Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: CTPS1

Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.

Created: 14 Oct 2020, 12:41 p.m. | Last Modified: 14 Oct 2020, 12:41 p.m.

Panel Version: 2.242

The following PubMed IDs were added to gene CTPS1 (OMIM gene MIM#123860): 24870241;29884857. These publications have been associated with the gene by the immunedysregulation subgroup of the Human Phenotype Ontology Immune Mediated Disorders Consortium (https://hpo-immune-mediated-disorders.groups.io/g/update) in August 2020.

Created: 13 Oct 2020, 9:36 a.m. | Last Modified: 13 Oct 2020, 9:36 a.m.

Panel Version: 2.208

Publications

• 24870241
• 29884857

Green List (high evidence)

agree with green gene

Created: 17 Sep 2019, 3:18 p.m. | Last Modified: 17 Sep 2019, 3:18 p.m.

Panel Version: 1.94

Green List (high evidence)

YES- this is covered on our targeted exome

Created: 17 Sep 2019, 3:18 p.m. | Last Modified: 17 Sep 2019, 3:18 p.m.

Panel Version: 1.94

Green List (high evidence)

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Green List (high evidence)

Gene rating submitted by Kimberly Gilmour and Austen Worth on behalf of London North GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email 6th September the Specialist Test Group all agreed there is enough evidence to rate this gene Green.

Created: 17 Sep 2019, 3:18 p.m. | Last Modified: 17 Sep 2019, 3:18 p.m.

Panel Version: 1.94

Gene rating submitted by Tracy Briggs, David Gokhale and Abigal Rousseau on behalf of North West GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email on 20th June the Specialist Test Group all agreed there is enough evidence to rate this gene Green.

Created: 17 Sep 2019, 3:18 p.m. | Last Modified: 17 Sep 2019, 3:18 p.m.

Panel Version: 1.94

OriginaI Metadata from IUIS classification table (February, 2018) downloaded 20180614. IUIS Genetic defect (original gene symbol in IUIS download): CTPS1 .PanelApp HGNC gene symbol check: CTPS1 . IUIS Disease: CTPS1 deficiency . IUIS Inheritance: AR .T cells: Increased activated T cells, .B cells: Nl/low , .IUIS Other affected cells: N/A. IUIS Associated features: Recurrent/chronic bacterial and viral infections (EBV, VZV), EBV lymphoproliferation, B-cell non-Hodgkin lymphoma. IUIS Major category: Diseases of Immune Dysregulation. IUIS Subcategory: Susceptibility to EBV and Lymphoproliferative Conditions

Created: 2 Jul 2018, 10:35 a.m.

Comment on list classification: Changed from Amber to Green after internal clinical review. Clinical consensus is that CTPS1 should be rated green, in view of meeting the threshold for numbers of cases but also some additional information pointing towards a deleterious effect from the variant (effect on splicing and expression pattern). This is considered further evidence for this gene, within the founder region. Consensus was sought in view of going against the current PanelApp founder variant rule.

Created: 8 Jun 2018, 8:32 a.m.

Past onto clinical team for further discussion. Our current PanelApp rules denote that for a founder mutation we cannot make these genes Green. There are exceptions to this rule (reviewed by clinical team) if there has been an additional pathogenic var. conformed/reported. In this instance there is currently only one mutation that gives rise to observed PID phenotype.

Created: 4 Jun 2018, 10 a.m.

From ClinVar : This variant is present in population databases (rs145092287, ExAC 0.02%). This variant has been reported to segregate with combined immunodeficiency in several families (PMID: 24870241, 27638562). ClinVar contains an entry for this variant (Variation ID: 140454). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant leads to skipping of exon 18 and reduced CTPS1 protein expression (PMID: 24870241). For these reasons, this variant has been classified as Pathogenic.

Created: 4 Jun 2018, 8:41 a.m.

Comment on publications: Added PMID: 27638562 (2016) report details two sisters with homozygous CTPS1 mutations, identified by exome sequencing. Similar to the previously published cases (Martin et al. 2014 PMID :24870241), these siblings, born to a non-consanguineous family, whose ancestors emigrated from Northern England, suffered from recurrent sino-pulmonary and viral infections, due to VZV and EBV.

Created: 4 Jun 2018, 8:39 a.m.

added found-effect tag

Created: 1 Jun 2018, 3:51 p.m.

from Genomics of Rare Immune Disorders (GRID) platform which is supported by Cambridge Biomedical Research centre/NHS East England NHS GMC : CTPS1 is associated to a type of SCID, with noted phenotype attributes via clinical review Prof T.W. Kuijpers: Patients develop Epstein-Barr Virus (EBV) driven Hemophagocytic Lymphohistiocytosis (HLH ). Severe EBV infection can be associated with immunodeficiencies that also predispose a patient to other viral infections PMID: 26424649.

Created: 1 Jun 2018, 3:24 p.m.

Only one variant has been reported (CTPS1, IVS17, G-C, -1 (rs145092287) NM_001905.2:c.1692-1G>C in the literature which seems to have a founder effect. from OMIM: 8 children from 5 families from the northwest region of England who manifested a combined deficiency of adaptive immunity Martin et al. (2014) PMID: 24870241 detected a homozygous G-to-C transversion at the -1 position of intron 17 of the CTPS1 gene (rs145092287) using whole-exome and confirmatory Sanger sequencing. The mutation was considered deleterious since CTPS1 protein expression could not be detected in lysates of EBV-transformed B cells and T-cell blasts from patients. All parents and unaffected sibs tested were heterozygous carriers. Sequencing of a cohort of 752 healthy individuals from the northwest of England gave an estimated frequency of homozygosity of 1 in 560,000. This frequency represented a more than 10-fold increase compared to the frequency estimated from available exome databases. Whole-exome sequencing data and analysis of polymorphic microsatellite markers in all patients revealed a common region of homozygosity of 1.1 Mb surrounding the mutation. These data indicated a founder effect.

Created: 1 Jun 2018, 3:19 p.m.

Comment on phenotypes: added phenotype from GRID/ BRIDGE PID project

Created: 1 Jun 2018, 2:12 p.m.

Comment on phenotypes: Added MIMid from OMIM and phenotype from Orphanet

Created: 1 Jun 2018, 2:04 p.m.

This gene was absent from the original PanelApp PID panel dataset (review April 2018). However it was listed in external expert immunodeficiency diagnostic gene list(s) GOSH or GRID. In this combined PID panel, this gene has been rated as AMBER and needs further curational review to assess pertinence prior to v1.

Created: 20 Apr 2018, 12:25 p.m.

Original metadata supplied by GRID. GRID Gene Symbol HGNC PanelApp check: CTPS1, GRID_Gene_Symbol: CTPS1, GRID_Transcript_ENS_Community submitted: ENST00000372621, GRID_Transcript_RefSeq: NM_001905.3, GRID_Transcript_ENS_used_on_Production: ENST00000372621

Created: 17 Apr 2018, 12:12 p.m.