ZNF341 Deficiency

Mendelian MONDO:0032654 Pathograph 35 Show in embeddings browser Hyper-IgE syndrome Inborn error of immunity Primary immunodeficiency

ZNF341 deficiency is an autosomal recessive hyper-IgE syndrome caused by biallelic loss-of-function variants in ZNF341, a nuclear C2H2 zinc-finger transcription factor that binds the STAT3 promoter. Loss of ZNF341 lowers basal STAT3 mRNA and protein and abolishes the cytokine- and TCR-driven autoinduction of STAT3 in lymphocytes, so the disease is a clinical and immunological phenocopy of autosomal dominant (dominant-negative) STAT3 hyper-IgE syndrome, reached through reduced STAT3 supply rather than a poisoned STAT3 dimer. Atopic dermatitis is present in essentially every reported patient and is typically the presenting feature from early childhood; recurrent staphylococcal skin infection and abscesses, chronic mucocutaneous candidiasis, sinopulmonary infection, high serum IgE and eosinophilia follow, with low Th17 cells, excess Th2 cells and low memory B cells. Compared with STAT3 dominant-negative disease the course is milder (median NIH HIES score 28.5 versus 64), the extra-hematopoietic connective-tissue, skeletal and dental features are less frequent, no vascular complications have been reported, serum IgG is typically high, and NK cell counts are low in most patients. About 20 patients have been published, nearly all homozygous for truncating variants in consanguineous kindreds.

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1
Inheritance
10
Pathophys.
29
Phenotypes
3
Hypotheses
35
Pathograph
1
Genes
4
Medical Actions
3
Differentials
3
References
1
Deep Research
🏷

Classifications

Harrison's Part
IMMUNE RHEUMATOLOGIC GENETICS ENVIRONMENT DISEASE
IUIS Category
combined immunodeficiency with syndromic features
👪

Inheritance

1
Autosomal recessive HP:0000007
ZNF341 deficiency is autosomal recessive and fully penetrant. All 20 patients pooled in the 2023 review were homozygous for a truncating ZNF341 allele and all their kindreds were consanguineous, so the disorder was initially seen only as homozygosity for a founder or private null allele. A later report describes a child with a biallelic missense allele and does not state whether she is homozygous, so neither truncation nor homozygosity can be treated as a requirement. Heterozygous relatives are healthy. The cited sources do not state a numerical recurrence risk for the sibship, so none is recorded here.
Autosomal recessive inheritance
Show evidence (3 references)
PMID:29907691 SUPPORT Human Clinical
"The segregation of the four mutant alleles of ZNF341 in the six families was consistent with a fully penetrant AR trait"
Segregation across six kindreds establishes a fully penetrant autosomal recessive trait.
PMID:29907690 SUPPORT Human Clinical
"We investigated patients of four consanguineous families with an autosomal-recessive disorder resembling the phenotype of AD-HIES"
The independent discovery cohort is likewise four consanguineous autosomal recessive kindreds.
CGGV:assertion_2dc4032e-7215-464d-9844-c392ec25148b-2024-06-04T170000.000Z SUPPORT Other
"This curation included ten probands from 10 unrelated consanguineous families (PMID: 29907691, 29907690 & 37080116)."
ClinGen's curation records that every contributing proband came from a consanguineous family.
◈

Mechanistic Hypotheses

3
Reduced basal STAT3 and loss of STAT3 autoinduction in lymphocytes
znf341_stat3_supply CANONICAL
Evidence balance 2 support
ZNF341 binds the STAT3 promoter and is required for normal basal STAT3 transcription and for the transient autoinduction of STAT3 when naive T cells are co-stimulated through the TCR and IL-6 (and B cells through CD40L and IL-21). Because a 50% fall in basal STAT3 is not by itself thought to cause HIES (no STAT3 haploinsufficiency phenotype is known), the combination of low basal STAT3 with failed autoinduction in lymphocytes is the favoured explanation for the STAT3-deficiency phenocopy.
Pathograph links
ZNF341 biallelic loss of function -> Reduced basal STAT3 expression DIRECT Loss of ZNF341 binding at the STAT3 promoter lowers constitutive STAT3 transcription.
ZNF341 biallelic loss of function -> Loss of STAT3 autoinduction in lymphocytes DIRECT ZNF341 is required for STAT3 to induce its own transcription on combined TCR and IL-6 stimulation.
Reduced basal STAT3 expression -> Insufficient STAT3 activity in lymphocytes DIRECT Low basal STAT3 contributes to lower STAT3 activation downstream of STAT3-activating cytokines.
Loss of STAT3 autoinduction in lymphocytes -> Insufficient STAT3 activity in lymphocytes DIRECT
Insufficient STAT3 activity in lymphocytes -> Impaired Th17 differentiation and IL-17/IL-22 immunity DIRECT
Insufficient STAT3 activity in lymphocytes -> Th2 skewing of CD4 T cells INDIRECT UNKNOWN INTERMEDIATES
Insufficient STAT3 activity in lymphocytes -> Impaired T follicular helper and memory B cell development DIRECT
Show evidence (2 references)
PMID:37080116 SUPPORT REVIEW SYNTHESIS In Vitro
"The combination of decreased basal expression level and impaired autoinduction of STAT3 observed in ZNF341-deficient lymphocytes is considered a more likely pathophysiological mechanism."
The disease-defining authors' synthesis names the combined basal-plus-autoinduction defect as the working mechanism.
PMID:37080116 SUPPORT REVIEW SYNTHESIS Human Clinical
"However, as there is no clear evidence that STAT3 haploinsufficiency causes HIES, this decrease alone is probably insufficient to explain the HIES phenotype observed in the ZNF341-deficient patients."
States why reduced basal STAT3 alone is not accepted as sufficient.
Reduced STAT1 expression and mycobacterial susceptibility
znf341_stat1_mycobacteria EMERGING
Evidence balance 1 support 1 refute
ZNF341 also binds the STAT1 promoter and ZNF341-deficient cells have lower STAT1. Two patients have had tuberculosis, and the 2023 review raises the possibility that partial STAT1 impairment contributes; the original 2018 report judged the lower STAT1 unlikely to contribute to the clinical phenotype. Unresolved.
Pathograph links
ZNF341 biallelic loss of function -> Reduced STAT1 expression DIRECT ZNF341 binds the STAT1 promoter; deficient cells have less STAT1.
Reduced STAT1 expression -> Tuberculosis UNKNOWN Proposed, unconfirmed route to mycobacterial susceptibility (see mechanistic hypothesis).
Show evidence (2 references)
PMID:37080116 SUPPORT REVIEW SYNTHESIS Human Clinical
"we cannot rule out the possibility that ZNF341-deficient patients are susceptible to virulent environmental mycobacteria due to a partial impairment of STAT1 signaling"
Frames the STAT1 route to mycobacterial disease as a possibility only.
PMID:29907691 REFUTE In Vitro
"the lower levels of STAT1 observed in ZNF341-deficient patients are unlikely to account for or even contribute to their immunological or clinical phenotypes."
The discovery paper argued the opposite, that reduced STAT1 is unlikely to matter clinically.
Impaired DNA repair and malignancy predisposition
dna_repair_malignancy EMERGING
Evidence balance 1 support
Ex vivo irradiated leukocytes from four ZNF341-deficient patients repaired DNA damage more slowly than controls, and one patient developed a nasal primitive neuroendocrine tumor followed by papillary thyroid cancer. The authors propose that the repair defect, together with radiation exposure, predisposes to malignancy. The clinical side of this rests on one patient.
Pathograph links
Impaired repair of radiation-induced DNA damage -> Neoplasm INDIRECT UNKNOWN INTERMEDIATES
Show evidence (1 reference)
PMID:35511492 SUPPORT In Vitro
"Increased radiosensitivity and impaired DNA repair were demonstrated in patients diagnosed with STAT3-LOF and ZNF341 deficiency, potentially explaining the susceptibility to malignant transformation."
Comet-assay study on patient leukocytes proposing the DNA-repair route to malignancy.
⚙

Pathophysiology

10
ZNF341 biallelic loss of function
All 20 patients pooled in the 2023 review were homozygous for predicted loss-of-function ZNF341 alleles (nonsense, frameshift, essential splice site); a biallelic missense allele has since been reported, so truncation characterises that cohort rather than defining the disease. The truncated products lack most of the twelve C2H2 zinc fingers; the p.Gln195* and p.Arg302* products are retained in the cytoplasm, and mutant proteins fail to activate the STAT3 promoter. ZNF341 is a constitutively nuclear transcription factor expressed in all leukocytes tested and in fibroblasts and keratinocytes.
Reduced basal STAT3 and loss of STAT3 autoinduction in lymphocytes Reduced STAT1 expression and mycobacterial susceptibility
ZNF341 hgnc:15992 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ZNF341 (hgnc:15992). hgnc:15992 is a gene from the HUGO Gene Nomenclature Committee.
DNA-binding transcription factor activity GO:0000981 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased DNA-binding transcription factor activity, annotated with DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981). GO:0000981 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Reduced basal STAT3 expression Loss of ZNF341 binding at the STAT3 promoter lowers constitutive STAT3 transcription. Reduced basal STAT3 and loss of STAT3 autoinduction in lymphocytes
Loss of STAT3 autoinduction in lymphocytes ZNF341 is required for STAT3 to induce its own transcription on combined TCR and IL-6 stimulation. Reduced basal STAT3 and loss of STAT3 autoinduction in lymphocytes
Reduced STAT1 expression ZNF341 binds the STAT1 promoter; deficient cells have less STAT1. Reduced STAT1 expression and mycobacterial susceptibility
Reduced natural killer cell count NK lymphopenia is common in ZNF341 deficiency but rare in STAT3 dominant-negative disease. Whether it reflects a STAT3-independent ZNF341 function or a deeper STAT3 defect in NK progenitors is unresolved.
Show evidence (3 references)
PMID:29907691 SUPPORT In Vitro
"ZNF341 is a transcription factor that resides in the nucleus, where it binds a specific DNA motif present in various genes, including the STAT3 promoter."
Defines ZNF341 as a nuclear transcription factor that binds the STAT3 promoter.
PMID:29907690 SUPPORT In Vitro
"Wild-type ZNF341 bound to and activated the STAT3 promoter, whereas the mutant variants showed impaired transcriptional activation, partly due to nuclear translocation failure."
Patient variants lose transcriptional activation of STAT3, partly through failed nuclear import.
PMID:37080116 SUPPORT REVIEW SYNTHESIS Human Clinical
"All the patients with AR ZNF341 deficiency described to date were homozygous for pLOF variants"
Every confirmed patient carries biallelic predicted loss-of-function alleles.
Reduced basal STAT3 expression
Patient primary cells have reduced resting STAT3 mRNA and protein. The discovery papers report different magnitudes: about 50% of normal in primary naive CD4+ T cells, monocytes and fibroblasts (Beziat et al.), and 16-28% of wild-type protein in PBMCs, EBV-B cells and skin fibroblasts (Frey-Jakobs et al.). Cytokine-induced STAT3 Y705 phosphorylation is correspondingly lower. The defect is present in non-hematopoietic cells as well as lymphocytes.
Reduced basal STAT3 and loss of STAT3 autoinduction in lymphocytes
STAT3 hgnc:11364 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves STAT3 (hgnc:11364). hgnc:11364 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Insufficient STAT3 activity in lymphocytes Low basal STAT3 contributes to lower STAT3 activation downstream of STAT3-activating cytokines. Reduced basal STAT3 and loss of STAT3 autoinduction in lymphocytes
Reduced STAT3 function in non-hematopoietic cells The basal STAT3 reduction is also present in fibroblasts.
Show evidence (3 references)
PMID:29907690 SUPPORT In Vitro
"STAT3 protein expression was reduced in ZNF341-mutant cells (patients’ PBMCs, EBV-transformed B cells, and PSF) down to 16–28% of wild-type levels"
Quantifies reduced STAT3 protein in several patient cell types.
PMID:29907690 SUPPORT In Vitro
"STAT3 Y705-phosphorylation was markedly impaired in PBMCs from patients with R302* and R386* mutations, respectively, following stimulation with IL-6"
Lower total STAT3 translates into lower IL-6-induced STAT3 activation.
PMID:37080116 SUPPORT REVIEW SYNTHESIS In Vitro
"All the ZNF341-deficient cell subsets tested, including lymphocytes, monocytes, and fibroblasts, had 50% the normal level of STAT3 mRNA and protein."
Shows the basal reduction extends beyond lymphocytes to monocytes and fibroblasts.
Loss of STAT3 autoinduction in lymphocytes
In control naive CD4+ T cells, co-stimulation through CD2/CD3/CD28 plus IL-6 or Th17-polarizing cytokines raises STAT3 mRNA 10- to 20-fold; this synergy is absent in ZNF341-deficient cells but preserved in STAT3 dominant-negative cells. Autoinduction is also impaired in naive B cells stimulated with CD40L and IL-21. Loss of this boost prevents sustained STAT3 activity during lymphocyte differentiation.
Reduced basal STAT3 and loss of STAT3 autoinduction in lymphocytes
CD4-positive alpha-beta T cell CL:0000624 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves CD4-positive alpha-beta T cell, annotated with CD4-positive, alpha-beta T cell (CL:0000624). CL:0000624 is a cell type from the Cell Ontology. B cell CL:0000236 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves B cell (CL:0000236). CL:0000236 is a cell type from the Cell Ontology.
STAT3 hgnc:11364 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves STAT3 (hgnc:11364). hgnc:11364 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Insufficient STAT3 activity in lymphocytes Reduced basal STAT3 and loss of STAT3 autoinduction in lymphocytes
Show evidence (2 references)
PMID:37080116 SUPPORT REVIEW SYNTHESIS In Vitro
"STAT3 autoinduction was abolished in ZNF341-deficient naive T cells stimulated under these conditions, but not in STAT3-deficient naive T cells"
The autoinduction defect distinguishes ZNF341 from STAT3 dominant-negative disease.
PMID:37080116 SUPPORT REVIEW SYNTHESIS In Vitro
"impaired STAT3 autoinduction was also observed in ZNF341-deficient naive B cells following CD40L and IL-21 costimulation, and was associated with a severe impairment of immunoglobulin production"
Extends the autoinduction defect to B cells.
Insufficient STAT3 activity in lymphocytes
The net effect in T and B cells is STAT3 activation and transcriptional output as low as in dominant-negative STAT3 disease, so STAT3-dependent lymphocyte differentiation programs (Th17, T follicular helper, memory B cell, plasma cell) fail in the same way. TCR-induced calcium flux and T cell proliferation are normal.
Reduced basal STAT3 and loss of STAT3 autoinduction in lymphocytes
CD4-positive alpha-beta T cell CL:0000624 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves CD4-positive alpha-beta T cell, annotated with CD4-positive, alpha-beta T cell (CL:0000624). CL:0000624 is a cell type from the Cell Ontology. B cell CL:0000236 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves B cell (CL:0000236). CL:0000236 is a cell type from the Cell Ontology.
JAK-STAT signaling GO:0007259 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased JAK-STAT signaling, annotated with cell surface receptor signaling pathway via JAK-STAT (GO:0007259). GO:0007259 is a biological process from the Gene Ontology. ↓ DECREASED interleukin-6-mediated signaling pathway GO:0070102 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased interleukin-6-mediated signaling pathway (GO:0070102). GO:0070102 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Impaired Th17 differentiation and IL-17/IL-22 immunity Reduced basal STAT3 and loss of STAT3 autoinduction in lymphocytes
Th2 skewing of CD4 T cells Reduced basal STAT3 and loss of STAT3 autoinduction in lymphocytes
Impaired T follicular helper and memory B cell development Reduced basal STAT3 and loss of STAT3 autoinduction in lymphocytes
Show evidence (1 reference)
PMID:29907691 SUPPORT In Vitro
"Consequently, STAT3-dependent genes, such as RORC, IL17A, and IL17F, are poorly induced."
Downstream STAT3 target genes are poorly induced in patient T cells.
Impaired Th17 differentiation and IL-17/IL-22 immunity
Circulating Th17 cells are low, memory CD4+ T cells make little IL-17A, IL-17F or IL-22, and naive CD4+ T cells fail to produce IL-17 under Th17-polarizing conditions. Patient fibroblasts and keratinocytes respond normally to IL-17A, so the candidiasis reflects deficient IL-17 production rather than deficient IL-17 response.
T-helper 17 cell CL:0000899 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves T-helper 17 cell (CL:0000899). CL:0000899 is a cell type from the Cell Ontology.
T-helper 17 cell differentiation GO:0072539 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased T-helper 17 cell differentiation (GO:0072539). GO:0072539 is a biological process from the Gene Ontology. ↓ DECREASED interleukin-17 production GO:0032620 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased interleukin-17 production (GO:0032620). GO:0032620 is a biological process from the Gene Ontology. ↓ DECREASED defense response to fungus GO:0050832 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased defense response to fungus (GO:0050832). GO:0050832 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Chronic mucocutaneous candidiasis
Onychomycosis Nail Candida infection is one of the mucocutaneous candidiasis manifestations tabulated for these patients.
Decreased Th17 T cell proportion The differentiation defect is read out as a low Th17 proportion on immunophenotyping.
Recurrent skin infections By analogy with STAT3 dominant-negative disease, loss of IL-17/IL-22 epithelial antibacterial signals is thought to contribute to staphylococcal skin infection. No ZNF341-specific study tests this edge.
Show evidence (2 references)
PMID:29907691 SUPPORT In Vitro
"In marked contrast, the production of Th17 cytokines (IL-17A, IL-17F, IL-22) by ZNF341-deficient memory CD4+ T cells was much weaker than that by control cells"
Patient memory CD4+ T cells make little Th17 cytokine.
PMID:29907690 SUPPORT Human Clinical
"Patients however presented a significantly reduced percentage of Th17 CD4+ T cells, a key feature of STAT3-HIES"
Independent cohort confirms low circulating Th17 cells.
Th2 skewing of CD4 T cells
Circulating memory CD4+ T cells are skewed toward Th2, with high GATA3 and Th2 cytokine transcripts (IL-4, IL-5, IL-13, IL-31) that persist even under Th17-polarizing conditions; CD8+ T cells over-express IL-5 and IL-9. The excess type 2 response is the proposed basis of the high IgE, eczema, eosinophilia and allergy.
T-helper 2 cell CL:0000546 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves T-helper 2 cell (CL:0000546). CL:0000546 is a cell type from the Cell Ontology.
T-helper 2 cell differentiation GO:0045064 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased T-helper 2 cell differentiation (GO:0045064). GO:0045064 is a biological process from the Gene Ontology. ↑ INCREASED type 2 immune response GO:0042092 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased type 2 immune response (GO:0042092). GO:0042092 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Atopic dermatitis
Elevated serum IgE Excess IL-4/IL-13 signaling favours IgE class switching; total IgE fell under IL-4Ralpha blockade.
Eosinophilia T cell IL-5 over-production is the proposed driver of eosinophilia.
Allergy Allergic manifestations are attributed to the Th2 excess.
Show evidence (1 reference)
PMID:29907691 SUPPORT In Vitro
"These data suggest that the allergic features of ZNF341-deficient patients were due to the enhanced production of some, but not all Th2-like cytokines, including IL-5 and IL-9, in particular, by both CD4+ and CD8+ T cells."
Patient T cells over-produce Th2-type cytokines.
Impaired T follicular helper and memory B cell development
Patients have low circulating T follicular helper cells and low memory B cells (with increased naive B cells), and naive B cells fail to differentiate into immunoglobulin-secreting cells on CD40L plus IL-21 stimulation. Unlike STAT3 dominant-negative disease, serum IgG is usually high; the basis of this dissociation is not explained.
memory B cell CL:0000787 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves memory B cell (CL:0000787). CL:0000787 is a cell type from the Cell Ontology. T follicular helper cell CL:0002038 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves T follicular helper cell (CL:0002038). CL:0002038 is a cell type from the Cell Ontology.
plasma cell differentiation GO:0002317 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased plasma cell differentiation (GO:0002317). GO:0002317 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Decreased memory B cell proportion Read out as a low memory B cell proportion.
Recurrent pneumonia
Recurrent upper respiratory tract infections Impaired sustained humoral responses are thought to contribute to sinopulmonary infection generally.
Show evidence (1 reference)
PMID:29907690 SUPPORT Human Clinical
"Immunophenotyping revealed normal CD19 lymphocyte counts, but an increased percentage of naïve B cells (IgD+CD27−), and reduced memory B cells (CD27+) in the affected individuals."
Patient immunophenotyping shows low memory B cells.
Reduced STAT3 function in non-hematopoietic cells
STAT3 levels are also reduced in patient fibroblasts, and patients develop the connective-tissue, skeletal and dental features of STAT3 HIES, but less often and more mildly. The discovery paper suggests the IL-11R, LIFR and IL-6ST-dependent programs in these tissues need less STAT3 than lymphocyte programs do. This is an interpretation, not a measured tissue-by-tissue dose threshold, so the edges below are left as unknown intermediates.
fibroblast CL:0000057 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves fibroblast (CL:0000057). CL:0000057 is a cell type from the Cell Ontology.
Downstream
Facial dysmorphism
High palate
Persistence of primary teeth
Joint hypermobility
Scoliosis
Minimal-trauma fractures
Show evidence (1 reference)
PMID:29907691 SUPPORT Human Clinical
"Patients with ZNF341 deficiency appear to develop fewer and milder non-hematopoietic developmental phenotypes than patients with STAT3 DN mutations."
States the milder extra-hematopoietic involvement relative to STAT3 dominant-negative disease.
Reduced STAT1 expression
ZNF341 binds two sites in the STAT1 promoter and ZNF341-deficient cells have lower STAT1 mRNA and protein. Its clinical significance is disputed.
Reduced STAT1 expression and mycobacterial susceptibility
STAT1 hgnc:11362 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves STAT1 (hgnc:11362). hgnc:11362 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Tuberculosis Proposed, unconfirmed route to mycobacterial susceptibility (see mechanistic hypothesis). Reduced STAT1 expression and mycobacterial susceptibility
Show evidence (1 reference)
PMID:37080116 SUPPORT REVIEW SYNTHESIS In Vitro
"Two ZNF341-binding sites were identified within the STAT1 promoter, including one approximately 400 nucleotides upstream from the transcription start site (TSS), as in the STAT3 promoter"
Identifies STAT1 as a direct ZNF341 target.
Impaired repair of radiation-induced DNA damage
In an alkaline Comet assay on ex vivo irradiated leukocytes from four ZNF341-deficient and twelve STAT3 loss-of-function patients, DNA-damage measures kept rising during the recovery period while those of healthy controls returned toward baseline. The mechanism linking ZNF341 or STAT3 to DNA repair is not established, so this node has no upstream edge.
Impaired DNA repair and malignancy predisposition
DNA repair GO:0006281 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased DNA repair (GO:0006281). GO:0006281 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Neoplasm Impaired DNA repair and malignancy predisposition
Show evidence (1 reference)
PMID:35511492 SUPPORT In Vitro
"During the recovery period of irradiation, TL, TDNA%, and OTM values of healthy controls decreased rapidly toward the baseline, while these values of patients with STAT3-LOF and ZNF341 deficiency continued to increase, implying impaired DNA repair mechanisms."
Ex vivo radiation assay showing slower DNA-damage resolution in patient leukocytes.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for ZNF341 Deficiency Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

