hyper-IgE recurrent infection syndrome 1, autosomal dominant

Summary

hyper-IgE recurrent infection syndrome 1, autosomal dominant (MONDO:0007818) is a disease caused by STAT3 (GenCC Strong), with 5 cohort genes and 8 clinical trials. Top therapeutic interventions include omalizumab, posaconazole, and ranitidine.

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Causal gene: STAT3 (GenCC Strong)
• Cohort genes: 5
• ClinVar variants: 762
• Phenotypes (HPO): 49
• Clinical trials: 8

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	1-9 / 1 000 000	0.1	Europe	Validated
Point prevalence	1-9 / 100 000		Europe	Validated

Signs & symptoms

Clinical features (HPO)

49 HPO clinical features (Orphanet curated; top 49 by frequency):

HPO ID	Term	Frequency
HP:0000964	Eczematoid dermatitis	Very frequent (80-99%)
HP:0000988	Skin rash	Very frequent (80-99%)
HP:0000989	Pruritus	Very frequent (80-99%)
HP:0002205	Recurrent respiratory infections	Very frequent (80-99%)
HP:0002719	Recurrent infections	Very frequent (80-99%)
HP:0003212	Increased circulating IgE level	Very frequent (80-99%)
HP:0011354	Generalized abnormality of skin	Very frequent (80-99%)
HP:0100750	Atelectasis	Very frequent (80-99%)
HP:0200042	Skin ulcer	Very frequent (80-99%)
HP:0000164	Abnormality of the dentition	Frequent (30-79%)
HP:0000175	Cleft palate	Frequent (30-79%)
HP:0000230	Gingivitis	Frequent (30-79%)
HP:0000271	Abnormality of the face	Frequent (30-79%)
HP:0000303	Mandibular prognathia	Frequent (30-79%)
HP:0000324	Facial asymmetry	Frequent (30-79%)
HP:0000389	Chronic otitis media	Frequent (30-79%)
HP:0000431	Wide nasal bridge	Frequent (30-79%)
HP:0000490	Deeply set eye	Frequent (30-79%)
HP:0000684	Delayed eruption of teeth	Frequent (30-79%)
HP:0000703	Dentinogenesis imperfecta	Frequent (30-79%)
HP:0000938	Osteopenia	Frequent (30-79%)
HP:0000939	Osteoporosis	Frequent (30-79%)
HP:0001114	Xanthelasma	Frequent (30-79%)
HP:0001595	Abnormality of the hair	Frequent (30-79%)
HP:0001818	Paronychia	Frequent (30-79%)
HP:0001880	Eosinophilia	Frequent (30-79%)
HP:0002020	Gastroesophageal reflux	Frequent (30-79%)
HP:0002110	Bronchiectasis	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0002726	Recurrent Staphylococcus aureus infections	Frequent (30-79%)
HP:0002728	Chronic mucocutaneous candidiasis	Frequent (30-79%)
HP:0002757	Recurrent fractures	Frequent (30-79%)
HP:0006532	Recurrent pneumonia	Frequent (30-79%)
HP:0008391	Dystrophic fingernails	Frequent (30-79%)
HP:0011220	Prominent forehead	Frequent (30-79%)
HP:0012735	Cough	Frequent (30-79%)
HP:0025419	Pulmonary pneumatocele	Frequent (30-79%)
HP:0031292	Cutaneous abscess	Frequent (30-79%)
HP:0031690	Opportunistic infection	Frequent (30-79%)
HP:0200034	Papule	Frequent (30-79%)
HP:0001382	Joint hypermobility	Frequent (30-79%)
HP:0001363	Craniosynostosis	Occasional (5-29%)
HP:0001945	Fever	Occasional (5-29%)
HP:0002617	Dilatation	Occasional (5-29%)
HP:0002665	Lymphoma	Occasional (5-29%)
HP:0002754	Osteomyelitis	Occasional (5-29%)
HP:0007099	Chiari type I malformation	Occasional (5-29%)
HP:0100658	Cellulitis	Occasional (5-29%)
HP:0200037	Skin vesicle	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hyper-IgE recurrent infection syndrome 1, autosomal dominant
Mondo ID	MONDO:0007818
MeSH	C564135, C567925
OMIM	146840, 147060
Orphanet	2314
DOID	DOID:3261
NCIT	C126342
SNOMED CT	50926003
UMLS	C2936739
MedGen	445391
GARD	0006800
Is cancer (heuristic)	no

