Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: CASP10

I don't know

The rating of this gene has been updated to amber and the mode of inheritance updated to BOTH monoallelic and biallelic, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.

Created: 24 Feb 2025, 12:01 p.m. | Last Modified: 24 Feb 2025, 12:01 p.m.

Panel Version: 7.26

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

I don't know

Comment on mode of inheritance: Both monoallelic and biallelic variant have been reported (PMID: 38704374).

Created: 8 Aug 2024, 3:40 p.m. | Last Modified: 8 Aug 2024, 3:40 p.m.

Panel Version: 6.4

PMID: 38704374, aimed to assess the impact of CASP10 variants on autoimmune lymphoproliferative syndrome (ALPS) pathogenesis, by assessing the effect of CASP10 variants within the Imagine Institute's genetic platform (INSERM UMR 1163, Paris, France). Using this large dataset, the authors were able to confirm that the missense variants p.V410I and p.Y446C, are present in the general population at a high frequency. Furthermore, these variants do not affect the CASP10 catalytic domain and no difference was observed in CASP10 protein expression or FAS-mediated apoptosis between healthy controls and subjects bearing these variants in both homozygous and heterozygous states. Two patient had the CASP10 variant p.C401LfsX15, which is lies within QACQG catalytic site in the CASP10 catalytic domain. The patient S2 was homozygous for this variant, resulting in a lack of Caspase-10 RNA and protein. However, the authors report that "FAS-mediated apoptosis was surprisingly comparable to healthy controls in each of the tested cell lines suspected to have a role in ALPS". In patient S1, who was heterozygous p.C401LfsX15, the authors report that although the levels of CASP10 protein expression was reduced, there was normal FAS-mediated apoptosis compared to healthy controls. From these results, the authors conclude that it appears that "Caspase-10 is dispensable for FAS-mediated apoptosis: an undetectable CASP10 protein expression has no impact on lymphocyte apoptosis and on individuals’ clinical and laboratory phenotype". Although they do comment, that post-translational or epigenetic mechanisms may play a role, as yet unidentified.

Created: 8 Aug 2024, 3:35 p.m. | Last Modified: 8 Aug 2024, 3:35 p.m.

Panel Version: 6.2

Comment on phenotypes: Autoimmune lymphoproliferative syndrome (ALPS); Adenopathies, splenomegaly, autoimmunity; Diseases of Immune Dysregulation

Created: 8 Aug 2024, 2:40 p.m. | Last Modified: 8 Aug 2024, 2:40 p.m.

Panel Version: 6.2

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Publications

• 38704374

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, 12:27 p.m. | Last Modified: 14 Oct 2020, 12:27 p.m.

Panel Version: 2.228

The following PubMed IDs were added to gene CASP10 (OMIM gene MIM#601762): 16446975;27378136. 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

• 16446975
• 27378136

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)

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): CASP10 .PanelApp HGNC gene symbol check: CASP10 . IUIS Disease: ALPS-Caspase10 . IUIS Inheritance: AD .T cells: responses to PHA may be decreased, .B cells: Normal, .IUIS Other affected cells: N/A. IUIS Associated features: Adenopathies, splenomegaly, autoimmunity. IUIS Major category: Diseases of Immune Dysregulation. IUIS Subcategory: Autoimmune Lymphoproliferative Syndrome (ALPS, Canale Smith syndrome)

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

Comment on list classification: Changed status from Amber to Green, there are more than 3 unrelated cases to support the PID phenotype

Created: 1 May 2018, 2:47 p.m.

Comment on phenotypes: Added MIMid from OMIM

Created: 1 May 2018, 2:46 p.m.

Comment on publications: Added publications to support the PID phenotype in more than three unrelated cases

Created: 1 May 2018, 2:44 p.m.

From Orphanet: ALPS is clinically heterogeneous with the following primary clinical signs: lymphoproliferation, manifesting as lymphadenopathy and hepatosplenomegaly with or without hypersplenism, often improving with age, autoimmune disease, mostly involving blood cells, and an increased risk of lymphoma lifelong. Autoimmunity has been reported to potentially affect almost any organ, leading to uveitis, pulmonary fibrosis, gastritis, colitis, nephritis, urticaria, arthritis, or rarely autoimmune neurological complications. The disease course is also variable. Several genetic subtypes based on the causative genes and types of mutations have been proposed and result in often similar clinical presentations and outcomes. These include ALPS-FAS, ALPS-FASLG (FASgene), ALPS-CASP10 (CASP10), and ALPS-U (undetermined genetic defect).

Created: 1 May 2018, 2:40 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 downloaded from ESID Registry. ESID_Gene_original: Caspase 10 (ALPS IIA), PanelApp HGNC gene symbol check: CASP10, ESID classification: Main_category/ Sub_category/ PID_Diagnosis Diseases of immune dysregulation / Autoimmune lymphoproliferative syndrome (ALPS) / Autoimmune lymphoproliferative syndrome (ALPS)

Created: 17 Apr 2018, 12:29 p.m.

Original metadata supplied by GRID. GRID Gene Symbol HGNC PanelApp check: CASP10, GRID_Gene_Symbol: CASP10, GRID_Transcript_ENS_Community submitted: ENST00000286186, GRID_Transcript_RefSeq: NM_032977.3, GRID_Transcript_ENS_used_on_Production: ENST00000286186

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