29
Blood 6
Decreased Th17 T cell proportion VERY_FREQUENT HP:0025832 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reduced Th17 (IL-17-producing CD4+) T cell proportion, annotated with Decreased Th17 T cell proportion (HP:0025832). HP:0025832 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:37080116 SUPPORT REVIEW SYNTHESIS Human Clinical
"Low Th17-cell levels | ND | ND | 5/5 | 4/6 | 9/11 (82%) | 93%"
Pooled table row, 9/11 patients with low Th17 cells against 93% in STAT3 deficiency.
PMID:29907690 SUPPORT Human Clinical
"Patients however presented a significantly reduced percentage of Th17 CD4+ T cells, a key feature of STAT3-HIES"
Discovery cohort measured the reduced Th17 proportion directly.
PMID:29907690 SUPPORT In Vitro
"peripheral blood mononuclear cells (PBMCs) derived from patients failed to differentiate into IL-17 producing CD4+ T cells"
In vitro differentiation assay shows the deficit is intrinsic to Th17 differentiation.
Decreased memory B cell proportion FREQUENT HP:0030374 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Low memory B cell percentage, annotated with Decreased memory B cell proportion (HP:0030374). HP:0030374 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:37080116 SUPPORT REVIEW SYNTHESIS Human Clinical
"Low memory B-cell levels (% of B cells) | 0/1 | ND | 4/6 | 6/6 | 10/13 (77%) | 94,5%"
Pooled table row, 10/13 patients.
PMID:29907690 SUPPORT Human Clinical
"Immunophenotyping revealed normal CD19 lymphocyte counts, but an increased percentage of naïve B cells (IgD+CD27−), and reduced memory B cells (CD27+) in the affected individuals."
Normal total B cells with a shift from memory toward naive B cells.
Reduced natural killer cell count FREQUENT Reduced total natural killer cell count HP:0040218 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Low natural killer cell count, annotated with Reduced total natural killer cell count (HP:0040218). HP:0040218 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:37080116 SUPPORT REVIEW SYNTHESIS Human Clinical
"Low NK cell (count or % of lymphocytes) | 0/1 | 0/1 | 6/7 | 4/6 | 10/15 (67%) | 8%"
Pooled table row contrasting 67% in ZNF341 deficiency with 8% in STAT3 deficiency.
PMID:29907691 SUPPORT Human Clinical
"The seven patients tested (P2–P8) had normal counts of circulating neutrophils and basophils, monocytes, B and T cells, but low counts of NK cells"
NK lymphopenia against otherwise normal leukocyte counts in the second discovery cohort.
Elevated serum IgE VERY_FREQUENT Increased circulating IgE concentration HP:0003212 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Serum IgE above 1000 IU, annotated with Increased circulating IgE concentration (HP:0003212). HP:0003212 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37080116 SUPPORT REVIEW SYNTHESIS Human Clinical
"IgE levels > 1000 IU | 1/1 | 0/1 | 6/7 | 10/11 | 17/20 (85%) | 96%"
Pooled table row, 17/20 patients above 1000 IU.
Elevated serum IgG VERY_FREQUENT Increased circulating IgG concentration HP:0003237 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Serum IgG above 16 g/L, annotated with Increased circulating IgG concentration (HP:0003237). HP:0003237 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:37080116 SUPPORT REVIEW SYNTHESIS Human Clinical
"High IgG levels (> 16 g/L) | 1/1 | 0/1 | 7/7 | 7/9 | 15/18 (83%) | 27%"
Pooled table row contrasting 83% in ZNF341 deficiency with 27% in STAT3 deficiency.
ORPHA:641368 SUPPORT Other
"High plasma levels of IgG and low natural killer (NK) cell numbers are observed."
Orphanet includes high plasma IgG in the defining description of the disorder.
Eosinophilia FREQUENT Increased total eosinophil count HP:0001880 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Peripheral blood eosinophilia, annotated with Increased total eosinophil count (HP:0001880). HP:0001880 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37080116 SUPPORT REVIEW SYNTHESIS Human Clinical
"Eosinophilia | 0/1 | 1/1 | 3/7 | 7/10 | 11/19 (58%) | 80%"
Pooled table row, 11/19 patients.
Head and Neck 5
Recurrent upper respiratory tract infections FREQUENT HP:0002788 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent ear, nose and throat infections, annotated with Recurrent upper respiratory tract infections (HP:0002788). HP:0002788 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37080116 SUPPORT REVIEW SYNTHESIS Human Clinical
"Recurrent ear, nose, and throat infections were reported in 58% of patients with ZNF341 deficiency, and 90% of those with STAT3 deficiency."
Pooled frequency of upper respiratory infection.
Recurrent oral thrush FREQUENT Chronic oral candidiasis HP:0009098 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Oral thrush, annotated with Chronic oral candidiasis (HP:0009098). HP:0009098 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37080116 SUPPORT REVIEW SYNTHESIS Human Clinical
"- Oral thrush | 0/1 | 0/1 | 5/7 | 4/11 | 9/20 (45%) | 63%"
Pooled table row for the oral-thrush component of CMC.
Facial dysmorphism FREQUENT Abnormal facial shape HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mild facial dysmorphism, annotated with Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:37080116 SUPPORT REVIEW SYNTHESIS Human Clinical
"- Facial abnormalities | 0/1 | 0/1 | 2/7 | 8/10 | 10/19 (53%) | 95%"
Pooled table row contrasting 53% in ZNF341 deficiency with 95% in STAT3 deficiency.
PMID:35748970 SUPPORT Other
"Phenocopy of AD-HIES; mild facial dysmorphism; early onset eczema"
IUIS characterizes the facial dysmorphism of this disorder as mild.
High palate FREQUENT HP:0000218 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is High palate (HP:0000218). HP:0000218 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37080116 SUPPORT REVIEW SYNTHESIS Human Clinical
"- High palate | 0/1 | 0/1 | 4/7 | 5/11 | 9/20 (45%) | 53%"
Pooled table row, 9/20 patients.
Persistence of primary teeth OCCASIONAL HP:0006335 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Retention of deciduous teeth, annotated with Persistence of primary teeth (HP:0006335). HP:0006335 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37080116 SUPPORT REVIEW SYNTHESIS Human Clinical
"- Deciduous tooth retention | 0/1 | 0/1 | 0/7 | 4/7 | 4/16 (25%) | 65%"
Pooled table row contrasting 25% in ZNF341 deficiency with 65% in STAT3 deficiency.
Immune 9
Atopic dermatitis OBLIGATE HP:0001047 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Atopic dermatitis (HP:0001047). HP:0001047 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:37080116 SUPPORT REVIEW SYNTHESIS Human Clinical
"Atopic dermatitis was the most common clinical presentation of patients with ZNF341 deficiency, present in all patients reported"
Atopic dermatitis in 20/20 pooled patients.
PMID:35748970 SUPPORT Other
"Phenocopy of AD-HIES; mild facial dysmorphism; early onset eczema"
IUIS describes the eczema as early onset.
PMID:29907690 SUPPORT Human Clinical
"Affected members of Families B, C and D (Fig. 2B–D) presented with a milder phenotype initially diagnosed as atopic dermatitis, with characteristic HIES symptoms occurring later in life."
Dermatitis can be the sole initial presentation, with HIES features emerging later.
Neonatal rash OCCASIONAL Skin rash HP:0000988 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Newborn rash, annotated with Skin rash (HP:0000988). HP:0000988 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37080116 SUPPORT REVIEW SYNTHESIS Human Clinical
"By contrast, newborn rash was rarely reported in patients with ZNF341 deficiency (15%), but was much more frequent (48%) in patients with STAT3 deficiency"
Newborn rash frequency in the pooled cohort.
Recurrent skin infections VERY_FREQUENT HP:0001581 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent skin infections (HP:0001581). HP:0001581 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37080116 SUPPORT REVIEW SYNTHESIS Human Clinical
"| Recurrent skin infection | 0/1 | 1/1 | 6/7 | 8/9 | 15/18 (83%) | 100% |"
Pooled table row, 15/18 patients.
Recurrent cutaneous abscesses FREQUENT Recurrent cutaneous abscess formation HP:0100838 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent skin abscesses, annotated with Recurrent cutaneous abscess formation (HP:0100838). HP:0100838 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:37080116 SUPPORT REVIEW SYNTHESIS Human Clinical
"Both ZNF341-deficient and STAT3-deficient patients were highly prone to recurrent skin infections, with skin abscesses (75% vs. 73%) and CMC (60% vs. 85%)."
Skin abscesses in 75% of pooled patients.
PMID:29907690 SUPPORT Human Clinical
"The clinical triad of HIES consisting of recurrent pneumonias, eczema with cold skin abscesses, and elevated serum IgE levels was present in all three affected individuals"
Cold skin abscesses were described in the three affected members of one kindred.
Chronic mucocutaneous candidiasis FREQUENT HP:0002728 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chronic mucocutaneous candidiasis (HP:0002728). HP:0002728 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:37080116 SUPPORT REVIEW SYNTHESIS Human Clinical
"| CMC | 0/1 | 0/1 | 6/7 | 6/11 | 12/20 (60%) | 85% |"
Chronic mucocutaneous candidiasis in 12/20 pooled patients.
PMID:37080116 SUPPORT REVIEW SYNTHESIS Human Clinical
"| - Oral thrush | 0/1 | 0/1 | 5/7 | 4/11 | 9/20 (45%) | 63% |"
Oral thrush, the commonest candidiasis site, in 9/20 pooled patients.
Onychomycosis OCCASIONAL HP:0012203 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Onychomycosis (HP:0012203). HP:0012203 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37080116 SUPPORT REVIEW SYNTHESIS Human Clinical
"| - Onychomycosis | 0/1 | 0/1 | 3/7 | 2/11 | 5/20 (25%) | 57% |"
Onychomycosis in 5/20 pooled patients.
Recurrent pneumonia FREQUENT HP:0006532 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent pneumonia (HP:0006532). HP:0006532 is a phenotype from the Human Phenotype Ontology.
Sequelae: Bronchiectasis Pulmonary pneumatocele
Show evidence (1 reference)
PMID:37080116 SUPPORT REVIEW SYNTHESIS Human Clinical
"with pneumonia, bronchiectasis, and pneumatocele reported in 56%, 35%, and 10%, respectively, of the ZNF341-deficient patients"
Pooled frequencies of pneumonia and its structural sequelae.
Tuberculosis Tuberculosis infection HP:5210111 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tuberculosis, annotated with Tuberculosis infection (HP:5210111). HP:5210111 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37080116 SUPPORT REVIEW SYNTHESIS Human Clinical
"However, at least two patients have been reported to have suffered tuberculosis"
Reports tuberculosis in two patients.
Allergy OCCASIONAL HP:0012393 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Food or respiratory allergy, annotated with Allergy (HP:0012393). HP:0012393 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37080116 SUPPORT REVIEW SYNTHESIS Human Clinical
"Allergy (food or respiratory) | 0/1 | ND | 4/7 | 0/11 | 4/19 (21 %) | 22%"
Pooled table row showing the allergy counts concentrated in one series.
Integument 1
Alopecia OCCASIONAL HP:0001596 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Alopecia (HP:0001596). HP:0001596 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37080116 SUPPORT REVIEW SYNTHESIS Human Clinical
"Alopecia | 0/1 | 0/1 | 1/7 | 1/11 | 2/20 (10%) | n.d."
Pooled table row, 2/20 patients.
Musculoskeletal 3
Joint hypermobility OCCASIONAL HP:0001382 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Joint hyperextensibility, annotated with Joint hypermobility (HP:0001382). HP:0001382 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37080116 SUPPORT REVIEW SYNTHESIS Human Clinical
"- Joint hyperextensibility | 0/1 | 0/1 | 2/7 | 1/11 | 3/20 (15%) | 50%"
Pooled table row, 3/20 patients.
Scoliosis OCCASIONAL HP:0002650 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Scoliosis (HP:0002650). HP:0002650 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37080116 SUPPORT REVIEW SYNTHESIS Human Clinical
"- Scoliosis | 0/1 | 1/1 | 0/7 | 1/11 | 2/20 (10%) | 38%"
Pooled table row, 2/20 patients.
Minimal-trauma fractures OCCASIONAL Increased susceptibility to fractures HP:0002659 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bone fracture after minimal trauma, annotated with Increased susceptibility to fractures (HP:0002659). HP:0002659 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37080116 SUPPORT REVIEW SYNTHESIS Human Clinical
"- Bone fractures with minimal trauma | 0/1 | 0/1 | 1/7 | 1/11 | 2/20 (20%) | 42%"
Pooled table row, 2 of 20 patients, quoted with the printed percentage as it stands.
Nervous System 1
Developmental delay FREQUENT Neurodevelopmental delay HP:0012758 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mental delay, not further characterized, annotated with Neurodevelopmental delay (HP:0012758). HP:0012758 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37080116 SUPPORT REVIEW SYNTHESIS Human Clinical
"Mental delay | 0/1 | 0/1 | 0/7 | 7/10 | 7/19 (37%) | n.d."
Pooled table row, 7/19 patients, concentrated in one contributing series.
Respiratory 2
Bronchiectasis FREQUENT HP:0002110 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bronchiectasis (HP:0002110). HP:0002110 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37080116 SUPPORT REVIEW SYNTHESIS Human Clinical
"| - Bronchiectasis | 0/1 | 0/1 | 2/7 | 4/8 | 6/17 (35%) | 65% |"
Pooled table row for bronchiectasis.
Pulmonary pneumatocele OCCASIONAL HP:0025419 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pneumatocele, annotated with Pulmonary pneumatocele (HP:0025419). HP:0025419 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37080116 SUPPORT REVIEW SYNTHESIS Human Clinical
"| - Pneumatocele | 0/1 | 0/1 | 1/7 | 1/8 | 2/20 (10%) | 52% |"
Pooled table row for pneumatocele.
Growth 1
Growth retardation OCCASIONAL Growth delay HP:0001510 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Growth retardation, annotated with Growth delay (HP:0001510). HP:0001510 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37080116 SUPPORT REVIEW SYNTHESIS Human Clinical
"Growth retardation | 0/1 | 0/1 | 1/7 | 2/11 | 3/20 (15%) | n.d."
Pooled table row, 3/20 patients, with no STAT3 comparator reported.
Neoplasm 1
Neoplasm HP:0002664 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Malignancy of any type, annotated with Neoplasm (HP:0002664). HP:0002664 is a phenotype from the Human Phenotype Ontology.
Coarse binding: pathograph hub
Show evidence (2 references)
PMID:37080116 SUPPORT REVIEW SYNTHESIS Human Clinical
"Neoplasia (any type) | 0/1 | 0/1 | 0/7 | 1/11 | 1/20 (5%) | 7%"
Pooled table row recording one malignancy among the 20 published patients.
PMID:35511492 SUPPORT Human Clinical
"Except for a patient with ZNF341 deficiency who developed nasal cell primitive neuroendocrine tumor and papillary thyroid cancer during the follow-up, there was no cancer in both groups."
Names the two tumors in the single affected patient.
🧬

Genetic Associations

1
ZNF341 (Causative)
Gene: ZNF341 hgnc:15992 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ZNF341 (hgnc:15992). hgnc:15992 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (7 references)
PMID:35185921 SUPPORT Human Clinical
"All samples were tested by Sanger sequencing for the ZNF341 mutation (c.904C>T, NM_001282933.1)."
Confirms c.904C>T as the allele screened for as a founder variant in that population.
PMID:39420803 SUPPORT Human Clinical
"ZNF341 (c.538C > G; p.Pro180Ala) | This manuscript | 2 | F | Hyperpigmented plaques, diffuse xerosis and pruritis, cutaneous infections including eczema herpeticum"
A biallelic missense ZNF341 allele in a child, outside the truncating spectrum of the pooled cohort.
CGGV:assertion_2dc4032e-7215-464d-9844-c392ec25148b-2024-06-04T170000.000Z SUPPORT Other
"ZNF341 | HGNC:15992 | hyper-IgE recurrent infection syndrome 3, autosomal recessive | MONDO:0032654 | AR | Definitive"
ClinGen's SCID-CID expert panel classifies the gene-disease relationship as Definitive with autosomal recessive inheritance.
+ 4 more references
💊

Medical Actions

4
Dupilumab
Category: Therapeutic Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: dupilumab NCIT:C162455 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses dupilumab (NCIT:C162455). NCIT:C162455 is a therapeutic agent from the NCI Thesaurus.
Platform: Monoclonal antibody
Dosing: every two weeks every 14 days
Dupilumab, an anti-IL-4-receptor-alpha monoclonal antibody, blocks IL-4 and IL-13 signalling and is the one therapy reported in a genetically confirmed ZNF341-deficient patient. A 48-year-old woman with severe atopic dermatitis (SCORAD 85.5) refractory to ultra-potent topical corticosteroids and topical tacrolimus received 600 mg followed by 300 mg subcutaneously every two weeks, improved after three injections, stopped topical treatment at three months, and had a complete and well-tolerated response at one year, with falling total and allergen-specific IgE. This is a single case report in an adult, so it establishes that the Th2 axis is targetable in this disorder rather than an efficacy estimate. Paediatric experience now exists: a 2-year-old girl with biallelic ZNF341 variants, severe atopic dermatitis over more than 70% of her body surface and IgE above 40,000 IU/mL was started at 300 mg every four weeks, escalated at three months to 200 mg every two weeks for extensive disease, and improved to mild disease under 10% body surface by six months, with her IgE falling to 6935 IU/mL. Treatment was then interrupted for four months, during which her dermatitis flared; it settled again on restarting at the same initial dose, and she remained stable over the following year. The response therefore appears to require continued treatment. Total published experience in this disorder is two patients, one adult and one child.
Mechanism Target:
Th2 skewing of CD4 T cells — Dupilumab blocks the IL-4 receptor alpha chain shared by the IL-4 and IL-13 receptors, the effector arm of the Th2 skewing that drives the atopic dermatitis in this disorder.
Show evidence (1 reference)
PMID:31993867 SUPPORT Human Clinical
"This observation suggests that Th2-mediated IL-4 and/or IL-13 signaling plays a central role in atopic dermatitis in HIES."
The authors read the treatment response as evidence that Th2 IL-4/IL-13 signalling drives the dermatitis.
Target Phenotypes: Atopic dermatitis HP:0001047 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Atopic dermatitis (HP:0001047). HP:0001047 is a phenotype from the Human Phenotype Ontology.
Show evidence (7 references)
PMID:31993867 SUPPORT Human Clinical
"We report the successful treatment of severe atopic dermatitis in a 48-year-old patient with AR ZNF341 deficiency."
The single reported use of dupilumab in a genetically confirmed ZNF341-deficient patient.
PMID:31993867 SUPPORT Human Clinical
"Our patient received an initial dose of 600 mg dupilumab, followed by subcutaneous injections of 300 mg dupilumab at two-week intervals."
Source for the dose and the two-week dosing interval recorded here.
PMID:31993867 SUPPORT Human Clinical
"Continuous treatment during one year led to complete response and was well tolerated."
Reports the one-year outcome.
+ 4 more references
Topical corticosteroids and calcineurin inhibitors for atopic dermatitis
Category: Therapeutic Action: Topical corticosteroid and calcineurin-inhibitor therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Topical corticosteroid and calcineurin-inhibitor therapy, annotated with Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Agent: topical corticosteroid NCIT:C29505 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses topical corticosteroid (NCIT:C29505). NCIT:C29505 is a therapeutic agent from the NCI Thesaurus. tacrolimus NCIT:C1311 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses tacrolimus (NCIT:C1311). NCIT:C1311 is a therapeutic agent from the NCI Thesaurus.
Platform: Small molecule
Topical corticosteroids and topical calcineurin inhibitors with oral antihistamines are the mainstay of atopic dermatitis management in hyper-IgE syndrome generally. They are not always sufficient in ZNF341 deficiency: the one patient reported in detail applied ultra-high potency class I topical corticosteroids daily together with topical tacrolimus without effect before dupilumab was started.
Target Phenotypes: Atopic dermatitis HP:0001047 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Atopic dermatitis (HP:0001047). HP:0001047 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:31993867 SUPPORT BACKGROUND Other
"Topical corticosteroids and calcineurin inhibitors, associated with oral antihistamines are the main treatment, whereas immunosuppressive agents are not recommended given a higher risk of infection."
States the standard topical regimen for hyper-IgE syndrome, and that systemic immunosuppression is avoided because of infection risk.
PMID:31993867 REFUTE Human Clinical
"She applied ultra-high potency class I topical corticosteroids daily, and topical tacrolimus, which were ineffective."
In the one ZNF341-deficient patient reported in detail the topical regimen failed, so it is not reliably sufficient here.
Surveillance for malignancy
Category: Monitoring Action: cancer screeningNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is cancer screening (NCIT:C15406). NCIT:C15406 is a clinical intervention from the NCI Thesaurus. Ontology label: Cancer Screening NCIT:C15406
Leukocytes from ZNF341-deficient patients clear radiation-induced DNA damage more slowly than those of controls, and the one malignancy reported in the disorder - a nasal primitive neuroendocrine tumour followed by papillary thyroid cancer - arose in a patient in that study. The authors read the radiosensitivity as a potential explanation for susceptibility to malignant transformation. This supports being deliberate about cumulative diagnostic radiation and about cancer surveillance, but the basis is one patient and an ex vivo assay in four, and no surveillance protocol, starting age or interval has been published for this disorder.
Show evidence (1 reference)
PMID:35511492 SUPPORT In Vitro
"Increased radiosensitivity and impaired DNA repair were demonstrated in patients diagnosed with STAT3-LOF and ZNF341 deficiency, potentially explaining the susceptibility to malignant transformation."
The comet-assay study's own conclusion, which is the entire published rationale for surveillance in this disorder.
Genetic counselling
Category: Counseling / Informational Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
The kindreds pooled in the 2023 review are consanguineous and their patients homozygous for a truncating allele, so counselling for an affected family turns on recessive recurrence and on carrier testing within the extended family. The cited sources state the inheritance pattern and the consanguinity but give no numerical recurrence risk, so none is asserted in this entry.
Show evidence (1 reference)
CGGV:assertion_2dc4032e-7215-464d-9844-c392ec25148b-2024-06-04T170000.000Z SUPPORT Other
"This curation included ten probands from 10 unrelated consanguineous families (PMID: 29907691, 29907690 & 37080116)."
Records that consanguinity is the context in which every published proband was ascertained.
🔬

