Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: CD40

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, 12:34 p.m. | Last Modified: 14 Oct 2020, 12:34 p.m.

Panel Version: 2.235

The following PubMed IDs were added to gene CD40 (OMIM gene MIM#109535): 12584544;24122029. These publications have been associated with the gene by the immunodeficiencies 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

• 12584544
• 24122029

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): CD40 (TNFRSF5) .PanelApp HGNC gene symbol check: CD40 . IUIS Disease: CD40 deficiency . IUIS Inheritance: AR .T cells: N/A, .B cells: sIgM+, IgD+ cells present, absent sIgG+, IgA+ and IgE+ cells, .IUIS Other affected cells: N/A. IUIS Associated features: Neutropenia, opportunistic infections, gastrointestinal and biliary tract and liver disease, Cryptosporidium infections. IUIS Major category: Immunodeficiencies affecting cellular and humoral immunity. IUIS Subcategory: Combined Immunodeficiencies Generally Less Profound than Severe Combined Immunodeficiency

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

TNFRSF5 (gene name tumor necrosis factor receptor superfamily, member 5) is the previous gene symbol for CD40 (gene name CD40 molecule)

Created: 4 May 2018, 3:22 p.m.

Comment on list classification: changed from Amber to Green

Created: 4 May 2018, 12:35 p.m.

Comment on publications: Added PMID: 17502893 (2007) First report of successful stem cell transplantation in a child with CD40 deficiency

Created: 4 May 2018, 12:33 p.m.

from genereview PMID: 20301287 (2017) on Autoimmune Lymphoproliferative Syndrome: Variants in CD40 cause non-X-linked forms of hyper IgM syndrome (HIGM type) in varying degrees, they share features with the X-linked form caused by pathogenic variants in CD40LG. Shared features include recurrent bacterial infections such as otitis media, sinusitis, and pneumonias. Autoimmune hematologic disorders including neutropenia, thrombocytopenia, and hemolytic anemia are also found. Other complications may include lymphomas and other malignancies as well as gastrointestinal complications. Serum concentration of IgM is elevated while other immunoglobulin levels are normal; specific antibody responses are defective. Hyper IgM syndrome type 2, hyper IgM syndrome type 3 (which this entry describes), Hyper IgM syndrome type 4 and Hyper IgM syndrome type 5 are other forms of non-X-linked hyper IgM syndrome (OMIM PS308230). Their inclusion in the differential diagnosis of ALPS is less clear on the basis of known clinical presentation and inheritance pattern Ferrari et al 2001, PMID:11675497, Imai et al 2003 PMID:12584544.

Created: 4 May 2018, 11:24 a.m.

Comment on publications: Added publications to support the PID phenotype PMID: 11675497 describes 3 affected (2 unrelated) and PMID: 12584544 a further affected patient unrelated to those reported in PMID:11675497. Also added Genereview.

Created: 4 May 2018, 11:14 a.m.

from OMIM autosomal recessive hyper-IgM immunodeficiency type 3 (HIGM3) results from homozygous mutation in the CD40 gene

Created: 4 May 2018, 10:56 a.m.

Comment on phenotypes: added orphanet synonym phenotype. HIGM3 is clinically identical to XHIGM (the disease with the defect in CD40 ligand). The autosomal recessive forms of HIGM can be suspected if a patient has the characteristics of XHIGM but is either a female and/or has a normal CD40 ligand gene with normal expression on activated T-lymphocytes.

Created: 4 May 2018, 10:54 a.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: CD40 (TNFRSF5), PanelApp HGNC gene symbol check: CD40, ESID classification: Main_category/ Sub_category/ PID_Diagnosis Predominantly antibody disorders / Class switch recombination defects (CSR) / HIGM syndromes / CSR defects and Hyper IgM (HIGM) syndromes

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

Original metadata supplied by GRID. GRID Gene Symbol HGNC PanelApp check: CD40, GRID_Gene_Symbol: CD40, GRID_Transcript_ENS_Community submitted: ENST00000372285, GRID_Transcript_RefSeq: NM_001250.4, GRID_Transcript_ENS_used_on_Production: ENST00000372285

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

Publications

• 11675497
• 12584544
• 2030128
• 7 17502893