STAT3-related early-onset multisystem autoimmune disease: genes and variants

Genes linked to STAT3-related early-onset multisystem autoimmune disease

• STAT3: Signal transducer and activator of transcription 3

  It translates cytokine and growth-factor signals into transcriptional programs governing immune regulation, survival, proliferation, and tissue repair. Dominant-negative variants cause hyper-IgE syndrome, while activating germline variants cause early autoimmunity and lymphoproliferation and somatic activation contributes to cancer.

  21 disease-causing and 7 uncertain variants in STAT3 are linked to STAT3-related early-onset multisystem autoimmune disease.

Where STAT3-related early-onset multisystem autoimmune disease variants cluster

• STAT3 SH2 (positions 580–670): 5 of 21 disease-causing changes, 2.0× more than its size predicts.

Known disease-causing variants in STAT3-related early-onset multisystem autoimmune disease

Which prediction tools work for STAT3-related early-onset multisystem autoimmune disease

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• CATVariant: 84 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 72 out of 100
• PolyPhen-2: 71 out of 100 (learned from overlapping clinical labels, so this is optimistic)

Same protein, different disease

• Hyper-IgE recurrent infection syndrome 1, autosomal dominant is also caused by STAT3 variants; they fall partly in the same places as the STAT3-related early-onset multisystem autoimmune disease variants (65 disease-causing).
• STAT3 gain of function is also caused by STAT3 variants; they fall partly in the same places as the STAT3-related early-onset multisystem autoimmune disease variants (49 disease-causing).

Diseases related to STAT3-related early-onset multisystem autoimmune disease

• Hyper-IgE recurrent infection syndrome 1, autosomal dominant, also linked to STAT3
• STAT3 gain of function, also linked to STAT3
• Inherited Immunodeficiency Diseases, also linked to STAT3
• Hyper-IgE syndrome 6, autosomal dominant, with recurrent infections, also linked to STAT3

Frequently asked questions

Which genes are linked to STAT3-related early-onset multisystem autoimmune disease?

In CATVariant, STAT3-related early-onset multisystem autoimmune disease is linked to 1 analyzed protein: STAT3 (Signal transducer and activator of transcription 3).

How many genetic variants are linked to STAT3-related early-onset multisystem autoimmune disease?

28 variants: 21 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 7 are of uncertain significance or have conflicting reports.

Which uncertain variants in STAT3-related early-onset multisystem autoimmune disease look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

Which variant effect predictor works best for STAT3-related early-onset multisystem autoimmune disease?

Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.72, based on 19 disease-causing and 27 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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