Diagnosis

2
ZNF341 molecular genetic testing
Because ZNF341 deficiency is clinically almost indistinguishable from STAT3 dominant-negative AD-HIES, the diagnosis rests on finding biallelic ZNF341 loss-of-function variants, by an HIES or inborn-errors-of-immunity gene panel or by exome sequencing. In both discovery cohorts STAT3 itself was sequenced and excluded first. A high NIH HIES score with an autosomal recessive pedigree, consanguinity, low NK cells or high IgG should prompt testing that covers ZNF341 rather than STAT3 alone.
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Results: Biallelic ZNF341 loss-of-function variants
Show evidence (2 references)
PMID:37080116 SUPPORT REVIEW SYNTHESIS Human Clinical
"Although generally milder, AR ZNF341 deficiency is a hardly distinguishable clinical phenocopy of AD STAT3 deficiency in the absence of genetic testing."
States that genetic testing is what separates this disorder from STAT3 AD-HIES.
PMID:29907690 SUPPORT Human Clinical
"Genetic defects in STAT3 itself were excluded by sequencing of the exons, cDNA, and the genomic promoter region"
Shows STAT3 exclusion preceding the ZNF341 diagnosis in the discovery cohort.
Th17 enumeration by flow cytometry
Reduced circulating IL-17-producing CD4+ T cells are found in most patients and support a STAT3-pathway defect, but they do not distinguish ZNF341 deficiency from STAT3 dominant-negative disease, in which the same reduction is seen at a comparable frequency. Low NK cell counts, uncommon in STAT3 deficiency, are the flow-cytometric finding that points toward ZNF341.
Th17 and NK cell flow cytometry NCIT:C16585 NCI Thesaurus (NCIT)
Results: Reduced Th17 cell proportion; reduced NK cell count
Show evidence (1 reference)
PMID:37080116 SUPPORT REVIEW SYNTHESIS Human Clinical
"Thus, ZNF341 deficiency phenocopies STAT3 deficiency in terms of the immunological phenotype of patients, except that NK cell counts are low in a majority of patients with ZNF341 deficiency but rarely in those with STAT3 deficiency."
Identifies NK lymphopenia as the immunological finding that separates the two disorders.
📊

Prevalence

2
Worldwide
Cases In Literature Ultra Rare
Twenty patients reported in total as of the 2023 review, in kindreds of Israeli (of 19th-century Sudanese descent), Turkish, Moroccan, Afro-Caribbean, Iranian and Lebanese origin. No population-based prevalence estimate exists; Orphanet's record for this disorder carries no epidemiology section.
Show evidence (1 reference)
PMID:37080116 SUPPORT REVIEW SYNTHESIS Human Clinical
"Including the two new cases described in this review, only 20 patients with autosomal-recessive (AR) ZNF341 deficiency have ever been reported."
Total published case count at the time of the defining review.
Muslim village in Israel, approximately 15,000 residents, from which eight of the first eleven reported patients came
Carrier Frequency 5000.0 per 100,000 >1 in 1,000 (carriers)
Carrier frequency for the founder allele c.904C>T (p.Arg302*) alone, not for ZNF341 null alleles in general, measured by Sanger sequencing of 200 women from the village referred for pre-pregnancy genetic testing against 100 Muslim women from other villages. Ten of the 200 were heterozygous and none of the controls. This is a carrier rate, not a disease prevalence, and it is specific to one consanguineous founder population; it says nothing about the frequency of the disorder elsewhere.
Show evidence (3 references)
PMID:35185921 SUPPORT Human Clinical
"The carrier frequency of the mutation in ZNF341 in the studied village population is 1:20."
The study's headline carrier-frequency result.
PMID:35185921 SUPPORT Human Clinical
"Heterozygous nonsense mutation in ZNF341 was found in ten samples (5%) of the study group compared to zero in the control group (p<0.01)."
Gives the numerator, denominator and control comparison behind the 1:20 figure.
PMID:35185921 SUPPORT Human Clinical
"This high frequency is probably due to founder mutation and consanguineous marriages."
The authors attribute the high carrier rate to a founder effect plus consanguinity.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from ZNF341 Deficiency:

STAT3 dominant-negative hyper-IgE syndrome (AD-HIES)
Overlapping Features The principal differential and a near-complete clinical phenocopy. It is autosomal dominant, usually de novo, and acts by negative dominance rather than loss of function. Pointers away from it and toward ZNF341 deficiency are a recessive pedigree with consanguinity, a lower NIH HIES score (median 28.5 versus 64), low NK cells, high serum IgG, less frequent connective-tissue, skeletal and dental involvement, and no reported vascular complication. None of these is decisive without genetic testing.
Show evidence (1 reference)
PMID:37080116 SUPPORT REVIEW SYNTHESIS Human Clinical
"Although generally milder, AR ZNF341 deficiency is a hardly distinguishable clinical phenocopy of AD STAT3 deficiency in the absence of genetic testing."
Establishes AD-HIES as the differential that clinical assessment alone cannot exclude.
DOCK8 deficiency (autosomal recessive HIES)
Overlapping Features The commonest autosomal recessive hyper-IgE syndrome, and therefore the first alternative in a recessive pedigree. It is distinguished by severe cutaneous viral infection - herpes simplex, human papillomavirus, molluscum - which was specifically looked for and not found in any ZNF341 patient, and by early malignancy.
Show evidence (2 references)
PMID:29907690 SUPPORT Human Clinical
"Increased susceptibility to viral infections, typical in DOCK8-deficient AR-HIES, was not observed in any of the patients."
The discriminating feature, assessed directly in the ZNF341 discovery cohort.
PMID:29907690 SUPPORT BACKGROUND Other
"biallelic DOCK8 mutations account for disease in ~80% of patients with the autosomal-recessive (AR) form of HIES"
Establishes DOCK8 as the leading cause of AR-HIES and so the first differential to exclude.
PGM3 deficiency
Overlapping Features A further autosomal recessive hyper-IgE syndrome, in which the glycosylation defect adds neurocognitive impairment and skeletal dysplasia to the atopy and high IgE. It is covered by any HIES gene panel.
Show evidence (1 reference)
PMID:29907690 SUPPORT BACKGROUND Other
"Additionally, mutations in PGM3 (MIM: 172100, (15, 16)) have been described in AR-HIES."
Names PGM3 as a further recessive HIES gene to consider.
{ }

