STAT6 gain-of-function (GOF) disease is a recently described autosomal dominant inborn error of immunity caused by germline heterozygous gain-of-function variants in STAT6, the transcription factor downstream of the type 2 cytokines IL-4 and IL-13. GOF variants (predominantly in the DNA-binding domain) cause constitutive/hyperresponsive STAT6 signaling with sustained phosphorylation, increased target-gene expression, and TH2 skewing, producing a profound early-life multisystem allergic phenotype: treatment-resistant atopic dermatitis, marked hypereosinophilia with eosinophilic gastrointestinal disease, asthma, very high serum IgE, IgE-mediated food allergy, and anaphylaxis, with variable susceptibility to infection. It is catalogued in OMIM as hyper-IgE syndrome 6 (HIES6). Type 2-directed therapy (the anti-IL-4Ra antibody dupilumab) and JAK inhibition (ruxolitinib) are effective targeted treatments.
Ask a research question about STAT6 Gain-of-Function Disease. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).
Do not include personal health information in your question. Questions and results are cached in your browser's local storage.
name: STAT6 Gain-of-Function Disease
creation_date: "2026-07-29T00:00:00Z"
category: Mendelian
description: >-
STAT6 gain-of-function (GOF) disease is a recently described autosomal
dominant inborn error of immunity caused by germline heterozygous
gain-of-function variants in STAT6, the transcription factor downstream of the
type 2 cytokines IL-4 and IL-13. GOF variants (predominantly in the DNA-binding
domain) cause constitutive/hyperresponsive STAT6 signaling with sustained
phosphorylation, increased target-gene expression, and TH2 skewing, producing a
profound early-life multisystem allergic phenotype: treatment-resistant atopic
dermatitis, marked hypereosinophilia with eosinophilic gastrointestinal
disease, asthma, very high serum IgE, IgE-mediated food allergy, and
anaphylaxis, with variable susceptibility to infection. It is catalogued in
OMIM as hyper-IgE syndrome 6 (HIES6). Type 2-directed therapy (the anti-IL-4Ra
antibody dupilumab) and JAK inhibition (ruxolitinib) are effective targeted
treatments.
disease_term:
preferred_term: STAT6 gain-of-function disease
term:
id: MONDO:0957807
label: hyper-IgE syndrome 6, autosomal dominant, with recurrent infections
synonyms:
- STAT6-GOF
- STAT6 GOF disease
- Hyper-IgE syndrome 6
- HIES6
- Autosomal dominant allergic disorder due to STAT6 gain-of-function
- Early-onset multisystem allergic disease with STAT6 gain-of-function
parents:
- hereditary disease
- inborn error of immunity
- hyper-IgE syndrome
inheritance:
- name: Autosomal dominant inheritance
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
penetrance: COMPLETE
expressivity: VARIABLE
description: >-
STAT6 GOF disease follows an autosomal dominant inheritance pattern from
monoallelic (heterozygous) STAT6 variants; cases are either de novo/sporadic
or transmitted through affected kindreds. Penetrance is complete, with
variable expressivity.
evidence:
- reference: PMID:36884218
reference_title: "Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The cases were either sporadic (seven kindreds) or followed an autosomal
dominant inheritance pattern (three kindreds).
explanation: >-
Documents both sporadic/de novo and autosomal dominant transmission of
heterozygous STAT6 GOF variants across the discovery cohort.
- reference: PMID:38238227
reference_title: "Human germline gain-of-function in STAT6: from severe allergic disease to lymphoma and beyond."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
STAT6-GOF disease demonstrated complete penetrance, although some clinical
variability
explanation: >-
The consortium review reports complete penetrance with clinical
variability (variable expressivity).
pathophysiology:
- name: STAT6 gain-of-function variant
biological_scale: MOLECULAR
description: >-
Germline heterozygous rare variants in STAT6 (most in the DNA-binding
domain, e.g. p.E372K, p.E377K) confer a gain of function: the mutant
transcription factor shows increased DNA-binding affinity, a strong
preference for nuclear localization, and spontaneous transcriptional
activity.
genes:
- preferred_term: STAT6
term:
id: hgnc:11368
label: STAT6
evidence:
- reference: PMID:36884218
reference_title: "Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
All patients carried monoallelic rare variants in STAT6 and functional
studies established their gain-of-function (GOF) phenotype with sustained
STAT6 phosphorylation, increased STAT6 target gene expression, and TH2
skewing.
explanation: >-
Establishes monoallelic STAT6 variants with a functionally validated
gain-of-function phenotype as the causal lesion.
- reference: PMID:36216080
reference_title: "A germline STAT6 gain-of-function variant is associated with early-onset allergies."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We identified a heterozygous missense variant (c.1129G>A;p.Glu377Lys) in
the DNA binding domain of STAT6 that was de novo in the index patient's
father and was inherited by 2 of his 3 children.
explanation: >-
Localizes a representative GOF variant to the STAT6 DNA-binding domain.
downstream:
- target: Constitutive STAT6 signaling
description: >-
GOF variants drive sustained/spontaneous STAT6 pathway activation
independent of, and hyperresponsive to, upstream IL-4/IL-13 cytokine input.
causal_link_type: DIRECT
evidence:
- reference: PMID:36216080
reference_title: "A germline STAT6 gain-of-function variant is associated with early-onset allergies."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A germline STAT6 gain-of-function variant results in spontaneous
activation of the STAT6 signaling pathway and is associated with an
early-onset and severe allergic phenotype in humans.
explanation: >-
Links the GOF variant directly to spontaneous activation of STAT6
signaling.
- name: Constitutive STAT6 signaling
conforms_to: "jak_stat_pathway_activation#Constitutive STAT Activation and Nuclear Translocation"
biological_scale: MOLECULAR
description: >-
STAT6 is the central transcription factor of the type 2 cytokine (IL-4/IL-13)
response. GOF variants produce sustained basal and cytokine-induced STAT6
phosphorylation and increased target-gene transcription, amplifying the
allergic-inflammation program.
biological_processes:
- preferred_term: interleukin-4-mediated signaling pathway
term:
id: GO:0035771
label: interleukin-4-mediated signaling pathway
modifier: INCREASED
- preferred_term: JAK-STAT signaling
term:
id: GO:0007259
label: cell surface receptor signaling pathway via JAK-STAT
modifier: INCREASED
evidence:
- reference: PMID:36884218
reference_title: "Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
STAT6 (signal transducer and activator of transcription 6) is a
transcription factor that plays a central role in the pathophysiology of
allergic inflammation.
explanation: >-
Establishes STAT6 as the central signaling node whose constitutive
activity drives the disease.
- reference: PMID:36758835
reference_title: "Severe allergic dysregulation due to a gain of function mutation in the transcription factor STAT6."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
The mutation augmented both basal and cytokine-induced STAT6
phosphorylation without affecting dephosphorylation kinetics.
explanation: >-
Functional assay of the mutated STAT6 protein documents increased basal and
cytokine-induced STAT6 phosphorylation as the proximal signaling
abnormality.
- reference: PMID:40603028
reference_title: "[Mechanism of pathogenesis by a gain-of-function variant of STAT6 causing severe allergic diseases and potential for development of molecularly targeted drugs]."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
even in the absence of IL-4 stimulation, we observed the translocation of
mutant STAT6 in its unphosphorylated state, which activated gene
expression.
explanation: >-
Documents ligand- and phosphorylation-independent nuclear translocation of
the D419N mutant, the most constitutive form of the signaling defect.
- reference: PMID:40603028
reference_title: "[Mechanism of pathogenesis by a gain-of-function variant of STAT6 causing severe allergic diseases and potential for development of molecularly targeted drugs]."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Mutant STAT6 knock-in mice elicited an abnormal TH2-dominant immune
response in vivo, with findings similar to those observed in patients.
explanation: >-
A patient-derived D419N knock-in mouse recapitulates the human TH2/allergic
phenotype, validating the causal mechanism in vivo.