Also known as: AD hyperimmunoglobulin E syndrome · AD-HIES · autosomal dominant HIES · autosomal dominant hyper IgE syndrome · autosomal dominant hyper-IgE syndrome · autosomal dominant hyperimmunoglobulin E syndrome · Buckley syndrome · HIES autosomal dominant · HIES, autosomal dominant · hyper Ig E syndrome, autosomal dominant · hyper-IgE recurrent infection syndrome · hyper-IgE recurrent infection syndrome, autosomal dominant · hyper-IgE syndrome, autosomal dominant · hyperimmunoglobulin E recurrent infection syndrome, autosomal dominant · hyperimmunoglobulin E syndrome type 1 · hyperimmunoglobulin E-recurrent infection syndrome · immunodeficiency with defective leukocyte and lymphocyte function and with response to histamine-1 antagonist · JOB syndrome · Job syndrome autosomal dominant · Job’s syndrome (+1 more)

Data availability: 762 ClinVar variants · 4 GenCC gene-disease records · 5 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › hyper-IgE recurrent infection syndrome 1, autosomal dominant

Related subtypes (191): autosomal dominant polycystic liver disease, cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1, tuberous sclerosis, Treacher-Collins syndrome, hereditary breast ovarian cancer syndrome, autosomal dominant polycystic kidney disease, Lynch syndrome, branchio-oto-renal syndrome, autosomal dominant Aarskog syndrome, acroosteolysis dominant type, ADULT syndrome, autosomal dominant Alport syndrome, amelogenesis imperfecta type 1B, Townes-Brocks syndrome, nevoid basal cell carcinoma syndrome, blepharophimosis, ptosis, and epicanthus inversus syndrome, autosomal dominant brachyolmia, branchiooculofacial syndrome, pheochromocytoma/paraganglioma syndrome 4, cataract-aberrant oral frenula-growth delay syndrome, cherubism, autosomal dominant chondrodysplasia punctata, autosomal dominant popliteal pterygium syndrome, blepharocheilodontic syndrome, cochleosaccular degeneration-cataract syndrome, renal coloboma syndrome, Beare-Stevenson cutis gyrata syndrome, autosomal dominant vibratory urticaria, neurohypophyseal diabetes insipidus, autosomal dominant Kenny-Caffey syndrome, Rapp-Hodgkin syndrome, Ehlers-Danlos syndrome, classic type, autosomal dominant Ehlers-Danlos syndrome, vascular type, multiple endocrine neoplasia type 1, Coffin-Siris syndrome 1, isolated congenital adermatoglyphia, Flynn-Aird syndrome, Frasier syndrome, hand-foot-genital syndrome, Holt-Oram syndrome, hyperkeratosis-hyperpigmentation syndrome, autosomal dominant ichthyosis vulgaris, autosomal dominant keratitis, autosomal dominant keratitis-ichthyosis-hearing loss syndrome, LADD syndrome, trichorhinophalangeal syndrome type II, Noonan syndrome with multiple lentigines, microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability, Marfan syndrome, melanoma, cutaneous malignant, susceptibility to, 2, autosomal dominant primary microcephaly, autosomal dominant progressive external ophthalmoplegia, monilethrix, Muir-Torre syndrome, autosomal dominant myoglobinuria, autosomal dominant centronuclear myopathy, nail-patella syndrome, multiple endocrine neoplasia type 2B, autosomal dominant omodysplasia, pheochromocytoma/paraganglioma syndrome 1, Pelger-Huet anomaly, multiple endocrine neoplasia type 2A, piebaldism, autosomal dominant medullary cystic kidney disease with or without hyperuricemia, generalized juvenile polyposis/juvenile polyposis coli, juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, Peutz-Jeghers syndrome, contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A, autosomal dominant distal renal tubular acidosis, retinoschisis, autosomal dominant, autosomal dominant Robinow syndrome, scapuloperoneal spinal muscular atrophy, autosomal dominant, autosomal dominant sideroblastic anemia, spondyloepiphyseal dysplasia tarda, autosomal dominant, proximal symphalangism, calcaneonavicular coalition, thanatophoric dysplasia type 1, trichorhinophalangeal syndrome type I, Muckle-Wells syndrome, autosomal dominant hypophosphatemic rickets, von Hippel-Lindau disease, Denys-Drash syndrome, autosomal dominant severe congenital neutropenia, Costello syndrome, EEC syndrome, multiple cutaneous and mucosal venous malformations, diffuse nonepidermolytic palmoplantar keratoderma, Timothy syndrome, pheochromocytoma/paraganglioma syndrome 2, spondyloepimetaphyseal dysplasia with multiple dislocations, Brooke-Spiegler