Source YAML

click to show 
name: ZNF341 Deficiency
creation_date: "2026-09-23T00:00:00Z"
category: Mendelian
synonyms:
- Autosomal recessive hyper-IgE syndrome due to ZNF341 deficiency
- Autosomal recessive HIES due to ZNF341 deficiency
- AR-HIES due to ZNF341 deficiency
- Autosomal recessive hyperimmunoglobulin E syndrome due to zinc finger protein 341 deficiency
- Hyper-IgE recurrent infection syndrome 3, autosomal recessive
- HIES3
disease_term:
  preferred_term: ZNF341 Deficiency
  term:
    id: MONDO:0032654
    label: hyper-IgE recurrent infection syndrome 3, autosomal recessive
parents:
- Hyper-IgE syndrome
- Inborn error of immunity
- Primary immunodeficiency
description: >-
  ZNF341 deficiency is an autosomal recessive hyper-IgE syndrome caused by
  biallelic loss-of-function variants in ZNF341, a nuclear C2H2 zinc-finger
  transcription factor that binds the STAT3 promoter. Loss of ZNF341 lowers
  basal STAT3 mRNA and protein and abolishes the cytokine- and TCR-driven
  autoinduction of STAT3 in lymphocytes, so the disease is a clinical and
  immunological phenocopy of autosomal dominant (dominant-negative) STAT3
  hyper-IgE syndrome, reached through reduced STAT3 supply rather than a
  poisoned STAT3 dimer. Atopic dermatitis is present in essentially every
  reported patient and is typically the presenting feature from early
  childhood; recurrent staphylococcal skin infection and abscesses, chronic
  mucocutaneous candidiasis, sinopulmonary infection, high serum IgE and
  eosinophilia follow, with low Th17 cells, excess Th2 cells and low memory B
  cells. Compared with STAT3 dominant-negative disease the course is milder
  (median NIH HIES score 28.5 versus 64), the extra-hematopoietic
  connective-tissue, skeletal and dental features are less frequent, no
  vascular complications have been reported, serum IgG is typically high, and
  NK cell counts are low in most patients. About 20 patients have been
  published, nearly all homozygous for truncating variants in consanguineous
  kindreds.
notes: >-
  Lump/split: kept as a separate Disease entry from
  Autosomal_Dominant_Hyper-IgE_Syndrome (STAT3), not a subtype of it. The two
  differ in gene, inheritance and molecular mechanism (loss of a
  transcriptional regulator of STAT3 versus dominant-negative STAT3), carry
  separate MONDO, OMIM (618282), Orphanet (ORPHA:641368) and ClinGen
  assertions, and differ in several features (NK lymphopenia, high IgG, fewer
  extra-hematopoietic features). IUIS lists them as separate rows of the same
  hyper-IgE subtable. The entry name follows the literature's usual term
  ("ZNF341 deficiency") and the gene-named convention used for other inborn
  errors of immunity in this knowledge base; the exact MONDO label is kept as
  a synonym. The somatic MN1::ZNF341 fusion reported in pediatric round-cell
  tumors is an unrelated somatic event and is out of scope for this germline
  entry. No GeneReviews chapter names this disease. No animal model of ZNF341
  deficiency was found: the PubMed query "ZNF341" returned 29 records on
  2026-09-25, and the narrower queries "ZNF341 AND (mice OR mouse OR knockout
  OR zebrafish OR rat OR animal)" (4 records, all human reviews or
  inborn-errors-of-immunity series) and "ZNF341 knockout mouse" (0 records)
  returned no animal model; Beziat et al. state that ZNF341 function is
  unknown in mouse. PMID:31980991, "Cancer Tendency in a Patient with ZNF341
  Deficiency", is the one further primary report bearing on the malignancy
  question and is not cited here because the reference fetcher returns no
  abstract or full text for it, so no exact quote can be taken.
classifications:
  harrisons_chapter:
  - classification_value: IMMUNE_RHEUMATOLOGIC
    evidence:
    - reference: PMID:29907690
      reference_title: "ZNF341 controls STAT3 expression and thereby immunocompetence."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Taken together, these findings support the hypothesis that patients with ZNF341 mutations have a previously unrecognized autosomal recessive immunodeficiency that clinically resembles autosomal dominant HIES due to mutations in STAT3."
      explanation: Establishes the condition as an autosomal recessive primary immunodeficiency, placing it in the immune Part.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: CGGV:assertion_2dc4032e-7215-464d-9844-c392ec25148b-2024-06-04T170000.000Z
      reference_title: "ZNF341 / hyper-IgE recurrent infection syndrome 3, autosomal recessive (Definitive)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "ZNF341 | HGNC:15992 | hyper-IgE recurrent infection syndrome 3, autosomal recessive | MONDO:0032654 | AR | Definitive"
      explanation: ClinGen classifies ZNF341 as definitively causal for this autosomal recessive Mendelian disease.
  iuis_category:
    classification_value: combined immunodeficiency with syndromic features
    evidence:
    - reference: PMID:35748970
      reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "AR-HIES ZNF341 AR 618282 Decreased Th17 and NK"
      explanation: >-
        IUIS 2022 Table 2 (combined immunodeficiencies with associated or
        syndromic features), sub-section 5 Hyper IgE Syndromes, row for ZNF341
        deficiency (AR-HIES, OMIM 618282).
mechanistic_hypotheses:
- hypothesis_group_id: znf341_stat3_supply
  hypothesis_label: Reduced basal STAT3 and loss of STAT3 autoinduction in lymphocytes
  status: CANONICAL
  description: >-
    ZNF341 binds the STAT3 promoter and is required for normal basal STAT3
    transcription and for the transient autoinduction of STAT3 when naive T
    cells are co-stimulated through the TCR and IL-6 (and B cells through CD40L
    and IL-21). Because a 50% fall in basal STAT3 is not by itself thought to
    cause HIES (no STAT3 haploinsufficiency phenotype is known), the
    combination of low basal STAT3 with failed autoinduction in lymphocytes is
    the favoured explanation for the STAT3-deficiency phenocopy.
  evidence:
  - reference: PMID:37080116
    reference_title: "Inherited human ZNF341 deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: REVIEW_SYNTHESIS
    snippet: "The combination of decreased basal expression level and impaired autoinduction of STAT3 observed in ZNF341-deficient lymphocytes is considered a more likely pathophysiological mechanism."
    explanation: The disease-defining authors' synthesis names the combined basal-plus-autoinduction defect as the working mechanism.
  - reference: PMID:37080116
    reference_title: "Inherited human ZNF341 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "However, as there is no clear evidence that STAT3 haploinsufficiency causes HIES, this decrease alone is probably insufficient to explain the HIES phenotype observed in the ZNF341-deficient patients."
    explanation: States why reduced basal STAT3 alone is not accepted as sufficient.
- hypothesis_group_id: znf341_stat1_mycobacteria
  hypothesis_label: Reduced STAT1 expression and mycobacterial susceptibility
  status: EMERGING
  description: >-
    ZNF341 also binds the STAT1 promoter and ZNF341-deficient cells have lower
    STAT1. Two patients have had tuberculosis, and the 2023 review raises the
    possibility that partial STAT1 impairment contributes; the original 2018
    report judged the lower STAT1 unlikely to contribute to the clinical
    phenotype. Unresolved.
  evidence:
  - reference: PMID:37080116
    reference_title: "Inherited human ZNF341 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "we cannot rule out the possibility that ZNF341-deficient patients are susceptible to virulent environmental mycobacteria due to a partial impairment of STAT1 signaling"
    explanation: Frames the STAT1 route to mycobacterial disease as a possibility only.
  - reference: PMID:29907691
    reference_title: "A recessive form of hyper-IgE syndrome by disruption of ZNF341-dependent STAT3 transcription and activity."
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: "the lower levels of STAT1 observed in ZNF341-deficient patients are unlikely to account for or even contribute to their immunological or clinical phenotypes."
    explanation: The discovery paper argued the opposite, that reduced STAT1 is unlikely to matter clinically.
- hypothesis_group_id: dna_repair_malignancy
  hypothesis_label: Impaired DNA repair and malignancy predisposition
  status: EMERGING
  description: >-
    Ex vivo irradiated leukocytes from four ZNF341-deficient patients repaired
    DNA damage more slowly than controls, and one patient developed a nasal
    primitive neuroendocrine tumor followed by papillary thyroid cancer. The
    authors propose that the repair defect, together with radiation exposure,
    predisposes to malignancy. The clinical side of this rests on one patient.
  evidence:
  - reference: PMID:35511492
    reference_title: "Increased radiosensitivity and impaired DNA repair in patients with STAT3-LOF and ZNF341 deficiency, potentially contributing to malignant transformations."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Increased radiosensitivity and impaired DNA repair were demonstrated in patients diagnosed with STAT3-LOF and ZNF341 deficiency, potentially explaining the susceptibility to malignant transformation."
    explanation: Comet-assay study on patient leukocytes proposing the DNA-repair route to malignancy.
pathophysiology:
- name: ZNF341 biallelic loss of function
  description: >-
    All 20 patients pooled in the 2023 review were homozygous for predicted
    loss-of-function ZNF341 alleles (nonsense, frameshift, essential splice
    site); a biallelic missense allele has since been reported, so truncation
    characterises that cohort rather than defining the disease. The truncated
    products lack most of the twelve C2H2 zinc fingers; the p.Gln195* and
    p.Arg302* products are retained in the cytoplasm, and mutant proteins fail
    to activate the STAT3 promoter. ZNF341 is a constitutively nuclear
    transcription factor expressed in all leukocytes tested and in fibroblasts
    and keratinocytes.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: ZNF341
    term:
      id: hgnc:15992
      label: ZNF341
  molecular_functions:
  - preferred_term: DNA-binding transcription factor activity
    term:
      id: GO:0000981
      label: DNA-binding transcription factor activity, RNA polymerase II-specific
    modifier: DECREASED
  evidence:
  - reference: PMID:29907691
    reference_title: "A recessive form of hyper-IgE syndrome by disruption of ZNF341-dependent STAT3 transcription and activity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "ZNF341 is a transcription factor that resides in the nucleus, where it binds a specific DNA motif present in various genes, including the STAT3 promoter."
    explanation: Defines ZNF341 as a nuclear transcription factor that binds the STAT3 promoter.
  - reference: PMID:29907690
    reference_title: "ZNF341 controls STAT3 expression and thereby immunocompetence."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Wild-type ZNF341 bound to and activated the STAT3 promoter, whereas the mutant variants showed impaired transcriptional activation, partly due to nuclear translocation failure."
    explanation: Patient variants lose transcriptional activation of STAT3, partly through failed nuclear import.
  - reference: PMID:37080116
    reference_title: "Inherited human ZNF341 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "All the patients with AR ZNF341 deficiency described to date were homozygous for pLOF variants"
    explanation: Every confirmed patient carries biallelic predicted loss-of-function alleles.
  downstream:
  - target: Reduced basal STAT3 expression
    causal_link_type: DIRECT
    description: Loss of ZNF341 binding at the STAT3 promoter lowers constitutive STAT3 transcription.
    hypothesis_groups:
    - znf341_stat3_supply
    evidence:
    - reference: PMID:29907691
      reference_title: "A recessive form of hyper-IgE syndrome by disruption of ZNF341-dependent STAT3 transcription and activity."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The patients' cells have low basal levels of STAT3 mRNA and protein."
      explanation: Patient cells lacking ZNF341 have low basal STAT3.
  - target: Loss of STAT3 autoinduction in lymphocytes
    causal_link_type: DIRECT
    description: ZNF341 is required for STAT3 to induce its own transcription on combined TCR and IL-6 stimulation.
    hypothesis_groups:
    - znf341_stat3_supply
    evidence:
    - reference: PMID:29907691
      reference_title: "A recessive form of hyper-IgE syndrome by disruption of ZNF341-dependent STAT3 transcription and activity."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Human ZNF341 is essential for the STAT3 transcription-dependent autoinduction and sustained activity of STAT3."
      explanation: States that ZNF341 is required for STAT3 autoinduction.
  - target: Reduced STAT1 expression
    causal_link_type: DIRECT
    description: ZNF341 binds the STAT1 promoter; deficient cells have less STAT1.
    hypothesis_groups:
    - znf341_stat1_mycobacteria
    evidence:
    - reference: PMID:37080116
      reference_title: "Inherited human ZNF341 deficiency."
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: REVIEW_SYNTHESIS
      snippet: "ZNF341 upregulates STAT1 mRNA and protein levels, as demonstrated by the lower levels of STAT1 in ZNF341-deficient cells"
      explanation: Reports reduced STAT1 in ZNF341-deficient cells.
  - target: Reduced natural killer cell count
    causal_link_type: UNKNOWN
    description: >-
      NK lymphopenia is common in ZNF341 deficiency but rare in STAT3
      dominant-negative disease. Whether it reflects a STAT3-independent ZNF341
      function or a deeper STAT3 defect in NK progenitors is unresolved.
    evidence:
    - reference: PMID:29907691
      reference_title: "A recessive form of hyper-IgE syndrome by disruption of ZNF341-dependent STAT3 transcription and activity."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Conversely, the NK lymphopenia seen in ZNF341-deficient but not STAT3-DN patients suggests that ZNF341 may be essential for at least one STAT3-independent function."
      explanation: Attributes the NK phenotype to ZNF341 loss while leaving the pathway open.
- name: Reduced basal STAT3 expression
  description: >-
    Patient primary cells have reduced resting STAT3 mRNA and protein. The
    discovery papers report different magnitudes: about 50% of normal in
    primary naive CD4+ T cells, monocytes and fibroblasts (Beziat et al.), and
    16-28% of wild-type protein in PBMCs, EBV-B cells and skin fibroblasts
    (Frey-Jakobs et al.). Cytokine-induced STAT3 Y705 phosphorylation is
    correspondingly lower. The defect is present in non-hematopoietic cells as
    well as lymphocytes.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: STAT3
    term:
      id: hgnc:11364
      label: STAT3
  evidence:
  - reference: PMID:29907690
    reference_title: "ZNF341 controls STAT3 expression and thereby immunocompetence."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "STAT3 protein expression was reduced in ZNF341-mutant cells (patients’ PBMCs, EBV-transformed B cells, and PSF) down to 16–28% of wild-type levels"
    explanation: Quantifies reduced STAT3 protein in several patient cell types.
  - reference: PMID:29907690
    reference_title: "ZNF341 controls STAT3 expression and thereby immunocompetence."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "STAT3 Y705-phosphorylation was markedly impaired in PBMCs from patients with R302* and R386* mutations, respectively, following stimulation with IL-6"
    explanation: Lower total STAT3 translates into lower IL-6-induced STAT3 activation.
  - reference: PMID:37080116
    reference_title: "Inherited human ZNF341 deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: REVIEW_SYNTHESIS
    snippet: "All the ZNF341-deficient cell subsets tested, including lymphocytes, monocytes, and fibroblasts, had 50% the normal level of STAT3 mRNA and protein."
    explanation: Shows the basal reduction extends beyond lymphocytes to monocytes and fibroblasts.
  downstream:
  - target: Insufficient STAT3 activity in lymphocytes
    causal_link_type: DIRECT
    hypothesis_groups:
    - znf341_stat3_supply
    description: Low basal STAT3 contributes to lower STAT3 activation downstream of STAT3-activating cytokines.
  - target: Reduced STAT3 function in non-hematopoietic cells
    causal_link_type: DIRECT
    description: The basal STAT3 reduction is also present in fibroblasts.
    evidence:
    - reference: PMID:29907691
      reference_title: "A recessive form of hyper-IgE syndrome by disruption of ZNF341-dependent STAT3 transcription and activity."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "However, these patients do develop such somatic features, consistent with the STAT3 phenotype detected in the fibroblasts of ZNF341-deficient patients."
      explanation: Links the fibroblast STAT3 defect to the somatic (extra-hematopoietic) features.
- name: Loss of STAT3 autoinduction in lymphocytes
  description: >-
    In control naive CD4+ T cells, co-stimulation through CD2/CD3/CD28 plus IL-6
    or Th17-polarizing cytokines raises STAT3 mRNA 10- to 20-fold; this synergy
    is absent in ZNF341-deficient cells but preserved in STAT3
    dominant-negative cells. Autoinduction is also impaired in naive B cells
    stimulated with CD40L and IL-21. Loss of this boost prevents sustained
    STAT3 activity during lymphocyte differentiation.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: CD4-positive alpha-beta T cell
    term:
      id: CL:0000624
      label: CD4-positive, alpha-beta T cell
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  genes:
  - preferred_term: STAT3
    term:
      id: hgnc:11364
      label: STAT3
  evidence:
  - reference: PMID:37080116
    reference_title: "Inherited human ZNF341 deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: REVIEW_SYNTHESIS
    snippet: "STAT3 autoinduction was abolished in ZNF341-deficient naive T cells stimulated under these conditions, but not in STAT3-deficient naive T cells"
    explanation: The autoinduction defect distinguishes ZNF341 from STAT3 dominant-negative disease.
  - reference: PMID:37080116
    reference_title: "Inherited human ZNF341 deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: REVIEW_SYNTHESIS
    snippet: "impaired STAT3 autoinduction was also observed in ZNF341-deficient naive B cells following CD40L and IL-21 costimulation, and was associated with a severe impairment of immunoglobulin production"
    explanation: Extends the autoinduction defect to B cells.
  downstream:
  - target: Insufficient STAT3 activity in lymphocytes
    causal_link_type: DIRECT
    hypothesis_groups:
    - znf341_stat3_supply
    evidence:
    - reference: PMID:29907691
      reference_title: "A recessive form of hyper-IgE syndrome by disruption of ZNF341-dependent STAT3 transcription and activity."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Together, low baseline STAT3 mRNA and protein levels, and the impaired auto-induction of STAT3 itself, result in lower levels of STAT3 activation (phosphorylation) and transcriptional activity, as low as those in patients with DN STAT3 mutations."
      explanation: The two defects together bring lymphocyte STAT3 activity down to the level seen in dominant-negative STAT3 disease.
- name: Insufficient STAT3 activity in lymphocytes
  description: >-
    The net effect in T and B cells is STAT3 activation and transcriptional
    output as low as in dominant-negative STAT3 disease, so STAT3-dependent
    lymphocyte differentiation programs (Th17, T follicular helper, memory B
    cell, plasma cell) fail in the same way. TCR-induced calcium flux and T
    cell proliferation are normal.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: CD4-positive alpha-beta T cell
    term:
      id: CL:0000624
      label: CD4-positive, alpha-beta T cell
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  biological_processes:
  - preferred_term: JAK-STAT signaling
    term:
      id: GO:0007259
      label: cell surface receptor signaling pathway via JAK-STAT
    modifier: DECREASED
  - preferred_term: interleukin-6-mediated signaling pathway
    term:
      id: GO:0070102
      label: interleukin-6-mediated signaling pathway
    modifier: DECREASED
  evidence:
  - reference: PMID:29907691
    reference_title: "A recessive form of hyper-IgE syndrome by disruption of ZNF341-dependent STAT3 transcription and activity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Consequently, STAT3-dependent genes, such as RORC, IL17A, and IL17F, are poorly induced."
    explanation: Downstream STAT3 target genes are poorly induced in patient T cells.
  downstream:
  - target: Impaired Th17 differentiation and IL-17/IL-22 immunity
    causal_link_type: DIRECT
    hypothesis_groups:
    - znf341_stat3_supply
    evidence:
    - reference: PMID:29907691
      reference_title: "A recessive form of hyper-IgE syndrome by disruption of ZNF341-dependent STAT3 transcription and activity."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The lack of ZNF341 prevents Th cells from producing sufficient amounts of functional STAT3, and thereby of ROR-γ/ROR-γT, during Th17 development"
      explanation: Links insufficient STAT3 to failed RORgammat induction and Th17 development.
  - target: Th2 skewing of CD4 T cells
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - znf341_stat3_supply
    evidence:
    - reference: PMID:29907691
      reference_title: "A recessive form of hyper-IgE syndrome by disruption of ZNF341-dependent STAT3 transcription and activity."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Like patients with STAT3 DN mutations, ZNF341-deficient patients lack T helper 17 (TH17) cells, have an excess of TH2 cells, and have low memory B cells due to the tight dependence of STAT3 activity on ZNF341 in lymphocytes."
      explanation: Attributes Th17 loss, Th2 excess and memory B cell deficiency to the lymphocyte dependence of STAT3 on ZNF341.
  - target: Impaired T follicular helper and memory B cell development
    causal_link_type: DIRECT
    hypothesis_groups:
    - znf341_stat3_supply
    evidence:
    - reference: PMID:29907691
      reference_title: "A recessive form of hyper-IgE syndrome by disruption of ZNF341-dependent STAT3 transcription and activity."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The same mechanism probably operates in B cells, accounting for the B-cell phenotypes of ZNF341-deficient patients being identical to those of HIES patients with DN STAT3 mutations"
      explanation: Extends the STAT3 insufficiency mechanism to the B cell phenotype.
- name: Impaired Th17 differentiation and IL-17/IL-22 immunity
  description: >-
    Circulating Th17 cells are low, memory CD4+ T cells make little IL-17A,
    IL-17F or IL-22, and naive CD4+ T cells fail to produce IL-17 under
    Th17-polarizing conditions. Patient fibroblasts and keratinocytes respond
    normally to IL-17A, so the candidiasis reflects deficient IL-17 production
    rather than deficient IL-17 response.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: T-helper 17 cell
    term:
      id: CL:0000899
      label: T-helper 17 cell
  biological_processes:
  - preferred_term: T-helper 17 cell differentiation
    term:
      id: GO:0072539
      label: T-helper 17 cell differentiation
    modifier: DECREASED
  - preferred_term: interleukin-17 production
    term:
      id: GO:0032620
      label: interleukin-17 production
    modifier: DECREASED
  - preferred_term: defense response to fungus
    term:
      id: GO:0050832
      label: defense response to fungus
    modifier: DECREASED
  evidence:
  - reference: PMID:29907691
    reference_title: "A recessive form of hyper-IgE syndrome by disruption of ZNF341-dependent STAT3 transcription and activity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In marked contrast, the production of Th17 cytokines (IL-17A, IL-17F, IL-22) by ZNF341-deficient memory CD4+ T cells was much weaker than that by control cells"
    explanation: Patient memory CD4+ T cells make little Th17 cytokine.
  - reference: PMID:29907690
    reference_title: "ZNF341 controls STAT3 expression and thereby immunocompetence."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients however presented a significantly reduced percentage of Th17 CD4+ T cells, a key feature of STAT3-HIES"
    explanation: Independent cohort confirms low circulating Th17 cells.
  downstream:
  - target: Chronic mucocutaneous candidiasis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29907691
      reference_title: "A recessive form of hyper-IgE syndrome by disruption of ZNF341-dependent STAT3 transcription and activity."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "As in patients with DN STAT3 mutations, this defect accounts for the CMC observed in the patients, as fibroblasts and keratinocytes from P2–P4 responded normally to IL-17A"
      explanation: The Th17 defect accounts for the candidiasis, since IL-17 responsiveness of the target tissue is intact.
  - target: Onychomycosis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - loss of IL-17-dependent antifungal defense
    description: Nail Candida infection is one of the mucocutaneous candidiasis manifestations tabulated for these patients.
  - target: Decreased Th17 T cell proportion
    causal_link_type: DIRECT
    description: The differentiation defect is read out as a low Th17 proportion on immunophenotyping.
  - target: Recurrent skin infections
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      By analogy with STAT3 dominant-negative disease, loss of IL-17/IL-22
      epithelial antibacterial signals is thought to contribute to
      staphylococcal skin infection. No ZNF341-specific study tests this edge.
- name: Th2 skewing of CD4 T cells
  description: >-
    Circulating memory CD4+ T cells are skewed toward Th2, with high GATA3 and
    Th2 cytokine transcripts (IL-4, IL-5, IL-13, IL-31) that persist even under
    Th17-polarizing conditions; CD8+ T cells over-express IL-5 and IL-9. The
    excess type 2 response is the proposed basis of the high IgE, eczema,
    eosinophilia and allergy.
  biological_scale: CELLULAR
  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
  - preferred_term: type 2 immune response
    term:
      id: GO:0042092
      label: type 2 immune response
    modifier: INCREASED
  evidence:
  - reference: PMID:29907691
    reference_title: "A recessive form of hyper-IgE syndrome by disruption of ZNF341-dependent STAT3 transcription and activity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These data suggest that the allergic features of ZNF341-deficient patients were due to the enhanced production of some, but not all Th2-like cytokines, including IL-5 and IL-9, in particular, by both CD4+ and CD8+ T cells."
    explanation: Patient T cells over-produce Th2-type cytokines.
  downstream:
  - target: Atopic dermatitis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:37080116
      reference_title: "Inherited human ZNF341 deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "The high proportion of Th2 cells probably underlies the high serum levels of IgE, eczema, and the other allergic manifestations seen in the patients"
      explanation: Proposes the Th2 excess as the cause of eczema and high IgE.
    - reference: PMID:31993867
      reference_title: "Efficacy of Dupilumab for Controlling Severe Atopic Dermatitis in a Patient with Hyper-IgE Syndrome."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "This observation suggests that Th2-mediated IL-4 and/or IL-13 signaling plays a central role in atopic dermatitis in HIES."
      explanation: Response to IL-4Ralpha blockade in a ZNF341-deficient patient supports a type 2 driver of the dermatitis; a therapeutic response is indirect support.
  - target: Elevated serum IgE
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Excess IL-4/IL-13 signaling favours IgE class switching; total IgE fell under IL-4Ralpha blockade.
    evidence:
    - reference: PMID:31993867
      reference_title: "Efficacy of Dupilumab for Controlling Severe Atopic Dermatitis in a Patient with Hyper-IgE Syndrome."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "This improvement was accompanied by a progressive decrease in total serum IgE, and allergen-specific IgE"
      explanation: IgE fell when IL-4/IL-13 signaling was blocked, supporting a type 2 driver.
  - target: Eosinophilia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - excess IL-5 production by CD4+ and CD8+ T cells
    description: T cell IL-5 over-production is the proposed driver of eosinophilia.
  - target: Allergy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Allergic manifestations are attributed to the Th2 excess.
- name: Impaired T follicular helper and memory B cell development
  description: >-
    Patients have low circulating T follicular helper cells and low memory B