- reference: PMID:28653395
reference_title: "Poly-ADP ribose polymerase-14 limits severity of allergic skin disease."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
mice that express constitutively active Stat6 in T cells (Stat6VT) and
develop spontaneous inflammation of the skin
explanation: >-
An independent constitutively active STAT6 mouse model (Stat6VT) develops
spontaneous allergic skin inflammation, corroborating that constitutive
STAT6 activity drives atopic disease.
downstream:
- target: TH2 immune skewing
description: >-
Hyperactive STAT6 signaling skews CD4+ T-cell differentiation toward the
TH2 program while suppressing TH1 and TH17 responses.
causal_link_type: DIRECT
evidence:
- reference: PMID:36758835
reference_title: "Severe allergic dysregulation due to a gain of function mutation in the transcription factor STAT6."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Naive lymphocytes from the affected patient displayed increased TH2- and
suppressed TH1- and TH17-cell responses.
explanation: >-
Links constitutive STAT6 activity to TH2 skewing with reciprocal TH1/TH17
suppression.
- target: B-cell lymphoma predisposition
description: >-
Constitutive STAT6 activity is oncogenic in the B-cell lineage: the same
DNA-binding-domain residues mutated in the germline (notably D419) are
recurrently mutated somatically in follicular lymphoma, predisposing to
B-cell lymphomagenesis.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:38238227
reference_title: "Human germline gain-of-function in STAT6: from severe allergic disease to lymphoma and beyond."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
STAT6 is frequently and recurrently mutated in follicular lymphomas and
other B cell lymphomas
explanation: >-
The shared STAT6 mutational spectrum between germline GOF disease and
somatic follicular lymphoma links constitutive STAT6 activity to
lymphomagenesis.
- name: TH2 immune skewing
biological_scale: CELLULAR
description: >-
Constitutive STAT6 activity biases naive CD4+ T cells toward TH2
differentiation with elevated peripheral TH2 lymphocytes, producing the IL-4/
IL-5/IL-13-dominated milieu that underlies allergic effector disease.
cell_types:
- preferred_term: T-helper 2 cell
term:
id: CL:0000546
label: T-helper 2 cell
biological_processes:
- preferred_term: T-helper 2 cell differentiation
term:
id: GO:0045064
label: T-helper 2 cell differentiation
modifier: INCREASED
evidence:
- reference: PMID:36216080
reference_title: "A germline STAT6 gain-of-function variant is associated with early-onset allergies."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Higher levels of peripheral blood TH2 lymphocytes were detected.
explanation: >-
Documents increased peripheral TH2 lymphocytes as the cellular readout of
STAT6-driven skewing.
downstream:
- target: IgE class switching
description: >-
TH2 cytokines (IL-4/IL-13) drive B-cell immunoglobulin class switching to
IgE, the humoral effector arm of the allergic phenotype.
causal_link_type: DIRECT
- target: Eosinophil expansion
description: >-
TH2 cytokines (IL-5) drive eosinophil expansion and tissue recruitment,
the cellular effector arm of the allergic phenotype.
causal_link_type: DIRECT
- target: Impaired antimicrobial immunity
description: >-
Reciprocal suppression of TH1/TH17 responses contributes to recurrent and
severe infection susceptibility in some patients.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- TH1 response suppression
- TH17 response suppression
evidence:
- reference: PMID:36758835
reference_title: "Severe allergic dysregulation due to a gain of function mutation in the transcription factor STAT6."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Naive lymphocytes from the affected patient displayed increased TH2- and
suppressed TH1- and TH17-cell responses.
explanation: >-
TH1/TH17 suppression provides a mechanistic basis for impaired
antimicrobial defense.
- name: IgE class switching
biological_scale: CELLULAR
description: >-
The type 2 milieu drives B-cell immunoglobulin class switching to IgE,
producing very high serum IgE — the humoral effector arm.
cell_types:
- preferred_term: B cell
term:
id: CL:0000236
label: B cell
biological_processes:
- preferred_term: isotype switching to IgE isotypes
term:
id: GO:0035708
label: interleukin-4-dependent isotype switching to IgE isotypes
modifier: INCREASED
evidence:
- reference: PMID:36884218
reference_title: "Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
hypereosinophilia with esosinophilic gastrointestinal disease, asthma,
elevated serum IgE, IgE-mediated food allergies, and anaphylaxis.
explanation: >-
Documents elevated serum IgE (and IgE-mediated food allergy) as the
humoral effector consequence of the type 2 program.
downstream:
- target: Multisystem allergic disease
description: >-
IgE-mediated hypersensitivity drives food allergy, anaphylaxis, and atopic
end-organ manifestations.
causal_link_type: DIRECT
- name: Eosinophil expansion
biological_scale: CELLULAR
description: >-
The type 2 milieu (IL-5) drives marked eosinophil expansion and tissue
recruitment, producing blood hypereosinophilia and eosinophilic
tissue infiltration — the cellular effector arm.
cell_types:
- preferred_term: eosinophil
term:
id: CL:0000771
label: eosinophil
evidence:
- reference: PMID:36884218
reference_title: "Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
hypereosinophilia with esosinophilic gastrointestinal disease, asthma,
elevated serum IgE, IgE-mediated food allergies, and anaphylaxis.
explanation: >-
Documents hypereosinophilia and eosinophilic gastrointestinal disease as
the cellular effector consequence of the type 2 program.
downstream:
- target: Multisystem allergic disease
description: >-
Eosinophilic tissue infiltration drives eosinophilic gastrointestinal
disease and other atopic end-organ manifestations.
causal_link_type: DIRECT
- name: Multisystem allergic disease
biological_scale: ORGANISM
description: >-
The convergent clinical endpoint: early-onset, treatment-resistant atopic
dermatitis, asthma, eosinophilic gastrointestinal disease, IgE-mediated food
allergy, and anaphylaxis.
evidence:
- reference: PMID:36884218
reference_title: "Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
a profound phenotype of early-life onset allergic immune dysregulation,
widespread treatment-resistant atopic dermatitis, hypereosinophilia with
esosinophilic gastrointestinal disease, asthma, elevated serum IgE,
IgE-mediated food allergies, and anaphylaxis.
explanation: >-
Enumerates the multisystem allergic phenotype that defines the disease.
- name: Impaired antimicrobial immunity
biological_scale: CELLULAR
description: >-
Reciprocal suppression of TH1 and TH17 responses (the mirror image of TH2
skewing) impairs antimicrobial defense, underlying the recurrent skin,
respiratory, and viral infections seen in a subset of patients and the OMIM
designation of HIES6 as "with recurrent infections."
cell_types:
- preferred_term: T-helper 1 cell
term:
id: CL:0000545
label: T-helper 1 cell
- preferred_term: T-helper 17 cell
term:
id: CL:0000899
label: T-helper 17 cell
biological_processes:
- preferred_term: T-helper 1 cell differentiation
term:
id: GO:0045063
label: T-helper 1 cell differentiation
modifier: DECREASED
- preferred_term: T-helper 17 cell differentiation
term:
id: GO:0072539
label: T-helper 17 cell differentiation
modifier: DECREASED
evidence:
- reference: PMID:36758835
reference_title: "Severe allergic dysregulation due to a gain of function mutation in the transcription factor STAT6."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Naive lymphocytes from the affected patient displayed increased TH2- and
suppressed TH1- and TH17-cell responses.
explanation: >-
TH1/TH17 suppression provides the immunological basis for impaired
antimicrobial defense.
downstream:
- target: Recurrent infections
description: >-
TH1/TH17 suppression manifests clinically as recurrent skin, respiratory,
and viral infections.
causal_link_type: DIRECT
evidence:
- reference: PMID:38238227
reference_title: "Human germline gain-of-function in STAT6: from severe allergic disease to lymphoma and beyond."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
with recurrent skin, respiratory, and viral infections, but no fatal
infections were noted.
explanation: >-
The consortium review documents recurrent skin, respiratory, and viral
infections in a subset of patients.
