Monocytopenia with susceptibility to infections

Summary

Monocytopenia with susceptibility to infections (MONDO:0013607) is a disease caused by GATA2 (GenCC Definitive), with 5 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: GATA2 (GenCC Definitive)
• Cohort genes: 5
• ClinVar variants: 1,331
• Phenotypes (HPO): 28

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		22	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

28 HPO clinical features (Orphanet curated; top 28 by frequency):

HPO ID	Term	Frequency
HP:0000407	Sensorineural hearing impairment	Very frequent (80-99%)
HP:0001004	Lymphedema	Very frequent (80-99%)
HP:0001873	Thrombocytopenia	Very frequent (80-99%)
HP:0002167	Abnormality of speech or vocalization	Very frequent (80-99%)
HP:0002488	Acute leukemia	Very frequent (80-99%)
HP:0002878	Respiratory failure	Very frequent (80-99%)
HP:0003010	Prolonged bleeding time	Very frequent (80-99%)
HP:0005528	Bone marrow hypocellularity	Very frequent (80-99%)
HP:0011991	Abnormal neutrophil count	Very frequent (80-99%)
HP:0012378	Fatigue	Very frequent (80-99%)
HP:0000389	Chronic otitis media	Frequent (30-79%)
HP:0000572	Visual loss	Frequent (30-79%)
HP:0000587	Abnormal optic nerve morphology	Frequent (30-79%)
HP:0000978	Bruising susceptibility	Frequent (30-79%)
HP:0000980	Pallor	Frequent (30-79%)
HP:0001744	Splenomegaly	Frequent (30-79%)
HP:0001824	Weight loss	Frequent (30-79%)
HP:0001945	Fever	Frequent (30-79%)
HP:0002017	Nausea and vomiting	Frequent (30-79%)
HP:0002076	Migraine	Frequent (30-79%)
HP:0002170	Intracranial hemorrhage	Frequent (30-79%)
HP:0002205	Recurrent respiratory infections	Frequent (30-79%)
HP:0002240	Hepatomegaly	Frequent (30-79%)
HP:0002321	Vertigo	Frequent (30-79%)
HP:0100724	Hypercoagulability	Frequent (30-79%)
HP:0001974	Leukocytosis	Occasional (5-29%)
HP:0002716	Lymphadenopathy	Occasional (5-29%)
HP:0005547	Myeloproliferative disorder	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	monocytopenia with susceptibility to infections
Mondo ID	MONDO:0013607
OMIM	614172
Orphanet	228423
DOID	DOID:0111947
ICD-11	1077753382
UMLS	C3280030
MedGen	481660
GARD	0010934
Is cancer (heuristic)	no

Also known as: DCML · IMD21 · immunodeficiency 21 · immunodeficiency type 21 · monocyte - B - natural killer - dendritic cell deficiency · monocytopenia and mycobacterial infection syndrome · MonoMAC

Data availability: 1,331 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › immunodeficiency disease › GATA2 deficiency with susceptibility to MDS/AML › monocytopenia with susceptibility to infections

Related subtypes (1): deafness-lymphedema-leukemia 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:

279 uncertain significance, 262 likely benign, 30 conflicting classifications of pathogenicity, 19 pathogenic, 6 benign, 2 pathogenic/likely pathogenic, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1375570	NC_000003.11:g.(?127771396)(128205874_?)del	DNAJB8	Pathogenic	criteria provided, single submitter
1069970	NM_032638.5(GATA2):c.437dup (p.Gly147fs)	GATA2	Pathogenic	criteria provided, single submitter
1075473	NM_032638.5(GATA2):c.839dup (p.Pro280_Lys281insTer)	GATA2	Pathogenic	criteria provided, single submitter
1075475	NM_032638.5(GATA2):c.476_479dup (p.Pro161fs)	GATA2	Pathogenic	criteria provided, single submitter
1184162	NM_032638.5(GATA2):c.1113C>G (p.Asn371Lys)	GATA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1184166	NM_032638.5(GATA2):c.130G>T (p.Glu44Ter)	GATA2	Pathogenic	criteria provided, multiple submitters, no conflicts
1184167	NM_032638.5(GATA2):c.161C>A (p.Ser54Ter)	GATA2	Pathogenic	criteria provided, multiple submitters, no conflicts
1184181	NM_032638.5(GATA2):c.1018-2A>G	GATA2	Pathogenic	criteria provided, multiple submitters, no conflicts
1184182	NM_032638.5(GATA2):c.1018-2A>T	GATA2	Pathogenic	criteria provided, multiple submitters, no conflicts
1376901	NM_032638.5(GATA2):c.1019C>A (p.Ser340Ter)	GATA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1454317	NM_032638.5(GATA2):c.751_752dup (p.Tyr252fs)	GATA2	Pathogenic	criteria provided, single submitter
1454555	NM_032638.5(GATA2):c.812dup (p.Pro274fs)	GATA2	Pathogenic	criteria provided, single submitter
2004099	NM_032638.5(GATA2):c.1148dup (p.Asn383fs)	GATA2	Pathogenic	criteria provided, single submitter
2011606	NM_032638.5(GATA2):c.202del (p.Ala68fs)	GATA2	Pathogenic	criteria provided, single submitter
2013207	NM_032638.5(GATA2):c.99C>A (p.Tyr33Ter)	GATA2	Pathogenic	criteria provided, multiple submitters, no conflicts
2017202	NM_032638.5(GATA2):c.1180C>T (p.Gln394Ter)	GATA2	Pathogenic	criteria provided, single submitter
2019898	NM_032638.5(GATA2):c.1217del (p.Lys406fs)	GATA2	Pathogenic	criteria provided, single submitter
2020366	NM_032638.5(GATA2):c.423C>G (p.Tyr141Ter)	GATA2	Pathogenic	criteria provided, single submitter
2027087	NM_032638.5(GATA2):c.288_289del (p.Trp97fs)	GATA2	Pathogenic	criteria provided, single submitter
2090522	NM_032638.5(GATA2):c.384dup (p.Ser129fs)	GATA2	Pathogenic	criteria provided, single submitter
2121725	NM_032638.5(GATA2):c.1126_1143+54del	GATA2	Pathogenic	criteria provided, single submitter
1184190	NM_032638.5(GATA2):c.1123C>T (p.Leu375Phe)	GATA2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2121724	NM_032638.5(GATA2):c.1192C>G (p.Arg398Gly)	GATA2	Likely pathogenic	criteria provided, single submitter
1003340	NM_032638.5(GATA2):c.298G>C (p.Gly100Arg)	GATA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1005061	NM_032638.5(GATA2):c.937C>T (p.His313Tyr)	GATA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1055835	NM_032638.5(GATA2):c.1069A>G (p.Thr357Ala)	GATA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1058413	NM_032638.5(GATA2):c.67G>A (p.Asp23Asn)	GATA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1077570	NM_032638.5(GATA2):c.1032A>G (p.Arg344=)	GATA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1079248	NM_032638.5(GATA2):c.981G>A (p.Gly327=)	GATA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1085758	NM_032638.5(GATA2):c.1170G>A (p.Lys390=)	GATA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 2 · 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
GATA2	Definitive	Autosomal dominant	monocytopenia with susceptibility to infections	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GATA2	Orphanet:228423	GATA2 deficiency spectrum
RPN1	Orphanet:402020	Acute myeloid leukemia with inv(3)(q21q26.2) or t(3;3)(q21;q26.2)

