Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: STAT6

Green List (high evidence)

The rating of this gene has been updated to green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted 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
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Green List (high evidence)

Comment on list classification: There is sufficient evidence available (12 unrelated families and functional data) for the promotion of this gene to green rating in the next GMS review.

Created: 4 Jan 2024, 11:02 a.m. | Last Modified: 4 Jan 2024, 11:02 a.m.

Panel Version: 4.147

As reviewed by Dmitrijs Rots, PMID:36884218 reported 16 cases from 10 families with heterozygous STAT6 variants and severe early-onset allergic disease consisting of clinical features including severe, treatment-resistant atopic dermatitis (15/16) and food allergies (15/16) were the most common clinical manifestations, followed by asthma (11/16) and eosinophilic gastrointestinal disease (10/16) and severe episodes of anaphylaxis (9/16).

PMID:36216080 reported heterozygous STAT6 variant with early-onset multiorgan allergies in a family with
3 affected members and PMID:36758835 reported another child with severe atopic dermatitis, eosinophilia and elevated IgE. All these publications also provided extensive functional data which confirms the mechanism as gain-of-function.

This gene has already been associated with relevant phenotypes in OMIM (MIM #620532), but not yet in Gene2Phenotype.

Created: 4 Jan 2024, 11:01 a.m. | Last Modified: 4 Jan 2024, 11:01 a.m.

Panel Version: 4.146

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Hyper-IgE syndrome 6, autosomal dominant, with recurrent infections, OMIM:620532

Publications

• 36216080
• 36758835
• 36884218

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

Green List (high evidence)

16 cases from 10 families with GOF STAT6 variants reported in 36884218.
Enough evidence for green rating.

Created: 15 Mar 2023, 2:28 p.m. | Last Modified: 15 Mar 2023, 2:28 p.m.

Panel Version: 3.9

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Eosinophilia, severe allergy

Publications

• 36884218

Comment on list classification: Two unrelated patients with early-life onset of allergic immune dysregulation described in preprint by Sharma et al. as per review by Boaz Palterer. Red rating may be reconsidered following peer review of paper but additional cases would be required to reach a diagnostic level of evidence.

Created: 18 Jul 2022, 12:59 p.m. | Last Modified: 18 Jul 2022, 12:59 p.m.

Panel Version: 2.569

Red List (low evidence)

Sharma et al. identified two patients from two kindreds with early-onset severe primary atopic disorder carrying de novo heterozygous STAT6 gain-of-function mutations ( https://www.medrxiv.org/content/10.1101/2022.04.25.22274265v1 ).
Extensive functional data is provided and the phenotype of GOF STAT6 variants was previously predicted (https://pubmed.ncbi.nlm.nih.gov/10747856/)
Sources: Literature

Created: 3 Jun 2022, 10:42 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Primary Atopic Disorder; Atopy; Vascular anomalies; Atopic dermamatitis; Allergy; Atopy; Hyper-IgE; elevated IgE; Eosinophilic esophagitis; Food allergies

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