Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: STAT3

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)

Heterozygous hypomorphic variants cause hyper-IgE syndrome.
Heterozygous gain-of-function variants cause immune dysregulation and/or combined immunodeficiency, not always of early onset

Created: 11 Jun 2018, 12:24 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Mode of pathogenicity
Other

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, 4:26 p.m. | Last Modified: 14 Oct 2020, 4:26 p.m.

Panel Version: 2.314

The following PubMed IDs were added to entity STAT3: 25349174;28402852;25359994;25038750. These publications have been associated with OMIM phenotype MIM#615952, which is listed for this entity, 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

Mode of Inheritance: OMIM has only autosomal dominant, and I can find no evidence for autosomal recessive, but GRID has marked this gene as both AD and AR so leaving the MOI as this just now.

Created: 3 May 2018, 9:56 p.m.

Added tag for early-onset

Created: 1 May 2018, 10:19 p.m.

Comment on publications: Added publications supporting association with hyper-IgE syndrome and infantile-onset multisystem autoimmune disease-1.

Created: 1 May 2018, 10:18 p.m.

Orphanet - Autosomal dominant hyper-IgE syndrome. In 70% of patients, the phenotype is associated with heterozygous mutations of the signal transducer and activator of transcription 3 gene (STAT3; 17q21.31).

Created: 1 May 2018, 10:16 p.m.

Comment on list classification: OMIM describes > 3 cases of mutations in STAT3 in patients with hyper-IgE syndrome. Minegishi et al. (2007) (PMID: 17676033) found that 8 of 15 unrelated nonfamilial HIES patients had heterozygous STAT3 mutations. All 5 mutants were nonfunctional by themselves and showed dominant-negative effects when coexpressed with wildtype STAT3. Holland et al. (2007) (PMID: 17881745) identified missense mutations and single-codon in-frame deletions in STAT3 in 50 familial and sporadic cases of HIES. Flanagan et al. (2014) (PMID: 25038750) identified 4 different de novo heterozygous missense mutations in the STAT3 gene in 5 unrelated patients with infantile-onset multisystem autoimmune disease-1. Milner et al. (2015) (PMID: 25359994) identified 9 different heterozygous missense mutations in the STAT3 gene in 13 patients from 10 families with ADMIO1. Changing the rating of this gene from Amber to Green based on > 3 cases of likely disease causing mutations.

Created: 1 May 2018, 10:09 p.m.

Comment on phenotypes: Added MIM IDs to the first two phenotypes

Created: 1 May 2018, 9:41 p.m.

Publications

• 25349174
• 28402852
• 25359994
• 25038750

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): STAT3 .PanelApp HGNC gene symbol check: STAT3 . IUIS Disease: AD-HIES Job syndrome . IUIS Inheritance: AD LOF .T cells: Nl number, poor proliferation, .B cells: Normal, reduced switched and non-switched memory B cells, BAFF expression increased, .IUIS Other affected cells: N/A. IUIS Associated features: Distinctive facial features (broad nasal bridge), bacterial infections (boils and pulmonary abscesses, pneumatoceles) due to S. aureus, pulmonary aspergillus, Pneumocystis jirovecii, eczema, mucocutaneous candidiasis, hyperextensible joints, osteoporosis and bone fractures, scoliosis, retention of primary teeth, coronary and cerebral aneurysm formation. IUIS Major category: Combined immunodeficiencies with associated or syndromic features. IUIS Subcategory: Hyper IgE Syndromes (HIES). // OriginaI Metadata from IUIS classification table (February, 2018) downloaded 20180614. IUIS Genetic defect (original gene symbol in IUIS download): STAT3 .PanelApp HGNC gene symbol check: STAT3 . IUIS Disease: STAT3 GOF mutation . IUIS Inheritance: AD (GOF) .T cells: N/A, .B cells: Decreased, .IUIS Other affected cells: N/A. IUIS Associated features: Lymphoproliferation, solid organ autoimmunity, recurrent infections. IUIS Major category: Diseases of Immune Dysregulation. IUIS Subcategory: Regulatory T Cell Defects

Created: 2 Jul 2018, 11:01 a.m.

Comment on phenotypes: from IUIS (unable to add to phenotype directly due to limited word count. Distinctive facial features broad nasal bridge, bacterial infections boils and pulmonary abscesses, pneumatoceles due to S aureus, pulmonary aspergillus, Pneumocystis jirovecii, eczema, mucocutaneous candidiasis, hyperextensible joints, osteoporosis and bone fractures, scoliosis, retention of primary teeth, coronary and cerebral aneurysm formation; Combined immunodeficiencies with associated or syndromic features;Lymphoproliferation, solid organ autoimmunity, recurrent infections; Diseases of Immune Dysregulation

Created: 1 Jul 2018, 3:46 p.m.

Comment on mode of pathogenicity: from expert review comment: Heterozygous hypomorphic variants cause hyper-IgE syndrome. Heterozygous gain-of-function variants cause immune dysregulation and/or combined immunodeficiency, not always of early onset

Created: 13 Jun 2018, 10:35 a.m.

Comment on mode of inheritance: changed MOI due to expert review comment

Created: 13 Jun 2018, 10:34 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: 19 Apr 2018, 2:11 p.m.

Original metadata downloaded from ESID Registry. ESID_Gene_original: STAT3 GOF, PanelApp HGNC gene symbol check: STAT3, ESID classification: Main_category/ Sub_category/ PID_Diagnosis Diseases of immune dysregulation / Early-onset multi-organ autoimmune disease / Early-onset multi-organ autoimmune disease; Other well defined PIDs / Hyper IgE syndromes / Hyper IgE syndrome (HIES)

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

Original metadata supplied by GRID. GRID Gene Symbol HGNC PanelApp check: STAT3, GRID_Gene_Symbol: STAT3, GRID_Transcript_ENS_Community submitted: ENST00000264657, GRID_Transcript_RefSeq: NM_139276.2, GRID_Transcript_ENS_used_on_Production: ENST00000264657

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