Intellectual disability - microarray and sequencing
Gene: PIGH Green List (high evidence)The rating of this gene has been updated following NHS Genomic Medicine Service approval.Created: 9 Mar 2022, 3:40 p.m. | Last Modified: 9 Mar 2022, 3:40 p.m.
Panel Version: 3.1510
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
Comment on list classification: Changed from Red to Amber, recent publications support gene-disease association three affecteds (2 unrelated) casesCreated: 13 Sep 2018, 9:19 a.m.
Comment on publications: Added publications suggested from external expert review to support upgrading of the gene to AmberCreated: 13 Sep 2018, 9:15 a.m.
Comment on phenotypes: added phenotypes suggested by external reviewerCreated: 13 Sep 2018, 9:13 a.m.
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
Tag for-review was removed from gene: PIGH.
Source Expert Review Green was added to PIGH. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
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
Gene: pigh has been classified as Amber List (Moderate Evidence).
Tag for-review tag was added to gene: PIGH.
Gene: pigh has been classified as Amber List (Moderate Evidence).
Publications for gene: PIGH were set to 29603516
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
PIGH was added to Intellectual disability panel. Sources: Literature
PIGH was created by Ellen McDonagh
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 [email protected]
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.