hyper-IgE recurrent infection syndrome 3, autosomal recessive

Summary

hyper-IgE recurrent infection syndrome 3, autosomal recessive (MONDO:0032654) is a disease caused by ZNF341 (GenCC Definitive), with 4 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ZNF341 (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 184

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		61	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	hyper-IgE recurrent infection syndrome 3, autosomal recessive
Mondo ID	MONDO:0032654
OMIM	618282
Orphanet	641368
DOID	DOID:0080595
UMLS	C4748969
MedGen	1648483
GARD	0025713
Is cancer (heuristic)	no

Also known as: AR-HIES due to ZNF341 deficiency · Autosomal recessive HIES due to ZNF341 deficiency · autosomal recessive hyper-IgE syndrome due to ZNF341 deficiency · Autosomal recessive hyperimmunoglobulin E syndrome due to zinc finger protein 341 deficiency · HIES3

Data availability: 184 ClinVar variants · 3 GenCC gene-disease records.

Disease family

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 › hyper-IgE recurrent infection syndrome 3, autosomal recessive

Related subtypes (13): 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 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

184 retrieved; paginated sample, class counts are floors:

108 uncertain significance, 45 pathogenic, 16 likely pathogenic, 11 conflicting classifications of pathogenicity, 2 benign, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1070493	NC_000009.11:g.(?214977)(215049_?)del	DOCK8	Pathogenic	criteria provided, single submitter
1070494	NC_000009.11:g.(?214957)(286656_?)del	DOCK8	Pathogenic	criteria provided, single submitter
1072705	NC_000009.11:g.(?271607)(334404_?)del	DOCK8	Pathogenic	criteria provided, single submitter
1072707	NC_000009.11:g.(?271607)(370320_?)del	DOCK8	Pathogenic	criteria provided, single submitter
1072708	NC_000009.11:g.(?426865)(429874_?)del	DOCK8	Pathogenic	criteria provided, single submitter
1072709	NC_000009.11:g.(?289490)(399279_?)del	DOCK8	Pathogenic	criteria provided, single submitter
1072710	NC_000009.11:g.(?325651)(386446_?)del	DOCK8	Pathogenic	criteria provided, single submitter
1349421	NC_000009.11:g.(?271607)(289601_?)del	DOCK8	Pathogenic	criteria provided, single submitter
1454702	NC_000009.11:g.(?271607)(332498_?)del	DOCK8	Pathogenic	criteria provided, single submitter
1454704	NC_000009.11:g.(?325651)(332498_?)del	DOCK8	Pathogenic	criteria provided, single submitter
1456361	NC_000009.11:g.(?214977)(377231_?)del	DOCK8	Pathogenic	criteria provided, single submitter
1456362	NC_000009.11:g.(?214977)(399279_?)del	DOCK8	Pathogenic	criteria provided, single submitter
1457238	NC_000009.11:g.(?271607)(434995_?)del	DOCK8	Pathogenic	criteria provided, single submitter
1457993	NC_000009.11:g.(?271607)(382705_?)del	DOCK8	Pathogenic	criteria provided, single submitter
1460365	NC_000009.11:g.(?386311)(422155_?)del	DOCK8	Pathogenic	criteria provided, single submitter
1460425	NC_000009.11:g.(?271607)(328191_?)del	DOCK8	Pathogenic	criteria provided, single submitter
1460432	NC_000009.11:g.(?322388)(376266_?)del	DOCK8	Pathogenic	criteria provided, single submitter
2427690	NC_000009.11:g.(?334205)(334404_?)del	DOCK8	Pathogenic	criteria provided, single submitter
2427691	NC_000009.11:g.(?426865)(427001_?)del	DOCK8	Pathogenic	criteria provided, single submitter
2427692	NC_000009.11:g.(?214977)(368155_?)del	DOCK8	Pathogenic	criteria provided, single submitter
2427693	NC_000009.11:g.(?334205)(452137_?)del	DOCK8	Pathogenic	criteria provided, single submitter
2427694	NC_000009.11:g.(?367998)(464219_?)del	DOCK8	Pathogenic	criteria provided, single submitter
2427695	NC_000009.11:g.(?376190)(377231_?)del	DOCK8	Pathogenic	criteria provided, single submitter
2427696	NC_000009.11:g.(?216117)(399130_?)del	DOCK8	Pathogenic	criteria provided, single submitter
2427698	NC_000009.11:g.(?386311)(407089_?)del	DOCK8	Pathogenic	criteria provided, single submitter
2427700	NC_000009.11:g.(?390451)(422155_?)del	DOCK8	Pathogenic	criteria provided, single submitter
2427701	NC_000009.11:g.(?396765)(407089_?)del	DOCK8	Pathogenic	criteria provided, single submitter
2427702	NC_000009.11:g.(?399126)(422155_?)del	DOCK8	Pathogenic	criteria provided, single submitter
2427703	NC_000009.11:g.(?304561)(414971_?)del	DOCK8	Pathogenic	criteria provided, single submitter
2427705	NC_000009.11:g.(?311934)(317148_?)del	DOCK8	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 4 · 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
ZNF341	Definitive	Autosomal recessive	hyper-IgE recurrent infection syndrome 3, autosomal recessive	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ZNF341	Orphanet:641368	Autosomal recessive hyper-IgE syndrome due to ZNF341 deficiency
DOCK8	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
DOCK8	Orphanet:217390	Combined immunodeficiency due to DOCK8 deficiency
DMRT1	Orphanet:242	46,XY complete gonadal dysgenesis

