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Primary immunodeficiency

Gene: ADAM17

Amber List (moderate evidence)

ADAM17 (ADAM metallopeptidase domain 17)
EnsemblGeneIds (GRCh38): ENSG00000151694
EnsemblGeneIds (GRCh37): ENSG00000151694
OMIM: 603639, Gene2Phenotype
ADAM17 is in 6 panels

7 reviews

Arina Puzriakova (Genomics England Curator)

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

Eleanor Williams (Genomics England Curator)

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

Zornitza Stark (Australian Genomics)

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

Kimberly Gilmour (Great Ormond Street Hopsital)

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

Tracy Briggs (Manchester Genomic Medicine Centre)

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

Sophie Hambleton (Newcastle University)

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

Louise Daugherty (Genomics England Curator)

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.

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Amber
  • Other
  • IUIS Classification December 2019
  • North West GLH
  • London North GLH
  • NHS GMS
  • IUIS Classification February 2018
  • Victorian Clinical Genetics Services
  • GRID V2.0
  • GOSH PID v.8.0
Phenotypes
  • inflammatory skin
  • Inflammatory skin and bowel disease, neonatal, 1
  • Inflammatory skin and bowel disease, neonatal 1, 614328
  • ADAM17 deficiency
  • Autoinflammatory Disorders
  • IBD-1
  • Early onset diarrhea and skin lesions
  • Recurrent infections
Tags
for-review
OMIM
603639
Clinvar variants
Variants in ADAM17
Penetrance
None
Publications
Panels with this gene

History Filter Activity

20 Oct 2020, Gel status: 2

Entity classified by Genomics England curator

Arina Puzriakova (Genomics England Curator)

Gene: adam17 has been classified as Amber List (Moderate Evidence).

20 Oct 2020, Gel status: 3

Added Tag

Arina Puzriakova (Genomics England Curator)

Tag for-review tag was added to gene: ADAM17.

13 Oct 2020, Gel status: 3

Added New Source, Set publications

Eleanor Williams (Genomics England Curator)

Source Other was added to ADAM17. Publications for gene ADAM17 were updated from 22010916; 28930861; 20603312; 32048120; 25171914; 11149563; 25058236; 32086639; 29560122; 26683521; 25804906 to 29560122; 22010916; 25058236; 32048120; 20603312; 32086639; 26683521; 11149563; 25804906; 25171914; 28930861

23 Apr 2020, Gel status: 3

Entity classified by Genomics England curator

Eleanor Williams (Genomics England Curator)

Gene: adam17 has been classified as Green List (High Evidence).

23 Apr 2020, Gel status: 2

Set Phenotypes

Eleanor Williams (Genomics England Curator)

Phenotypes for gene: ADAM17 were changed from inflammatory skin; Inflammatory skin and bowel disease, neonatal, 1; Inflammatory skin and bowel disease, neonatal 1, 614328; ADAM17 deficiency; Autoinflammatory Disorders; IBD-1; Early onset diarrhea and skin lesions to inflammatory skin; Inflammatory skin and bowel disease, neonatal, 1; Inflammatory skin and bowel disease, neonatal 1, 614328; ADAM17 deficiency; Autoinflammatory Disorders; IBD-1; Early onset diarrhea and skin lesions; Recurrent infections

23 Apr 2020, Gel status: 2

Set publications

Eleanor Williams (Genomics England Curator)

Publications for gene: ADAM17 were set to 22010916; 28930861; 20603312; 32048120; 25171914; 11149563; 25058236; 32086639

28 Feb 2020, Gel status: 2

Added New Source, Set Phenotypes, Set publications

Louise Daugherty (Genomics England Curator)

Source IUIS Classification December 2019 was added to ADAM17. Added phenotypes Early onset diarrhea and skin lesions; Autoinflammatory Disorders for gene: ADAM17 Publications for gene ADAM17 were updated from 25058236; 28930861; 22010916; 25171914; 11149563; 20603312 to 22010916; 28930861; 20603312; 32048120; 25171914; 11149563; 25058236; 32086639

17 Sep 2019, Gel status: 2

Added New Source

Louise Daugherty (Genomics England Curator)

Source North West GLH was added to ADAM17.

17 Sep 2019, Gel status: 2

Added New Source

Louise Daugherty (Genomics England Curator)

Source London North GLH was added to ADAM17.

17 Sep 2019, Gel status: 2

Added New Source

Louise Daugherty (Genomics England Curator)

Source NHS GMS was added to ADAM17.

