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Intellectual disability

Gene: PIGU

Green List (high evidence)

PIGU (phosphatidylinositol glycan anchor biosynthesis class U)
EnsemblGeneIds (GRCh38): ENSG00000101464
EnsemblGeneIds (GRCh37): ENSG00000101464
OMIM: 608528, Gene2Phenotype
PIGU is in 4 panels

2 reviews

Rebecca Foulger (Genomics England curator)

PIGU (together with other PIGx genes) were discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 to discuss R59 Early onset or syndromic epilepsy. Agreed that there is enough evidence to rate PIGU Green on the 'Genetic epilepsy syndromes' panel (402). Therefore applied Green rating to the ID panel also: although PIGU is not yet associated with a disorder in OMIM or Gene2Phenotype, there are sufficient unrelated cases described in PMID:31353022.
Created: 15 Aug 2019, 8:03 a.m. | Last Modified: 15 Aug 2019, 8:03 a.m.
Panel Version: 2.998
Added 'missense' tag as missense variants only reported so far (PMID:31353022).
Created: 15 Aug 2019, 8 a.m. | Last Modified: 15 Aug 2019, 8 a.m.
Panel Version: 2.998
PMID:31353022 (Knaus et al. 2019) report two homozygous missense mutations (c.209T>A [p.Ile70Lys] and c.1149C>A [p.Asn383Lys]) in 5 individuals from 3 unrelated families. All individuals presented with global DD severe-to-profound ID, muscular hypotonia, seizures, brain anomalies, scoliosis, and mild facial dysmorphism. Sequencing confirmed that all parents were healthy carriers. c.209T>A has not been observed in gnomAD while c.1149C>A has been observed only in the heterozygous state (7/277194).
Created: 15 Aug 2019, 7:59 a.m. | Last Modified: 15 Aug 2019, 7:59 a.m.
Panel Version: 2.998
PIGU was added to the Intellectual disability and Genetic epilepsy syndromes panels, and rated Green, by Konstantinos Varvagiannis.
Created: 15 Aug 2019, 7:59 a.m. | Last Modified: 15 Aug 2019, 7:59 a.m.
Panel Version: 2.998

Konstantinos Varvagiannis (Other)

Green List (high evidence)

Knaus et al. (2019 - PMID: 31353022) report on 5 affected individuals (from 3 unrelated families) with biallelic pathogenic PIGU variants.

Common features included tone abnormalities, global DD, ID, seizures, CNS anomalies (cerebral atrophy and/or cerebellar hypoplasia), scoliosis. Affected individuals presented also with facial similarities. DD/ID were universal features and their severity appears to be relevant to the panel. Seizures were also reported in all individuals (myoclonic in 3, for whom this was specified). ALP was normal in all.

Three individuals from 2 non-consanguineous families (one from Norway, the other not specified) were homozygous for a missense variant NM_080476.4:c.1149C>A (or p.Asn383Lys) present with an AF of 7/277197 in Europeans. Two individuals born to consanguineous parents from Turkey were homozygous for another missense variant (c.209T>A or p.Ile70Lys - same RefSeq).

Segregation analyses in parents and unaffected sibs were carried out.

PIGU encodes a subunit of the GPI transaminidase, a heteropentameric complex (other subunits encoded by PIGK, PIGS, PIGT and GPAA1) that mediates attachment in the endoplasmic reticulum of glycosylphosphatidylinositol (GPI) to the C-termini of proteins which are subsequently anchored to the cell surface.

Pathogenic variants in 18 of 29 genes implicated in biosynthesis of the GPI anchor have been identified as a cause of GPI biosynthesis disorders, with ID and seizures as principal features. Mutations in other genes encoding components of the GPI transaminidase complex (GPAA1, PIGT and PIGS) lead to neurodevelopmental disorders.

Functional impairment of PIGU was supported by flow-cytometric analysis showing significant reduction of cell surface expression of GPI anchored proteins (mainly FLAER, CD16 and CD24) on granulocytes from affected individuals. In addition accumulation of free GPI anchors on the cell surface of B cells from affected individuals further suggested deficiency of the GPI transaminidase.

Transient expression of mutant (Asn383Lys) protein failed to rescue expression of GPI-APs to the same extent as wt in a CHO cell line deficient for PIGU.

Feature analysis demonstrated similarities among individuals with mutations in other genes of the GPI transamidase complex (GPAA1 and PIGT) as well as with GPI biosynthesis disorders. Facial analysis was also suggestive of facial similarities between individuals with GPAA1 and PIGU mutations.

PIGU is not associated with any phenotype in OMIM or G2P.

As a result this gene can be considered for inclusion in the ID and epilepsy panels probably as green (3 families, ID of relevant severity and seizures in all affected individuals, known group of disorders and supportive evidence) or amber.
Sources: Literature
Created: 7 Aug 2019, 5:16 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Global developmental delay; Intellectual disability; Seizures; Cerebral atrophy; Cerebellar hypoplasia; Scoliosis

Publications

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
Phenotypes
  • Glycosylphosphatidylinositol biosynthesis defect 2, 618590
  • Global developmental delay
  • Intellectual disability
  • Seizures
  • Cerebral atrophy
  • Cerebellar hypoplasia
  • Scoliosis
Tags
missense
OMIM
608528
Clinvar variants
Variants in PIGU
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

3 Oct 2019, Gel status: 3

Set Phenotypes

Rebecca Foulger (Genomics England curator)

Phenotypes for gene: PIGU were changed from Global developmental delay; Intellectual disability; Seizures; Cerebral atrophy; Cerebellar hypoplasia; Scoliosis to Glycosylphosphatidylinositol biosynthesis defect 2, 618590; Global developmental delay; Intellectual disability; Seizures; Cerebral atrophy; Cerebellar hypoplasia; Scoliosis

15 Aug 2019, Gel status: 3

Entity classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

Gene: pigu has been classified as Green List (High Evidence).

15 Aug 2019, Gel status: 0

Added Tag

Rebecca Foulger (Genomics England curator)

Tag missense tag was added to gene: PIGU.

7 Aug 2019, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes, Set penetrance

Konstantinos Varvagiannis (Other)

gene: PIGU was added gene: PIGU was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: PIGU was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PIGU were set to 31353022 Phenotypes for gene: PIGU were set to Global developmental delay; Intellectual disability; Seizures; Cerebral atrophy; Cerebellar hypoplasia; Scoliosis Penetrance for gene: PIGU were set to Complete Review for gene: PIGU was set to GREEN