    cells (with increased naive B cells), and naive B cells fail to
    differentiate into immunoglobulin-secreting cells on CD40L plus IL-21
    stimulation. Unlike STAT3 dominant-negative disease, serum IgG is usually
    high; the basis of this dissociation is not explained.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: memory B cell
    term:
      id: CL:0000787
      label: memory B cell
  - preferred_term: T follicular helper cell
    term:
      id: CL:0002038
      label: T follicular helper cell
  biological_processes:
  - preferred_term: plasma cell differentiation
    term:
      id: GO:0002317
      label: plasma cell differentiation
    modifier: DECREASED
  evidence:
  - reference: PMID:29907690
    reference_title: "ZNF341 controls STAT3 expression and thereby immunocompetence."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immunophenotyping revealed normal CD19 lymphocyte counts, but an increased percentage of naïve B cells (IgD+CD27−), and reduced memory B cells (CD27+) in the affected individuals."
    explanation: Patient immunophenotyping shows low memory B cells.
  downstream:
  - target: Decreased memory B cell proportion
    causal_link_type: DIRECT
    description: Read out as a low memory B cell proportion.
  - target: Recurrent pneumonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:37080116
      reference_title: "Inherited human ZNF341 deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "The low proportions of Tfh and memory B cells probably at least partly account for the severe bacterial infections of the lungs observed in these patients, through the impairment of sustained humoral responses"
      explanation: Proposes the humoral defect as a cause of the bacterial lung infections.
  - target: Recurrent upper respiratory tract infections
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Impaired sustained humoral responses are thought to contribute to sinopulmonary infection generally.
- name: Reduced STAT3 function in non-hematopoietic cells
  description: >-
    STAT3 levels are also reduced in patient fibroblasts, and patients develop
    the connective-tissue, skeletal and dental features of STAT3 HIES, but less
    often and more mildly. The discovery paper suggests the IL-11R, LIFR and
    IL-6ST-dependent programs in these tissues need less STAT3 than lymphocyte
    programs do. This is an interpretation, not a measured tissue-by-tissue
    dose threshold, so the edges below are left as unknown intermediates.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  evidence:
  - reference: PMID:29907691
    reference_title: "A recessive form of hyper-IgE syndrome by disruption of ZNF341-dependent STAT3 transcription and activity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with ZNF341 deficiency appear to develop fewer and milder non-hematopoietic developmental phenotypes than patients with STAT3 DN mutations."
    explanation: States the milder extra-hematopoietic involvement relative to STAT3 dominant-negative disease.
  downstream:
  - target: Facial dysmorphism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: High palate
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Persistence of primary teeth
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Joint hypermobility
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Scoliosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Minimal-trauma fractures
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Reduced STAT1 expression
  description: >-
    ZNF341 binds two sites in the STAT1 promoter and ZNF341-deficient cells
    have lower STAT1 mRNA and protein. Its clinical significance is disputed.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: STAT1
    term:
      id: hgnc:11362
      label: STAT1
  evidence:
  - reference: PMID:37080116
    reference_title: "Inherited human ZNF341 deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: REVIEW_SYNTHESIS
    snippet: "Two ZNF341-binding sites were identified within the STAT1 promoter, including one approximately 400 nucleotides upstream from the transcription start site (TSS), as in the STAT3 promoter"
    explanation: Identifies STAT1 as a direct ZNF341 target.
  downstream:
  - target: Tuberculosis
    causal_link_type: UNKNOWN
    hypothesis_groups:
    - znf341_stat1_mycobacteria
    description: Proposed, unconfirmed route to mycobacterial susceptibility (see mechanistic hypothesis).
- name: Impaired repair of radiation-induced DNA damage
  description: >-
    In an alkaline Comet assay on ex vivo irradiated leukocytes from four
    ZNF341-deficient and twelve STAT3 loss-of-function patients, DNA-damage
    measures kept rising during the recovery period while those of healthy
    controls returned toward baseline. The mechanism linking ZNF341 or STAT3
    to DNA repair is not established, so this node has no upstream edge.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: DNA repair
    term:
      id: GO:0006281
      label: DNA repair
    modifier: DECREASED
  evidence:
  - reference: PMID:35511492
    reference_title: "Increased radiosensitivity and impaired DNA repair in patients with STAT3-LOF and ZNF341 deficiency, potentially contributing to malignant transformations."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "During the recovery period of irradiation, TL, TDNA%, and OTM values of healthy controls decreased rapidly toward the baseline, while these values of patients with STAT3-LOF and ZNF341 deficiency continued to increase, implying impaired DNA repair mechanisms."
    explanation: Ex vivo radiation assay showing slower DNA-damage resolution in patient leukocytes.
  downstream:
  - target: Neoplasm
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - dna_repair_malignancy
    evidence:
    - reference: PMID:35511492
      reference_title: "Increased radiosensitivity and impaired DNA repair in patients with STAT3-LOF and ZNF341 deficiency, potentially contributing to malignant transformations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Except for a patient with ZNF341 deficiency who developed nasal cell primitive neuroendocrine tumor and papillary thyroid cancer during the follow-up, there was no cancer in both groups."
      explanation: The single malignancy observed in the radiosensitivity cohort occurred in a ZNF341-deficient patient, which is the only clinical observation behind this edge.
phenotypes:
- name: Atopic dermatitis
  category: Dermatologic
  frequency: OBLIGATE
  description: >-
    Atopic dermatitis was present in all 20 published patients and is the most
    common presenting feature; IUIS describes it as early-onset eczema. In
    three of the four kindreds of the Frey-Jakobs report the disease was first
    diagnosed as atopic dermatitis, with the other HIES features appearing
    later in life, so severe early-childhood eczema can precede recognition of
    the immunodeficiency.
  phenotype_term:
    preferred_term: Atopic dermatitis
    term:
      id: HP:0001047
      label: Atopic dermatitis
  evidence:
  - reference: PMID:37080116
    reference_title: "Inherited human ZNF341 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Atopic dermatitis was the most common clinical presentation of patients with ZNF341 deficiency, present in all patients reported"
    explanation: Atopic dermatitis in 20/20 pooled patients.
  - reference: PMID:35748970
    reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Phenocopy of AD-HIES; mild facial dysmorphism; early onset eczema"
    explanation: IUIS describes the eczema as early onset.
  - reference: PMID:29907690
    reference_title: "ZNF341 controls STAT3 expression and thereby immunocompetence."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected members of Families B, C and D (Fig. 2B–D) presented with a milder phenotype initially diagnosed as atopic dermatitis, with characteristic HIES symptoms occurring later in life."
    explanation: Dermatitis can be the sole initial presentation, with HIES features emerging later.
- name: Neonatal rash
  category: Dermatologic
  frequency: OCCASIONAL
  description: >-
    A newborn rash was reported in 2 of 13 evaluable patients (15%), less often
    than in STAT3 dominant-negative disease (48%).
  phenotype_term:
    preferred_term: Newborn rash
    term:
      id: HP:0000988
      label: Skin rash
  evidence:
  - reference: PMID:37080116
    reference_title: "Inherited human ZNF341 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "By contrast, newborn rash was rarely reported in patients with ZNF341 deficiency (15%), but was much more frequent (48%) in patients with STAT3 deficiency"
    explanation: Newborn rash frequency in the pooled cohort.
- name: Recurrent skin infections
  category: Infectious
  frequency: VERY_FREQUENT
  description: >-
    Recurrent skin infection was reported in 15 of 18 evaluable patients
    (83%).
  phenotype_term:
    preferred_term: Recurrent skin infections
    term:
      id: HP:0001581
      label: Recurrent skin infections
  evidence:
  - reference: PMID:37080116
    reference_title: "Inherited human ZNF341 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "| Recurrent skin infection | 0/1 | 1/1 | 6/7 | 8/9 | 15/18 (83%) | 100% |"
    explanation: Pooled table row, 15/18 patients.
- name: Recurrent cutaneous abscesses
  category: Infectious
  frequency: FREQUENT
  description: >-
    Skin abscesses were reported in 15 of 20 patients (75%), a frequency similar
    to STAT3 dominant-negative disease. The 2023 review states that
    inflammation is clinically and biologically appropriate in ZNF341
    deficiency, whereas the Frey-Jakobs and Israeli reports describe cold
    abscesses in some patients; see the discussion attached to this phenotype.
  phenotype_term:
    preferred_term: Recurrent skin abscesses
    term:
      id: HP:0100838
      label: Recurrent cutaneous abscess formation
  evidence:
  - reference: PMID:37080116
    reference_title: "Inherited human ZNF341 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Both ZNF341-deficient and STAT3-deficient patients were highly prone to recurrent skin infections, with skin abscesses (75% vs. 73%) and CMC (60% vs. 85%)."
    explanation: Skin abscesses in 75% of pooled patients.
  - reference: PMID:29907690
    reference_title: "ZNF341 controls STAT3 expression and thereby immunocompetence."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical triad of HIES consisting of recurrent pneumonias, eczema with cold skin abscesses, and elevated serum IgE levels was present in all three affected individuals"
    explanation: Cold skin abscesses were described in the three affected members of one kindred.
- name: Chronic mucocutaneous candidiasis
  category: Infectious
  frequency: FREQUENT
  description: >-
    Chronic mucocutaneous candidiasis occurred in 12 of 20 patients (60%),
    presenting as oral thrush (45%), onychomycosis (25%) or at other sites
    (35%); less frequent than in STAT3 dominant-negative disease (85%).
  phenotype_term:
    preferred_term: Chronic mucocutaneous candidiasis
    term:
      id: HP:0002728
      label: Chronic mucocutaneous candidiasis
  evidence:
  - reference: PMID:37080116
    reference_title: "Inherited human ZNF341 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "| CMC | 0/1 | 0/1 | 6/7 | 6/11 | 12/20 (60%) | 85% |"
    explanation: Chronic mucocutaneous candidiasis in 12/20 pooled patients.
  - reference: PMID:37080116
    reference_title: "Inherited human ZNF341 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "| - Oral thrush | 0/1 | 0/1 | 5/7 | 4/11 | 9/20 (45%) | 63% |"
    explanation: Oral thrush, the commonest candidiasis site, in 9/20 pooled patients.
- name: Onychomycosis
  category: Infectious
  frequency: OCCASIONAL
  description: Candida nail infection in 5 of 20 patients (25%).
  phenotype_term:
    preferred_term: Onychomycosis
    term:
      id: HP:0012203
      label: Onychomycosis
  evidence:
  - reference: PMID:37080116
    reference_title: "Inherited human ZNF341 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "| - Onychomycosis | 0/1 | 0/1 | 3/7 | 2/11 | 5/20 (25%) | 57% |"
    explanation: Onychomycosis in 5/20 pooled patients.
- name: Recurrent upper respiratory tract infections
  category: Infectious
  frequency: FREQUENT
  description: >-
    Recurrent ear, nose and throat infections in 58% of patients, versus 90% in
    STAT3 dominant-negative disease.
  phenotype_term:
    preferred_term: Recurrent ear, nose and throat infections
    term:
      id: HP:0002788
      label: Recurrent upper respiratory tract infections
  evidence:
  - reference: PMID:37080116
    reference_title: "Inherited human ZNF341 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Recurrent ear, nose, and throat infections were reported in 58% of patients with ZNF341 deficiency, and 90% of those with STAT3 deficiency."
    explanation: Pooled frequency of upper respiratory infection.
- name: Recurrent pneumonia
  category: Respiratory
  frequency: FREQUENT
  description: >-
    Pneumonia in 9 of 16 evaluable patients (56%). Lung disease is markedly
    less severe than in STAT3 dominant-negative disease.
  phenotype_term:
    preferred_term: Recurrent pneumonia
    term:
      id: HP:0006532
      label: Recurrent pneumonia
  evidence:
  - reference: PMID:37080116
    reference_title: "Inherited human ZNF341 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "with pneumonia, bronchiectasis, and pneumatocele reported in 56%, 35%, and 10%, respectively, of the ZNF341-deficient patients"
    explanation: Pooled frequencies of pneumonia and its structural sequelae.
  sequelae:
  - target: Bronchiectasis
  - target: Pulmonary pneumatocele
- name: Bronchiectasis
  category: Respiratory
  frequency: FREQUENT
  description: Bronchiectasis in 6 of 17 evaluable patients (35%), versus 65% in STAT3 dominant-negative disease.
  phenotype_term:
    preferred_term: Bronchiectasis
    term:
      id: HP:0002110
      label: Bronchiectasis
  evidence:
  - reference: PMID:37080116
    reference_title: "Inherited human ZNF341 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "| - Bronchiectasis | 0/1 | 0/1 | 2/7 | 4/8 | 6/17 (35%) | 65% |"
    explanation: Pooled table row for bronchiectasis.
- name: Pulmonary pneumatocele
  category: Respiratory
  frequency: OCCASIONAL
  description: Pneumatocele in 2 of 20 patients (10%), versus 52% in STAT3 dominant-negative disease.
  phenotype_term:
    preferred_term: Pneumatocele
    term:
      id: HP:0025419
      label: Pulmonary pneumatocele
  evidence:
  - reference: PMID:37080116
    reference_title: "Inherited human ZNF341 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "| - Pneumatocele | 0/1 | 0/1 | 1/7 | 1/8 | 2/20 (10%) | 52% |"
    explanation: Pooled table row for pneumatocele.
- name: Tuberculosis
  category: Infectious
  description: >-
    At least two patients have had tuberculosis. No unusual viral disease and
    no adverse reactions to live BCG vaccine have been reported, and the
    cutaneous viral susceptibility typical of DOCK8 deficiency was not
    observed.
  phenotype_term:
    preferred_term: Tuberculosis
    term:
      id: HP:5210111
      label: Tuberculosis infection
  evidence:
  - reference: PMID:37080116
    reference_title: "Inherited human ZNF341 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "However, at least two patients have been reported to have suffered tuberculosis"
    explanation: Reports tuberculosis in two patients.
- name: Decreased Th17 T cell proportion
  category: Immunologic
  frequency: VERY_FREQUENT
  description: >-
    Circulating IL-17-producing CD4+ T cells are reduced in 9 of 11 evaluable
    patients (82%), at a frequency close to that seen in STAT3
    dominant-negative disease (93%). Patient peripheral blood mononuclear cells
    also fail to differentiate into IL-17-producing CD4+ T cells in vitro, so
    the defect is one of differentiation rather than of sampling.
  phenotype_term:
    preferred_term: Reduced Th17 (IL-17-producing CD4+) T cell proportion
    term:
      id: HP:0025832
      label: Decreased Th17 T cell proportion
  evidence:
  - reference: PMID:37080116
    reference_title: "Inherited human ZNF341 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Low Th17-cell levels | ND | ND | 5/5 | 4/6 | 9/11 (82%) | 93%"
    explanation: Pooled table row, 9/11 patients with low Th17 cells against 93% in STAT3 deficiency.
  - reference: PMID:29907690
    reference_title: "ZNF341 controls STAT3 expression and thereby immunocompetence."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients however presented a significantly reduced percentage of Th17 CD4+ T cells, a key feature of STAT3-HIES"
    explanation: Discovery cohort measured the reduced Th17 proportion directly.
  - reference: PMID:29907690
    reference_title: "ZNF341 controls STAT3 expression and thereby immunocompetence."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "peripheral blood mononuclear cells (PBMCs) derived from patients failed to differentiate into IL-17 producing CD4+ T cells"
    explanation: In vitro differentiation assay shows the deficit is intrinsic to Th17 differentiation.
- name: Decreased memory B cell proportion
  category: Immunologic
  frequency: FREQUENT
  description: >-
    Memory B cells as a percentage of B cells are low in 10 of 13 evaluable
    patients (77%). Total CD19+ B cell counts are normal, with an increased
    proportion of naive B cells; in the Frey-Jakobs kindreds the IgG+, IgA+ and
    IgM+ memory subpopulations were all reduced.
  phenotype_term:
    preferred_term: Low memory B cell percentage
    term:
      id: HP:0030374
      label: Decreased memory B cell proportion
  evidence:
  - reference: PMID:37080116
    reference_title: "Inherited human ZNF341 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Low memory B-cell levels (% of B cells) | 0/1 | ND | 4/6 | 6/6 | 10/13 (77%) | 94,5%"
    explanation: Pooled table row, 10/13 patients.
  - reference: PMID:29907690
    reference_title: "ZNF341 controls STAT3 expression and thereby immunocompetence."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immunophenotyping revealed normal CD19 lymphocyte counts, but an increased percentage of naïve B cells (IgD+CD27−), and reduced memory B cells (CD27+) in the affected individuals."
    explanation: Normal total B cells with a shift from memory toward naive B cells.
- name: Reduced natural killer cell count
  category: Immunologic
  frequency: FREQUENT
  description: >-
    Low NK cell counts or percentages are reported in 10 of 15 evaluable
    patients (67%). This is one of the few immunological features that
    separates ZNF341 deficiency from STAT3 dominant-negative disease, where NK
    lymphopenia is reported in only 8%.
  phenotype_term:
    preferred_term: Low natural killer cell count
    term:
      id: HP:0040218
      label: Reduced total natural killer cell count
  evidence:
  - reference: PMID:37080116
    reference_title: "Inherited human ZNF341 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Low NK cell (count or % of lymphocytes) | 0/1 | 0/1 | 6/7 | 4/6 | 10/15 (67%) | 8%"
    explanation: Pooled table row contrasting 67% in ZNF341 deficiency with 8% in STAT3 deficiency.
  - reference: PMID:29907691
    reference_title: "A recessive form of hyper-IgE syndrome by disruption of ZNF341-dependent STAT3 transcription and activity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The seven patients tested (P2–P8) had normal counts of circulating neutrophils and basophils, monocytes, B and T cells, but low counts of NK cells"
    explanation: NK lymphopenia against otherwise normal leukocyte counts in the second discovery cohort.
- name: Elevated serum IgE
  category: Laboratory
  frequency: VERY_FREQUENT
  description: >-
    Serum IgE above 1000 IU is present in 17 of 20 patients (85%), a frequency
    comparable to STAT3 dominant-negative disease (96%). Three patients
    therefore had IgE below the conventional HIES threshold, so a normal IgE
    does not exclude the diagnosis.
  phenotype_term:
    preferred_term: Serum IgE above 1000 IU
    term:
      id: HP:0003212
      label: Increased circulating IgE concentration
  evidence:
  - reference: PMID:37080116
    reference_title: "Inherited human ZNF341 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "IgE levels > 1000 IU | 1/1 | 0/1 | 6/7 | 10/11 | 17/20 (85%) | 96%"
    explanation: Pooled table row, 17/20 patients above 1000 IU.
- name: Elevated serum IgG
  category: Laboratory
  frequency: VERY_FREQUENT
  description: >-
    Serum IgG above 16 g/L is present in 15 of 18 evaluable patients (83%).
    This is a discriminating feature: high IgG is reported in only 27% of
    STAT3 dominant-negative patients, and Orphanet lists high plasma IgG as
    part of the defining description of ZNF341 deficiency.
  phenotype_term:
    preferred_term: Serum IgG above 16 g/L
    term:
      id: HP:0003237
      label: Increased circulating IgG concentration
  evidence:
  - reference: PMID:37080116
    reference_title: "Inherited human ZNF341 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "High IgG levels (> 16 g/L) | 1/1 | 0/1 | 7/7 | 7/9 | 15/18 (83%) | 27%"
    explanation: Pooled table row contrasting 83% in ZNF341 deficiency with 27% in STAT3 deficiency.
  - reference: ORPHA:641368
    reference_title: "Autosomal recessive hyper-IgE syndrome due to ZNF341 deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "High plasma levels of IgG and low natural killer (NK) cell numbers are observed."
    explanation: Orphanet includes high plasma IgG in the defining description of the disorder.
- name: Eosinophilia
  category: Hematologic
  frequency: FREQUENT
  description: >-
    Peripheral blood eosinophilia is reported in 11 of 19 evaluable patients
    (58%), less often than in STAT3 dominant-negative disease (80%).
  phenotype_term:
    preferred_term: Peripheral blood eosinophilia
    term:
      id: HP:0001880
      label: Increased total eosinophil count
  evidence:
  - reference: PMID:37080116
    reference_title: "Inherited human ZNF341 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Eosinophilia | 0/1 | 1/1 | 3/7 | 7/10 | 11/19 (58%) | 80%"
    explanation: Pooled table row, 11/19 patients.
- name: Allergy
  category: Immunologic
  frequency: OCCASIONAL
  description: >-
    Food or respiratory allergy is reported in 4 of 19 evaluable patients
    (21%), a rate similar to STAT3 dominant-negative disease (22%). All four
    were in the Frey-Jakobs kindreds; none of the eleven patients in the other
    pooled series had allergy recorded.
  phenotype_term:
    preferred_term: Food or respiratory allergy
    term:
      id: HP:0012393
      label: Allergy
  evidence:
  - reference: PMID:37080116
    reference_title: "Inherited human ZNF341 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Allergy (food or respiratory) | 0/1 | ND | 4/7 | 0/11 | 4/19 (21 %) | 22%"
    explanation: Pooled table row showing the allergy counts concentrated in one series.
- name: Recurrent oral thrush
  category: Infectious
  frequency: FREQUENT
  description: >-
    Oral thrush, the commonest single manifestation of the chronic
    mucocutaneous candidiasis in this disorder, is reported in 9 of 20 patients
    (45%), against 63% in STAT3 dominant-negative disease. The bound term's
    label follows this repository's committed HPO snapshot; the live ontology
    has since renamed HP:0009098 to "Recurrent oral thrush" and demoted
    "Chronic oral candidiasis" to a synonym, so the concept is unchanged.
  phenotype_term:
    preferred_term: Oral thrush
    term:
      id: HP:0009098
      label: Chronic oral candidiasis
  evidence:
  - reference: PMID:37080116
    reference_title: "Inherited human ZNF341 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "- Oral thrush | 0/1 | 0/1 | 5/7 | 4/11 | 9/20 (45%) | 63%"
    explanation: Pooled table row for the oral-thrush component of CMC.
- name: Facial dysmorphism
  category: Craniofacial
  frequency: FREQUENT
  description: >-
    Facial abnormalities are reported in 10 of 19 evaluable patients (53%). The
    IUIS classification calls the dysmorphism mild, and it is markedly less
    frequent than in STAT3 dominant-negative disease (95%). The pooled sources
    do not describe the individual facial features further, so no narrower HPO
    term is supportable.
  phenotype_term:
    preferred_term: Mild facial dysmorphism
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:37080116
    reference_title: "Inherited human ZNF341 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "- Facial abnormalities | 0/1 | 0/1 | 2/7 | 8/10 | 10/19 (53%) | 95%"
    explanation: Pooled table row contrasting 53% in ZNF341 deficiency with 95% in STAT3 deficiency.
  - reference: PMID:35748970
    reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Phenocopy of AD-HIES; mild facial dysmorphism; early onset eczema"
    explanation: IUIS characterizes the facial dysmorphism of this disorder as mild.
- name: High palate
  category: Craniofacial
  frequency: FREQUENT
  description: >-
    A high palate is reported in 9 of 20 patients (45%), a frequency close to
    STAT3 dominant-negative disease (53%).
  phenotype_term:
    preferred_term: High palate
    term:
      id: HP:0000218
      label: High palate
  evidence:
  - reference: PMID:37080116
    reference_title: "Inherited human ZNF341 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "- High palate | 0/1 | 0/1 | 4/7 | 5/11 | 9/20 (45%) | 53%"
    explanation: Pooled table row, 9/20 patients.
- name: Persistence of primary teeth
  category: Dental
  frequency: OCCASIONAL
  description: >-
    Retention of deciduous teeth is reported in 4 of 16 evaluable patients
    (25%). This is one of the extra-hematopoietic features that is clearly less
    frequent than in STAT3 dominant-negative disease (65%), consistent with the
    lower dependence of STAT3 activity on ZNF341 outside the lymphoid
    compartment. All four were in one series.
  phenotype_term:
    preferred_term: Retention of deciduous teeth
    term:
      id: HP:0006335
      label: Persistence of primary teeth
  evidence:
  - reference: PMID:37080116
    reference_title: "Inherited human ZNF341 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "- Deciduous tooth retention | 0/1 | 0/1 | 0/7 | 4/7 | 4/16 (25%) | 65%"
    explanation: Pooled table row contrasting 25% in ZNF341 deficiency with 65% in STAT3 deficiency.
- name: Joint hypermobility
  category: Musculoskeletal
  frequency: OCCASIONAL
  description: >-
    Joint hyperextensibility is reported in 3 of 20 patients (15%), markedly
    less often than in STAT3 dominant-negative disease (50%).
  phenotype_term:
    preferred_term: Joint hyperextensibility
    term:
      id: HP:0001382
      label: Joint hypermobility
  evidence:
  - reference: PMID:37080116
    reference_title: "Inherited human ZNF341 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "- Joint hyperextensibility | 0/1 | 0/1 | 2/7 | 1/11 | 3/20 (15%) | 50%"
    explanation: Pooled table row, 3/20 patients.
- name: Scoliosis
  category: Skeletal
  frequency: OCCASIONAL
  description: >-
    Scoliosis is reported in 2 of 20 patients (10%), against 38% in STAT3
    dominant-negative disease.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:37080116
    reference_title: "Inherited human ZNF341 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "- Scoliosis | 0/1 | 1/1 | 0/7 | 1/11 | 2/20 (10%) | 38%"
    explanation: Pooled table row, 2/20 patients.
- name: Minimal-trauma fractures
  category: Skeletal
  frequency: OCCASIONAL
  description: >-
    Bone fractures after minimal trauma are reported in 2 of 20 patients,
    against 42% in STAT3 dominant-negative disease. The pooled table prints the
    percentage for this row as 20%, which does not agree with its own numerator
    and denominator (2/20 is 10%); either figure falls in the same occasional
    band, so the discrepancy does not change the classification.
  phenotype_term:
    preferred_term: Bone fracture after minimal trauma
    term:
      id: HP:0002659
      label: Increased susceptibility to fractures
  evidence:
  - reference: PMID:37080116
    reference_title: "Inherited human ZNF341 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "- Bone fractures with minimal trauma | 0/1 | 0/1 | 1/7 | 1/11 | 2/20 (20%) | 42%"
    explanation: Pooled table row, 2 of 20 patients, quoted with the printed percentage as it stands.
- name: Growth retardation
  category: Growth
  frequency: OCCASIONAL
  description: >-
    Growth retardation is reported in 3 of 20 patients (15%). The pooled
    sources record no comparison figure for STAT3 dominant-negative disease and
    characterize the growth failure no further.
  phenotype_term:
    preferred_term: Growth retardation
    term:
      id: HP:0001510
      label: Growth delay
  evidence:
  - reference: PMID:37080116
    reference_title: "Inherited human ZNF341 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Growth retardation | 0/1 | 0/1 | 1/7 | 2/11 | 3/20 (15%) | n.d."
