hyper-IgE syndrome

Summary

hyper-IgE syndrome (MONDO:0018037) is a disease (an umbrella term covering 14 Mondo subtypes) with 3 cohort genes and 5 clinical trials. Top therapeutic interventions include omalizumab and ranitidine.

At a glance

• Umbrella term: 14 Mondo subtypes
• Cohort genes: 3
• ClinVar variants: 5
• Clinical trials: 5

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hyper-IgE syndrome
Mondo ID	MONDO:0018037
OMIM	147060
Orphanet	331223
DOID	DOID:0080545
ICD-11	223461798
NCIT	C3144
UMLS	C3887645
MedGen	854488
GARD	0010956
Is cancer (heuristic)	no

Also known as: HIES · hyper-IgE recurrent infection syndrome · hyperimmunoglobulin E syndrome

Data availability: 5 ClinVar variants · 5 cell lines.

Disease family

An umbrella term covering 14 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › immune system disorder › inborn error of immunity › B cell deficiency › hyperimmunoglobulin syndrome › hyper-IgE syndrome

Related subtypes (1): hyper-IgM syndrome

Subtypes (14): hyper-IgE recurrent infection syndrome 1, autosomal dominant, combined immunodeficiency due to DOCK8 deficiency, Netherton syndrome, hyper-IgE recurrent infection syndrome 5, autosomal recessive, immunodeficiency 94 with autoinflammation and dysmorphic facies, hyper-IgE recurrent infection syndrome 3, autosomal recessive, hyper-IgE recurrent infection syndrome 4, autosomal recessive, hyper-IgE recurrent infection syndrome 4A, autosomal dominant, hyper-IgE syndrome 6, autosomal dominant, with recurrent infections, autosomal recessive combined immunodeficiency due to complete IL6ST deficiency, autosomal recessive combined immunodeficiency due to partial IL6ST deficiency, autosomal dominant combined immunodeficiency due to partial IL6ST deficiency, autosomal recessive combined immunodeficiency due to IL6R deficiency, autosomal dominant combined immunodeficiency due to ERBIN deficiency

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

5 retrieved; paginated sample, class counts are floors:

3 pathogenic, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
133321	NM_015599.3(PGM3):c.1504G>T (p.Asp502Tyr)	DOP1A	Pathogenic	no assertion criteria provided
133320	NM_015599.3(PGM3):c.248T>C (p.Leu83Ser)	PGM3	Pathogenic	no assertion criteria provided
156471	NM_015599.3(PGM3):c.1016AAG[1] (p.Glu340del)	PGM3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
18308	NM_139276.3(STAT3):c.1909G>A (p.Val637Met)	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

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 8 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

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
PGM3	Orphanet:443811	PGM3-CDG

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
STAT3	HGNC:11364	ENSG00000168610	P40763	Signal transducer and activator of transcription 3	clinvar
DOP1A	HGNC:21194	ENSG00000083097	Q5JWR5	Protein DOP1A	clinvar
PGM3	HGNC:8907	ENSG00000013375	O95394	Phosphoacetylglucosamine mutase	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.
DOP1A	Protein DOP1A	May be involved in protein traffic between late Golgi and early endosomes.
PGM3	Phosphoacetylglucosamine mutase	Catalyzes the conversion of GlcNAc-6-P into GlcNAc-1-P during the synthesis of uridine diphosphate/UDP-GlcNAc, a sugar nucleotide critical to multiple glycosylation pathways including protein N- and O-glycosylation.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.33

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
Enzyme (other)	1	4.0×	0.482
Transcription factor	1	2.8×	0.482
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
STAT3	Transcription factor	no		SH2, STAT, p53-like_TF_DNA-bd_sf
DOP1A	Other/Unknown	no		DOP1_N, DOP1, DOP1_C
PGM3	Enzyme (other)	yes	5.4.2.3	A-D-PHexomutase_C, A-D-PHexomutase_a/b/a-I, A-D-PHexomutase_a/b/a-I/II/III

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
lower lobe of lung	1
pericardium	1
type B pancreatic cell	1
calcaneal tendon	1
middle temporal gyrus	1
right hemisphere of cerebellum	1
body of pancreas	1
islet of Langerhans	1
pancreas	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
DOP1A	289	ubiquitous	marker	calcaneal tendon, middle temporal gyrus, right hemisphere of cerebellum
PGM3	270	ubiquitous	marker	body of pancreas, pancreas, islet of Langerhans

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
STAT3	10,108
PGM3	2,858
DOP1A	831

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
STAT3	P40763	6

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PGM3	O95394	95.54
DOP1A	Q5JWR5	67.63

