Intellectual disability - microarray and sequencing
Gene: TPP2 Green List (high evidence)Green List (high evidence)
The rating of this gene has been updated to Green and the mode of inheritance set to 'BIALLELIC, autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.Created: 30 Jan 2023, 5:50 p.m. | Last Modified: 30 Jan 2023, 5:50 p.m.
Panel Version: 4.53
Comment on list classification: Promoting this gene from red to amber with a recommendation for GREEN rating following GMS review. Clinical advice was to be inclusive since the intellectual disability phenotype is relatively consistent.Created: 28 Sep 2022, 6:38 p.m. | Last Modified: 28 Sep 2022, 6:38 p.m.
Panel Version: 3.1730
As the first presentation for patients is features of immune deficiency and autoimmunity, seeking clinical input before proposing a rating for this gene on the intellectual disability panel.Created: 10 Aug 2022, 7:25 p.m. | Last Modified: 10 Aug 2022, 7:25 p.m.
Panel Version: 3.1668
Associated with Immunodeficiency 78 with autoimmunity and developmental delay, #619220 in OMIM.
Cases from 5 families (2 with the same deletion, from the same area) reported, who present in early childhood with features of immune deficiency and autoimmunity. Developmental delay is also a feature.
PMID: 33586135 - Atallah et al 2021 - 4 individuals from 2 families of Swiss origin (same region) with immune system dysregulation (severe immunodeficiency with autoimmunity) and intellectual disability who were found by WGS to be homozygous for a 4.4 Kb deletion removing exons 20–23 of the TPP2 gene, predicting a frameshift with premature termination of the protein. The parents and unaffected siblings were heterozygous for the deletion.
PMID: 25414442 - Stepensky et al 2015 - describe 2 siblings with Evans syndrome, viral infections, and progressive leukopenia. DNA available from one patient showed a homozygous frameshift mutation in TPP2. This patient is reported to have mild developmental delay, the sibling did not show this phenotype.
PMID: 25525876 - Lu et al 2014 - 4 patients from 2 families with a clinical phenotype of combined immunodeficiency, severe autoimmunity, and developmental delay were found to have homozygous variants in the TTP2 gene (nonsense variant and missense variant). The parents were heterozygous. For all except one (who was screened in early infancy) the patients presented in early childhood with recurrent bacterial and viral infections of the respiratory tract and middle ear. All patients had mild to moderate developmental delay.
Reinthaler et al 2018 (PMID:30533531) report a Syrian family with milder symptoms of sterile brain inflammation mimicking MS and no developmental delay. A missense variant, c.82T>G, p.Cys28Gly, in TPP2 was identified in all 3 affected siblings of the family. In a Jordian patient with MS a further homozygous missense variant (c.2027C>T, p.Thr676Ile) in TPP2 was identified.Created: 10 Aug 2022, 5:37 p.m. | Last Modified: 10 Aug 2022, 5:37 p.m.
Panel Version: 3.1667
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Publications
Tag Q3_22_rating was removed from gene: TPP2.
Source NHS GMS was added to TPP2. Source Expert Review Green was added to TPP2. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Tag Q3_22_MOI was removed from gene: TPP2.
Gene: tpp2 has been classified as Amber List (Moderate Evidence).
Tag Q3_22_rating tag was added to gene: TPP2. Tag Q3_22_MOI tag was added to gene: TPP2.
Publications for gene: TPP2 were set to
gene: TPP2 was added gene: TPP2 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: TPP2 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: TPP2 were set to Immunodeficiency 78 with autoimmunity and developmental delay, OMIM:619220
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.