syndrome, macrocephaly-autism syndrome, pheochromocytoma/paraganglioma syndrome 3, Duane-radial ray syndrome, PCWH syndrome, heart-hand syndrome, Slovenian type, congenital stationary night blindness autosomal dominant 3, mandibulofacial dysostosis-microcephaly syndrome, multiple endocrine neoplasia type 4, juvenile cataract-microcornea-renal glucosuria syndrome, Crouzon syndrome-acanthosis nigricans syndrome, Birk-Barel syndrome, thrombophilia due to protein S deficiency, autosomal dominant, dyskeratosis congenita, autosomal dominant 2, dyskeratosis congenita, autosomal dominant 3, colorectal cancer, hereditary nonpolyposis, type 6, colorectal cancer, hereditary nonpolyposis, type 7, brain small vessel disease 2A, autosomal dominant, intellectual disability, autosomal dominant 14, intellectual disability, autosomal dominant 15, intellectual disability, autosomal dominant 16, hypopigmentation-punctate palmoplantar keratoderma syndrome, intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency, postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome, intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism, intellectual disability, autosomal dominant 29, intellectual disability, autosomal dominant 30, Houge-Janssens syndrome 2, severe achondroplasia-developmental delay-acanthosis nigricans syndrome, dyskeratosis congenita, autosomal dominant 6, epidermolysis bullosa simplex 6, generalized, with scarring and hair loss, autosomal dominant complex spastic paraplegia, early-onset autosomal dominant Alzheimer disease, muscular dystrophy, limb-girdle, autosomal dominant, Feingold syndrome, Carney complex, neuronopathy, distal hereditary motor, autosomal dominant, autosomal dominant coarctation of aorta, autosomal dominant spondylocostal dysostosis, autosomal dominant hypohidrotic ectodermal dysplasia, Cowden disease, autosomal dominant distal myopathy, autosomal dominant rhegmatogenous retinal detachment, palmoplantar keratoderma-spastic paralysis syndrome, Alagille syndrome due to a JAG1 point mutation, PTEN hamartoma tumor syndrome, gastric adenocarcinoma and proximal polyposis of the stomach, autosomal dominant proximal renal tubular acidosis, autosomal dominant spastic ataxia, Waardenburg syndrome, hereditary retinoblastoma, autosomal dominant hypocalcemia, Li-Fraumeni syndrome, Loeys-Dietz syndrome, hereditary hemorrhagic telangiectasia, hereditary inclusion body myopathy-joint contractures-ophthalmoplegia syndrome, microcephalic osteodysplastic dysplasia, Saul-Wilson type, autosomal dominant intermediate Charcot-Marie-Tooth disease, autosomal dominant cutis laxa, autosomal dominant nonsyndromic hearing loss, autosomal dominant optic atrophy, autosomal dominant Emery-Dreifuss muscular dystrophy, autosomal dominant cerebellar ataxia, autosomal dominant osteopetrosis, autosomal dominant epidermolytic ichthyosis, ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome, distal arthrogryposis type 2B1, neurofibromatosis, autosomal dominant cataract, arthrogryposis, distal, type 2B2, arthrogryposis, distal, type 2B3, Charcot-Marie-Tooth disease, demyelinating, type 1G, Delpire-McNeill syndrome, LAMA5-related multisystemic syndrome, autosomal dominant oculocutaneous albinism, Charcot-Marie-tooth disease, axonal, type 2DD, Pilarowski-Bjornsson syndrome, intellectual disability, autosomal dominant, fatty acyl-CoA reductase 1 upregulation, GUCY2D-related dominant retinopathy, RPE65-related dominant retinopathy, autosomal dominant titinopathy, NOG-related symphalangism spectrum disorder, ALPL-related autosomal dominant hypophosphatasia, MYH10-related neurodevelopmental disorder with congenital anomalies, spastic paraplegia 30A, autosomal dominant, TMEM127-related tumor predisposition, MAX-related tumor predisposition, BMPR1A-related juvenile polyposis syndrome, RP1-related dominant retinopathy, Birt-Hogg-Dube syndrome, inclusion body myopathy and brain white matter abnormalities, KINSSHIP syndrome, autosomal dominant nebulin-related myopathy, IMPG1-related dominant retinopathy, PROM1-related dominant retinopathy, PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome, ALG8-related autosomal dominant polycystic kidney and/or liver disease, NOTCH1-related AOS spectrum disorder, FLNB-associated autosomal dominant filamin related bone disorder, familial antiphospholipid syndrome

