Human Germline Heterozygous Gain-of-Function <i>STAT6</i> Variants Cause Severe Allergic Disease
Bibliographic record
Abstract
ABSTRACT STAT6 (Signal transducer and activator of transcription 6) is a transcription factor that plays a central role in the pathophysiology of allergic inflammation. STAT6 mediates the biological effects of IL-4, a cytokine necessary for type 2 differentiation of T cells and B cell survival, proliferation and class switching to IgE. We have identificated two unrelated patients with a phenotype notable for their early-life onset of profound allergic immune dysregulation, widespread treatment-resistant atopic dermatitis, hypereosinophilia with esosinophilic esophagitis, elevated serum IgE, IgE-mediated food allergies, and vascular anomalies of the brain. Both patients harbored heterozygous de novo missense variants in the DNA binding domain of STAT6 (c.1144G>C, p.E382Q; and c.1256A>G, p.D419G). Functional studies established that both variants caused a gain-of-function (GOF) phenotype associated with enhanced phosphorylation and transcriptional activity of STAT6, in addition to increased transcript abundance of known STAT6 target genes and other genes implicated in allergic disease. JAK inhibitors decreased the enhanced STAT6 responses associated with both these STAT6 GOF variants. This study identifies heterozygous GOF variants in STAT6 as a novel autosomal dominant allergic disorder. We anticipate that our discovery of the first humans with germline STAT6 GOF variants will facilitate the recognition of more affected individuals and the full definition of this new primary atopic disorder.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".