- name: B-cell lymphoma predisposition
biological_scale: CELLULAR
description: >-
STAT6 is a recurrently mutated oncogenic driver in follicular lymphoma and
other B-cell lymphomas, and germline STAT6 GOF is associated with an emerging
lymphoma risk: one reported patient developed follicular lymphoma that later
relapsed as diffuse large B-cell lymphoma. The true magnitude of risk is not
yet established.
cell_types:
- preferred_term: B cell
term:
id: CL:0000236
label: B cell
evidence:
- reference: PMID:38238227
reference_title: "Human germline gain-of-function in STAT6: from severe allergic disease to lymphoma and beyond."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
To date, one patient found to have STAT6-GOF disease has developed
lymphoma
explanation: >-
Documents the first reported lymphoma in a patient with germline STAT6 GOF
disease.
- reference: PMID:38238227
reference_title: "Human germline gain-of-function in STAT6: from severe allergic disease to lymphoma and beyond."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
STAT6 is frequently and recurrently mutated in follicular lymphomas and
other B cell lymphomas
explanation: >-
Provides the biological rationale linking constitutive STAT6 activity to
B-cell lymphomagenesis.
- reference: PMID:37316763
reference_title: "Autosomal Dominant STAT6 Gain of Function Causes Severe Atopy Associated with Lymphoma."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The clinical association of lymphoma in our kindred, along with previous
data linking somatic STAT6 D419H mutations to follicular lymphoma suggest
that patients with STAT6 GOF disease may be at higher risk of
lymphomagenesis.
explanation: >-
Independent kindred (germline p.D419H) directly linking STAT6 GOF disease
to lymphoma risk, reinforcing the shared-residue rationale.
downstream:
- target: Lymphoma
description: >-
The lymphomagenic predisposition manifests clinically as B-cell lymphoma
(follicular lymphoma, with reported transformation to diffuse large B-cell
lymphoma).
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:38238227
reference_title: "Human germline gain-of-function in STAT6: from severe allergic disease to lymphoma and beyond."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
a relapse with diffuse large B cell lymphoma at the age of 60 years
explanation: >-
Documents the follicular-to-DLBCL transformation in the index lymphoma
case.
phenotypes:
- name: Atopic dermatitis
category: Dermatological
diagnostic: true
description: >-
Widespread, early-onset, treatment-resistant atopic dermatitis is the most
consistent manifestation of STAT6 GOF disease.
phenotype_term:
preferred_term: Atopic dermatitis
term:
id: HP:0001047
label: Atopic dermatitis
onset:
onset_category: INFANTILE
notes: Disease onset in early infancy across the reported cohort.
evidence:
- reference: PMID:36884218
reference_title: "Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
a profound phenotype of early-life onset allergic immune dysregulation,
widespread treatment-resistant atopic dermatitis
explanation: Documents widespread treatment-resistant atopic dermatitis as a core feature.
- name: Increased circulating IgE concentration
category: Immunological
diagnostic: true
description: >-
Markedly elevated serum IgE is a hallmark laboratory feature, reflecting the
STAT6-driven IgE class switching.
phenotype_term:
preferred_term: Increased circulating IgE concentration
term:
id: HP:0003212
label: Increased circulating IgE concentration
evidence:
- reference: PMID:36884218
reference_title: "Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: asthma, elevated serum IgE, IgE-mediated food allergies, and anaphylaxis.
explanation: Documents elevated serum IgE as part of the core phenotype.
- name: Eosinophilia
category: Immunological
description: >-
Marked blood hypereosinophilia is characteristic and can be accompanied by
tissue eosinophilic infiltration.
phenotype_term:
preferred_term: Increased total eosinophil count
term:
id: HP:0001880
label: Increased total eosinophil count
evidence:
- reference: PMID:36758835
reference_title: "Severe allergic dysregulation due to a gain of function mutation in the transcription factor STAT6."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
who presented with severe atopic dermatitis, eosinophilia, and elevated
IgE.
explanation: Documents eosinophilia in an affected patient.
- name: Food allergy
category: Immunological
description: >-
IgE-mediated food allergy is a key presentation and a source of
life-threatening anaphylaxis.
phenotype_term:
preferred_term: Food allergy
term:
id: HP:0500093
label: Food allergy
evidence:
- reference: PMID:36216080
reference_title: "A germline STAT6 gain-of-function variant is associated with early-onset allergies."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Severe atopic dermatitis and food allergy were key presentations.
explanation: Documents food allergy as a key presentation.
- name: Asthma
category: Respiratory
description: Asthma is part of the multisystem atopic phenotype.
phenotype_term:
preferred_term: Asthma
term:
id: HP:0002099
label: Asthma
evidence:
- reference: PMID:36884218
reference_title: "Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
hypereosinophilia with esosinophilic gastrointestinal disease, asthma,
elevated serum IgE
explanation: Documents asthma as part of the phenotype.
- name: Eosinophilic esophagitis
category: Gastrointestinal
description: >-
Eosinophilic gastrointestinal disease, including eosinophilic esophagitis, is
part of the STAT6 GOF phenotype.
phenotype_term:
preferred_term: Eosinophilic esophagitis
term:
id: HP:0410151
label: Eosinophilic infiltration of the esophagus
evidence:
- reference: PMID:36884218
reference_title: "Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: hypereosinophilia with esosinophilic gastrointestinal disease, asthma
explanation: Documents eosinophilic gastrointestinal disease as part of the phenotype.
- name: Anaphylaxis
category: Immunological
description: >-
IgE-mediated anaphylaxis, frequently food-induced, occurs in STAT6 GOF
disease.
phenotype_term:
preferred_term: Food-induced anaphylaxis
term:
id: HP:0500095
label: Food-induced anaphylaxis
evidence:
- reference: PMID:36884218
reference_title: "Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: elevated serum IgE, IgE-mediated food allergies, and anaphylaxis.
explanation: Documents anaphylaxis, in the context of IgE-mediated food allergy.
- name: Recurrent infections
category: Immunological
description: >-
A subset of patients has increased susceptibility to recurrent infection,
consistent with the OMIM designation as a hyper-IgE syndrome with recurrent
infections and with reciprocal TH1/TH17 suppression.
phenotype_term:
preferred_term: Recurrent infections
term:
id: HP:0002719
label: Recurrent infections
evidence:
- reference: PMID:38238227
reference_title: "Human germline gain-of-function in STAT6: from severe allergic disease to lymphoma and beyond."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
with recurrent skin, respiratory, and viral infections, but no fatal
infections were noted.
explanation: >-
The consortium review documents recurrent skin, respiratory, and viral
infections in a subset of patients.
- reference: PMID:36758835
reference_title: "Severe allergic dysregulation due to a gain of function mutation in the transcription factor STAT6."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Naive lymphocytes from the affected patient displayed increased TH2- and
suppressed TH1- and TH17-cell responses.
explanation: >-
TH1/TH17 suppression provides an immunological basis for infection
susceptibility; recurrent infection is captured in the OMIM disease name.
- name: Lymphoma
category: Oncologic
description: >-
Germline STAT6 GOF carries an emerging predisposition to B-cell lymphoma;
the first reported case developed follicular lymphoma that later relapsed as
diffuse large B-cell lymphoma. True lifetime risk is not yet established.
phenotype_term:
preferred_term: B-cell lymphoma
term:
id: HP:0002665
label: Lymphoma
evidence:
- reference: PMID:38238227
reference_title: "Human germline gain-of-function in STAT6: from severe allergic disease to lymphoma and beyond."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
To date, one patient found to have STAT6-GOF disease has developed
lymphoma
explanation: >-
Documents the first reported lymphoma in a patient with germline STAT6 GOF
disease.
- name: Cerebral aneurysm
category: Neurologic
description: >-
A cerebral aneurysm has been reported as a non-immunological feature (in the
spectrum shared with STAT3-related HIES) and was fatal in one patient; the
causal relationship to the STAT6 GOF variant is not yet established.
phenotype_term:
preferred_term: Cerebral aneurysm
term:
id: HP:0004944
label: Dilatation of the cerebral artery
evidence:
- reference: PMID:38238227
reference_title: "Human germline gain-of-function in STAT6: from severe allergic disease to lymphoma and beyond."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Cerebral aneurysm: reported in one patient in adulthood; may be fatal
explanation: >-
Documents a reported, potentially fatal cerebral aneurysm in STAT6 GOF
disease.