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

253 likely benign, 212 uncertain significance, 43 benign, 31 pathogenic, 21 likely pathogenic, 20 conflicting classifications of pathogenicity, 10 pathogenic/likely pathogenic, 9 benign/likely benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
13564	NM_000212.3(ITGB3):c.2248C>T (p.Arg750Ter)	EFCAB13-DT	Pathogenic	reviewed by expert panel
1005984	NM_139276.3(STAT3):c.2141C>T (p.Thr714Ile)	STAT3	Pathogenic	criteria provided, single submitter
1039785	NM_139276.3(STAT3):c.1228C>T (p.His410Tyr)	STAT3	Pathogenic	criteria provided, single submitter
1068485	NM_139276.3(STAT3):c.1859C>G (p.Thr620Ser)	STAT3	Pathogenic	criteria provided, single submitter
1398166	NM_139276.3(STAT3):c.1110-2A>G	STAT3	Pathogenic	criteria provided, single submitter
1429110	NM_139276.3(STAT3):c.2116C>A (p.Leu706Met)	STAT3	Pathogenic	criteria provided, single submitter
1429145	NM_139276.3(STAT3):c.1915C>G (p.Pro639Ala)	STAT3	Pathogenic	criteria provided, single submitter
1701323	NM_139276.3(STAT3):c.994C>T (p.His332Tyr)	STAT3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1705748	NM_139276.3(STAT3):c.1910T>C (p.Val637Ala)	STAT3	Pathogenic	no assertion criteria provided
1804642	NM_139276.3(STAT3):c.985A>G (p.Met329Val)	STAT3	Pathogenic	no assertion criteria provided
1804643	NM_139276.3(STAT3):c.1858A>G (p.Thr620Ala)	STAT3	Pathogenic	no assertion criteria provided
18303	NM_139276.3(STAT3):c.1384GTG[1] (p.Val463del)	STAT3	Pathogenic	criteria provided, multiple submitters, no conflicts
18304	NM_139276.3(STAT3):c.1144C>T (p.Arg382Trp)	STAT3	Pathogenic	criteria provided, multiple submitters, no conflicts
18305	NM_139276.3(STAT3):c.1145G>A (p.Arg382Gln)	STAT3	Pathogenic	criteria provided, multiple submitters, no conflicts
18306	NM_139276.3(STAT3):c.1268G>A (p.Arg423Gln)	STAT3	Pathogenic	criteria provided, multiple submitters, no conflicts
18307	NM_139276.3(STAT3):c.1145G>T (p.Arg382Leu)	STAT3	Pathogenic	no assertion criteria provided
18308	NM_139276.3(STAT3):c.1909G>A (p.Val637Met)	STAT3	Pathogenic	criteria provided, multiple submitters, no conflicts
2099076	NM_139276.3(STAT3):c.1145G>C (p.Arg382Pro)	STAT3	Pathogenic	criteria provided, single submitter
2138013	NM_139276.3(STAT3):c.1915C>A (p.Pro639Thr)	STAT3	Pathogenic	criteria provided, single submitter
