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Intellectual disability

Gene: TPP2

Green List (high evidence)
TPP2 (tripeptidyl peptidase 2)
EnsemblGeneIds (GRCh38): ENSG00000134900
EnsemblGeneIds (GRCh37): ENSG00000134900
OMIM: 190470, Gene2Phenotype
TPP2 is in 5 panels

2 reviews

Arina Puzriakova (Genomics England Curator)

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
Created: 30 Jan 2023, 5:50 p.m.
Last Modified: 30 Jan 2023, 5:50 p.m.
Panel version: 4.53

Eleanor Williams (Genomics England Curator)

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

Created: 10 Aug 2022, 5:37 p.m.
Last Modified: 10 Aug 2022, 5:37 p.m.
Panel version: 3.1668

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • NHS GMS
  • Literature
Phenotypes
  • Immunodeficiency 78 with autoimmunity and developmental delay, OMIM:619220
OMIM
190470
Clinvar variants
Variants in TPP2
Penetrance
None
Publications
Panels with this gene

History Filter Activity

31 Jan 2023, Gel status: 3

Removed Tag

Arina Puzriakova (Genomics England Curator)

Tag Q3_22_rating was removed from gene: TPP2.

30 Jan 2023, Gel status: 3

Added New Source, Added New Source, Status Update

Arina Puzriakova (Genomics England Curator)

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)

29 Sep 2022, Gel status: 2

Removed Tag

Arina Puzriakova (Genomics England Curator)

Tag Q3_22_MOI was removed from gene: TPP2.

28 Sep 2022, Gel status: 2

Entity classified by Genomics England curator

Eleanor Williams (Genomics England Curator)

Gene: tpp2 has been classified as Amber List (Moderate Evidence).

28 Sep 2022, Gel status: 1

Added Tag, Added Tag

Eleanor Williams (Genomics England Curator)

Tag Q3_22_rating tag was added to gene: TPP2. Tag Q3_22_MOI tag was added to gene: TPP2.

10 Aug 2022, Gel status: 1

Set publications

Eleanor Williams (Genomics England Curator)

Publications for gene: TPP2 were set to

10 Aug 2022, Gel status: 1

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

Eleanor Williams (Genomics England Curator)

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