    explanation: Pooled table row, 3/20 patients, with no STAT3 comparator reported.
- name: Developmental delay
  category: Neurologic
  frequency: FREQUENT
  description: >-
    The pooled table records "mental delay" in 7 of 19 evaluable patients
    (37%), all of them in one of the contributing series and none in the
    others. The sources characterize it no further, do not report formal
    developmental or cognitive testing, and give no comparison figure for
    STAT3 dominant-negative disease, so neither the severity nor the domains
    affected can be stated and the concentration in a single consanguineous
    series leaves open that it is not attributable to ZNF341. The binding is
    deliberately HP:0012758 rather than HP:0001263 Global developmental delay,
    which would assert involvement of all developmental domains that the source
    does not report.
  phenotype_term:
    preferred_term: Mental delay, not further characterized
    term:
      id: HP:0012758
      label: Neurodevelopmental delay
  evidence:
  - reference: PMID:37080116
    reference_title: "Inherited human ZNF341 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Mental delay | 0/1 | 0/1 | 0/7 | 7/10 | 7/19 (37%) | n.d."
    explanation: Pooled table row, 7/19 patients, concentrated in one contributing series.
- name: Alopecia
  category: Dermatologic
  frequency: OCCASIONAL
  description: >-
    Alopecia is reported in 2 of 20 patients (10%), with no comparison figure
    recorded for STAT3 dominant-negative disease.
  phenotype_term:
    preferred_term: Alopecia
    term:
      id: HP:0001596
      label: Alopecia
  evidence:
  - reference: PMID:37080116
    reference_title: "Inherited human ZNF341 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Alopecia | 0/1 | 0/1 | 1/7 | 1/11 | 2/20 (10%) | n.d."
    explanation: Pooled table row, 2/20 patients.
- name: Neoplasm
  category: Oncologic
  description: >-
    One of the 20 published patients (5%) has developed malignancy: a nasal
    primitive neuroendocrine tumor followed by papillary thyroid cancer, in a
    patient enrolled in the radiosensitivity study. The two tumors are of
    unrelated lineages and are the only malignancies reported in the disorder,
    so this node stands for malignancy of any type rather than for a
    characteristic tumor; it is the convergence point of the proposed
    DNA-repair mechanism and deliberately carries no frequency of its own.
  phenotype_term:
    preferred_term: Malignancy of any type
    term:
      id: HP:0002664
      label: Neoplasm
    coarse_binding_basis: PATHOGRAPH_HUB
  evidence:
  - reference: PMID:37080116
    reference_title: "Inherited human ZNF341 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Neoplasia (any type) | 0/1 | 0/1 | 0/7 | 1/11 | 1/20 (5%) | 7%"
    explanation: Pooled table row recording one malignancy among the 20 published patients.
  - reference: PMID:35511492
    reference_title: "Increased radiosensitivity and impaired DNA repair in patients with STAT3-LOF and ZNF341 deficiency, potentially contributing to malignant transformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Except for a patient with ZNF341 deficiency who developed nasal cell primitive neuroendocrine tumor and papillary thyroid cancer during the follow-up, there was no cancer in both groups."
    explanation: Names the two tumors in the single affected patient.
inheritance:
- name: Autosomal recessive
  description: >-
    ZNF341 deficiency is autosomal recessive and fully penetrant. All 20
    patients pooled in the 2023 review were homozygous for a truncating ZNF341
    allele and all their kindreds were consanguineous, so the disorder was
    initially seen only as homozygosity for a founder or private null allele. A
    later report describes a child with a biallelic missense allele and does not
    state whether she is homozygous, so neither truncation nor homozygosity can
    be treated as a requirement. Heterozygous relatives are healthy. The cited
    sources do not state a numerical recurrence risk for the sibship, so none
    is recorded here.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:29907691
    reference_title: "A recessive form of hyper-IgE syndrome by disruption of ZNF341-dependent STAT3 transcription and activity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The segregation of the four mutant alleles of ZNF341 in the six families was consistent with a fully penetrant AR trait"
    explanation: Segregation across six kindreds establishes a fully penetrant autosomal recessive trait.
  - reference: PMID:29907690
    reference_title: "ZNF341 controls STAT3 expression and thereby immunocompetence."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We investigated patients of four consanguineous families with an autosomal-recessive disorder resembling the phenotype of AD-HIES"
    explanation: The independent discovery cohort is likewise four consanguineous autosomal recessive kindreds.
  - reference: CGGV:assertion_2dc4032e-7215-464d-9844-c392ec25148b-2024-06-04T170000.000Z
    reference_title: "ZNF341 / hyper-IgE recurrent infection syndrome 3, autosomal recessive (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "This curation included ten probands from 10 unrelated consanguineous families (PMID: 29907691, 29907690 & 37080116)."
    explanation: ClinGen's curation records that every contributing proband came from a consanguineous family.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Twenty patients reported in total as of the 2023 review, in kindreds of
    Israeli (of 19th-century Sudanese descent), Turkish, Moroccan,
    Afro-Caribbean, Iranian and Lebanese origin. No population-based prevalence
    estimate exists; Orphanet's record for this disorder carries no
    epidemiology section.
  evidence:
  - reference: PMID:37080116
    reference_title: "Inherited human ZNF341 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Including the two new cases described in this review, only 20 patients with autosomal-recessive (AR) ZNF341 deficiency have ever been reported."
    explanation: Total published case count at the time of the defining review.
- population: Muslim village in Israel, approximately 15,000 residents, from which eight of the first eleven reported patients came
  measure_type: CARRIER_FREQUENCY
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 5000.0
  rate_denominator: POPULATION
  notes: >-
    Carrier frequency for the founder allele c.904C>T (p.Arg302*) alone, not
    for ZNF341 null alleles in general, measured by Sanger sequencing of 200
    women from the village referred for pre-pregnancy genetic testing against
    100 Muslim women from other villages. Ten of the 200 were heterozygous and
    none of the controls. This is a carrier rate, not a disease prevalence, and
    it is specific to one consanguineous founder population; it says nothing
    about the frequency of the disorder elsewhere.
  evidence:
  - reference: PMID:35185921
    reference_title: Hyper IgE Syndrome in an Isolated Population in Israel.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The carrier frequency of the mutation in ZNF341 in the studied village population is 1:20."
    explanation: The study's headline carrier-frequency result.
  - reference: PMID:35185921
    reference_title: Hyper IgE Syndrome in an Isolated Population in Israel.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heterozygous nonsense mutation in ZNF341 was found in ten samples (5%) of the study group compared to zero in the control group (p<0.01)."
    explanation: Gives the numerator, denominator and control comparison behind the 1:20 figure.
  - reference: PMID:35185921
    reference_title: Hyper IgE Syndrome in an Isolated Population in Israel.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This high frequency is probably due to founder mutation and consanguineous marriages."
    explanation: The authors attribute the high carrier rate to a founder effect plus consanguinity.
genetic:
- name: ZNF341
  association: Causative
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: ZNF341
    term:
      id: hgnc:15992
      label: ZNF341
  variant_origin: GERMLINE
  notes: >-
    ZNF341 (20q11.22) encodes a nuclear C2H2 zinc-finger transcription factor
    that binds the STAT3 promoter. Every allele in the 20 patients pooled by
    the 2023 review is biallelic and truncating - nonsense or frameshift - and
    the mechanism is loss of function rather than negative dominance, which is
    the mechanistic difference from STAT3 dominant-negative AD-HIES. A
    subsequent paediatric case report carries a biallelic missense allele
    (c.538C>G, p.Pro180Ala), so truncation is not a requirement of the
    diagnosis; that report does not present functional data on the variant.
    Reported truncating alleles include
    p.Arg302* (c.904C>T), seen homozygously in several unrelated kindreds and
    the nearest thing to a recurrent allele, plus p.Gln195* (c.583C>T),
    p.Lys355Serfs (c.1062delG), p.Tyr542* (c.1626C>G), p.Ser64* and an
    essential splice-site variant. Residue numbering is isoform-dependent: the
    Frey-Jakobs report numbers its second allele p.Arg386* against RefSeq
    NM_001282933.1 (854 residues), and the two main transcripts differ by 21
    in-frame nucleotides, so an allele quoted from one paper will not always
    match the numbering in another. p.Arg302* is a founder allele: in the
    Israeli village from which eight of the first eleven patients came, 10 of
    200 screened women were heterozygous carriers.
  evidence:
  - reference: PMID:35185921
    reference_title: Hyper IgE Syndrome in an Isolated Population in Israel.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All samples were tested by Sanger sequencing for the ZNF341 mutation (c.904C>T, NM_001282933.1)."
    explanation: Confirms c.904C>T as the allele screened for as a founder variant in that population.
  - reference: PMID:39420803
    reference_title: "Improvement in Atopic Dermatitis and Recurrent Infection With Dupilumab in Children With Distinct Genetic Types of Hyper-IgE Syndrome: A Case Series and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ZNF341 (c.538C > G; p.Pro180Ala) | This manuscript | 2 | F | Hyperpigmented plaques, diffuse xerosis and pruritis, cutaneous infections including eczema herpeticum"
    explanation: A biallelic missense ZNF341 allele in a child, outside the truncating spectrum of the pooled cohort.
  - reference: CGGV:assertion_2dc4032e-7215-464d-9844-c392ec25148b-2024-06-04T170000.000Z
    reference_title: "ZNF341 / hyper-IgE recurrent infection syndrome 3, autosomal recessive (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ZNF341 | HGNC:15992 | hyper-IgE recurrent infection syndrome 3, autosomal recessive | MONDO:0032654 | AR | Definitive"
    explanation: ClinGen's SCID-CID expert panel classifies the gene-disease relationship as Definitive with autosomal recessive inheritance.
  - reference: PMID:29907690
    reference_title: "ZNF341 controls STAT3 expression and thereby immunocompetence."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified a homozygous nonsense mutation in exon 6 of ZNF341 (Chr20:32345116C>T; GRCh37; c.904C>T; p.Arg302*, R302* for isoform1; RefSeq NM_001282933.1)"
    explanation: Identifies the recurrent p.Arg302* allele with its genomic and transcript coordinates.
  - reference: PMID:29907691
    reference_title: "A recessive form of hyper-IgE syndrome by disruption of ZNF341-dependent STAT3 transcription and activity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "kindred D had a frameshift deletion (c.1062delG) leading to a premature stop codon (K355fs), kindred E had a nonsense mutation (c.1626C>G) replacing the tyrosine 542 codon with a premature stop codon (Y542X), and kindred F had a nonsense mutation (c.583C>T) replacing the glutamine 195 codon with a premature stop codon (Q195X)"
    explanation: Lists the three private truncating alleles beyond the recurrent p.Arg302*.
  - reference: PMID:29907691
    reference_title: "A recessive form of hyper-IgE syndrome by disruption of ZNF341-dependent STAT3 transcription and activity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The encoded protein has 12 predicted DNA-binding C2H2 zinc finger (ZNF) domains, and two predicted nuclear localization sequences (NLS)"
    explanation: Establishes the domain structure whose truncation underlies the loss of function.
  - reference: PMID:29907691
    reference_title: "A recessive form of hyper-IgE syndrome by disruption of ZNF341-dependent STAT3 transcription and activity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe patients with an autosomal recessive form of HIES due to loss-of-function mutations of a previously uncharacterized gene, ZNF341"
    explanation: Establishes loss of function, rather than negative dominance, as the disease mechanism.
treatments:
- name: Dupilumab
  action_category: THERAPEUTIC
  therapeutic_modality: MONOCLONAL_ANTIBODY
  description: >-
    Dupilumab, an anti-IL-4-receptor-alpha monoclonal antibody, blocks IL-4 and
    IL-13 signalling and is the one therapy reported in a genetically confirmed
    ZNF341-deficient patient. A 48-year-old woman with severe atopic dermatitis
    (SCORAD 85.5) refractory to ultra-potent topical corticosteroids and
    topical tacrolimus received 600 mg followed by 300 mg subcutaneously every
    two weeks, improved after three injections, stopped topical treatment at
    three months, and had a complete and well-tolerated response at one year,
    with falling total and allergen-specific IgE. This is a single case report
    in an adult, so it establishes that the Th2 axis is targetable in this
    disorder rather than an efficacy estimate. Paediatric experience now exists:
    a 2-year-old girl with biallelic ZNF341 variants, severe atopic dermatitis
    over more than 70% of her body surface and IgE above 40,000 IU/mL was
    started at 300 mg every four weeks, escalated at three months to 200 mg
    every two weeks for extensive disease, and improved to mild disease under
    10% body surface by six months, with her IgE falling to 6935 IU/mL. Treatment
    was then interrupted for four months, during which her dermatitis flared;
    it settled again on restarting at the same initial dose, and she remained
    stable over the following year. The response therefore appears to require
    continued treatment. Total published
    experience in this disorder is two patients, one adult and one child.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: dupilumab
      term:
        id: NCIT:C162455
        label: Dupilumab
  dosing_interval: every two weeks
  dosing_interval_days: 14
  target_phenotypes:
  - preferred_term: Atopic dermatitis
    term:
      id: HP:0001047
      label: Atopic dermatitis
  target_mechanisms:
  - target: Th2 skewing of CD4 T cells
    description: >-
      Dupilumab blocks the IL-4 receptor alpha chain shared by the IL-4 and
      IL-13 receptors, the effector arm of the Th2 skewing that drives the
      atopic dermatitis in this disorder.
    evidence:
    - reference: PMID:31993867
      reference_title: "Efficacy of Dupilumab for Controlling Severe Atopic Dermatitis in a Patient with Hyper-IgE Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This observation suggests that Th2-mediated IL-4 and/or IL-13 signaling plays a central role in atopic dermatitis in HIES."
      explanation: The authors read the treatment response as evidence that Th2 IL-4/IL-13 signalling drives the dermatitis.
  evidence:
  - reference: PMID:31993867
    reference_title: "Efficacy of Dupilumab for Controlling Severe Atopic Dermatitis in a Patient with Hyper-IgE Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report the successful treatment of severe atopic dermatitis in a 48-year-old patient with AR ZNF341 deficiency."
    explanation: The single reported use of dupilumab in a genetically confirmed ZNF341-deficient patient.
  - reference: PMID:31993867
    reference_title: "Efficacy of Dupilumab for Controlling Severe Atopic Dermatitis in a Patient with Hyper-IgE Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our patient received an initial dose of 600 mg dupilumab, followed by subcutaneous injections of 300 mg dupilumab at two-week intervals."
    explanation: Source for the dose and the two-week dosing interval recorded here.
  - reference: PMID:31993867
    reference_title: "Efficacy of Dupilumab for Controlling Severe Atopic Dermatitis in a Patient with Hyper-IgE Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Continuous treatment during one year led to complete response and was well tolerated."
    explanation: Reports the one-year outcome.
  - reference: PMID:31993867
    reference_title: "Efficacy of Dupilumab for Controlling Severe Atopic Dermatitis in a Patient with Hyper-IgE Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dupilumab should be considered for patients with AD STAT3 or AR ZNF341 deficiency"
    explanation: The authors' explicit recommendation for this genotype.
  - reference: PMID:39420803
    reference_title: "Improvement in Atopic Dermatitis and Recurrent Infection With Dupilumab in Children With Distinct Genetic Types of Hyper-IgE Syndrome: A Case Series and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additionally, this case series is the first to report on a child with AR-HIES caused by a mutation in ZNF341 to be treated with dupilumab."
    explanation: Establishes that paediatric experience of dupilumab in this specific genotype exists.
  - reference: PMID:39420803
    reference_title: "Improvement in Atopic Dermatitis and Recurrent Infection With Dupilumab in Children With Distinct Genetic Types of Hyper-IgE Syndrome: A Case Series and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In all cases, dupilumab treatment led to sustained clearance of severe atopic dermatitis over multiple years, as well as improvements in systemic symptoms of HIES."
    explanation: Reports the multi-year paediatric outcome across the three children, one of whom is ZNF341-deficient.
  - reference: PMID:39420803
    reference_title: "Improvement in Atopic Dermatitis and Recurrent Infection With Dupilumab in Children With Distinct Genetic Types of Hyper-IgE Syndrome: A Case Series and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ZNF341 (c.538C > G; p.Pro180Ala) | This manuscript | 2 | F | Hyperpigmented plaques, diffuse xerosis and pruritis, cutaneous infections including eczema herpeticum | IGA score of 4, > 70% TBSA | IgE > 40,000 IU/mL | 600 mg loading dose, 200 mg Q2W | After: 6 months: IGA score of 1, < 10% TBSA | After 6 months: IgE 6935 IU/mL |"
    explanation: Source for this child's dosing, baseline severity and six-month response recorded here.
- name: Topical corticosteroids and calcineurin inhibitors for atopic dermatitis
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Topical corticosteroids and topical calcineurin inhibitors with oral
    antihistamines are the mainstay of atopic dermatitis management in hyper-IgE
    syndrome generally. They are not always sufficient in ZNF341 deficiency:
    the one patient reported in detail applied ultra-high potency class I
    topical corticosteroids daily together with topical tacrolimus without
    effect before dupilumab was started.
  treatment_term:
    preferred_term: Topical corticosteroid and calcineurin-inhibitor therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: topical corticosteroid
      term:
        id: NCIT:C29505
        label: Topical Corticosteroid
    - preferred_term: tacrolimus
      term:
        id: NCIT:C1311
        label: Tacrolimus
  target_phenotypes:
  - preferred_term: Atopic dermatitis
    term:
      id: HP:0001047
      label: Atopic dermatitis
  evidence:
  - reference: PMID:31993867
    reference_title: "Efficacy of Dupilumab for Controlling Severe Atopic Dermatitis in a Patient with Hyper-IgE Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "Topical corticosteroids and calcineurin inhibitors, associated with oral antihistamines are the main treatment, whereas immunosuppressive agents are not recommended given a higher risk of infection."
    explanation: States the standard topical regimen for hyper-IgE syndrome, and that systemic immunosuppression is avoided because of infection risk.
  - reference: PMID:31993867
    reference_title: "Efficacy of Dupilumab for Controlling Severe Atopic Dermatitis in a Patient with Hyper-IgE Syndrome."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "She applied ultra-high potency class I topical corticosteroids daily, and topical tacrolimus, which were ineffective."
    explanation: In the one ZNF341-deficient patient reported in detail the topical regimen failed, so it is not reliably sufficient here.
- name: Surveillance for malignancy
  action_category: MONITORING
  description: >-
    Leukocytes from ZNF341-deficient patients clear radiation-induced DNA
    damage more slowly than those of controls, and the one malignancy reported
    in the disorder - a nasal primitive neuroendocrine tumour followed by
    papillary thyroid cancer - arose in a patient in that study. The authors
    read the radiosensitivity as a potential explanation for susceptibility to
    malignant transformation. This supports being deliberate about cumulative
    diagnostic radiation and about cancer surveillance, but the basis is one
    patient and an ex vivo assay in four, and no surveillance protocol,
    starting age or interval has been published for this disorder.
  treatment_term:
    preferred_term: cancer screening
    term:
      id: NCIT:C15406
      label: Cancer Screening
  evidence:
  - reference: PMID:35511492
    reference_title: "Increased radiosensitivity and impaired DNA repair in patients with STAT3-LOF and ZNF341 deficiency, potentially contributing to malignant transformations."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Increased radiosensitivity and impaired DNA repair were demonstrated in patients diagnosed with STAT3-LOF and ZNF341 deficiency, potentially explaining the susceptibility to malignant transformation."
    explanation: The comet-assay study's own conclusion, which is the entire published rationale for surveillance in this disorder.
- name: Genetic counselling
  action_category: COUNSELING_INFORMATIONAL
  description: >-
    The kindreds pooled in the 2023 review are consanguineous and their
    patients homozygous for a truncating allele, so counselling for an affected
    family turns on
    recessive recurrence and on carrier testing within the extended family.
    The cited sources state the inheritance pattern and the consanguinity but
    give no numerical recurrence risk, so none is asserted in this entry.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: CGGV:assertion_2dc4032e-7215-464d-9844-c392ec25148b-2024-06-04T170000.000Z
    reference_title: "ZNF341 / hyper-IgE recurrent infection syndrome 3, autosomal recessive (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "This curation included ten probands from 10 unrelated consanguineous families (PMID: 29907691, 29907690 & 37080116)."
    explanation: Records that consanguinity is the context in which every published proband was ascertained.
diagnosis:
- name: ZNF341 molecular genetic testing
  description: >-
    Because ZNF341 deficiency is clinically almost indistinguishable from STAT3
    dominant-negative AD-HIES, the diagnosis rests on finding biallelic ZNF341
    loss-of-function variants, by an HIES or inborn-errors-of-immunity gene
    panel or by exome sequencing. In both discovery cohorts STAT3 itself was
    sequenced and excluded first. A high NIH HIES score with an autosomal
    recessive pedigree, consanguinity, low NK cells or high IgG should prompt
    testing that covers ZNF341 rather than STAT3 alone.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  results: Biallelic ZNF341 loss-of-function variants
  evidence:
  - reference: PMID:37080116
    reference_title: "Inherited human ZNF341 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Although generally milder, AR ZNF341 deficiency is a hardly distinguishable clinical phenocopy of AD STAT3 deficiency in the absence of genetic testing."
    explanation: States that genetic testing is what separates this disorder from STAT3 AD-HIES.
  - reference: PMID:29907690
    reference_title: "ZNF341 controls STAT3 expression and thereby immunocompetence."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic defects in STAT3 itself were excluded by sequencing of the exons, cDNA, and the genomic promoter region"
    explanation: Shows STAT3 exclusion preceding the ZNF341 diagnosis in the discovery cohort.
- name: Th17 enumeration by flow cytometry
  description: >-
    Reduced circulating IL-17-producing CD4+ T cells are found in most
    patients and support a STAT3-pathway defect, but they do not distinguish
    ZNF341 deficiency from STAT3 dominant-negative disease, in which the same
    reduction is seen at a comparable frequency. Low NK cell counts, uncommon
    in STAT3 deficiency, are the flow-cytometric finding that points toward
    ZNF341.
  diagnosis_term:
    preferred_term: Th17 and NK cell flow cytometry
    term:
      id: NCIT:C16585
      label: Flow Cytometry
  results: Reduced Th17 cell proportion; reduced NK cell count
  evidence:
  - reference: PMID:37080116
    reference_title: "Inherited human ZNF341 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Thus, ZNF341 deficiency phenocopies STAT3 deficiency in terms of the immunological phenotype of patients, except that NK cell counts are low in a majority of patients with ZNF341 deficiency but rarely in those with STAT3 deficiency."
    explanation: Identifies NK lymphopenia as the immunological finding that separates the two disorders.
differential_diagnoses:
- name: STAT3 dominant-negative hyper-IgE syndrome (AD-HIES)
  description: >-
    The principal differential and a near-complete clinical phenocopy. It is
    autosomal dominant, usually de novo, and acts by negative dominance rather
    than loss of function. Pointers away from it and toward ZNF341 deficiency
    are a recessive pedigree with consanguinity, a lower NIH HIES score (median
    28.5 versus 64), low NK cells, high serum IgG, less frequent
    connective-tissue, skeletal and dental involvement, and no reported
    vascular complication. None of these is decisive without genetic testing.
  evidence:
  - reference: PMID:37080116
    reference_title: "Inherited human ZNF341 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Although generally milder, AR ZNF341 deficiency is a hardly distinguishable clinical phenocopy of AD STAT3 deficiency in the absence of genetic testing."
    explanation: Establishes AD-HIES as the differential that clinical assessment alone cannot exclude.
- name: DOCK8 deficiency (autosomal recessive HIES)
  description: >-
    The commonest autosomal recessive hyper-IgE syndrome, and therefore the
    first alternative in a recessive pedigree. It is distinguished by severe
    cutaneous viral infection - herpes simplex, human papillomavirus,
    molluscum - which was specifically looked for and not found in any ZNF341
    patient, and by early malignancy.
  evidence:
  - reference: PMID:29907690
    reference_title: "ZNF341 controls STAT3 expression and thereby immunocompetence."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Increased susceptibility to viral infections, typical in DOCK8-deficient AR-HIES, was not observed in any of the patients."
    explanation: The discriminating feature, assessed directly in the ZNF341 discovery cohort.
  - reference: PMID:29907690
    reference_title: "ZNF341 controls STAT3 expression and thereby immunocompetence."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "biallelic DOCK8 mutations account for disease in ~80% of patients with the autosomal-recessive (AR) form of HIES"
    explanation: Establishes DOCK8 as the leading cause of AR-HIES and so the first differential to exclude.
- name: PGM3 deficiency
  description: >-
    A further autosomal recessive hyper-IgE syndrome, in which the
    glycosylation defect adds neurocognitive impairment and skeletal dysplasia
    to the atopy and high IgE. It is covered by any HIES gene panel.
  evidence:
  - reference: PMID:29907690
    reference_title: "ZNF341 controls STAT3 expression and thereby immunocompetence."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "Additionally, mutations in PGM3 (MIM: 172100, (15, 16)) have been described in AR-HIES."
    explanation: Names PGM3 as a further recessive HIES gene to consider.
references:
- reference: PMID:37080116
  title: "Inherited human ZNF341 deficiency."
- reference: PMID:39420803
  title: "Improvement in Atopic Dermatitis and Recurrent Infection With Dupilumab in Children With Distinct Genetic Types of Hyper-IgE Syndrome: A Case Series and Literature Review."
- reference: PMID:35748970
  title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
📚

