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Intellectual disability - microarray and sequencing v3.981 PIGU Arina Puzriakova Phenotypes for gene: PIGU were changed from Glycosylphosphatidylinositol biosynthesis defect 2, 618590; Global developmental delay; Intellectual disability; Seizures; Cerebral atrophy; Cerebellar hypoplasia; Scoliosis to Neurodevelopmental disorder with brain anomalies, seizures, and scoliosis, OMIM:618590
Intellectual disability - microarray and sequencing v2.1059 PIGU Rebecca Foulger 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
Intellectual disability - microarray and sequencing v2.999 PIGU Rebecca Foulger Classified gene: PIGU as Green List (high evidence)
Intellectual disability - microarray and sequencing v2.999 PIGU Rebecca Foulger Gene: pigu has been classified as Green List (High Evidence).
Intellectual disability - microarray and sequencing v2.998 PIGU Rebecca Foulger commented on gene: PIGU: 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.
Intellectual disability - microarray and sequencing v2.998 PIGU Rebecca Foulger commented on gene: PIGU: Added 'missense' tag as missense variants only reported so far (PMID:31353022).
Intellectual disability - microarray and sequencing v2.998 PIGU Rebecca Foulger Tag missense tag was added to gene: PIGU.
Intellectual disability - microarray and sequencing v2.998 PIGU Rebecca Foulger commented on gene: PIGU: 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).
Intellectual disability - microarray and sequencing v2.998 PIGU Rebecca Foulger commented on gene: PIGU
Intellectual disability - microarray and sequencing v2.996 PIGU Konstantinos Varvagiannis 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
Added comment: 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