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Intellectual disability

Gene: PIGH

Amber List (moderate evidence)

PIGH (phosphatidylinositol glycan anchor biosynthesis class H)
EnsemblGeneIds (GRCh38): ENSG00000100564
EnsemblGeneIds (GRCh37): ENSG00000100564
OMIM: 600154, Gene2Phenotype
PIGH is in 3 panels

3 reviews

Eleanor Williams (Genomics England Curator)

Green List (high evidence)

Comment on list classification: Leaving as amber for now, but this gene should be reviewed at the next GMS update. It is borderline green as there are 5 families reported with DD/ID but only two without epilepsy.
Created: 12 Nov 2020, 6:33 p.m. | Last Modified: 12 Nov 2020, 6:33 p.m.
Panel Version: 3.527
Associated with Glycosylphosphatidylinositol biosynthesis defect 17 #618010 (AR) in OMIM with delayed development and Learning disabilities as clinical features.

5 families reported, with all probands with mild to severe DD/ID. Only 2 families have probands with no epilepsy reported, therefore borderline green/amber rating.

PMID: 33156547 - Tremblay-Laganière et al 2020 - report three new unrelated families with two different bi-allelic PIGH variants. Family 1 - 4 year old boy of Indian origin with significantly impaired language acquisition and autism spectrum disorder. No seizures. Family 2 - 2 siblings Guatemalan origin both with severe DD/ID and poorly controlled early-onset seizures. Family 3 - 4-year-old girl, of Azerbaijani origin. She had febrile seizures at 7 months old and mild motor delay. From 1.5 year old, she developed afebrile seizures.

PMID: 29573052 - Pagnamenta et al 2018 - report 2 siblings from a consanguineous Pakistani family harboring a homozygous c.1A > T variant in PIGH resulting in defective GPI-anchor biogenesis. There was low exome coverage of the region but both parents were heterozygous carriers of c.1A > T. The initial proband was reported with short stature, epilepsy, developmental delay, and behavioral difficulties and his sister was similarly affected. He is described as having mild learning difficulties. Seizures were first noted at 14 months, but were well controlled by treatment. The sister developed epilepsy at 3.5 years and has not been well controlled. Initial development was normal but she has difficulties with both verbal and nonverbal communication. Functional studies show that the variant results in a truncated version of PIGH.

PMID: 29603516 - Nguyen et al 2018 - report an individual with a homozygous missense variant (p.Ser103Pro) in PIGH, identified by exome sequencing, who had hypotonia, moderate developmental delay, and autism. The parents were consanguineous couple of Indian origin. The proband did not have epilepsy; however, he did have two episodes of febrile seizures at 17 months of age. Using patient granulocytes, they show that homozygosity of the Ser103Pro leads to a decreased ability to synthesize GPI anchored proteins.
Created: 12 Nov 2020, 6:31 p.m. | Last Modified: 12 Nov 2020, 6:31 p.m.
Panel Version: 3.526

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Glycosylphosphatidylinositol biosynthesis defect 17 OMIM:618010

Publications

Louise Daugherty (Genomics England Curator)

Comment on list classification: Changed from Red to Amber, recent publications support gene-disease association three affecteds (2 unrelated) cases
Created: 13 Sep 2018, 9:19 a.m.
Comment on publications: Added publications suggested from external expert review to support upgrading of the gene to Amber
Created: 13 Sep 2018, 9:15 a.m.
Comment on phenotypes: added phenotypes suggested by external reviewer
Created: 13 Sep 2018, 9:13 a.m.

Zornitza Stark (Australian Genomics)

Green List (high evidence)

I note this gene is Green on the epilepsy panel, and I agree this family of genes cause similar phenotypes, there is some functional data to support the gene-disease relationship, so we have rated it Green on both panels.
Created: 10 Feb 2020, 5:34 a.m. | Last Modified: 10 Feb 2020, 5:34 a.m.
Panel Version: 3.0
Please note two recent reports.
Created: 3 Sep 2018, 2:41 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Glycosylphosphatidylinositol biosynthesis defect 17, MIM#618010

Publications

Variants in this GENE are reported as part of current diagnostic practice

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Amber
Phenotypes
  • Glycosylphosphatidylinositol biosynthesis defect, 17 OMIM:618010
  • Hypotonia, moderate developmental delay, and autism, two episodes of febrile seizures
Tags
Autism Spectrum Disorder for-review
OMIM
600154
Clinvar variants
Variants in PIGH
Penetrance
None
Publications
Panels with this gene

History Filter Activity

12 Nov 2020, Gel status: 2

Set Phenotypes

Eleanor Williams (Genomics England Curator)

Phenotypes for gene: PIGH were changed from Glycosylphosphatidylinositol biosynthesis defect, 17; 618010; Hypotonia, moderate developmental delay, and autism, two episodes of febrile seizures to Glycosylphosphatidylinositol biosynthesis defect, 17 OMIM:618010; Hypotonia, moderate developmental delay, and autism, two episodes of febrile seizures

12 Nov 2020, Gel status: 2

Entity classified by Genomics England curator

Eleanor Williams (Genomics England Curator)

Gene: pigh has been classified as Amber List (Moderate Evidence).

12 Nov 2020, Gel status: 2

Added Tag

Eleanor Williams (Genomics England Curator)

Tag for-review tag was added to gene: PIGH.

13 Sep 2018, Gel status: 2

Entity classified by Genomics England curator

Louise Daugherty (Genomics England Curator)

Gene: pigh has been classified as Amber List (Moderate Evidence).

13 Sep 2018, Gel status: 1

Set publications

Louise Daugherty (Genomics England Curator)

Publications for gene: PIGH were set to 29603516

13 Sep 2018, Gel status: 1

Set Phenotypes

Louise Daugherty (Genomics England Curator)

Phenotypes for gene: PIGH were changed from hypotonia, moderate developmental delay, and autism, two episodes of febrile seizures to Glycosylphosphatidylinositol biosynthesis defect, 17; 618010; Hypotonia, moderate developmental delay, and autism, two episodes of febrile seizures

4 Apr 2018, Gel status: 1

Added New Source

Ellen McDonagh (Genomics England Curator)

PIGH was added to Intellectual disability panel. Sources: Literature

4 Apr 2018, Gel status: 1

Created

Ellen McDonagh (Genomics England Curator)

PIGH was created by Ellen McDonagh