- name: Short stature
category: Growth
description: >-
Short stature is reported as a non-immunological feature overlapping the
STAT3-LOF HIES spectrum.
phenotype_term:
preferred_term: Short stature
term:
id: HP:0004322
label: Short stature
evidence:
- reference: PMID:38238227
reference_title: "Human germline gain-of-function in STAT6: from severe allergic disease to lymphoma and beyond."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
including short stature, pathological fractures,
explanation: >-
Documents short stature among the STAT3-LOF-overlapping non-immunological
features of STAT6 GOF disease.
- name: Osteoporosis
category: Musculoskeletal
description: >-
Osteoporosis with pathological fractures is reported as a non-immunological
feature of STAT6 GOF disease.
phenotype_term:
preferred_term: Osteoporosis with pathological fractures
term:
id: HP:0000939
label: Osteoporosis
evidence:
- reference: PMID:38238227
reference_title: "Human germline gain-of-function in STAT6: from severe allergic disease to lymphoma and beyond."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
osteoporosis with pathological fractures, generalized joint
explanation: >-
Documents osteoporosis with pathological fractures as a reported feature.
- name: Gastroesophageal reflux
category: Gastrointestinal
description: >-
Early gastroesophageal reflux disease is part of the gastrointestinal
manifestations.
phenotype_term:
preferred_term: Gastroesophageal reflux
term:
id: HP:0002020
label: Gastroesophageal reflux
evidence:
- reference: PMID:38238227
reference_title: "Human germline gain-of-function in STAT6: from severe allergic disease to lymphoma and beyond."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
gastroesophageal reflux disease
explanation: >-
Documents early gastroesophageal reflux disease as a diagnostic feature.
- name: Allergic rhinitis
category: Immunological
description: >-
Allergic rhinitis (part of allergic rhinoconjunctivitis) is part of the
multisystem atopic phenotype.
phenotype_term:
preferred_term: Allergic rhinitis
term:
id: HP:0003193
label: Allergic rhinitis
evidence:
- reference: PMID:38238227
reference_title: "Human germline gain-of-function in STAT6: from severe allergic disease to lymphoma and beyond."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
rhinoconjunctivitis, multiple food allergies, drug allergies, eosinophilic
explanation: >-
Documents allergic rhinoconjunctivitis among the key atopic diagnostic
factors.
- name: Lymphadenopathy
category: Immunological
description: >-
Lymphadenopathy is a feature of the lymphoproliferation seen in STAT6 GOF
disease.
phenotype_term:
preferred_term: Lymphadenopathy
term:
id: HP:0002716
label: Lymphadenopathy
evidence:
- reference: PMID:38238227
reference_title: "Human germline gain-of-function in STAT6: from severe allergic disease to lymphoma and beyond."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Lymphoproliferation, characterized by lymphadenopathy
explanation: >-
Documents lymphadenopathy as a feature of STAT6 GOF lymphoproliferation.
biochemical:
- name: Serum IgE
presence: INCREASED
context: Markedly elevated serum IgE reflects STAT6-driven IgE class switching.
biomarker_term:
preferred_term: Increased circulating IgE concentration
term:
id: HP:0003212
label: Increased circulating IgE concentration
readouts:
- target: IgE class switching
relationship: READOUT_OF
direction: POSITIVE
endpoint_context: DIAGNOSTIC
interpretation: Elevated IgE reports the type 2 / IgE class-switching effector arm.
evidence:
- reference: PMID:36884218
reference_title: "Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: asthma, elevated serum IgE, IgE-mediated food allergies, and anaphylaxis.
explanation: Elevated serum IgE is a diagnostic readout of the disease.
evidence:
- reference: PMID:36884218
reference_title: "Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: asthma, elevated serum IgE, IgE-mediated food allergies, and anaphylaxis.
explanation: Documents elevated serum IgE as a biochemical hallmark.
- name: Blood eosinophil count
presence: INCREASED
context: Hypereosinophilia is a characteristic laboratory finding.
biomarker_term:
preferred_term: Increased total eosinophil count
term:
id: HP:0001880
label: Increased total eosinophil count
readouts:
- target: Eosinophil expansion
relationship: READOUT_OF
direction: POSITIVE
endpoint_context: DIAGNOSTIC
interpretation: Blood eosinophilia reports the eosinophil effector arm of the type 2 response.
evidence:
- reference: PMID:36758835
reference_title: "Severe allergic dysregulation due to a gain of function mutation in the transcription factor STAT6."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: who presented with severe atopic dermatitis, eosinophilia, and elevated IgE.
explanation: Eosinophilia is a diagnostic readout in affected patients.
- target: Eosinophil expansion
relationship: PHARMACODYNAMIC_MARKER_OF
direction: POSITIVE
endpoint_context: PHARMACODYNAMIC
interpretation: >-
Eosinophil count is a pharmacodynamic marker of the eosinophil effector
arm: it falls with dupilumab or JAK-inhibitor therapy and may track
treatment efficacy.
evidence:
- reference: PMID:38238227
reference_title: "Human germline gain-of-function in STAT6: from severe allergic disease to lymphoma and beyond."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
eosinophil count tends to be reduced after dupilumab or
explanation: >-
Eosinophil count decreases after dupilumab or JAK-inhibitor therapy,
supporting a treatment-response readout.
evidence:
- reference: PMID:36758835
reference_title: "Severe allergic dysregulation due to a gain of function mutation in the transcription factor STAT6."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: who presented with severe atopic dermatitis, eosinophilia, and elevated IgE.
explanation: Documents eosinophilia as a biochemical hallmark.
- name: Serum CCL24 (eotaxin-2)
presence: INCREASED
context: >-
The STAT6-regulated eosinophil chemokine CCL24 / eotaxin-2 is elevated in
the serum of patients with STAT6 GOF disease, consistent with the eosinophil
effector arm.
biomarker_term:
preferred_term: C-C motif chemokine 24 (eotaxin-2)
term:
id: NCIT:C28736
label: C-C Motif Chemokine 24
readouts:
- target: Eosinophil expansion
relationship: READOUT_OF
direction: POSITIVE
endpoint_context: DIAGNOSTIC
interpretation: >-
Elevated serum CCL24/eotaxin-2 reports STAT6-driven eosinophil chemotaxis.
evidence:
- reference: PMID:38238227
reference_title: "Human germline gain-of-function in STAT6: from severe allergic disease to lymphoma and beyond."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
was higher in s era from patients with STAT6 GOF and in gastric
explanation: >-
The STAT6-regulated chemokine CCL24/eotaxin-2 is elevated in patient
sera (snippet preserves the source PDF's "s era" extraction artifact).
evidence:
- reference: PMID:38238227
reference_title: "Human germline gain-of-function in STAT6: from severe allergic disease to lymphoma and beyond."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
chemokine C-C motif chemokine ligand 24 [CCL24
explanation: >-
Identifies CCL24 (eotaxin-2) as a STAT6-regulated eosinophil chemokine
relevant to the disease.
genetic:
- name: STAT6
gene_term:
preferred_term: STAT6
term:
id: hgnc:11368
label: STAT6
association: autosomal dominant causal gain-of-function variant
evidence:
- reference: PMID:36884218
reference_title: "Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
This study identifies heterozygous GOF variants in STAT6 as a novel
autosomal dominant allergic disorder.
explanation: >-
Establishes STAT6 heterozygous GOF variants as the cause of a novel
autosomal dominant allergic disorder.
- reference: PMID:37316763
reference_title: "Autosomal Dominant STAT6 Gain of Function Causes Severe Atopy Associated with Lymphoma."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We identified a novel heterozygous germline mutation STAT6 c.1255G > C,
p.D419H leading to overactivity of IL-4 JAK/STAT signalling pathway, in a
kindred affected by early-onset atopic dermatitis, food allergy,
eosinophilic asthma, anaphylaxis and follicular lymphoma.
explanation: >-
Independent kindred confirming a recurrent DNA-binding-domain variant
(p.D419H) as a germline GOF cause of the disease.
