Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: STAT5B

Green List (high evidence)

The mode of inheritance of this gene has been updated to BOTH monoallelic and biallelic, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.

Created: 3 May 2024, 8:36 p.m. | Last Modified: 3 May 2024, 8:36 p.m.

Panel Version: 5.3

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Comment on mode of inheritance: MOI to be further discussed by the NHS Genomic Medicine Service team (added TBC tag). Reverted back to biallelic so the MOI matches the previous signed-off version (v2.1)

Created: 4 Mar 2022, 10:44 a.m. | Last Modified: 4 Mar 2022, 10:45 a.m.

Panel Version: 2.530

Added 'for-review' tag as the MOI has changed since previous sign-off of this panel (version 2.1) and requires review by the Specialist Test Group.

Created: 21 Oct 2020, 4:36 p.m. | Last Modified: 21 Oct 2020, 4:36 p.m.

Panel Version: 2.368

Comment on mode of inheritance: Changed MOI from Biallelic to Both Monoallelic and biallelic based on expert review and evidence provided by Zornitza Stark (Australian Genomics). It should be noted that the AD has a dominant-negative effect.

Created: 15 Apr 2020, 2:25 p.m. | Last Modified: 15 Apr 2020, 2:25 p.m.

Panel Version: 2.60

Green List (high evidence)

Please note reports of mono-allelic variants associated with disease.

Created: 12 Apr 2020, 4:56 a.m. | Last Modified: 12 Apr 2020, 4:56 a.m.

Panel Version: 2.51

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Publications

• 29844444

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)

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, 4:27 p.m. | Last Modified: 14 Oct 2020, 4:27 p.m.

Panel Version: 2.315

The following PubMed IDs were added to gene STAT5B (OMIM gene MIM#604260): 13679528;16920911. 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

Comment on list classification: Changing this gene from Amber to Green as there are >3 independant cases providing association of this gene and the disorder

Created: 3 May 2018, 9:59 p.m.

In OMIM this gene is associated with Growth hormone insensitivity with immunodeficiency 245590. They report that in Kofoed et al. (2003) (PMID: 13679528) a patient is described with a homozygous ala630-to-pro mutation (A630P) in the STATB gene and a combined phenotype of GH insensitivity and immunodeficiency consistent with the presence of a defect in the JAK/STAT system. Cohen et al. (2006) (PMID: 16920911) further investigated this patient and observed immune dysregulation with decreased numbers of regulatory CD4+/CD25-high T cells (Tregs). Hwa et al. (2005) (PMID: 15827093) report a 16.4-year-old Turkish girl with postnatal growth retardation and insensitivity to growth hormone, who also had recurrent pulmonary infections and a bleeding diathesis due to defective thrombocyte aggregation, and a homozygous 1-bp insertion in the STAT5B gene. The insertion resulted in a frame shift, leading to early protein termination and consequent lack of immunodetectable STAT5b protein. Vidarsdottir et al. (2006) (PMID: 16787985) report a 30-year-old man born in the Dutch Antilles who had short stature and delayed puberty with normal GH and GHBP levels, an elevated plasma prolactin level, and extremely low levels of IGF1, IGFBP3, and acid-labile subunit identified homozygosity for a 1-bp insertion in the STAT5B gene . The authors stated that the patient was diagnosed with congenital ichthyosis at birth and had hemorrhagic varicella at 16 years of age, but had NO history of pulmonary or immunologic problems. Bernasconi et al. (2006) (PMID:17030597) report a 16-year-old girl with severe postnatal growth failure, GH insensitivity, and immunodeficiency and homozygosity for a nonsense mutation in the STAT5B gene. Hwa et al. (2007) (PMID: 17389811) report 2 Kuwaiti sisters from a consanguineous family with severe postnatal growth retardation, normal GH and GHBP levels, and no mutation in the GH receptor gene, Hwa et al. (2007) (PMID: 17389811) identified homozygosity for a 1-bp deletion in the STAT5B gene (604260.0005). In addition to GHI, siblings 2 and 1 presented with, respectively, a diagnosis of juvenile idiopathic arthritis and recurrent pulmonary infections. A PubMed search also finds Pugliese-Pires et al (2010) (PMID: 20538865) who report 2 male siblings with GH insensitivity syndrome associated with hyperprolactinemia and immune dysfunction with a novel STAT5B mutation. Both siblings were homozygous for a 4 bp deletion in STAT5B. One sibling also had a heterozygous missense mutation in the GHR gene. Rating this gene green because there are >3 cases of plausable disease causing mutations in the STAT5B gene.

Created: 2 May 2018, 1:59 p.m.

Comment on phenotypes: Added MIM ID to first phenotype

Created: 2 May 2018, 10:21 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

• 13679528
• 16920911

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

Reviewed gene as Green. Red ratings highly likely to be historical ratings made in view of the panel (SCID). This panel will be retired when this PID panel is V. In view of poor growth, recurrent infections and T-cell abnormalities associated to STAT5B variants, these are appropriate phenotypes for the PID panel so gene should be Green

Created: 11 Jul 2018, 4:26 p.m.

OriginaI Metadata from IUIS classification table (February, 2018) downloaded 20180614. IUIS Genetic defect (original gene symbol in IUIS download): STAT5B .PanelApp HGNC gene symbol check: STAT5B . IUIS Disease: STAT5b deficiency . IUIS Inheritance: AR .T cells: N/A, .B cells: Normal, .IUIS Other affected cells: N/A. IUIS Associated features: Growth-hormone insensitive dwarfism, dysmorphic features, eczema, lymphocytic interstitial pneumonitis, autoimmunity. IUIS Major category: Combined immunodeficiencies with associated or syndromic features. IUIS Subcategory: Other Combined immunodeficiencies with associated or syndromic features

Created: 2 Jul 2018, 10:35 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: 19 Apr 2018, 2:07 p.m.

Original metadata downloaded from ESID Registry. ESID_Gene_original: STAT5b, PanelApp HGNC gene symbol check: STAT5B, ESID classification: Main_category/ Sub_category/ PID_Diagnosis Combined immunodeficiencies / Combined immunodeficiency (CID) / Combined immunodeficiency

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

Original metadata supplied by GRID. GRID Gene Symbol HGNC PanelApp check: STAT5B, GRID_Gene_Symbol: STAT5B, GRID_Transcript_ENS_Community submitted: ENST00000293328, GRID_Transcript_RefSeq: NM_012448.3, GRID_Transcript_ENS_used_on_Production: ENST00000293328

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

Red List (low evidence)

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

agree, CID with growth problems

Created: 20 Oct 2015, 1:44 p.m.

Red List (low evidence)

Not linked to SCID

Created: 19 Oct 2015, 7:52 p.m.