Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: CASP8

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, 12:30 p.m. | Last Modified: 14 Oct 2020, 12:30 p.m.

Panel Version: 2.229

The following PubMed IDs were added to gene CASP8 (OMIM gene MIM#601763): 12353035;15492869. 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

• 12353035
• 15492869

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): CASP8 .PanelApp HGNC gene symbol check: CASP8 . IUIS Disease: ALPS-Caspase 8 . IUIS Inheritance: AR .T cells: N/A, .B cells: Normal, .IUIS Other affected cells: N/A. IUIS Associated features: Adenopathies, splenomegaly, bacterial and viral infections, hypogammaglobulinemia. 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 Amber to Green from external review recommendation. This gene is also "Green" high evidence on the following external panel: Immunological disorders Victorian Clinical Genetics Services, GRID, GOSH

Created: 21 Jun 2018, 12:48 p.m.

Comment on mode of inheritance: corrected MOI from external clinical review

Created: 21 Jun 2018, 12:45 p.m.

After internal clinical review it was decided to leave as amber, whilst awaiting more information on this gene and potential disease association.

Created: 11 May 2018, 3:48 p.m.

Kept as amber until further evidence in the literature or from external expert review input. The gene is on both the GRID and GOSH diagnostic panels for Autoimmune lymphoproliferative syndrome.

Created: 1 May 2018, 3:42 p.m.

Recently, two more patients from the same extended family as those described in Chun et al 2002 PMID:12353035 (2002) have been identified Niemela J et al. PMID: 25814141 (2015). These patients had immunodeficiency, with recurrent sino pulmonary infections, warts, molluscum contagiosum, poor pneumococcal antibodies, and normal DNTs. Besides their splenomegaly and lymphocytosis, they also had accumulation of lymphocytes in multiple organs such as liver, spleen, lung, and brain. Patient 1 died from complications of a pulmonary transplant for interstitial lung disease of unknown etiology. Patient 2 died due to progressive pulmonary and neurological problems. The lymphocytic infiltration seen in these older patients is similar to the one seen in parenchymal organs of older mice lacking caspase-8 within their T cells PMID: 24240292 (2013). Thus, CEDS in both humans and mice is characterized by a mild combined immunodeficiency with pronounced lymphocyte accumulation and infiltration but minimal autoimmunity.

Created: 1 May 2018, 3:22 p.m.

Comment on publications: added GeneReview publication PMID:20301287, Mouse model PMID:24240292, and another case PMID:25814141. Additional autoimmune lymphoproliferative syndromes review PMID:24240292.

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

From GeneReview PMID: 20301287: CEDS is a rare, autosomal recessive immunodeficiency syndrome resulting in lymphadenopathy, splenomegaly, marginal elevation of double-negative T cells, and defective FAS-mediated apoptosis, in addition to frequent bacterial and viral infections secondary to defective activation of T and B lymphocytes and NK cells. Autoimmunity has not been reported to date in individuals with CEDS. The risk of lymphoma in people with CASP8 pathogenic variants is not known, nor has the full spectrum of the disease been elucidated given the rarity of individuals with known pathogenic variants Chun et al 2002 (PMID: 12353035) and Niemela J 2015 (PMID: 25814141)

Created: 1 May 2018, 3:16 p.m.

Comment on publications: PMID:12353035 (2002) identified a homozygous mutation in the CASP8 gene in one family with 2 affected sibs from a consanguineous family with caspase-8 deficiency. They had autoimmune lymphoproliferative syndrome (ALPS) accompanied by infections, and T, B and NK cell defects.

Created: 1 May 2018, 3:01 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, 2:57 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 8, PanelApp HGNC gene symbol check: CASP8, ESID classification: Main_category/ Sub_category/ PID_Diagnosis Combined immunodeficiencies / Combined immunodeficiency (CID) / Combined immunodeficiency; 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: CASP8, GRID_Gene_Symbol: CASP8, GRID_Transcript_ENS_Community submitted: ENST00000358485, GRID_Transcript_RefSeq: NM_001228.4, GRID_Transcript_ENS_used_on_Production: ENST00000358485

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