Cohort genes → proteins

4 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ZNF341	HGNC:15992	ENSG00000131061	Q9BYN7	Zinc finger protein 341	gencc,clinvar
DOCK8	HGNC:19191	ENSG00000107099	Q8NF50	Dedicator of cytokinesis protein 8	clinvar
DMRT1	HGNC:2934	ENSG00000137090	Q9Y5R6	Doublesex- and mab-3-related transcription factor 1	clinvar
ZNF341-AS1	HGNC:50736	ENSG00000230753		ZNF341 antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ZNF341	Zinc finger protein 341	Transcriptional activator of STAT3 involved in the regulation of immune homeostasis.
DOCK8	Dedicator of cytokinesis protein 8	Guanine nucleotide exchange factor (GEF) which specifically activates small GTPase CDC42 by exchanging bound GDP for free GTP.
DMRT1	Doublesex- and mab-3-related transcription factor 1	Transcription factor that plays a key role in male sex determination and differentiation by controlling testis development and male germ cell proliferation.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 3 · Druggable fraction: 0.0

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
Transcription factor	1	2.1×	0.404
Other/Unknown	3	1.3×	0.404

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ZNF341	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf
DOCK8	Other/Unknown	no		ARM-type_fold, DOCK_C/D_N, DOCK
DMRT1	Other/Unknown	no		DM_DNA-bd, DMRT1-like, DMRT
ZNF341-AS1	Other/Unknown	no

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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
primordial germ cell in gonad	2
male germ line stem cell (sensu Vertebrata) in testis	2
lower esophagus mucosa	1
mucosa of transverse colon	1
bone marrow cell	1
leukocyte	1
monocyte	1
buccal mucosa cell	1
colonic epithelium	1
cortical plate	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ZNF341	171	ubiquitous	marker	primordial germ cell in gonad, mucosa of transverse colon, lower esophagus mucosa
DOCK8	236	ubiquitous	marker	bone marrow cell, leukocyte, monocyte
DMRT1	23	tissue_specific	marker	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, buccal mucosa cell
ZNF341-AS1	130		yes	male germ line stem cell (sensu Vertebrata) in testis, colonic epithelium, cortical plate

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DOCK8	2,036
DMRT1	1,513
ZNF341	751
ZNF341-AS1	0

Intra-cohort edges

A	B	Sources
DMRT1	DOCK8	string_interaction
DOCK8	ZNF341	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DMRT1	Q9Y5R6	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DOCK8	Q8NF50	75.17
ZNF341	Q9BYN7	57.11

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 4 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
Transcriptional regulation of testis differentiation	1	356.9×	0.014	DMRT1
RHOJ GTPase cycle	1	100.2×	0.025	DOCK8
CDC42 GTPase cycle	1	36.1×	0.032	DOCK8
Factors involved in megakaryocyte development and platelet production	1	33.2×	0.032	DOCK8
RAC1 GTPase cycle	1	30.5×	0.032	DOCK8

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
memory T cell proliferation	1	5617.3×	0.004	DOCK8
positive regulation of meiosis I	1	2808.7×	0.004	DMRT1
regulation of nodal signaling pathway	1	2808.7×	0.004	DMRT1
male germ cell proliferation	1	1872.4×	0.004	DMRT1
male sex differentiation	1	1404.3×	0.004	DMRT1
positive regulation of establishment of T cell polarity	1	1404.3×	0.004	DOCK8
meiosis I	1	802.5×	0.005	DMRT1
negative regulation of meiotic nuclear division	1	702.2×	0.005	DMRT1
primordial germ cell migration	1	624.1×	0.005	DMRT1
dendritic cell migration	1	624.1×	0.005	DOCK8
negative regulation of T cell apoptotic process	1	561.7×	0.005	DOCK8
positive regulation of male gonad development	1	561.7×	0.005	DMRT1
Sertoli cell differentiation	1	510.7×	0.005	DMRT1
male sex determination	1	468.1×	0.005	DMRT1
immunological synapse formation	1	432.1×	0.005	DOCK8
Sertoli cell development	1	374.5×	0.005	DMRT1
cellular response to chemokine	1	330.4×	0.006	DOCK8
oocyte development	1	312.1×	0.006	DMRT1
sex differentiation	1	280.9×	0.006	DMRT1
positive regulation of T cell migration	1	244.2×	0.007	DOCK8
positive regulation of mitotic nuclear division	1	181.2×	0.008	DMRT1
regulation of Rho protein signal transduction	1	170.2×	0.009	DOCK8
positive regulation of GTPase activity	1	92.1×	0.015	DOCK8
small GTPase-mediated signal transduction	1	61.1×	0.022	DOCK8
cell morphogenesis	1	52.5×	0.024	DMRT1
regulation of small GTPase mediated signal transduction	1	48.0×	0.025	DOCK8
intracellular signal transduction	1	12.7×	0.091	DMRT1
spermatogenesis	1	11.7×	0.095	DMRT1
regulation of DNA-templated transcription	1	10.5×	0.102	ZNF341
negative regulation of transcription by RNA polymerase II	1	5.9×	0.171	DMRT1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 4

Druggability breadth: 0 of 4 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ZNF341	0	0
DOCK8	0	0
DMRT1	0	0
ZNF341-AS1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	ZNF341, DOCK8, DMRT1, ZNF341-AS1

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	—
DOCK8	0	—
DMRT1	0	—
ZNF341-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.