2138015	NM_139276.3(STAT3):c.1907C>A (p.Ser636Tyr)	STAT3	Pathogenic	criteria provided, single submitter
2138016	NM_139276.3(STAT3):c.1865C>T (p.Thr622Ile)	STAT3	Pathogenic	criteria provided, single submitter
2169593	NM_139276.3(STAT3):c.1934T>A (p.Leu645Gln)	STAT3	Pathogenic	criteria provided, single submitter
224844	NM_139276.3(STAT3):c.1261G>A (p.Gly421Arg)	STAT3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
224846	NM_139276.3(STAT3):c.454C>T (p.Arg152Trp)	STAT3	Pathogenic	criteria provided, multiple submitters, no conflicts
224848	NM_139276.3(STAT3):c.2147C>T (p.Thr716Met)	STAT3	Pathogenic	criteria provided, multiple submitters, no conflicts
265261	NM_139276.3(STAT3):c.1979T>C (p.Met660Thr)	STAT3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2925614	NM_139276.3(STAT3):c.1907C>T (p.Ser636Phe)	STAT3	Pathogenic	criteria provided, single submitter
2925616	NM_139276.3(STAT3):c.1181T>C (p.Met394Thr)	STAT3	Pathogenic	criteria provided, single submitter
2940006	NM_139276.3(STAT3):c.2137G>T (p.Val713Leu)	STAT3	Pathogenic	criteria provided, single submitter
3391073	NM_139276.3(STAT3):c.1309C>T (p.His437Tyr)	STAT3	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 12 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
STAT3	Strong	Autosomal dominant	hyper-IgE recurrent infection syndrome 1, autosomal dominant	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
STAT3	Orphanet:2314	Autosomal dominant hyper-IgE syndrome due to STAT3 deficiency
STAT3	Orphanet:438159	STAT3-related early-onset multisystem autoimmune disease
STAT3	Orphanet:512017	Chronic lymphoproliferative disorder of natural killer cells
STAT3	Orphanet:520	Acute promyelocytic leukemia
STAT3	Orphanet:667662	Breast implant-associated anaplastic large cell lymphoma
STAT3	Orphanet:86872	T-cell large granular lymphocyte leukemia
STAT3	Orphanet:99885	Isolated permanent neonatal diabetes mellitus
ZNF341	Orphanet:641368	Autosomal recessive hyper-IgE syndrome due to ZNF341 deficiency
IL6ST	Orphanet:656283	Autosomal recessive combined immunodeficiency due to complete IL6ST deficiency
IL6ST	Orphanet:656300	Autosomal recessive combined immunodeficiency due to partial IL6ST deficiency
IL6ST	Orphanet:656313	Autosomal dominant combined immunodeficiency due to partial IL6ST deficiency
CAVIN1	Orphanet:228429	Congenital generalized lipodystrophy type 4

