panel for a rare disease category (green list) should fit the criteria A-E outlined below.
These guidelines were developed as a combination of the ClinGen DEFINITIVE evidence for a causal role of the gene in the disease(a), and the Developmental Disorder Genotype-Phenotype (DDG2P) CONFIRMED DD Gene evidence level(b) (please see the original references provided below for full details). These help provide a guideline for expert reviewers when assessing whether a gene should be on the green or the red list of a panel.
A. There are plausible disease-causing mutations(i) within, affecting or encompassing an interpretable functional region(ii) of this gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
B. There are plausible disease-causing mutations(i) within, affecting or encompassing cis-regulatory elements convincingly affecting the expression of a single gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
C. As definitions A or B but in 2 or 3 unrelated cases/families with the phenotype, with the addition of convincing bioinformatic or functional evidence of causation e.g. known inborn error of metabolism with mutation in orthologous gene which is known to have the relevant deficient enzymatic activity in other species; existence of an animal model which recapitulates the human phenotype.
AND
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
AND
E. No convincing evidence exists or has emerged that contradicts the role of the gene in the specified phenotype.
(i)Plausible disease-causing mutations: Recurrent de novo mutations convincingly affecting gene function. Rare, fully-penetrant mutations - relevant genotype never, or very rarely, seen in controls. (ii) Interpretable functional region: ORF in protein coding genes miRNA stem or loop. (iii) Phenotype: the rare disease category, as described in the eligibility statement. (iv) Intermediate penetrance genes should not be included.
It’s assumed that loss-of-function variants in this gene can cause the disease/phenotype unless an exception to this rule is known. We would like to collect information regarding exceptions. An example exception is the PCSK9 gene, where loss-of-function variants are not relevant for a hypercholesterolemia phenotype as they are associated with increased LDL-cholesterol uptake via LDLR (PMID: 25911073).
If a curated set of known-pathogenic variants is available for this gene-phenotype, please contact us at panelapp@genomicsengland.co.uk
We classify loss-of-function variants as those with the following Sequence Ontology (SO) terms:
Term descriptions can be found on the PanelApp homepage and Ensembl.
If you are submitting this evaluation on behalf of a clinical laboratory please indicate whether you report variants in this gene as part of your current diagnostic practice by checking the box
Standardised terms were used to represent the gene-disease mode of inheritance, and were mapped to commonly used terms from the different sources. Below each of the terms is described, along with the equivalent commonly-used terms.
A variant on one allele of this gene can cause the disease, and imprinting has not been implicated.
A variant on the paternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on the maternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on one allele of this gene can cause the disease. This is the default used for autosomal dominant mode of inheritance where no knowledge of the imprinting status of the gene required to cause the disease is known. Mapped to the following commonly used terms from different sources: autosomal dominant, dominant, AD, DOMINANT.
A variant on both alleles of this gene is required to cause the disease. Mapped to the following commonly used terms from different sources: autosomal recessive, recessive, AR, RECESSIVE.
The disease can be caused by a variant on one or both alleles of this gene. Mapped to the following commonly used terms from different sources: autosomal recessive or autosomal dominant, recessive or dominant, AR/AD, AD/AR, DOMINANT/RECESSIVE, RECESSIVE/DOMINANT.
A variant on one allele of this gene can cause the disease, however a variant on both alleles of this gene can result in a more severe form of the disease/phenotype.
A variant in this gene can cause the disease in males as they have one X-chromosome allele, whereas a variant on both X-chromosome alleles is required to cause the disease in females. Mapped to the following commonly used term from different sources: X-linked recessive.
A variant in this gene can cause the disease in males as they have one X-chromosome allele. A variant on one allele of this gene may also cause the disease in females, though the disease/phenotype may be less severe and may have a later-onset than is seen in males. X-linked inactivation and mosaicism in different tissues complicate whether a female presents with the disease, and can change over their lifetime. This term is the default setting used for X-linked genes, where it is not known definitately whether females require a variant on each allele of this gene in order to be affected. Mapped to the following commonly used terms from different sources: X-linked dominant, x-linked, X-LINKED, X-linked.
The gene is in the mitochondrial genome and variants within this can cause this disease, maternally inherited. Mapped to the following commonly used term from different sources: Mitochondrial.
Mapped to the following commonly used terms from different sources: Unknown, NA, information not provided.
For example, if the mode of inheritance is digenic, please indicate this in the comments and which other gene is involved.