Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: ADAM17

The rating of this gene has been updated following NHS Genomic Medicine Service approval.

Created: 4 Mar 2022, 10:17 a.m. | Last Modified: 4 Mar 2022, 10:17 a.m.

Panel Version: 2.529

Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).

Created: 20 Oct 2020, 3:29 p.m. | Last Modified: 20 Oct 2020, 3:29 p.m.

Panel Version: 2.351

The following PubMed IDs were added to entity ADAM17: 22010916. These publications have been associated with OMIM phenotype MIM#614328, which is listed for this entity, by the autoinflammation 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

Comment on list classification: Changing rating from amber to green. 3 cases plus mouse model.

Created: 23 Apr 2020, 1:51 a.m. | Last Modified: 23 Apr 2020, 1:51 a.m.

Panel Version: 2.127

Provisionally associated with ?Inflammatory skin and bowel disease, neonatal, 1 #614328 (AR) in OMIM.

PMID: 22010916 - Blaydon et al 2011 - report 2 siblings with neonatal-onset inflammatory skin and bowel disease. The parents were consanguineous of Lebanese origin. One sibling died age 12 from fulminant parvovirus B19–associated myocarditis. A homozgyous 4 bp in exon 5 of ADAM17 (c.603–606delCAGA) segregated with the disease in this family; it was predicted that the mutation would introduce a frame shift and a premature stop codon (p.Asp201GlufsX11). The mutation is predicted to result in a protein that lacks all functional domains. There was reduced expression of ADAM17 in the affected brothers skin and small intestine.

PMID: 26683521 - Tsukerman et al 2015 - report a proband with consangiuneous parents with recurrent infections. He died at two years of age of respiratory failure and presumed sepsis. A homozygous deletion of exon 1 of ADAM17 was found. NK cells from the patient lacked ADAM17 protein expression. CD16 activity on the patient's NK cells is enhanced. In the study of Blaydon et al and in this study TNFα was barely secreted by the patient and in both cases this was accompanied by severe bacteremia.

PMID: 25804906 - Bandsma et al 2015 - report a proband presented with severe diarrhea, skin rash, and recurrent sepsis, eventually leading to her death at the age of 10 months. Exome sequencing identified a novel homozygous frameshift mutation in ADAM17 (NM_003183.4:c.308dupA) leading to a premature stop codon. CD4+ and CD8+ T-cell stimulation assays showed severely diminished tumor necrosis factor–α and interleukin-2 production.

PMID: 29560122 - Fuchslocher Chico et al 2018 - mouse model. ADAM17 knockout is lethal in mice, but hypomorphic ADAM17ex/ex mice have been created that express only ~5% of the original levels of ADAM17 in all tissues. These mice have increased susceptibility to dextran sulfate sodium (DSS)-induced colitis. They identify ADAM17 as a novel regulator of necroptosis.

Summary: 3 cases plus mouse model.

Created: 23 Apr 2020, 1:45 a.m. | Last Modified: 23 Apr 2020, 1:45 a.m.

Panel Version: 2.124

Publications

• 22010916

Green List (high evidence)

Three families and a mouse model.

Created: 9 Apr 2020, 12:27 a.m. | Last Modified: 9 Apr 2020, 12:27 a.m.

Panel Version: 2.46

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Inflammatory skin and bowel disease, neonatal, 1, MIM# 614328; Recurrent infections

Publications

• 22010916
• 29560122
• 26683521
• 25804906

I don't know

agree with all the Amber genes

Created: 25 Sep 2019, 1:49 p.m. | Last Modified: 25 Sep 2019, 1:49 p.m.

Panel Version: 1.115

I don't know

The amber genes are covered on our targeted exome, we feel that these should be covered in the testing

Created: 25 Sep 2019, 1:44 p.m. | Last Modified: 25 Sep 2019, 1:44 p.m.

Panel Version: 1.114

I don't know

Single kindred (2 siblings) described with skin and gut inflammation. Full mouse knockout not viable; conditional knockout recapitulates intestinal inflammation upon challenge with DSS

Created: 19 Jun 2018, 4:52 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

I don't know

Inflammatory skin and bowel disease neonatal: one family, moderately elevated IgE, no evidence of immunodeficiency although nail, ear, eye infections - a phenocopy? Phenotypic opinion? Amber on association

Created: 26 Sep 2019, 3:49 p.m. | Last Modified: 26 Sep 2019, 3:49 p.m.

Panel Version: 1.130

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 only enough evidence to rate this gene Amber.

Created: 25 Sep 2019, 3 p.m. | Last Modified: 25 Sep 2019, 3 p.m.

Panel Version: 1.116

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 only enough evidence to rate this gene Amber

Created: 25 Sep 2019, 3 p.m. | Last Modified: 25 Sep 2019, 3 p.m.

Panel Version: 1.116

OriginaI Metadata from IUIS classification table (February, 2018) downloaded 20180614. IUIS Genetic defect (original gene symbol in IUIS download): ADAM17 .PanelApp HGNC gene symbol check: ADAM17 . IUIS Disease: ADAM17 deficiency . IUIS Inheritance: AR .T cells: N/A, .B cells: N/A, .IUIS Other affected cells: Leukocytes and epithelial cells. IUIS Associated features: Early onset diarrhea and skin lesions. IUIS Major category: Autoinflammatory Disorders. IUIS Subcategory: Non-Inflammasome Related Conditions

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

After further comments from external clinical expert review this gene will remain Amber until more info on gene and disease association.

Created: 20 Jun 2018, 2:43 p.m.

Reviewed and decided to keep 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 neonatal Inflammatory skin and bowel disease.

Created: 1 May 2018, 10:38 a.m.

Immunodeficiency caused by hypomorphic mutations in ADAM17 deficiency cause epithelial and immune dysfunction. Only one family report found an affected brother and sister from a consanguineous family of Lebanese origin with neonatal inflammatory skin and bowel disease1, PMID: 22010916 (2011). Genetic deficiency of ADAM17 has been linked to neonatal inflammatory skin and bowel disease, yet the pathogenic mechanisms remain unclear. ADAM17 is likely critical for the maintenance of mucosal epithelial barriers, as shown by the defective regeneration of intestinal epithelial cells in response to experimental colitis in hypomorphic ADAM17 animal models. There is functional/mouse model evidence to support the association, and ADAM17 is known to have a role in controlling inflammation and tissue regeneration (PMID: 21752713). The phenotype was also rescued by treatment with EGFR ligands, further supporting ADAM17 maintaining epithelial barriers by providing soluble EGFR ligands.

Created: 1 May 2018, 9:45 a.m.

Comment on phenotypes: added phenotype and MIMid from OMIM

Created: 30 Apr 2018, 4:32 p.m.

Comment on publications: added publications to support phenotype of Inflammatory skin and bowel disease, neonatal.

Created: 30 Apr 2018, 4:30 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: ADAM17, GRID_Gene_Symbol: ADAM17, GRID_Transcript_ENS_Community submitted: ENST00000310823, GRID_Transcript_RefSeq: NM_003183.4, GRID_Transcript_ENS_used_on_Production: ENST00000310823

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