Cohort genes → proteins

5 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
STAT3	HGNC:11364	ENSG00000168610	P40763	Signal transducer and activator of transcription 3	gencc,clinvar
ZNF341	HGNC:15992	ENSG00000131061	Q9BYN7	Zinc finger protein 341	clinvar
EFCAB13-DT	HGNC:55338	ENSG00000263293		EFCAB13 divergent transcript	clinvar
IL6ST	HGNC:6021	ENSG00000134352	P40189	Interleukin-6 receptor subunit beta	clinvar
CAVIN1	HGNC:9688	ENSG00000177469	Q6NZI2	Caveolae-associated protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
STAT3	Signal transducer and activator of transcription 3	Signal transducer and transcription activator that mediates cellular responses to interleukins, KITLG/SCF, LEP and other growth factors.
ZNF341	Zinc finger protein 341	Transcriptional activator of STAT3 involved in the regulation of immune homeostasis.
IL6ST	Interleukin-6 receptor subunit beta	Signal-transducing molecule.
CAVIN1	Caveolae-associated protein 1	Plays an important role in caveolae formation and organization.

Protein-family classification

Druggable: 1 · Difficult: 2 · Unknown: 2 · Druggable fraction: 0.2

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Antibody/Immunoglobulin	1	5.8×	0.240
Transcription factor	2	3.3×	0.240
Other/Unknown	2	0.7×	0.877

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
STAT3	Transcription factor	no		SH2, STAT, p53-like_TF_DNA-bd_sf
ZNF341	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf
EFCAB13-DT	Other/Unknown	no
IL6ST	Antibody/Immunoglobulin	yes		Hematopoietin_rcpt_Gp130_CS, FN3_dom, IgC2-like_lig-bd
CAVIN1	Other/Unknown	no		Cavin_fam

Expression context

Cohort genes with no expression data: 0.

4 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
primordial germ cell in gonad	2
lower lobe of lung	1
pericardium	1
type B pancreatic cell	1
lower esophagus mucosa	1
mucosa of transverse colon	1
male germ line stem cell (sensu Vertebrata) in testis	1
right lobe of thyroid gland	1
germinal epithelium of ovary	1
parietal pleura	1
pleura	1
popliteal artery	1
right coronary artery	1
tendon of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
STAT3	301	ubiquitous	marker	type B pancreatic cell, pericardium, lower lobe of lung
ZNF341	171	ubiquitous	marker	primordial germ cell in gonad, mucosa of transverse colon, lower esophagus mucosa
EFCAB13-DT	155	tissue_specific	yes	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, right lobe of thyroid gland
IL6ST	295	ubiquitous	marker	parietal pleura, pleura, germinal epithelium of ovary
CAVIN1	281	ubiquitous	marker	right coronary artery, tendon of biceps brachii, popliteal artery

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
STAT3	10,108
CAVIN1	2,304
IL6ST	1,530
ZNF341	751
EFCAB13-DT	0

Intra-cohort edges

A	B	Sources
IL6ST	STAT3	string_interaction
IL6ST	ZNF341	string_interaction
STAT3	ZNF341	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
IL6ST	P40189	20
STAT3	P40763	6
CAVIN1	Q6NZI2	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ZNF341	Q9BYN7	57.11