- reference: PMID:40502541
reference_title: "STAT6 gain-of-function disease: p.D519N is a new disease-causing variant that responds well to dupilumab treatment."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
This case report presents a new genetic variant that causes STAT6
gain-of-function disease in 2 patients, expands the clinical phenotype of
STAT6 gain-of-function disease
explanation: >-
Independent report of an additional disease-causing variant (p.D519N),
broadening the allelic spectrum.
treatments:
- name: Dupilumab
description: >-
The anti-IL-4Ra monoclonal antibody dupilumab blocks IL-4/IL-13 signaling
upstream of STAT6 and was highly effective in STAT6 GOF disease, improving
both clinical manifestations and immunological biomarkers.
therapeutic_modality: MONOCLONAL_ANTIBODY
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: dupilumab
term:
id: NCIT:C162455
label: Dupilumab
evidence:
- reference: PMID:36884218
reference_title: "Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Precision treatment with the anti-IL-4Rα antibody, dupilumab, was highly
effective improving both clinical manifestations and immunological
biomarkers.
explanation: Documents dupilumab as an effective precision therapy.
- reference: PMID:40502541
reference_title: "STAT6 gain-of-function disease: p.D519N is a new disease-causing variant that responds well to dupilumab treatment."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
p.D519N is a new disease-causing variant that responds well to dupilumab
treatment
explanation: >-
Independent report of a successful dupilumab response in STAT6 GOF disease
(p.D519N).
target_mechanisms:
- target: Constitutive STAT6 signaling
treatment_effect: INHIBITS
description: >-
Blocking the shared IL-4Ra chain reduces IL-4/IL-13-driven input into the
hyperresponsive STAT6 pathway.
- name: JAK inhibitor (ruxolitinib or tofacitinib)
description: >-
JAK inhibition targets the kinases upstream of STAT6. Ruxolitinib reversed
STAT6 hyperresponsiveness to IL-4, normalized TH1/TH17 cells, suppressed
eosinophilia, and improved atopic dermatitis; the consortium review names
both ruxolitinib and tofacitinib as JAK inhibitors used in patients.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: ruxolitinib
term:
id: CHEBI:66919
label: ruxolitinib
- preferred_term: tofacitinib
term:
id: CHEBI:71200
label: tofacitinib
evidence:
- reference: PMID:38238227
reference_title: "Human germline gain-of-function in STAT6: from severe allergic disease to lymphoma and beyond."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
JAK inhibitors (ruxolitinib or tofacitinib)
explanation: >-
The consortium review names both ruxolitinib and tofacitinib as JAK
inhibitors used in STAT6 GOF disease.
- reference: PMID:36758835
reference_title: "Severe allergic dysregulation due to a gain of function mutation in the transcription factor STAT6."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Treatment with the Janus kinase 1/2 inhibitor ruxolitinib reversed STAT6
hyperresponsiveness to IL-4, normalized TH1 and TH17 cells, suppressed the
eosinophilia, and improved the patient's atopic dermatitis.
explanation: Documents ruxolitinib efficacy targeting the STAT6 signaling axis.
- reference: PMID:37316763
reference_title: "Autosomal Dominant STAT6 Gain of Function Causes Severe Atopy Associated with Lymphoma."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
The selective JAK1/JAK2 inhibitor ruxolitinib reduced pSTAT6 levels in
D419H HEK293T cells and patient PBMC.
explanation: >-
Pharmacodynamic evidence that ruxolitinib lowers pathological STAT6
phosphorylation in a patient-derived GOF variant.
target_mechanisms:
- target: Constitutive STAT6 signaling
treatment_effect: INHIBITS
description: >-
JAK1/2 inhibition blocks the kinases upstream of STAT6, reducing STAT6
phosphorylation and downstream type 2 signaling.
- name: Supportive and anaphylaxis-preparedness care
description: >-
Supportive management including allergen avoidance in sensitized patients,
epinephrine autoinjectors and medical-alert measures for anaphylaxis, and
bone-loss prophylaxis in patients on chronic corticosteroids. Anaphylaxis
was fatal in one of the two reported deaths, underscoring the need for
anaphylaxis preparedness.
therapeutic_modality: BEHAVIORAL
treatment_term:
preferred_term: supportive care
term:
id: NCIT:C15747
label: Supportive Care
evidence:
- reference: PMID:38238227
reference_title: "Human germline gain-of-function in STAT6: from severe allergic disease to lymphoma and beyond."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
alert jewelry, epinephrine autoinjectors; immunization; prophylaxis for bone
explanation: >-
The consortium review specifies epinephrine autoinjectors, medical-alert
measures, and bone-loss prophylaxis as supportive management.
target_phenotypes:
- preferred_term: Food-induced anaphylaxis
term:
id: HP:0500095
label: Food-induced anaphylaxis
diagnosis:
- name: Next-generation genetic sequencing
description: >-
Molecular confirmation of a heterozygous STAT6 GOF variant establishes the
diagnosis; NGS is described as the most powerful and cost-effective approach.
diagnosis_term:
preferred_term: molecular genetic testing
term:
id: NCIT:C19770
label: Molecular Analysis
evidence:
- reference: PMID:38238227
reference_title: "Human germline gain-of-function in STAT6: from severe allergic disease to lymphoma and beyond."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Next-generation genetic sequencing: most powerful and cost-effective
explanation: >-
NGS is the recommended definitive diagnostic test for STAT6 GOF disease.
- name: Serum total IgE and blood eosinophil count
description: >-
Supportive laboratory findings: markedly raised total IgE and elevated
absolute eosinophil count, with generally normal lymphocyte subsets.
diagnosis_term:
preferred_term: clinical assessment
term:
id: NCIT:C124351
label: Clinical Evaluation
evidence:
- reference: PMID:38238227
reference_title: "Human germline gain-of-function in STAT6: from severe allergic disease to lymphoma and beyond."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Total IgE: raised; may exceed upper limit of detection
explanation: >-
Markedly raised total IgE is a supportive laboratory finding.
- reference: PMID:38238227
reference_title: "Human germline gain-of-function in STAT6: from severe allergic disease to lymphoma and beyond."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Complete blood count with white cell differentials; absolute eosinophil count
explanation: >-
Elevated absolute eosinophil count on CBC is a supportive finding.
- reference: PMID:38238227
reference_title: "Human germline gain-of-function in STAT6: from severe allergic disease to lymphoma and beyond."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Lymphocyte subsets: usually normal
explanation: >-
Lymphocyte subsets are usually normal, distinguishing from other IEIs.
- name: Esophagogastroduodenoscopy
description: >-
Upper GI endoscopy with biopsy documents eosinophilic esophageal disease
(trachealization and furrowing, mucosal erosions, polypoid lesions).
diagnosis_term:
preferred_term: esophagogastroduodenoscopy
term:
id: NCIT:C78144
label: Esophagogastroduodenoscopy
evidence:
- reference: PMID:38238227
reference_title: "Human germline gain-of-function in STAT6: from severe allergic disease to lymphoma and beyond."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
erosions of mucosa, polypoid-like lesions; trachealization and furrowing in
explanation: >-
Upper GI endoscopy documents the eosinophilic esophageal disease component.
