Novel gain-of-function mutation in STAT1 protein with ALPS-like presentation
Bibliographic record
Abstract
Background: Germline mutations in STAT1 lead to primary immunodeficiency affecting both intrinsic and innate immunity. These immunodeficiencies can manifest as either loss-of-function (LOF) mutations or gain-of-function (GOF) mutations. LOF mutations result in a significant reduction in STAT1 protein functionality and are associated with Mendelian susceptibility to mycobacterial disease. Conversely, GOF mutations occur when a gene undergoes a change that enhances its normal function, resulting in an overactive form of the protein. Heterozygous STAT1 GOF mutations are the predominant cause of Chronic Mucocutaneous Candidiasis (CMC) in individuals with inborn errors of immunity. Aim: The study aims to report the clinical features, immune profile, and unique characteristics of a 9-year-old female patient with GOF mutations in STAT1. Results: We present a case of an 8-year-old female who has been genetically diagnosed with a GOF mutation in the STAT1 gene. The patient’s clinical presentation includes lymphadenopathy, splenomegaly, the presence of non-caseating granulomas, and cytopenia. Notably, there is no evidence of mycobacterial infection typically associated with LOF mutations, nor any indication of fungal, viral, or malignant conditions. Furthermore, there are no signs of endocrine abnormalities such as thyroiditis or diabetes mellitus. The patient’s immunological profile reveals evidence of autoimmunity, including symptoms of arthralgia and oral ulcers. Manual calculations of double negative T cells showed no increase in their numbers. The patient did not exhibit typical signs of CMC but presented with Autoimmune Lymphoproliferative Syndrome (ALPS)-like features, expanding the clinical spectrum of STAT1 GOF mutations. Discussion: The clinical and immunological characteristics of GOF mutations in STAT1 vary considerably among case reports. The current case had no evidence of CMC, thus raising the possibility of ALPS-like syndrome as an extension of the commonly addressed features of GOF mutations. Statement of novelty: The absence of CMC in a patient with GOF mutations in STAT1 is a rare presentation that should be considered when evaluating patients with inborn errors of immunity.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.002 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
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".