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Intellectual disability

Gene: PIGB

Green List (high evidence)

PIGB (phosphatidylinositol glycan anchor biosynthesis class B)
EnsemblGeneIds (GRCh38): ENSG00000069943
EnsemblGeneIds (GRCh37): ENSG00000069943
OMIM: 604122, Gene2Phenotype
PIGB is in 3 panels

2 reviews

Catherine Snow (Genomics England)

Green List (high evidence)

Konstantinos Varvagiannis left a review based on PMID: 31256876 which reported on 14 individuals from 10 families (4 of which consanguineous) with biallelic pathogenic PIGB variants.

Sufficient number of independent families with a number of variants identified, 8 missense, 1 stopgain as well as an intronic SNV are reported. Epilepsy with varied types of seizures reported in all affected individuals, age of onset ranging from age 1 day to 6 months. All individuals have DD/ID although no details are provided on whether developmental regression occurs.
The phenotype was similar to other inherited glycosylphosphatidylinositol (GPI) deficiencies (IGDs). As happens to be the case in some other GPI deficiencies alkaline phosphatase was also elevated in those tested, (except one).

PIGB is not associated with any phenotype terms in OMIM or any phenotypes in Gene2Phenotype.
Created: 1 Aug 2019, 3:51 p.m. | Last Modified: 1 Aug 2019, 3:51 p.m.
Panel Version: 2.992

Konstantinos Varvagiannis (Other)

Green List (high evidence)

Murakami et al. (2019 - PMID: 31256876) provide detailed information on 14 individuals from 10 families (4 of which consanguineous) with biallelic pathogenic PIGB variants.

Overlapping features included DD/ID (13/13), epilepsy (14/14), deafness (7/14), ophthalmological or brain anomalies, hand and feet anomalies as well as presence of dysmorphic features. ID was common, in those individuals with appropriate age. Some had a previous diagnosis of DOORS syndrome (deafness/onychodystrophy/osteodystrophy,retardation, seizures) and few showed 2-oxoglutatic aciduria which can also be seen in DOORS s.

PIGB encodes phosphatidylinositol glycan anchor biosynthesis class B protein.

Overall the phenotype was similar to other inherited glycosylphosphatidylinositol (GPI) deficiencies (IGDs). As happens to be the case in some other GPI deficiencies alkaline phosphatase was also elevated in those tested (8/9).

8 missense, 1 stopgain as well as an intronic SNV are reported. All variants were either absent or ultra-rare and with no homozygotes in gnomAD.

Affected individuals from 4 families, harbored an intronic SNV in the homozygous state. For this variant - with MAF of 0.0001592 or 6.51x10-5 in ExAC and gnomAD - activation of an aberrant splice acceptor site was shown [NM_004855.4:c.847-10A>G or p.Gln282_Trp283insArgCysGln].

Flow cytometric analysis of blood cells or fibroblasts showed decreased levels for various GPI-AP (GPI-anchored protein) markers in affected individuals. These levels were rescued upon transduction with a PIGB-encoding-Lx304 lentiviral vector of fibroblasts from one affected individual, suggesting that the PIGB defect was responsible.

The effect of the variants was evaluated using PIGB-deficient CHO cells, transfected with wt or mutant PIGB cDNAs. FACS analysis and immunoblotting demonstrated that variants were able to restore only slightly/partially - if at all - the surface presence of GPI-APs in the case of variants while the levels of mutant protein were reduced.

PIGB is not associated with any phenotype in OMIM/G2P. This gene is not commonly included in gene panels for ID offered by diagnostic laboratories.

As a result, this gene can be considered for inclusion in the ID and epilepsy panels probably as green (or amber).
Sources: Literature
Created: 15 Jul 2019, 5:31 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Hearing abnormality; Abnormality of vision; Elevated alkaline phosphatase; Abnormality of the head; Abnormality of the hand; Abnormality of the foot

Publications

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
Phenotypes
  • Epileptic encephalopathy, early infantile, 80, 618580
  • Generalized hypotonia
  • Global developmental delay
  • Intellectual disability
  • Seizures
  • Hearing abnormality
  • Abnormality of vision
  • Elevated alkaline phosphatase
  • Abnormality of the head
  • Abnormality of the hand
  • Abnormality of the foot
OMIM
604122
Clinvar variants
Variants in PIGB
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: PIGB were changed from Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Hearing abnormality; Abnormality of vision; Elevated alkaline phosphatase; Abnormality of the head; Abnormality of the hand; Abnormality of the foot to Epileptic encephalopathy, early infantile, 80, 618580; Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Hearing abnormality; Abnormality of vision; Elevated alkaline phosphatase; Abnormality of the head; Abnormality of the hand; Abnormality of the foot

1 Aug 2019, Gel status: 3

Entity classified by Genomics England curator

Catherine Snow (Genomics England)

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

1 Aug 2019, Gel status: 3

Entity classified by Genomics England curator

Catherine Snow (Genomics England)

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

15 Jul 2019, Gel status: 0

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

Konstantinos Varvagiannis (Other)

gene: PIGB was added gene: PIGB was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: PIGB was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PIGB were set to 31256876 Phenotypes for gene: PIGB were set to Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Hearing abnormality; Abnormality of vision; Elevated alkaline phosphatase; Abnormality of the head; Abnormality of the hand; Abnormality of the foot Penetrance for gene: PIGB were set to Complete Review for gene: PIGB was set to GREEN