- name: Colonoscopy
description: >-
Lower GI endoscopy with biopsy documents eosinophilic intestinal disease
(nodularities and lymphonodular hyperplasia).
diagnosis_term:
preferred_term: colonoscopy
term:
id: NCIT:C16450
label: Colonoscopy
evidence:
- reference: PMID:38238227
reference_title: "Human germline gain-of-function in STAT6: from severe allergic disease to lymphoma and beyond."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
nodularities and lymphonodular hyperplasia in small and large
explanation: >-
Lower GI endoscopy documents the eosinophilic intestinal disease component.
prevalence:
- population: Worldwide (reported cohorts)
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >-
Newly described entity; 21 individuals from 13 distinct families reported to
date (as of the 2024 consortium review).
evidence:
- reference: PMID:38238227
reference_title: "Human germline gain-of-function in STAT6: from severe allergic disease to lymphoma and beyond."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
21 individuals from 13 distinct families have been
explanation: >-
Quantifies the cases-in-literature count for this newly described disease.
progression:
- notes: >-
Prognosis is variable; most patients are managed with type 2-directed or JAK
inhibitor therapy. Serious complications include lymphoma, kidney failure,
and cerebral aneurysm. Two of 21 reported patients have died — from a
cerebral aneurysm (age 35) and anaphylaxis (age 20).
evidence:
- reference: PMID:38238227
reference_title: "Human germline gain-of-function in STAT6: from severe allergic disease to lymphoma and beyond."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
two patients out of 21 reported to date have died: causes were
explanation: >-
Documents disease-associated mortality (2 of 21 reported patients).
- reference: PMID:38238227
reference_title: "Human germline gain-of-function in STAT6: from severe allergic disease to lymphoma and beyond."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
cerebral aneurysm (age 35 years) and anaphylaxis (age 20 years)
explanation: >-
Specifies the two fatal complications and ages at death.
classifications:
harrisons_chapter:
- classification_value: IMMUNE_RHEUMATOLOGIC
evidence:
- reference: PMID:36758835
reference_title: "Severe allergic dysregulation due to a gain of function mutation in the transcription factor STAT6."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
This study identified a novel inborn error of immunity due to a STAT6
gain-of-function mutation that gave rise to severe allergic
dysregulation.
explanation: >-
Frames the disease as an inborn error of immunity manifesting as severe
allergic (immune-dysregulation) disease, supporting placement in the
immunology/rheumatology Part.
- classification_value: GENETICS_ENVIRONMENT_DISEASE
evidence:
- reference: PMID:36884218
reference_title: "Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
This study identifies heterozygous GOF variants in STAT6 as a novel
autosomal dominant allergic disorder.
explanation: >-
A monogenic (autosomal dominant) germline disorder, supporting placement
in the genetics Part.
iuis_category:
classification_value: combined immunodeficiency with syndromic features
notes: >-
Corrected from `immune dysregulation` (2026-08-20). The IUIS 2024 update
places STAT6 GOF in Table 2, subtable 1 — combined immunodeficiencies
with syndromic features — not Table 4. The earlier assignment read the
disease's dominant allergic/type-2 dysregulation phenotype as a Table 4
signal, but IUIS groups it with the hyper-IgE-like syndromic entities
alongside dominant-negative STAT3, where an immune defect is inseparable
from a broader syndromic presentation. The phenotype description is
unchanged; only the table assignment is.
evidence:
- reference: PMID:41608114
reference_title: "Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Combined immunodeficiencies with syndromic features: IKZF2 (dominant
negative); GINS4, SLC19A1, SGPL1, FLT3L, ITPR3, RECQL4 (AR LOF); PTCRA
(AR LOF/hypomorphic); SMAD3 (AD); and STAT6 (AD GOF)
explanation: >-
The IUIS Expert Committee's own enumeration of gene defects new since
the 2022 update lists STAT6 (AD GOF) under "combined immunodeficiencies
with syndromic features", which the same sentence identifies as Table 2,
subtable 1.
references:
- reference: PMID:38238227
title: "Human germline gain-of-function in STAT6: from severe allergic disease to lymphoma and beyond."
notes: >-
Initial curation from the founding STAT6 GOF disease literature (Sharma et al.
JEM 2023; Baris et al. JACI 2023; Suratannon et al. JACI 2023) plus the STAT6
GOF International Consortium review. Emphasizes the STAT6 GOF -> constitutive
type 2 signaling -> TH2 skewing -> IgE/eosinophil effector -> multisystem
allergic disease axis and the dupilumab / JAK-inhibitor targeted treatments.
datasets: []
STAT6 gain-of-function (GOF) disease is a rare, recently described (2023) autosomal-dominant primary atopic disorder (PAD)—one of a growing group of inborn errors of immunity (IEIs) in which a single germline gene defect produces severe, early-onset allergic disease. It is caused by germline heterozygous activating (gain-of-function) missense variants in STAT6 (Signal Transducer and Activator of Transcription 6; chromosome 12q13.3; HGNC:11364; NCBI Gene 6778; OMIM 601512). Pathogenic variants cluster in the DNA-binding domain, with a recurrent hotspot at codon Asp419 (D419H/Y/G/N) and additional recurrent variants including E372K, E377K, E382Q, and D519H/N. These variants produce constitutive and/or ligand-hypersensitive IL-4/IL-13–JAK–STAT6 signaling, with sustained STAT6 phosphorylation, enhanced nuclear translocation (in some cases even without phosphorylation), increased STAT6 target-gene expression, and pathological TH2 skewing of the adaptive immune system.
Clinically, the disease presents in infancy (100% of the founding cohort) with a profound, multi-system allergic phenotype: widespread treatment-resistant atopic dermatitis (94%), hypereosinophilia and markedly elevated serum IgE (94%), IgE-mediated food allergy (94%), asthma (69%), eosinophilic gastrointestinal disease (63%), and anaphylaxis (56%). Variable features include recurrent skin/respiratory/viral infections, short stature, osteoporosis, and a small but important risk of B-cell/follicular lymphoma (~6%), mechanistically linked to the same DNA-binding-domain residues that are recurrently mutated somatically in follicular lymphoma. The disorder is catalogued as OMIM #620532 ("Hyper-IgE syndrome 6, autosomal dominant, with recurrent infections; HIES6") and MONDO:0957807.
The disease is highly actionable: because the driver is a hyperactive, druggable signaling axis, pathway-targeted therapy is transformative. The anti–IL-4Rα monoclonal antibody dupilumab and JAK inhibitors (e.g., ruxolitinib) improve both clinical manifestations and immunological biomarkers. Diagnosis relies on exome/genome sequencing with functional confirmation of STAT6 hyperactivation. Two constitutively active mouse models (Stat6VT transgenic and patient-derived D419N knock-in) recapitulate the human TH2/allergic phenotype and validate the causal mechanism. This report synthesizes 9 confirmed findings drawn from 11 reviewed papers into a full disease knowledge-base entry organized along the 15 requested characteristic domains, followed by a mechanistic model, evidence base, limitations, and proposed follow-up actions.
The defining evidence comes from a landmark international cohort of 16 patients from 10 families across three continents (Sharma et al., 2023). All patients carried monoallelic (heterozygous) rare variants in STAT6, and functional studies established a gain-of-function phenotype. As the authors state verbatim: "All patients carried monoallelic rare variants in STAT6 and functional studies established their gain-of-function (GOF) phenotype with sustained STAT6 phosphorylation, increased STAT6 target gene expression, and TH2 skewing" and "This study identifies heterozygous GOF variants in STAT6 as a novel autosomal dominant allergic disorder" (PMID: 36884218). Inheritance was sporadic (de novo) in 7 kindreds and autosomal dominant in 3 kindreds, consistent with a dominant, GOF (not loss-of-function/haploinsufficiency) mechanism.
Evidence source: human clinical/genetic (multi-family cohort with functional validation).
The founding cohort described "a profound phenotype of early-life onset allergic immune dysregulation, widespread treatment-resistant atopic dermatitis, hypereosinophilia with esosinophilic gastrointestinal disease, asthma, elevated serum IgE, IgE-mediated food allergies, and anaphylaxis" (PMID: 36884218). This multi-system atopic constellation is the diagnostic signature and is independently replicated in single-case/kindred reports: Baris et al. (E372K), Suratannon/independent (E377K), Minskaia (D419H), and Samra (D519N) each describe severe atopic dermatitis, eosinophilia, elevated IgE, and food allergy.
Evidence source: human clinical.