12 Jul 2018, Gel status: 2

Panel promoted to version 1.0

Louise Daugherty (Genomics England Curator)

2018-07-12 Louise Daugherty (Genomics England Curator) promoted panel to v1.0. Reviews were assessed, and panel was revised according to expert reviews and further in-house curation based on PanelApp guidelines. Previous panels (A- or hypo-gammaglobulinaemia, Congenital neutropaenia, Agranulocytosis, Combined B and T cell defect, Inherited complement deficiency and SCID panels) that were merged with this panel, were checked again for any changes/new reviews prior to versioning of this panel, these merged panels are now retired/made internal.

1 Jul 2018, Gel status: 2

Set penetrance

Louise Daugherty (Genomics England Curator)

Phenotypes for gene ADAM17 were set to Inflammatory skin and bowel disease, neonatal, 1, IBD-1, inflammatory skin, Inflammatory skin and bowel disease, neonatal 1, 614328, ADAM17 deficiency, Early onset diarrhea and skin lesions, Autoinflammatory Disorders

26 Jun 2018, Gel status: 2

Added New Source

Louise Daugherty (Genomics England Curator)

IUIS Classification February 2018 was added to ADAM17. Panel: Primary immunodeficiency disorders

26 Jun 2018, Gel status: 2

Added New Source

Louise Daugherty (Genomics England Curator)

Victorian Clinical Genetics Services was added to ADAM17. Panel: Primary immunodeficiency disorders

20 Jun 2018, Gel status: 2

Entity classified by Genomics England curator

Louise Daugherty (Genomics England Curator)

Gene: adam17 has been classified as Amber List (Moderate Evidence).

1 May 2018, Gel status: 2

Set publications

Louise Daugherty (Genomics England Curator)

Publications for ADAM17 were set to 25058236; 28930861; 22010916; 25171914; 11149563; 20603312

1 May 2018, Gel status: 2

Set publications

Louise Daugherty (Genomics England Curator)

Publications for ADAM17 were set to 25058236; 28930861; 22010916; 25171914

1 May 2018, Gel status: 2

Set Phenotypes

Louise Daugherty (Genomics England Curator)

Phenotypes for ADAM17 were set to Inflammatory skin and bowel disease, neonatal, 1; IBD-1; inflammatory skin; Inflammatory skin and bowel disease, neonatal 1, 614328; ADAM17 deficiency

1 May 2018, Gel status: 2

Set Phenotypes

Louise Daugherty (Genomics England Curator)

Phenotypes for ADAM17 were set to Inflammatory skin and bowel disease, neonatal, 1; IBD-1; inflammatory skin; nflammatory skin and bowel disease, neonatal 1, 614328; ADAM17 deficiency

30 Apr 2018, Gel status: 2

Set Phenotypes

Louise Daugherty (Genomics England Curator)

Phenotypes for ADAM17 were set to Inflammatory skin and bowel disease, neonatal, 1; IBD-1; inflammatory skin; nflammatory skin and bowel disease, neonatal 1, 614328

30 Apr 2018, Gel status: 2

Set publications

Louise Daugherty (Genomics England Curator)

Publications for ADAM17 were set to 25058236; 28930861; 22010916

20 Apr 2018, Gel status: 2

Added New Source

Louise Daugherty (Genomics England Curator)

Expert Review Amber was added to ADAM17. Panel: Primary immunodeficiency disorders

17 Apr 2018, Gel status: 1

Set penetrance

Louise Daugherty (Genomics England Curator)

Phenotypes for gene ADAM17 were set to Inflammatory skin and bowel disease, neonatal, 1, IBD-1, inflammatory skin

17 Apr 2018, Gel status: 1

Added New Source, Set penetrance

Louise Daugherty (Genomics England Curator)

GRID V2.0 was added to ADAM17. Panel: Primary immunodeficiency disorders Phenotypes for gene ADAM17 were set to Inflammatory skin and bowel disease, neonatal, 1, IBD-1, inflammatory skin

6 Apr 2018, Gel status: 1

Clear Sources

Louise Daugherty (Genomics England Curator)

ADAM17 Source: GOSH PID 20171129 was removed from gene: ADAM17

6 Apr 2018, Gel status: 1

Added New Source

Louise Daugherty (Genomics England Curator)

GOSH PID v.8.0 was added to ADAM17. Panel: Primary immunodeficiency disorders

29 Mar 2018, Gel status: 1

Added New Source

Louise Daugherty (Genomics England Curator)

ADAM17 was added to Primary immunodeficiency disorders panel. Sources: GOSH PID 20171129

29 Mar 2018, Gel status: 1

Created

Louise Daugherty (Genomics England Curator)

ADAM17 was created by Louise Daugherty