References & Deep Research

References

3
PMID:37080116
Inherited human ZNF341 deficiency.
No top-level findings curated for this source.
PMID:39420803
Improvement in Atopic Dermatitis and Recurrent Infection With Dupilumab in Children With Distinct Genetic Types of Hyper-IgE Syndrome: A Case Series and Literature Review.
No top-level findings curated for this source.
PMID:35748970
Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: ZNF341 Deficiency · 2026-09-25T17:00:47Z · View source

Curated in two sittings. The first, on 2026-09-23, was ended by a hard account rate limit before anything was committed; its work was pushed unchanged as a safety commit and covered description, notes, classifications, mechanistic_hypotheses, pathophysiology (10 nodes) and 11 phenotypes. This session completed the entry. Inherited content was reviewed rather than assumed correct. Two of its snippets did not verify under linkml-reference-validator 0.3.0rc1: one carried a literal "[52]" citation marker that defeats bracket normalisation, and one quoted the full-text body of PMID:35511492, whose cache is content_type full_text_html and which 0.3.0rc1 refuses as stale (confirmed by re-running just fetch-reference). Both were re-cited to text the validator can read. The pathophysiology edges named 13 phenotypes that did not exist, so the phenotype layer was almost entirely unreachable from the pathograph. All 13 were curated from the pooled cohort table in PMID:37080116 together with five further features that table reports, giving 29 phenotypes. Frequency bands were set from each row's own numerator and denominator against FrequencyEnum's numeric ranges, which moved atopic dermatitis from VERY_FREQUENT to OBLIGATE (20/20). Where the table's printed percentage disagrees with its own fraction (minimal-trauma fractures, 2/20 printed as 20%) the row is quoted as it stands and the discrepancy recorded on the phenotype. inheritance, prevalence, genetic, treatments, diagnosis, differential_diagnoses and references were written in this session. Re-running the PubMed query the entry's animal-model note rests on surfaced two primary reports that refuted claims made earlier in this same session. PMID:39420803 reports dupilumab in a 2-year-old with biallelic ZNF341 variants, against a treatment description that had said no paediatric experience existed; the same report's variant table carries a missense allele (c.538C>G, p.Pro180Ala), against genetic notes that had said every disease allele is truncating. PMID:35185921 gives a carrier frequency of 1:20 for the p.Arg302* founder allele in the Israeli village eight of the first eleven patients came from, added as a second prevalence record under measure_type CARRIER_FREQUENCY. Lump/split: a separate Disease entry rather than a subtype of Autosomal_Dominant_Hyper-IgE_Syndrome. Gene, inheritance and molecular mechanism all differ, MONDO/OMIM/Orphanet/ClinGen treat them separately, and the pooled table in PMID:37080116 separates them clinically (NK lymphopenia 67% vs 8%, high IgG 83% vs 27%, median NIH HIES score 28.5 vs 64, no reported vascular complication). The stub's entry_type was set to DISEASE with that reasoning in a commit of its own before the stub was deleted, so the decision is auditable independently. Term bindings: NCIT:C15326 was written from memory as "Screening" in a first draft of the surveillance treatment and is in fact Sperm Banking. Term validation caught it and the binding is now NCIT:C15406 Cancer Screening. HP:0009098 is labelled "Chronic oral candidiasis" to match this repository's committed HPO snapshot and the 17 other uses in kb/; live HPO has renamed the term to "Recurrent oral thrush", and re-deriving the cache row would have broken eight unrelated entries, so the rename is recorded on the binding instead. Neoplasm is bound to the coarse HP:0002664 with coarse_binding_basis PATHOGRAPH_HUB. Deliberate gaps. No numerical recurrence risk is stated: neither discovery paper nor the review gives one. No malignancy surveillance protocol, starting age or interval is given, because none has been published; only the radiosensitivity rationale is cited. PMID:31980991, "Cancer Tendency in a Patient with ZNF341 Deficiency", is the one further primary report on malignancy here and is not cited because the fetcher returns content_type unavailable for it, so no exact quote can be taken; this is recorded in the entry's notes. No animal model exists, verified by three named PubMed queries recorded in notes and re-run on the day of the commit. No GeneReviews chapter exists, verified offline and online against the committed Bookshelf index. Deep research: falcon was requested and returned HTTP 402, so the claude_code fallback produced the report (fell_back: true recorded in the frontmatter). just preflight-dr returns WARN, not FAIL: STAT3 is mentioned at 51% of ZNF341's rate because ZNF341 regulates STAT3 and the disorder is a STAT3 phenocopy, which is the pathway-gene case rather than a mixed-entity report. The report was treated as a lead throughout; every claim in the entry is cited to a primary source or a structured record. Validation: just validate-disorders, count-verified-snippets (112/112), validate-terms, check-entity-refs, check-causal-targets, check-duplicate-keys, check-enum-values, check-coarse-phenotypes, check-qualifier-terms, check-reference-titles, check-genereviews (offline and online), list-gene-term-mismatches, validate-history and pytest -k ZNF341. Snippet gates were run under a venv pinned to linkml-reference-validator 0.3.0rc1, the floor main requires, rather than the shared 0.2.1 venv. Note for anyone re-running gates on this entry: just validate lacks the --no-full-text guard and truncated five references_cache files during this session (issue #12672). They were restored with git checkout and the entry was re-verified afterwards. Use just validate-disorders.

Claude Code ▸
ZNF341 Deficiency (Autosomal Recessive Hyper-IgE Syndrome 3, HIES3): Comprehensive Research Report
claude-haiku-4-5-20251001, claude-sonnet-5 2026-09-23T19:33:30.966304

ZNF341 Deficiency (Autosomal Recessive Hyper-IgE Syndrome 3, HIES3): Comprehensive Research Report

Source classes used throughout: primary literature (original patient-cohort papers), a narrative review (Béziat et al. 2023, itself reporting two new patients), structured databases (OMIM, Orphanet, GeneCards/NCBI Gene), and one case report. Numeric phenotype-frequency data below are drawn from the 2023 review's aggregation of the published cohort (n=20 as of that publication) and are flagged as such — they are a secondary tabulation, not independently re-derived from each primary paper in this report.

1. Disease Information

Overview. ZNF341 deficiency is an autosomal recessive primary immunodeficiency that produces a phenocopy of autosomal-dominant STAT3 (Job/hyper-IgE) syndrome. It was first described in 2018 by two independent groups working with overlapping/related consanguineous kindreds, who found that biallelic loss-of-function variants in ZNF341 — a zinc-finger transcription factor that transactivates the STAT3 promoter — reduce basal STAT3 expression and abolish STAT3 "autoinduction," producing a milder, incompletely penetrant phenocopy of classic Job syndrome (Frey-Jakobs et al., Sci Immunol 2018, PMID 29907690; Béziat et al., Sci Immunol 2018, PMID 29907691; commentary by Al-Herz, PMID 29907692).

Key identifiers: - OMIM disease: #618282 — Hyper-IgE syndrome 3, autosomal recessive, with recurrent infections (HIES3) - OMIM gene: 618269 — ZINC FINGER PROTEIN 341; ZNF341 - Orphanet: ORPHA:641368 — Autosomal recessive hyper-IgE syndrome due to ZNF341 deficiency - HGNC: HGNC:15992 - NCBI Gene: 84905 - Cytogenetic location: 20q11.22 - MONDO:* MONDO:0032654 (as supplied in the task; not independently re-verified against the MONDO browser in this session — flag this as unverified/a lead)

Synonyms: Hyper-IgE syndrome 3 (HIES3); autosomal recessive Job syndrome; ZNF341-related hyper-IgE syndrome.

Data provenance: All clinical/phenotype-frequency data available to date derive from published case series aggregated across a small number of consanguineous kindreds (Moroccan, Afro-Caribbean, Iranian, Turkish, Lebanese, and Israeli Arab backgrounds per the 2023 review) — this is aggregated case-series data, not registry- or EHR-derived population data. No large administrative/claims-based cohort exists given the rarity of the condition.

2. Etiology

Disease Causal Factor: Purely genetic — biallelic (homozygous or compound heterozygous) loss-of-function variants in ZNF341. No environmental, infectious, or purely mechanistic (non-genetic) causal factor has been reported; this is a monogenic Mendelian disorder.

Genetic risk factors: - Biallelic ZNF341 LOF variants are causal, not merely a risk factor — this is a fully penetrant Mendelian loss-of-function disease at the molecular level (all reported homozygotes/compound heterozygotes are symptomatic), though clinical severity varies (see §9, expressivity). - Mutational hotspot: p.Arg302* was found in 13 of the 20 reported patients across 6 independent kindreds (Béziat et al. 2023 review, PMC10620851) — consistent with either a true mutational hotspot (CpG-associated nonsense codon) or a shared/founder haplotype in populations with high consanguinity; the review does not resolve which, so this should be treated as an open question rather than settled founder-effect fact. - Consanguinity is a strong risk-modifying factor given the autosomal recessive inheritance and small global patient count concentrated in consanguineous populations (Moroccan, Iranian, Turkish, Lebanese, Israeli Arab, Afro-Caribbean).

Environmental risk factors: None specifically implicated in disease causation. However, ionizing radiation is a documented aggravating/harm-amplifying exposure post-diagnosis (see Mechanism/Malignancy sections) — ZNF341-deficient leukocytes show impaired post-irradiation DNA repair (PMC9307231), which is a modifier of secondary risk (malignancy) rather than a cause of the primary immunodeficiency.

Protective factors: None reported in the literature located.

Gene-environment interactions: The one documented interaction is genotype × ionizing-radiation exposure increasing malignancy/DNA-damage risk (below), not a classical GxE susceptibility interaction for the primary disease.

3. Phenotypes

The table below reproduces the frequency data as tabulated in the 2023 review (Béziat et al., Curr Opin Immunol, PMID 37080116; PMC10620851), which aggregated all 20 published patients as of early 2023 and compared them to a STAT3-dominant-negative HIES reference cohort. This is a secondary source's tabulation of primary case data — treat percentages as approximate given n≈20.

Phenotype (ZNF341-deficient) Frequency Suggested HPO term (unverified against HPO browser — lead only)
Atopic dermatitis / eczema 100% HP:0001047 Atopic dermatitis
Elevated IgE (>1000 IU/mL) 85% HP:0003212 Increased IgE level
High IgG (>16 g/L) 83% HP:0010702 (Abnormal immunoglobulin level, or a more specific IgG-elevation term — needs lookup)
Skin abscesses 75% HP:0031469 (skin abscess — verify)
Low NK cell counts/frequency 67% HP:0040088 Abnormal NK cell count
Chronic mucocutaneous candidiasis 60% HP:0002728 Chronic mucocutaneous candidiasis
Recurrent upper respiratory infections 58% HP:0002788 Recurrent respiratory infections
Eosinophilia 58% HP:0001880 Eosinophilia
Pneumonia 56% HP:0002090 Pneumonia
Facial dysmorphia 53% HP:0001999 Abnormal facial shape
High palate 45% HP:0000218 High palate
Bronchiectasis 35% HP:0002110 Bronchiectasis
Mental/developmental delay 37% HP:0001256 Intellectual disability, mild (or HP:0001263 Global developmental delay)
Deciduous tooth retention 25% HP:0006335 (retained primary teeth — verify exact ID)
Joint hyperextensibility 15% HP:0001382 Joint hypermobility
Growth retardation 15% HP:0001510 Growth delay
Newborn rash 15% HP:0001066 (neonatal dermatologic finding — verify)
Pneumatocele 10% HP:0025134 Pneumatocele
Scoliosis 10% HP:0002650 Scoliosis

Important caveat on HPO IDs: Per this repository's ontology-term contract, I have not independently looked up each of these CURIEs in an HPO adapter this session — they are supplied from memory as candidates and must be verified (runoak lookup or cache/hp/terms.csv) before use in curation. Treat every ID above as a lead, not a checked binding.

Onset/severity/progression: Onset is generally in early childhood, paralleling classic Job syndrome, with atopic dermatitis as the earliest and most penetrant feature (100%). The review explicitly frames severity via the NIH HIES clinical scoring system: median score 28.5 in ZNF341-deficient patients vs. 64 in STAT3-deficient patients — a roughly two-fold lower composite severity score, supporting the "phenocopy but milder" characterization (PMC10620851, direct quote: "The clinical phenotype of patients with AR ZNF341 deficiency is essentially a phenocopy of AD STAT3 deficiency. However, it has milder consequences.").

Distinguishing features vs. AD-STAT3 HIES (important for differential/lump-split reasoning): - NK cell deficiency is a discriminating feature: low NK cells/frequency in 67% of ZNF341-deficient patients vs. only 8% of STAT3-deficient patients. - Vascular complications (aneurysms, tortuosity) are absent in the reported ZNF341 cohort ("none of the ZNF341-deficient patients were reported to have vascular complications") vs. 84% in STAT3-deficient patients — a notable negative finding, though it may partly reflect the smaller/younger cohort rather than a true mechanistic absence. - Higher IgG despite low memory B cells in ZNF341 deficiency, contrasting with STAT3 deficiency. - Two reported cases of tuberculosis, suggesting a possible (unconfirmed) increased mycobacterial susceptibility signal not typical of classic AD-HIES.

Quality of life: No disease-specific QoL instrument data (EQ-5D, SF-36, PROMIS) were located for ZNF341 deficiency specifically; this is a genuine literature gap, not an omission from this report.

4. Genetic/Molecular Information

Causal gene: ZNF341 (HGNC:15992; NCBI Gene 84905; OMIM *618269), chromosome 20q11.22, 15 exons, encoding a Cys2His2 zinc-finger transcription factor with 12 zinc fingers.

Reported pathogenic variants (from Béziat et al. 2023 review, aggregating the full published cohort of 20 patients / 10 kindreds):

Variant Patients Notes
p.Arg302* 13 (6 kindreds) Described as a "mutational hotspot"
p.Arg379* 3
p.Gln195* 1
p.Lys355Serfs*28 1 Frameshift
p.Tyr542* 1
p.Ser64* 1 (new case, P20)
c.1943+1G>A / p.Gly611Glyfs*15 1 (new case, P19) Essential splice-site variant

All reported variants are predicted loss-of-function (nonsense/frameshift/splice), consistent with the biallelic LOF mechanism described below. No missense pathogenic variants have been reported to date in the literature I could access.

Variant classification / population frequency: I did not obtain gnomAD-specific constraint metrics (pLI, LOEUF, allele frequency) for ZNF341 in this session — searches for these returned generic gnomAD documentation rather than the gene-specific page. This is a gap; consult gnomAD directly (gnomad.broadinstitute.org, search ZNF341) before curating population-frequency slots.

Functional consequence — mechanism (per Frey-Jakobs 2018 and Béziat 2018, and elaborated in the 2023 review): - ZNF341 binds a bipartite DNA motif: a ZNF-like site (GGAAC/GA/GGC) and an SP1-like site (GGGAGG), separated by 13–14 nucleotides, located near a STAT3-binding element (SBE) in the STAT3 promoter. - ChIP-seq identified 1,457 ZNF341 binding regions in primary T cells (and many more in transformed cell lines), indicating ZNF341 is a broader transcriptional regulator than a single-target activator of STAT3 alone. - Truncating mutations impair transcriptional activation of the STAT3 promoter, "partly due to nuclear translocation failure" of the truncated protein. - Functional impact category: loss of function (complete, biallelic) — this is a haploinsufficiency-like/dosage mechanism in the affected cell, not a dominant-negative mechanism (contrast with AD-STAT3 HIES, where dominant-negative interference is confirmed in ≥95% of ~150 tested alleles per the review).

Modifier genes: None specifically reported.

Epigenetic information: ZNF341 itself appears to be autoregulated — it contains six canonical ZNF341-binding sites within its own intron 1, and ZNF341-deficient cells show elevated ZNF341 mRNA, consistent with loss of negative autoregulation (PMC10620851). This is a curator-relevant mechanistic detail (a feedback loop on the causal gene itself, not classical DNA methylation/histone epigenetics — no methylation/ChIP-histone data specific to ZNF341-deficient patients were found).

Chromosomal abnormalities: None reported; this is a point-mutation/small-indel disease, not associated with large structural chromosomal rearrangements.

Additional targets beyond STAT3 (mechanistically relevant, from the 2023 review): - STAT1: two ZNF341-binding sites ~400 bp upstream of the STAT1 transcription start site; ZNF341-deficient cells show reduced STAT1, which may explain the (unconfirmed) tuberculosis susceptibility signal. - KAT6A: one of the strongest ChIP-seq binding sites is in the KAT6A promoter; KAT6A mutations cause Arboleda-Tham syndrome with neurodevelopmental overlap — the functional relationship to ZNF341 deficiency's own neurodevelopmental features (37% mental delay) is stated as unclear in the source and should not be overstated. - Candidate protein interactions (UBTF, PCM1, PAF1) via affinity purification-mass spectrometry — explicitly described as requiring further validation; do not treat as established.

5. Environmental Information

No primary causal environmental factor, lifestyle factor, or infectious trigger has been identified for ZNF341 deficiency itself (it is monogenic). The one environmental factor with documented mechanistic relevance is ionizing radiation exposure post-diagnosis, which interacts with an underlying DNA-repair defect (see §6/§11) to elevate malignancy risk — this is a disease-consequence/modifier relationship, not a disease-causal environmental exposure, and should be modeled as such if curated (e.g., as an environmental[] entry with environmental_effect: EXACERBATES targeting a DNA-damage/malignancy-risk pathophysiology node, not TRIGGERS the primary immunodeficiency).

No infectious agent causes ZNF341 deficiency; rather, the disease predisposes to infection by S. aureus (skin/soft tissue), Candida species (mucocutaneous), and, per two case reports, Mycobacterium tuberculosis — these are consequences of immunodeficiency, not etiological agents.

6. Mechanism / Pathophysiology

Causal chain (ordered, with inference flags)

  1. Biallelic loss-of-function variant in ZNF341 (nonsense/frameshift/splice; e.g., p.Arg302) → truncated or absent ZNF341 protein. (Demonstrated — genetic/functional studies in both founding papers.)*
  2. Truncated ZNF341 fails to translocate normally to the nucleus and/or fails to bind its bipartite DNA motif (ZNF-like + SP1-like sites) in target gene promoters, including the STAT3 promoter. (Demonstrated in vitro — reporter assays, EMSA/ChIP in Frey-Jakobs 2018 and Béziat 2018.)
  3. This reduces basal transcriptional activation of STAT3 — ZNF341-deficient cells show approximately 50% of normal basal STAT3 mRNA/protein across lymphocytes, monocytes, and fibroblasts. (Demonstrated — patient-cell data.)
  4. Critically, STAT3 "autoinduction" — the positive-feedback loop by which STAT3, once activated by IL-6/TCR costimulation via PKC-θ→NF-κB/AP-1 signaling, binds its own promoter (with ZNF341 support) to further upregulate its own expression — is abolished in ZNF341-deficient naive T cells (but preserved, i.e., not the defective step, in STAT3-deficient cells stimulated the same way). (Demonstrated — the review's key mechanistic distinction from AD-STAT3 disease: "STAT3 autoinduction was abolished in ZNF341-deficient naive T cells stimulated under these conditions, but not in STAT3-deficient naive T cells.")
  5. Combined reduced-basal-expression + abolished-autoinduction → insufficient STAT3 protein/phosphorylation available downstream of IL-6, IL-21, IL-23 and other STAT3-activating cytokine signals, particularly under the sustained/repeated stimulation needed for full lymphocyte differentiation programs. (Demonstrated at the cell-biology level; the review states this combination — not either defect alone — "is considered a more likely pathophysiological mechanism" than the basal reduction alone, since "ZNF341 deficiency had only a modest impact on downstream signaling" from the basal reduction by itself — i.e., the review argues the autoinduction defect is the more mechanistically important lesion, though this is the authors' interpretive judgment rather than a directly measured attribution.)
  6. Insufficient STAT3 activity impairs Th17 differentiation (STAT3 is required for RORγt induction downstream of IL-6/IL-23/IL-21) → low/absent Th17 cells (reported in 82% of patients) and a compensatory/relative Th2 skew. (Demonstrated — flow cytometry in patient cohorts.) → contributes to elevated IgE (85% of patients) via IL-4/IL-13-driven B-cell class switching, and to atopic dermatitis (100%) and susceptibility to Candida (Th17 is central to mucosal antifungal immunity) and S. aureus skin infection.
  7. Reduced STAT3 signaling also impairs B-cell class-switching/memory formation, producing low memory B cells (77%) — yet, distinctively, preserved/elevated plasma IgG (83% with IgG >16 g/L) is seen, an apparent dissociation the source literature does not fully mechanistically resolve (flagged as an open question rather than an established downstream step).
  8. STAT3 signaling deficiency in NK-cell lineage development or maintenance contributes to low NK cell counts/frequency (67%, vs. only 8% in AD-STAT3 disease) — the review notes this NK phenotype is disproportionately more common in ZNF341 deficiency than in STAT3 deficiency, implying either (a) a ZNF341-specific, STAT3-independent NK effect, or (b) a quantitative dose-effect difference; the primary literature does not settle which, so this branch point should be marked as mechanistically underdetermined.
  9. Separately/in parallel: ZNF341 also transactivates STAT1 (via promoter sites ~400 bp upstream of the STAT1 TSS); reduced STAT1 in deficient cells is a plausible (not proven) contributor to the reported tuberculosis susceptibility signal in two patients. (Inferred — the source explicitly frames this as suggestive, not established: "no clear pattern of viral susceptibility emerged.")
  10. Independently of the STAT3/STAT1 axis: ZNF341-deficient leukocytes show impaired post-irradiation DNA repair (elevated Comet-assay tail length/%DNA-in-tail/Olive tail moment that fail to normalize during the 2-hour recovery window, versus rapid normalization in healthy controls), an effect of similar magnitude to that seen in STAT3-LOF cells. (Demonstrated — PMC9307231, n=4 ZNF341-deficient patients, n=12 STAT3-LOF, n=14 controls.) → this DNA-repair defect is proposed (not proven) to contribute to the reported malignancy tendency in this population (see §11), including one ZNF341-deficient patient who developed a nasal neuroendocrine tumor and a secondary papillary thyroid cancer, and a separate reported case of dual malignancy following chemotherapy (Çekiç/Hartberger et al. 2020, PMID 31980991 — I was unable to retrieve full abstract text on the exact malignancy subtype beyond secondary search snippets referencing diffuse large B-cell lymphoma biology in the surrounding literature; this attribution needs primary-source verification before it is quoted as fact in a KB entry).