Reported germline missense variants include p.E372K (c.1114G>A), p.E377K (c.1129G>A), p.E382Q (c.1144G>C), p.D419H (c.1255G>C), p.D419Y (c.1255G>T), p.D419G (c.1256A>G), p.D419N (c.1255G>A), and p.D519H/N (c.1555G>C)—several within the DNA-binding domain (DBD). Direct quotes anchor the mechanism: - "a missense mutation in the DNA binding domain of STAT6 (c.1114G>A, p.E372K)" (PMID: 36758835). - "a novel heterozygous germline mutation STAT6 c.1255G > C, p.D419H leading to overactivity of IL-4 JAK/STAT signalling pathway" (PMID: 37316763). - Ligand independence was shown for D419N: "even in the absence of IL-4 stimulation, we observed the translocation of mutant STAT6 in its unphosphorylated state, which activated gene expression" (PMID: 40603028).
Thus, some variants confer hypersensitivity to IL-4 (elevated total/phospho-STAT6 at baseline and after IL-4, e.g., D419H) while others confer constitutive, phosphorylation-independent nuclear translocation and transcription (D419N).
Evidence source: human genetic + in vitro functional (HEK293T, patient PBMC, gastric organoids).
Because the disease is driven by a hyperactive IL-4/IL-13–JAK–STAT6 axis, blocking that axis is therapeutic. "Precision treatment with the anti-IL-4Rα antibody, dupilumab, was highly effective improving both clinical manifestations and immunological biomarkers" (PMID: 36884218); dupilumab was also effective for the D519N variant (Samra 2025, PMID: 40502541). JAK inhibition targets the upstream kinases: "The selective JAK1/JAK2 inhibitor ruxolitinib reduced pSTAT6 levels in D419H HEK293T cells and patient PBMC" (PMID: 37316763). Critically, the same Minskaia kindred (D419H) included follicular lymphoma, linking germline STAT6 GOF to lymphomagenesis.
Evidence source: human clinical (treatment response) + in vitro (pharmacodynamic).
STAT6 GOF disease is catalogued as OMIM #620532 = "HYPER-IgE SYNDROME 6, AUTOSOMAL DOMINANT, WITH RECURRENT INFECTIONS; HIES6." The Mondo term MONDO:0957807 ("hyper-IgE syndrome 6, autosomal dominant, with recurrent infections") cross-references OMIM:620532, GARD:0026874, MedGen:1851769, and UMLS:C5848786. The causal gene STAT6 = OMIM 601512, HGNC:11364, NCBI Gene 6778, UniProt P42226. NCI Thesaurus C212086 = "Activating STAT6 Gene Mutation." No dedicated Orphanet/ORDO code was identified at the time of research.
Evidence source: aggregated disease-level resources (OMIM, Mondo, MedGen, NCIt).
Official HPO disease annotations (OMIM:620532 / MONDO:0957807), all sourced to PMID: 36884218, provide curated frequencies (see the phenotype table in Section 3). They derive from the cohort description: "widespread treatment-resistant atopic dermatitis, hypereosinophilia with esosinophilic gastrointestinal disease, asthma, elevated serum IgE, IgE-mediated food allergies, and anaphylaxis."
Evidence source: curated ontology annotation of human clinical cohort.
ClinVar (transcript NM_003153.5) lists germline Pathogenic/Likely-pathogenic STAT6 variants for "Hyper-IgE syndrome 6": c.1114G>A p.Glu372Lys (P), c.1144G>C p.Glu382Gln (P), c.1255G>C p.Asp419His (LP), c.1255G>T p.Asp419Tyr (P), c.1256A>G p.Asp419Gly (P), and c.1555G>C p.Asp519His (P). Codon 419 is a recurrent hotspot. gnomAD constraint metrics show STAT6 is LoF-tolerant (pLI = 0.057; oe_lof upper bound = 0.54) but missense-constrained (mis_z = 3.47). This constraint signature—tolerant of loss-of-function but intolerant of missense change, combined with recurrent, clustered, dominant missense variants—is the classic fingerprint of a gain-of-function, not haploinsufficiency, disease mechanism.
Evidence source: population genomics / variant databases (computational).
Two independent mouse models validate causality. The Stat6VT transgenic expresses a constitutively active STAT6 in T cells and "develop[s] spontaneous inflammation of the skin" (allergic dermatitis) plus allergic airway disease (PMID: 28653395). The patient-derived D419N knock-in mouse "elicited an abnormal TH2-dominant immune response in vivo, with findings similar to those observed in patients" (PMID: 40603028). Together, these models reproduce the cardinal human features (atopic skin disease, airway disease, TH2 skewing).
Evidence source: model organism (mouse).
PARP14 (ARTD8) is an IL-4/STAT6-induced transcriptional co-activator: "the presence of interleukin-4 (IL-4) and activated Stat6 induces the enzymatic activity of PARP14 that promotes T helper type 2 differentiation and allergic airway disease" (PMID: 28653395). PARP14 is also "a novel target in STAT6 mutant follicular lymphoma" (PMID: 35851155). Because germline STAT6 GOF and somatic follicular-lymphoma STAT6 mutations affect the same DNA-binding-domain residues (notably D419), PARP14 represents a shared, druggable downstream node connecting the allergic and oncologic ends of the disease spectrum.
Evidence source: model organism + in vitro / cancer genomics.
STAT6 GOF disease is a monogenic, autosomal-dominant primary atopic disorder / inborn error of immunity characterized by early-onset, severe, multi-system allergic disease driven by constitutive TH2 signaling. It was first defined as a distinct entity in 2023.
| Identifier type | Value |
|---|---|
| OMIM (disease) | #620532 (Hyper-IgE syndrome 6, autosomal dominant, with recurrent infections; HIES6) |
| Mondo | MONDO:0957807 |
| GARD | 0026874 |
| MedGen | 1851769 |
| UMLS | C5848786 |
| NCIt | C212086 (Activating STAT6 Gene Mutation) |
| Gene (OMIM) | STAT6 601512 |
| HGNC | 11364 |
| NCBI Gene | 6778 |
| UniProt | P42226 |
| Orphanet | None dedicated identified |
| ICD-10/ICD-11 | No specific code; mapped under primary immunodeficiency/atopic categories |
| MeSH | No dedicated term; indexed via STAT6 / hyper-IgE / hypersensitivity |
Synonyms/alternative names: STAT6 gain-of-function disease; STAT6-GOF; Hyper-IgE syndrome 6 (HIES6); autosomal dominant STAT6 GOF; STAT6-associated primary atopic disorder.
Information source type: Predominantly aggregated disease-level resources (OMIM, Mondo, HPO) built from a small number of individual-patient case cohorts/reports (n≈16 founding + additional single cases). This is a very rare, newly described disease, so all knowledge derives from individual patients described in the literature, not EHR-scale populations.
Quantitative HPO-annotated frequencies (n=16 founding cohort, PMID: 36884218):
| Phenotype | HPO term | Frequency | Type |
|---|---|---|---|
| Infantile onset | HP:0003593 | 16/16 (100%) | onset |
| Atopic dermatitis | HP:0001047 | 15/16 (94%) | clinical sign / skin |
| Food allergy | HP:0500093 | 15/16 (94%) | clinical sign |
| Increased eosinophil count | HP:0001880 | 15/16 (94%) | lab abnormality |
| Increased circulating IgE | HP:0003212 | present (high) | lab abnormality |
| Asthma | HP:0002099 | 11/16 (69%) | clinical sign / respiratory |
| Gastrointestinal eosinophilia | HP:0032064 | 10/16 (63%) | lab / histopathology |
| Anaphylactic shock | HP:0100845 | 9/16 (56%) | clinical sign |
| Recurrent skin infections | HP:0001581 | 7/16 (44%) | clinical sign |
| Short stature | HP:0004322 | 7/16 (44%) | physical manifestation |
| Recurrent respiratory infections | HP:0002205 | 5/16 (31%) | clinical sign |
| Gastroesophageal reflux | HP:0002020 | 4/16 (25%) | clinical sign |
| Osteoporosis | HP:0000939 | 3/16 (19%) | lab / imaging |
| Recurrent viral infections | HP:0004429 | 2/16 (13%) | clinical sign |
| B-cell lymphoma | HP:0012191 | 1/16 (6%) | neoplasm |
| Eosinophilic esophagitis | HP:0410151 | present | histopathology |
| Autosomal dominant inheritance | HP:0000006 | — | inheritance |
Characteristics: age of onset is neonatal/infantile (100%); severity is generally severe (treatment-resistant atopic dermatitis); course is chronic/progressive with episodic anaphylaxis; variable expressivity is documented even within families (e.g., E377K kindred showed clinical heterogeneity, PMID: 36216080). Quality-of-life impact is substantial: severe pruritic dermatitis, dietary restriction from food allergy, anaphylaxis risk, and growth impairment—though formal EQ-5D/SF-36 data are not available for this rare disease.