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 88. Enrichment computed across 5 evidence-associated genes (3 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Interleukin-27 signaling	2	692.1×	9e-05	STAT3, IL6ST
Interleukin-6 signaling	2	634.4×	9e-05	STAT3, IL6ST
Interleukin-35 Signalling	2	634.4×	9e-05	STAT3, IL6ST
Activation of STAT3 by cadherin engagement	2	108.8×	0.002	STAT3, IL6ST
Signalling to STAT3	1	1268.9×	0.012	STAT3
MET activates STAT3	1	1268.9×	0.012	STAT3
PTK6 Activates STAT3	1	951.7×	0.013	STAT3
Signaling by PDGFR in disease	1	543.8×	0.013	STAT3
Interleukin-6 family signaling	1	475.8×	0.013	STAT3
BH3-only proteins associate with and inactivate anti-apoptotic BCL-2 members	1	423.0×	0.013	STAT3
Interleukin-9 signaling	1	423.0×	0.013	STAT3
Interleukin-23 signaling	1	423.0×	0.013	STAT3
MAPK1 (ERK2) activation	1	380.7×	0.013	IL6ST
FGFR1 mutant receptor activation	1	380.7×	0.013	STAT3
Interleukin-21 signaling	1	380.7×	0.013	STAT3
Signaling by KIT in disease	1	380.7×	0.013	STAT3
MAPK3 (ERK1) activation	1	346.1×	0.013	IL6ST
Signaling by Leptin	1	346.1×	0.013	STAT3
STAT3 nuclear events downstream of ALK signaling	1	346.1×	0.013	STAT3
POU5F1 (OCT4), SOX2, NANOG activate genes related to proliferation	1	292.8×	0.014	STAT3
Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants	1	292.8×	0.014	STAT3
Signaling by PDGFRA extracellular domain mutants	1	292.8×	0.014	STAT3
Interleukin-15 signaling	1	253.8×	0.015	STAT3
Signaling by cytosolic FGFR1 fusion mutants	1	211.5×	0.015	STAT3
Interleukin-2 family signaling	1	211.5×	0.015	STAT3
IL-6-type cytokine receptor ligand interactions	1	211.5×	0.015	IL6ST
Signaling by ALK	1	190.3×	0.015	STAT3
Signaling by CSF3 (G-CSF)	1	190.3×	0.015	STAT3
Transcriptional regulation of pluripotent stem cells	1	181.3×	0.015	STAT3
Signaling by PTK6	1	181.3×	0.015	STAT3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
interleukin-11-mediated signaling pathway	2	1685.2×	5e-05	STAT3, IL6ST
T-helper 17 cell lineage commitment	2	766.0×	1e-04	STAT3, IL6ST
interleukin-6-mediated signaling pathway	2	561.7×	2e-04	STAT3, IL6ST
cell surface receptor signaling pathway via STAT	2	280.9×	5e-04	STAT3, IL6ST
positive regulation of vascular endothelial growth factor production	2	247.8×	5e-04	STAT3, IL6ST
positive regulation of Notch signaling pathway	2	175.5×	9e-04	STAT3, IL6ST
cytokine-mediated signaling pathway	2	65.3×	0.006	STAT3, IL6ST
negative regulation of interleukin-6-mediated signaling pathway	1	2106.5×	0.006	IL6ST
positive regulation of growth factor dependent skeletal muscle satellite cell proliferation	1	2106.5×	0.006	STAT3
termination of RNA polymerase I transcription	1	1404.3×	0.007	CAVIN1
eye photoreceptor cell differentiation	1	1053.2×	0.007	STAT3
negative regulation of hydrogen peroxide biosynthetic process	1	1053.2×	0.007	STAT3
oncostatin-M-mediated signaling pathway	1	1053.2×	0.007	IL6ST
leukemia inhibitory factor signaling pathway	1	1053.2×	0.007	IL6ST
negative regulation of primary miRNA processing	1	1053.2×	0.007	STAT3
ciliary neurotrophic factor-mediated signaling pathway	1	842.6×	0.007	IL6ST
T-helper 17 type immune response	1	842.6×	0.007	STAT3
postsynapse to nucleus signaling pathway	1	842.6×	0.007	STAT3
interleukin-23-mediated signaling pathway	1	702.2×	0.008	STAT3
regulation of cellular response to hypoxia	1	702.2×	0.008	STAT3
leptin-mediated signaling pathway	1	601.9×	0.008	STAT3
response to leptin	1	601.9×	0.008	STAT3
interleukin-27-mediated signaling pathway	1	601.9×	0.008	IL6ST
cellular response to interleukin-17	1	601.9×	0.008	STAT3
positive regulation of adaptive immune response	1	526.6×	0.008	IL6ST
interleukin-2-mediated signaling pathway	1	526.6×	0.008	STAT3
interleukin-9-mediated signaling pathway	1	526.6×	0.008	STAT3
transcription initiation at RNA polymerase I promoter	1	468.1×	0.008	CAVIN1
retinal rod cell differentiation	1	468.1×	0.008	STAT3
regulation of feeding behavior	1	468.1×	0.008	STAT3

