COVID-19 research

Gene: ICOS

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)

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): ICOS .PanelApp HGNC gene symbol check: ICOS . IUIS Disease: ICOS deficiency . IUIS Inheritance: AR .T cells: N/A, .B cells: Normal, .IUIS Other affected cells: N/A. IUIS Associated features: Recurrent infections, autoimmunity, gastroenteritis, granulomas . 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.

Comment on list classification: Changed from Amber to Green- enough evidence in the literature and external expert reivew

Created: 18 Jun 2018, 11:06 a.m.

No longer deemed founder-effect since the Salzer et al. (2004) publication, other variants (all deletions) have been observed and in other ethnicities (PMID: 29867948). Schepp et all (2017) PMID:28861081 reviewed seven families’ pedigrees. The inheritance was strictly autosomal-recessive in all families, and all mutations led to a failure to detect the protein on the surface of activated T-cells. Families 1-4 had a homozygous deletion of a 1,815 base pair region including exon 2, intron 2, exon 3, and parts of intron 3 of the ICOS gene (c.126-568.del) (PMID:12577056, 15507387). This out of frame deletion led to a premature stop codon and shortened transcript (PMID:12577056). A common ancestor is assumed for these four families. In the unrelated family 5, sequencing of the ICOS gene revealed a homozygous deletion of a T at codon 285, leading to a frameshift and the introduction of a stop codon at amino acid position 121 and resulting in a truncated ICOS transcript (c.285delT) (PMID:19380800). The patients from family 6 from Kuwait were found to carry a single nucleotide homozygous deletion in Exon 2 (c.90delG), leading to a frameshift and premature stop codon in Exon 2 (PMID: 25678089). In the children of the consanguineous family 7, a homozygous 10 base-pair deletion in ICOS (c.321_330del) led to a frameshift and a premature stop after 10 codons in the new reading frame (p.F108YfsX118) (PMID:26399252).

Created: 18 Jun 2018, 11:04 a.m.

Clinically, patients present with an increased susceptibility to infections, autoimmune manifestations, and an increased risk of malignancy PMID:10413651.

Created: 18 Jun 2018, 10:41 a.m.

from Jung et al. (2018) PMID: 29867948 : To date, homozygous mutations (deletions) in ICOS have been identified in 16 patients, resulting in the absence of ICOS protein on T cells. Following the initial description of this monogenic defect in 2003 (PMID:12577056 ), a number of other patients have been identified worldwide. Of the seven families, three came from Germany (12577056, 15507387), one from Austria (15507387), one from Japan (19380800), one from Kuwait (25678089), and one from UK with Pakistani background (26399252). ICOS deficiency was initially considered as a “predominantly antibody deficiency” by the IUIS PID expert committee (PMID:24795713), but following published patients with more complex phenotypes (28861081), allowed a reclassification of the disease as a CID (PMID:29226302, 29226301).

Created: 18 Jun 2018, 10:31 a.m.

In 5 affected individuals from 2 families with CVID due to ICOS deficiency, Salzer et al. (2004) identified the same homozygous deletion in the ICOS gene that was found by Grimbacher et al. (2003). All 4 families were from the same region along the Danube River in Germany and Austria, and haplotype analysis indicated a founder effect.

Created: 18 Jun 2018, 10:18 a.m.

added deletion tag

Created: 18 Jun 2018, 10:11 a.m.

Comment on publications: added recent publications PMID:28861081;29867948 to support ICOS deficiency in patients with prominent autoimmune features and opportunistic infection profiles, providing ample evidence that B-cell counts decline during the course of the disease. ICOS deficiency does not just produce isolated hypogammaglobulinemia.

Created: 18 Jun 2018, 10:05 a.m.

Comment on publications: added publications suggested from external expert reviews

Created: 18 Jun 2018, 9:40 a.m.

This gene was present in the original PanelApp PID panel dataset (review in April 2018) rated as Red. The gene is present in the 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: ICOS, PanelApp HGNC gene symbol check: ICOS, ESID classification: Main_category/ Sub_category/ PID_Diagnosis Predominantly antibody disorders / Hypogammaglobulinemias / Common variable immunodeficiency disorders (CVID); Predominantly antibody disorders / Hypogammaglobulinemias / Isolated IgG subclass deficiency

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

Original metadata supplied by GRID. GRID Gene Symbol HGNC PanelApp check: ICOS, GRID_Gene_Symbol: ICOS, GRID_Transcript_ENS_Community submitted: ENST00000316386, GRID_Transcript_RefSeq: NM_012092.3, GRID_Transcript_ENS_used_on_Production: ENST00000316386

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

Green List (high evidence)

Reports after the original description show that a CID phenotype is possible (with opportunistic infection, colitis etc)

Created: 6 Jan 2017, 2:58 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
hypogammaglobulinaemia, agammaglobulinaemia, combined immunodeficiency

Publications

• 26399252
• 25678089

Green List (high evidence)

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments

Comment when marking as ready: No expert reviews. No association with disease on Gen2Phen. Two publications reporting a defined deletion of exons 2-3 in 9 members of 4 families, haplotype analysis reveals founder effect

Created: 11 May 2016, 8:30 a.m.