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 81. Enrichment computed across 3 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Signalling to STAT3	1	1903.3×	0.009	STAT3
MET activates STAT3	1	1903.3×	0.009	STAT3
PTK6 Activates STAT3	1	1427.5×	0.009	STAT3
Signaling by PDGFR in disease	1	815.7×	0.009	STAT3
Synthesis of UDP-N-acetyl-glucosamine	1	713.8×	0.009	PGM3
Interleukin-6 family signaling	1	713.8×	0.009	STAT3
BH3-only proteins associate with and inactivate anti-apoptotic BCL-2 members	1	634.4×	0.009	STAT3
Interleukin-9 signaling	1	634.4×	0.009	STAT3
Interleukin-23 signaling	1	634.4×	0.009	STAT3
FGFR1 mutant receptor activation	1	571.0×	0.009	STAT3
Interleukin-21 signaling	1	571.0×	0.009	STAT3
Signaling by KIT in disease	1	571.0×	0.009	STAT3
Signaling by Leptin	1	519.1×	0.009	STAT3
Interleukin-27 signaling	1	519.1×	0.009	STAT3
STAT3 nuclear events downstream of ALK signaling	1	519.1×	0.009	STAT3
Interleukin-6 signaling	1	475.8×	0.009	STAT3
Interleukin-35 Signalling	1	475.8×	0.009	STAT3
POU5F1 (OCT4), SOX2, NANOG activate genes related to proliferation	1	439.2×	0.009	STAT3
Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants	1	439.2×	0.009	STAT3
Signaling by PDGFRA extracellular domain mutants	1	439.2×	0.009	STAT3
Interleukin-15 signaling	1	380.7×	0.010	STAT3
Signaling by cytosolic FGFR1 fusion mutants	1	317.2×	0.010	STAT3
Interleukin-2 family signaling	1	317.2×	0.010	STAT3
Signaling by ALK	1	285.5×	0.010	STAT3
Signaling by CSF3 (G-CSF)	1	285.5×	0.010	STAT3
Transcriptional regulation of pluripotent stem cells	1	271.9×	0.010	STAT3
Signaling by PTK6	1	271.9×	0.010	STAT3
Signaling by Non-Receptor Tyrosine Kinases	1	271.9×	0.010	STAT3
Interleukin-37 signaling	1	259.6×	0.010	STAT3
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	1	259.6×	0.010	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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
D-glucosamine metabolic process	1	5617.3×	0.008	PGM3
positive regulation of growth factor dependent skeletal muscle satellite cell proliferation	1	2808.7×	0.008	STAT3
eye photoreceptor cell differentiation	1	1404.3×	0.008	STAT3
negative regulation of hydrogen peroxide biosynthetic process	1	1404.3×	0.008	STAT3
negative regulation of primary miRNA processing	1	1404.3×	0.008	STAT3
interleukin-11-mediated signaling pathway	1	1123.5×	0.008	STAT3
T-helper 17 type immune response	1	1123.5×	0.008	STAT3
postsynapse to nucleus signaling pathway	1	1123.5×	0.008	STAT3
interleukin-23-mediated signaling pathway	1	936.2×	0.008	STAT3
regulation of cellular response to hypoxia	1	936.2×	0.008	STAT3
leptin-mediated signaling pathway	1	802.5×	0.008	STAT3
response to leptin	1	802.5×	0.008	STAT3
cellular response to interleukin-17	1	802.5×	0.008	STAT3
interleukin-2-mediated signaling pathway	1	702.2×	0.008	STAT3
interleukin-9-mediated signaling pathway	1	702.2×	0.008	STAT3
retinal rod cell differentiation	1	624.1×	0.008	STAT3
regulation of feeding behavior	1	624.1×	0.008	STAT3
interleukin-15-mediated signaling pathway	1	561.7×	0.008	STAT3
negative regulation of inflammatory response to wounding	1	561.7×	0.008	STAT3
UDP-N-acetylglucosamine biosynthetic process	1	510.7×	0.008	PGM3
cellular response to leptin stimulus	1	510.7×	0.008	STAT3
radial glial cell differentiation	1	510.7×	0.008	STAT3
growth hormone receptor signaling pathway via JAK-STAT	1	510.7×	0.008	STAT3
T-helper 17 cell lineage commitment	1	510.7×	0.008	STAT3
regulation of mitochondrial membrane permeability	1	468.1×	0.008	STAT3
interleukin-10-mediated signaling pathway	1	468.1×	0.008	STAT3
negative regulation of neuron migration	1	468.1×	0.008	STAT3
growth hormone receptor signaling pathway	1	401.2×	0.008	STAT3
positive regulation of extracellular matrix disassembly	1	401.2×	0.008	STAT3
positive regulation of ATP biosynthetic process	1	401.2×	0.008	STAT3

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 1 of 3 evidence-associated genes (33%) 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
DOP1A	0	0
PGM3	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): 1.

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

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PGM3	5.4.2.3	phosphoacetylglucosamine mutase

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: 3; 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	0
D	Druggable family + AlphaFold only, no drug	1	PGM3
E	Difficult family or no structure, no drug	1	DOP1A

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
DOP1A	0	—
PGM3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 5.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE1	2
PHASE2	1
PHASE1/PHASE2	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01852370	PHASE1/PHASE2	ENROLLING_BY_INVITATION	Sequential Cadaveric Lung and Bone Marrow Transplant for Immune Deficiency Diseases
NCT00527878	PHASE2	TERMINATED	Effect of Ranitidine on Hyper-IgE Recurrent Infection (Job’s) Syndrome
NCT07262983	PHASE1	RECRUITING	Evaluating the Safety and Tolerability of Baricitinib in Patients With Job Syndrome With Lupus-Like Disease and/or Atopic Dermatitis
NCT00260702	PHASE1	COMPLETED	Omalizumab to Treat Hyper-IgE (Job’s) Syndrome
NCT04897113	Not specified	UNKNOWN	Study of Efficacy and Safety of the Plasmapheresis Method With Albumin Compensation Compared With the Plasmapheresis Method Without Albumin Compensation for Aging Biomarkers Correction in Men and Women Aged 40 to 55 Years Old

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
OMALIZUMAB	4	1
RANITIDINE	4	1