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 4

Druggability breadth: 2 of 5 evidence-associated genes (40%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
STAT3	MOMELOTINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
STAT3	18	4
ZNF341	0	0
EFCAB13-DT	0	0
IL6ST	0	0
CAVIN1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOMELOTINIB	4	STAT3
NITAZOXANIDE	4	STAT3
NICLOSAMIDE	4	STAT3
DIGOXIN	4	STAT3
BARICITINIB	4	STAT3
DIGITOXIN	4	STAT3
DEUCRAVACITINIB	4	STAT3
CURCUMIN	3	STAT3
BARDOXOLONE METHYL	3	STAT3
NIFUROXAZIDE	3	STAT3
DELGOCITINIB	3	STAT3
LESTAURTINIB	3	STAT3
NAPABUCASIN	3	STAT3
LEVOMENOL	2	STAT3
AZD-1480	2	STAT3
WP 1066	2	STAT3
C-188-9	2	STAT3
GENISTEIN	2	STAT3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
STAT3	1,319	Binding:1304, Functional:12, Unclassified:2, ADMET:1
IL6ST	21	Binding:21

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
STAT3	1,319

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

18 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
MOMELOTINIB	4	STAT3
NITAZOXANIDE	4	STAT3
NICLOSAMIDE	4	STAT3
DIGOXIN	4	STAT3
BARICITINIB	4	STAT3
DIGITOXIN	4	STAT3
DEUCRAVACITINIB	4	STAT3
CURCUMIN	3	STAT3
BARDOXOLONE METHYL	3	STAT3
NIFUROXAZIDE	3	STAT3
DELGOCITINIB	3	STAT3
LESTAURTINIB	3	STAT3
NAPABUCASIN	3	STAT3
LEVOMENOL	2	STAT3
AZD-1480	2	STAT3
WP 1066	2	STAT3
C-188-9	2	STAT3
GENISTEIN	2	STAT3

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	STAT3
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	IL6ST
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	ZNF341, EFCAB13-DT, CAVIN1

Undrugged target profiles

4 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
ZNF341	0	—
EFCAB13-DT	0	—
IL6ST	21	—
CAVIN1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 8.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3
PHASE2	2
PHASE1	2
PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00033982	PHASE3	COMPLETED	Posaconazole to Treat Invasive Fungal Infections
NCT00527878	PHASE2	TERMINATED	Effect of Ranitidine on Hyper-IgE Recurrent Infection (Job’s) Syndrome
NCT02996448	PHASE2	TERMINATED	Safety, Tolerability, and Immunogenicity of One Dose of NDV 3A Vaccine in People With STAT3-Mutated Hyper-IgE Syndrome
NCT00001515	PHASE1	COMPLETED	Diagnostic Effectiveness of Virtual Bronchoscopy
NCT00260702	PHASE1	COMPLETED	Omalizumab to Treat Hyper-IgE (Job’s) Syndrome
NCT00006150	Not specified	RECRUITING	Natural History, Management, and Genetics of the Hyperimmunoglobulin E Recurrent Infection Syndrome (HIES)
NCT00005933	Not specified	COMPLETED	Learning and Behavior Problems in Children With Chronic Granulomatous Disease and Related Disorders
NCT02228941	Not specified	UNKNOWN	NFIL3-induced Pathological Enhancement of IgE Class Switch Recombination in Hyper-IgE Syndrome

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
OMALIZUMAB	4	1
POSACONAZOLE	4	1
RANITIDINE	4	1