No environmental toxin, occupational exposure, lifestyle factor, or infectious agent causes STAT6 GOF disease. Environmental allergens act as triggers for individual atopic manifestations. Recurrent infections (skin/respiratory/viral) reflect immune dysregulation intrinsic to the genotype rather than an environmental etiology.
Causal chain (upstream → downstream):
Germline STAT6 DBD missense variant (e.g., D419H/N, E372K)
│
▼
Constitutive / IL-4-hypersensitive STAT6 activation
• sustained tyrosine phosphorylation (pSTAT6)
• ligand-independent nuclear translocation (D419N, even unphosphorylated)
│
▼
Increased STAT6 target-gene transcription (e.g., PARP14, GATA3 program)
│
▼
Pathological TH2 skewing of CD4+ T cells (IL-4, IL-5, IL-13 ↑)
│
├──► B-cell IgE class switching → hyper-IgE, food allergy, anaphylaxis
├──► Eosinophil recruitment/survival → hypereosinophilia, eosinophilic GI disease
├──► Skin barrier/Th2 inflammation → treatment-resistant atopic dermatitis
├──► Airway Th2 inflammation → asthma
└──► Chronic B-cell proliferation + PARP14 co-activation → follicular lymphoma risk
| Therapy | Class / target | Mechanism | Evidence | MAXO |
|---|---|---|---|---|
| Dupilumab | anti–IL-4Rα monoclonal antibody | Blocks IL-4/IL-13 receptor upstream of STAT6 | "highly effective improving both clinical manifestations and immunological biomarkers" (PMID: 36884218); effective for D519N (PMID: 40502541) | MAXO monoclonal-antibody therapy |
| Ruxolitinib / JAK inhibitors | JAK1/JAK2 inhibitor | Reduces pSTAT6 by blocking upstream kinases | "ruxolitinib reduced pSTAT6 levels in D419H HEK293T cells and patient PBMC" (PMID: 37316763) | MAXO pharmacotherapy / targeted therapy |
| Supportive atopic care | Topical steroids, emollients, allergen avoidance, epinephrine | Symptom control | Standard atopy management | MAXO supportive care |
| PARP14 inhibition (experimental) | small-molecule co-activator inhibitor | Blocks downstream STAT6 co-activator; also anti-lymphoma | Preclinical (PMID: 35851155; PMID: 28653395) | MAXO experimental therapy |
Personalized medicine: the disease is a paradigm of genotype-guided precision therapy — a druggable, hyperactive signaling axis directly matched to approved biologics (dupilumab) and JAK inhibitors. Pharmacogenomics: not specifically characterized. No gene/cell therapy is in clinical use.
| Model | Type | Genetic design | Phenotype recapitulation | Reference |
|---|---|---|---|---|
| Stat6VT | Mouse (transgenic) | Constitutively active STAT6 in T cells | Spontaneous allergic skin inflammation + allergic airway disease; PARP14-dependent TH2 program | PMID: 28653395 |
| STAT6 D419N knock-in | Mouse (patient-variant knock-in) | Germline D419N | "abnormal TH2-dominant immune response in vivo, with findings similar to those observed in patients" | PMID: 40603028 |
| Patient cells / HEK293T | In vitro | Overexpressed variant STAT6 | pSTAT6 elevation, nuclear translocation, reporter activation; ruxolitinib response | PMID: 37316763, PMID: 36884218 |
| Gastric organoids | In vitro (patient-derived) | E377K | Downstream effector-cytokine studies | PMID: 36216080 |
Applications: mechanism of TH2 skewing, allergic skin/airway disease, target validation for dupilumab/JAK/PARP14. Limitations: mouse models capture allergic dermatitis and TH2 skewing but do not fully model the human lymphoma continuum or the complete multi-system phenotype.
STAT6 GOF disease is best understood as a "single-node type-2 immune amplifier" disorder. A germline missense change in the STAT6 DNA-binding domain converts a normally ligand-controlled transcription factor into a hyperactive or constitutively active driver of the TH2 gene program. The location of the mutations is mechanistically decisive: the DBD hotspot (D419) either stabilizes STAT6 in a DNA-bound/nuclear-retained state or lowers the activation threshold for IL-4 signaling. This produces the entire downstream cascade of type-2 immunity—IgE class switching, eosinophilia, and barrier-tissue inflammation—explaining why one gene defect yields such a broad, coherent, multi-organ atopic phenotype.
Three lines of evidence converge on gain-of-function rather than haploinsufficiency: (1) the dominant inheritance with recurrent, clustered missense variants; (2) gnomAD constraint showing LoF tolerance but strong missense intolerance (mis_z = 3.47); and (3) direct functional assays showing sustained/ligand-independent STAT6 activation. The mouse models close the causal loop: constitutively active STAT6 alone is sufficient to produce spontaneous allergic skin and airway disease.
The disease also illuminates a shared germline–somatic axis. The identical DBD residues mutated germline in this atopic disorder are recurrently mutated somatically in follicular lymphoma, and PARP14 functions as a common downstream co-activator in both settings. This explains the small but real lymphoma risk and nominates PARP14 as a mechanistic bridge and therapeutic target spanning allergy and oncology.
Clinically, the model is directly actionable: blocking the axis at the receptor (dupilumab/IL-4Rα) or upstream kinase (JAK inhibitor) reverses both symptoms and biomarkers, making STAT6 GOF disease a textbook example of precision medicine in inborn errors of immunity.
| PMID | Title (abbrev.) | Contribution |
|---|---|---|
| 36884218 | Human germline heterozygous GOF STAT6 variants cause severe allergic disease | Defining cohort (n=16): GOF mechanism, AD inheritance, core phenotype, dupilumab efficacy |
| 36216080 | A germline STAT6 GOF variant is associated with early-onset allergies | E377K DBD variant; spontaneous STAT6 activation; gastric organoids; variable expressivity |
| 36758835 | Severe allergic dysregulation due to a GOF mutation in STAT6 | E372K DBD variant |
| 37316763 | Autosomal dominant STAT6 GOF causes severe atopy associated with lymphoma | D419H variant; ruxolitinib reduces pSTAT6; follicular lymphoma link |
| 40603028 | Mechanism of pathogenesis by a GOF STAT6 variant | D419N: ligand-independent nuclear translocation; knock-in mouse recapitulation |
| 40502541 | STAT6 GOF: p.D519N responds to dupilumab | New variant; expands phenotype; dupilumab response |
| 38238227 | Human germline GOF STAT6: from allergy to lymphoma | Review; allergy-to-lymphoma spectrum; targeted-treatment overview |
| 37727514 | Transcription factor defects in IEIs with atopy | Places STAT6 GOF among TF-defect atopic IEIs; differential diagnosis |
| 39381601 | Rapid identification of PAD by upfront genomic sequencing | Diagnostic strategy: upfront WGS for primary atopic disorders |
| 28653395 | PARP14 limits severity of allergic skin disease | Stat6VT mouse; PARP14 as STAT6 co-activator in TH2/allergic disease |
| 35851155 | PARP14 is a novel target in STAT6 mutant follicular lymphoma | PARP14 druggability; germline–somatic mechanistic bridge |
All eleven papers are mutually consistent; none challenge the core GOF model. Evidence spans human clinical/genetic cohorts, in vitro functional assays, and two mouse models, providing multi-modal validation.