Branching/downstream summary

  • Th17 deficiency branch → mucocutaneous candidiasis, skin/soft-tissue S. aureus infection, recurrent sinopulmonary infection, bronchiectasis (35%), pneumatocele (10%).
  • Th2 skew / IgE branch → atopic dermatitis, elevated IgE, eosinophilia.
  • NK-cell branch → possible contribution to infection susceptibility (not fully characterized).
  • DNA-repair branch → malignancy predisposition, radiosensitivity (clinically actionable: minimize radiographic/radiotherapeutic exposure).
  • Connective tissue/skeletal branch (facial dysmorphia 53%, high palate 45%, joint hyperextensibility 15%, scoliosis 10%, retained primary teeth 25%) — mechanistically not explained by the STAT3/Th17 axis in the literature reviewed; these features are shared with AD-STAT3 HIES (where they are also incompletely mechanistically explained, historically attributed to broader STAT3 roles in connective tissue/bone remodeling), so should likely be modeled as a parallel/independent downstream branch of "STAT3 pathway insufficiency" rather than forced onto the immune causal chain.

Molecular pathway (KEGG/Reactome-style): JAK-STAT signaling pathway (STAT3 node), with ZNF341 acting as an upstream transcriptional gatekeeper rather than a canonical JAK-STAT pathway member — this is explicitly framed in the literature as "a previously unappreciated layer of transcriptional regulation controlling JAK-STAT signaling."

Suggested GO terms (unverified leads): GO:0007259 (JAK-STAT cascade — verify), GO:0045944 (positive regulation of transcription by RNA polymerase II), GO:0043433 (negative/positive regulation of DNA-binding transcription factor activity), GO:0030217 (T-helper 17 differentiation — verify exact ID), GO:0006974 (cellular response to DNA damage stimulus).

Suggested CL terms (unverified leads): CL:0000899 (Th17 cell), CL:0000623 (natural killer cell), CL:0000787 (memory B cell), CL:0000084 (T cell).

Suggested CHEBI/molecular entities: IL-6, IL-21, IL-23 (as cytokine drivers — CHEBI is not the right ontology for cytokines; these would be gene/protein descriptors, HGNC-bound, not CHEBI).

Multi-omics/single-cell/spatial data: No transcriptomic (GEO/ArrayExpress), proteomic, or single-cell atlas datasets specific to ZNF341-deficient patient material were located in this session. This is a genuine literature gap for a datasets: block — the mechanistic work to date is ChIP-seq (in cell lines/primary T cells for ZNF341 binding-site mapping) and flow cytometry, not bulk/single-cell RNA-seq of patient cells as far as I could determine.

7. Anatomical Structures Affected

Organ level (primary): - Skin (atopic dermatitis, abscesses) — primary and near-universal. - Respiratory tract (recurrent URI, pneumonia, bronchiectasis, pneumatocele). - Oral cavity/dentition (high palate, retained primary teeth). - Musculoskeletal system (scoliosis, joint hyperextensibility, facial dysmorphia). - Immune system broadly (thymus/lymphoid tissue — T-cell, B-cell, NK-cell compartments).

Secondary/complication-level: Thyroid (secondary papillary thyroid cancer in one reported case), nasal cavity (neuroendocrine tumor in the same case) — these are malignancy complications, not primary disease-organ involvement.

Body systems: Immune system (primary); integumentary; respiratory; skeletal/connective tissue; less consistently, endocrine (secondary, via reported malignancy only).

Tissue/cell level: Epithelial (skin, respiratory mucosa — site of infection); lymphoid (T cells — especially Th17 and Tfh subsets, memory CD4+/CD8+ T cells; B cells — memory B-cell compartment; NK cells; mucosal-associated invariant T cells; ILC1/ILC2 populations, per PMC10620851).

Suggested UBERON/CL terms (unverified leads): UBERON:0002097 (skin), UBERON:0001004 (respiratory system), UBERON:0002370 (thymus), CL:0000899 (Th17 cell), CL:0000623 (NK cell), CL:0000787 (memory B cell), CL:0000940 (mucosal invariant T cell).

Subcellular: Nucleus (site of ZNF341's transcriptional action; nuclear translocation failure of truncated protein is a described mechanism) — GO Cellular Component: GO:0005634 (nucleus).

Laterality: Not applicable/not reported as a distinguishing feature (skeletal features such as scoliosis are not described as lateralized in a disease-specific way).

8. Temporal Development

Onset: Childhood onset, with atopic dermatitis typically presenting earliest (consistent with the 100% frequency and the "newborn rash" feature reported in 15% of patients, suggesting a subset present in the neonatal period). This mirrors, but is generally reported as somewhat later/milder in onset timing than, classic AD-STAT3 HIES.

Progression: Chronic, with cumulative infectious and structural (bronchiectasis, pneumatocele) respiratory damage over time — consistent with other primary immunodeficiencies with recurrent sinopulmonary infection. The disease is lifelong (not self-limited); no spontaneous-remission pattern is reported.

Disease course pattern: Relapsing/recurrent infections superimposed on a chronic dermatologic/atopic baseline, rather than strictly progressive organ failure — though bronchiectasis, once established, is itself a progressive structural lesion.

Critical periods: Early childhood appears to be the critical window for both diagnosis (recurrent infection pattern becoming apparent) and for initiating interventions (e.g., antimicrobial prophylaxis, consideration of dupilumab for dermatitis) to limit cumulative organ damage — this is inferred from the general HIES management paradigm rather than ZNF341-deficiency-specific natural-history data, which does not yet exist at sufficient cohort size.

Disease stages: No formal staging system exists for ZNF341 deficiency specifically; the NIH HIES clinical scoring system (used for AD-STAT3 HIES) has been applied post hoc to grade ZNF341-deficient patients (median 28.5) for comparative severity purposes, not as a disease-specific staging tool.

9. Inheritance and Population

Epidemiology: Ultra-rare. Only 20 patients from 10 kindreds have been reported in the peer-reviewed literature as of the most recent comprehensive review (Béziat et al. 2023). No formal prevalence or incidence estimate (per 100,000) exists — this would fall in the Orphanet "not yet documented" prevalence class if curated, and should not be assigned a numeric rate_per_100000 without a source explicitly providing one (none was found).

Inheritance pattern: Autosomal recessive (biallelic — homozygous or compound heterozygous LOF variants required for disease).

Penetrance: Appears complete at the molecular/immunologic level (all reported biallelic LOF carriers are symptomatic), though clinical expressivity is variable — feature frequencies range from 100% (dermatitis) to 10% (pneumatocele, scoliosis), indicating substantial variable expressivity even among truly biallelic patients. No data on heterozygous carrier phenotype (asymptomatic carriers expected under standard AR inheritance, but not explicitly documented in a carrier-focused study).

Genetic anticipation: Not applicable/not reported — this is a nonsense/frameshift/splice-variant disease, not a repeat-expansion disorder.

Germline mosaicism: Not reported.

Founder effects: The p.Arg302 variant recurring across 6 independent kindreds (13/20 patients) is consistent with either a founder effect or a true mutational hotspot at a CpG-prone nonsense codon; the source literature does not distinguish between these*, and this distinction matters for population-genetics/counseling purposes — flag as unresolved rather than asserting "founder mutation."

Consanguinity: A major contributor to case ascertainment — reported kindreds are predominantly from populations/regions with high rates of consanguineous marriage (Moroccan, Afro-Caribbean, Iranian, Turkish, Lebanese, and Israeli Arab backgrounds).

Carrier frequency: Not established in any population database search performed in this session (gnomAD-specific allele-frequency data for ZNF341 was not successfully retrieved — see §4 gap).

Population demographics: Given the ascertainment pattern above, reported cases cluster in populations with elevated consanguinity rates, but this reflects ascertainment bias in a rare recessive condition, not necessarily true differential prevalence by ancestry — this distinction should be made explicit in any curated population field rather than asserting an "affected population."

Sex ratio: Not reported as skewed in any source reviewed (consistent with autosomal, non-sex-linked inheritance; no data located specifically quantifying M:F ratio across the 20 cases).

10. Diagnostics

Suggestive clinical picture: Childhood atopic dermatitis + recurrent bacterial/fungal infections + elevated IgE (>1000 IU/mL, 85% of patients) + eosinophilia (58%) — essentially the same initial clinical suspicion pattern as classic Job syndrome, refined by immunophenotyping.

Laboratory tests: - Serum total IgE (elevated in 85%) and IgG (elevated >16 g/L in 83% — notably higher than typical STAT3-deficient patients, a discriminating lab feature). - Eosinophil count (elevated in 58%). - Lymphocyte immunophenotyping: low/absent Th17 cells (82%), low memory B cells (77%), low NK cell frequency/count (67% — a key discriminator from AD-STAT3 disease, where this is seen in only 8%). - STAT3 phosphorylation assay (pSTAT3 by flow cytometry after IL-6/IL-21/IL-23 stimulation) — functionally demonstrates the reduced basal STAT3 and abolished autoinduction described in §6; this is the closest thing to a functional diagnostic assay reported in the primary literature, though it is a research-lab assay rather than a standardized clinical test.

Genetic testing: The definitive diagnostic step is sequencing of ZNF341 — either as part of a primary immunodeficiency/HIES-focused gene panel (alongside STAT3, IL6ST, DOCK8, PGM3, etc.), whole-exome sequencing, or single-gene Sanger sequencing/confirmation once biallelic candidate variants are found in a consanguineous family. Given the AR inheritance and consanguinity pattern, homozygosity mapping / autozygosity analysis was explicitly the ascertainment method in the founding papers (both were consanguineous-family linkage/exome studies).

Differential diagnosis: Primarily AD-STAT3 HIES (Job syndrome) — clinically near-identical but distinguished by: (1) inheritance pattern (AR family history/consanguinity vs. AD/de novo), (2) generally milder NIH HIES score, (3) more frequent NK-cell deficiency, (4) absence of reported vascular complications, (5) relatively preserved/elevated IgG despite low memory B cells. Also consider IL6ST (gp130) deficiency (another HIES phenocopy gene), DOCK8 deficiency (AR combined immunodeficiency with high IgE but distinct viral-susceptibility profile), and PGM3-CDG.

Screening: No specific newborn-screening or population carrier-screening program exists for ZNF341 given its rarity; not part of standard TREC/KREC-based SCID screening (this is not a T-cell-lymphopenic SCID phenotype).

Suggested NCIT/LOINC terms: general immunoglobulin quantification (IgE, IgG — LOINC codes exist generically, not disease-specific) and flow-cytometry lymphocyte subset panels; no ZNF341-specific commercial assay identified.

11. Outcome/Prognosis

Survival/mortality: No formal survival statistics (5-year, 10-year) exist for this ultra-rare condition; the literature is case-series-based, not registry/actuarial.

Morbidity: Chronic respiratory morbidity from recurrent infection (bronchiectasis in 35%, pneumatocele in 10%) is the principal long-term structural complication; chronic dermatitis is near-universal morbidity.

Malignancy risk — a specific, clinically important prognostic finding: - A documented case of dual malignancy in a ZNF341-deficient patient (Çekiç/Hartberger et al., J Clin Immunol 2020, PMID 31980991 — "Cancer Tendency in a Patient with ZNF341 Deficiency"). I was unable to fully verify the exact histologic malignancy type(s) from primary-source text in this session (access blocked); secondary sources associate the case discussion with tumorigenesis mechanisms in diffuse large B-cell lymphoma, but this specific attribution should be independently verified against the primary abstract/full text before being cited as fact in a KB entry — flagging this explicitly per the attribution standard (do not substitute a weaker adjacent citation). - A separate case within the 2022 radiosensitivity study cohort (PMC9307231) describes a ZNF341-deficient patient who developed a nasal neuroendocrine tumor and a secondary papillary thyroid cancer. - Mechanistic support: ZNF341-deficient leukocytes show impaired DNA repair after ionizing-radiation exposure (Comet-assay measures — tail length, %DNA in tail, Olive tail moment — remain elevated at 2 hours post-2Gy-irradiation rather than returning toward baseline as in healthy controls; effect sizes >1.30 across measures), of similar magnitude to STAT3-LOF patients (Alsina/Grimbacher-affiliated group, Clin Exp Immunol 2022, PMC9307231). - Clinical implication explicitly drawn by the source: clinicians should minimize ionizing-radiation exposure (diagnostic imaging, radiotherapy) in these patients where possible and maintain close malignancy surveillance.

Quality of life: No disease-specific instrument data located (see §3).

Prognostic factors: No formal prognostic-biomarker model exists; qualitatively, the NIH HIES severity score and specific complication burden (bronchiectasis, pneumatocele, malignancy history) are the closest available prognostic indicators, by extrapolation from the AD-STAT3 HIES literature rather than ZNF341-deficiency-specific validation.

12. Treatment

No disease-specific treatment guideline or FDA-approved therapy exists for ZNF341 deficiency. Management follows the general primary-immunodeficiency/HIES paradigm, with two published exceptions of ZNF341-deficiency-specific case reports of targeted biologic use:

Pharmacotherapy (general HIES management, inferred/extrapolated, not ZNF341-specific trial data): - Antimicrobial prophylaxis (anti-staphylococcal, antifungal) for recurrent infection — standard HIES practice; not explicitly detailed as ZNF341-specific in the sources reviewed. - Immunoglobulin replacement therapy (IVIG/SCIG) — referenced only implicitly via general HIES management context in the review; not explicitly documented as used/evaluated in the ZNF341 cohort specifically in the text I could access.

Targeted biologic therapy (ZNF341-specific case evidence): - Dupilumab (anti-IL-4Rα monoclonal antibody, blocking IL-4/IL-13 signaling): a patient with severe atopic dermatitis in the setting of ZNF341 deficiency showed "spectacular improvement of symptoms and biological parameters" (Lévy, Béziat, Barbieux et al., J Clin Immunol 2020 — "Efficacy of Dupilumab for Controlling Severe Atopic Dermatitis in a Patient with Hyper-IgE Syndrome"). Suggested NCIT term: dupilumab has an NCIT concept code (not independently verified in this session — look up via runoak before binding). - A more recent case series (Dick et al., Pediatric Dermatology 2025) reports dupilumab use in children with distinct genetic HIES types including a ZNF341 case, again for atopic dermatitis control and infection reduction — described in secondary search results as "the first to report... a child with AR-HIES... caused by a mutation in ZNF341 to be treated with dupilumab" (this framing should be checked against the primary text, since the 2020 Lévy case may predate it or involve an adult rather than child — potential inconsistency to resolve before citing).

Surgical/interventional: Not specifically documented (would follow standard management of bronchiectasis/abscess complications if they arise, per general practice, not ZNF341-specific literature).

Experimental/advanced therapeutics: No gene therapy, HSCT, or JAK-inhibitor use was documented in the ZNF341-deficiency literature located in this session. Given that this is a transcription-factor (not cytokine-receptor or kinase) defect acting upstream of JAK-STAT signaling via reduced STAT3 dosage/autoinduction rather than an activating/dominant-negative kinase-pathway lesion, the rationale for a JAK inhibitor is less direct than in some other STAT-pathway diseases (e.g., activated PI3K/STAT gain-of-function disorders) — no trial or case evidence either supports or refutes JAK-inhibitor use here; this is a genuine gap, not an oversight.

Radiation-exposure minimization: As above (§11), an explicit management recommendation from the DNA-repair/radiosensitivity study — this functions as a preventive/monitoring recommendation more than a "treatment."

13. Prevention

Primary prevention: Not applicable in the population-health sense (monogenic AR disease; no modifiable primary-prevention exposure identified). At the family level, genetic counseling for consanguineous couples/carrier parents in populations with known ZNF341 pathogenic alleles (and prenatal/preimplantation genetic testing where a familial variant is known) is the relevant "primary prevention" analog, by extrapolation from standard AR-disease counseling practice — not explicitly documented as implemented for ZNF341 deficiency specifically in the literature reviewed.

Secondary prevention: Early recognition of the clinical pattern (childhood dermatitis + recurrent infection + high IgE) prompting genetic testing, enabling earlier initiation of antimicrobial prophylaxis and directed therapy (e.g., dupilumab for dermatitis).

Tertiary prevention: Malignancy surveillance and minimization of ionizing radiation exposure given the documented DNA-repair defect — this is the most concrete, literature-supported tertiary-prevention recommendation specific to this disease.

Screening: No population or newborn screening program exists (see §10).

Prophylaxis: Standard antimicrobial (antibacterial/antifungal) prophylaxis by extrapolation from general HIES/PID management; not documented as a formally studied ZNF341-specific regimen.

14. Other Species / Natural Disease

No naturally occurring ZNF341-deficient disease in a non-human species was located in this session. No veterinary case reports, no OMIA (Online Mendelian Inheritance in Animals) entry, and no companion-animal or wildlife natural-disease reports surfaced in searches. This should be treated as an absence-of-evidence finding rather than a confirmed absence — I did not exhaustively query OMIA directly.

Orthologous gene: Znf341 exists in mouse (murine ortholog), referenced in passing in the mechanistic literature discussing the STAT3-promoter-binding assays, but I did not locate NCBI Gene ID data for the mouse ortholog or confirm cross-species conservation details in this session.

15. Model Organisms

No engineered animal model (knockout, knock-in, conditional, or humanized mouse) of ZNF341 deficiency was located in the literature searched in this session. Searches for a "Znf341 knockout mouse" returned only the human patient-based mechanistic papers, not a dedicated murine model study. This is a notable gap relative to many other monogenic PID genes and should be recorded as such (i.e., animal_models: may legitimately be left empty for this entry, with a note that a search was performed and returned no in vivo model, rather than fabricating one).

In vitro/cellular models used in the primary mechanistic literature (not "animal models" but relevant to a computational_models/experimental_models curation decision): - Patient-derived primary T cells, EBV-transformed B-cell lines, and monocytes/fibroblasts (Frey-Jakobs 2018, Béziat 2018) — used for STAT3 mRNA/protein quantification, pSTAT3 flow cytometry, and Th17/Tfh/NK/memory-B immunophenotyping. - Reporter-gene assays (luciferase, STAT3-promoter constructs) and EMSA/ChIP-seq in transfected/transformed cell lines — used to define the bipartite ZNF341 binding motif and map genome-wide binding sites (1,457 regions in primary T cells). - Peripheral blood leukocytes ex vivo, alkaline Comet assay — used in the 2022 radiosensitivity study (PMC9307231) to demonstrate impaired post-irradiation DNA repair; this is a functional ex vivo assay on patient material, not an animal or engineered cellular model, and should probably be captured as an Experiment/experimental_models entry with modeled_mechanisms targeting the DNA-repair/malignancy-risk pathophysiology node if this entry is curated into dismech, with fidelity: HIGH (it is direct patient-cell measurement) rather than treated as a model-organism proxy.

Summary Table of Key Primary Citations

Citation Role
Frey-Jakobs S et al., Sci Immunol 2018 (PMID 29907690) Co-founding discovery paper: "ZNF341 controls STAT3 expression and thereby immunocompetence"
Béziat V et al., Sci Immunol 2018 (PMID 29907691) Co-founding discovery paper: "A recessive form of hyper-IgE syndrome by disruption of ZNF341-dependent STAT3 transcription and activity"
Al-Herz W, Sci Immunol 2018 (PMID 29907692) Commentary: "Who regulates whom: ZNF341 is an additional player in the STAT3/TH17 song"
Béziat V et al., Curr Opin Immunol 2023 (PMID 37080116; PMC10620851) Comprehensive review + 2 new cases (total n=20); source of phenotype-frequency table and mechanistic synthesis above
Çekiç Ş / Hartberger J et al., J Clin Immunol 2020 (PMID 31980991) Case report: malignancy in a ZNF341-deficient patient — verify exact malignancy type from primary text before curating
(Alsina/Grimbacher group), Clin Exp Immunol 2022 (PMC9307231) Radiosensitivity/DNA-repair functional study, n=4 ZNF341-deficient patients
Lévy R, Béziat V, Barbieux C et al., J Clin Immunol 2020 Case report: dupilumab efficacy for atopic dermatitis in HIES (ZNF341 deficiency context)
Dick et al., Pediatric Dermatology 2025 Case series: dupilumab in children with genetically distinct HIES, including ZNF341

Explicit Gaps and Items Requiring Verification Before Curation

  1. gnomAD allele-frequency/constraint data for ZNF341 were not successfully retrieved — needed for any case_fractions/population-frequency work.
  2. Exact malignancy histology in the Çekiç/Hartberger 2020 case report was not confirmed from primary text (WebFetch was blocked by PubMed/cookie walls); do not cite a specific cancer subtype for that case without independent verification.
  3. MONDO:0032654 as supplied in the task header was not independently cross-checked against a MONDO browser in this session.
  4. All suggested HPO/GO/CL/UBERON CURIEs above are unverified leads, offered per the report template's request but explicitly not checked against an ontology adapter — per this repository's Ontology Term Contract, they must be looked up (not written from memory) before being bound in any KB entry.
  5. No animal model of ZNF341 deficiency was located — confirmed as a literature gap, not merely an unsearched area, though the search was not exhaustive of OMIA/IMPC databases directly.
  6. No formal prevalence/incidence estimate exists; only "20 patients reported" (a CASES_IN_LITERATURE measure_type, not a population rate) should be used if curating a Prevalence record.

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 7
Resolved 7
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 7
On topic 6
Off topic 0

All extracted references resolved successfully.