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GATA2	HGNC:4171	ENSG00000179348	P23769	Endothelial transcription factor GATA-2	gencc,clinvar
RPN1	HGNC:10381	ENSG00000163902	P04843	Dolichyl-diphosphooligosaccharide–protein glycosyltransferase subunit 1	clinvar
ABTB1	HGNC:18275	ENSG00000114626	Q969K4	Ankyrin repeat and BTB/POZ domain-containing protein 1	clinvar
DNAJB8	HGNC:23699	ENSG00000179407	Q8NHS0	DnaJ homolog subfamily B member 8	clinvar
PSMD2	HGNC:9559	ENSG00000175166	Q13200	26S proteasome non-ATPase regulatory subunit 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GATA2	Endothelial transcription factor GATA-2	Transcriptional activator which regulates endothelin-1 gene expression in endothelial cells.
RPN1	Dolichyl-diphosphooligosaccharide–protein glycosyltransferase subunit 1	Subunit of the oligosaccharyl transferase (OST) complex that catalyzes the initial transfer of a defined glycan (Glc(3)Man(9)GlcNAc(2) in eukaryotes) from the lipid carrier dolichol-pyrophosphate to an asparagine residue within an Asn-X-Se…
ABTB1	Ankyrin repeat and BTB/POZ domain-containing protein 1	May act as a mediator of the PTEN growth-suppressive signaling pathway.
DNAJB8	DnaJ homolog subfamily B member 8	Efficient suppressor of aggregation and toxicity of disease-associated polyglutamine proteins.
PSMD2	26S proteasome non-ATPase regulatory subunit 2	Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins.

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
Scaffold/PPI	1	3.5×	0.634
Enzyme (other)	1	2.4×	0.634
Transcription factor	1	1.6×	0.634
Other/Unknown	2	0.7×	0.877

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GATA2	Transcription factor	no		Znf_GATA, Znf_NHR/GATA, TF_GATA-2/3
RPN1	Enzyme (other)	yes	2.4.99.18	Ribophorin_I
ABTB1	Scaffold/PPI	no		BTB/POZ_dom, Ankyrin_rpt, SKP1/BTB/POZ_sf
DNAJB8	Other/Unknown	no		DnaJ_domain, DnaJ_domain_CS, J_dom_sf
PSMD2	Other/Unknown	no		Proteasome/cyclosome_rpt, ARM-like, ARM-type_fold

Expression context

Cohort genes with no expression data: 0.

5 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)	1
broad (>20)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left uterine tube	1
right lung	1
seminal vesicle	1
corpus epididymis	1
rectum	1
stromal cell of endometrium	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
left testis	1
right testis	1
sperm	1
endothelial cell	1
oocyte	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GATA2	273	ubiquitous	marker	seminal vesicle, right lung, left uterine tube
RPN1	294	ubiquitous	marker	stromal cell of endometrium, corpus epididymis, rectum
ABTB1	240	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
DNAJB8	19	tissue_specific	marker	sperm, left testis, right testis
PSMD2	304	ubiquitous	marker	secondary oocyte, oocyte, endothelial cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GATA2	4,979
PSMD2	4,293
RPN1	3,827
DNAJB8	2,176
ABTB1	1,621

Structural data

PDB: 4 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PSMD2	Q13200	123
RPN1	P04843	6
GATA2	P23769	2
DNAJB8	Q8NHS0	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ABTB1	Q969K4	86.59

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 86. 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
RUNX1 regulates transcription of genes involved in differentiation of HSCs	2	63.4×	0.028	GATA2, PSMD2
PD-L1(CD274) glycosylation and translocation to plasma membrane	1	173.0×	0.028	RPN1
Translation of Structural Proteins	1	135.9×	0.028	RPN1
Regulation of CDH1 posttranslational processing and trafficking to plasma membrane	1	112.0×	0.028	RPN1
Late SARS-CoV-2 Infection Events	1	97.6×	0.028	RPN1
Regulation of activated PAK-2p34 by proteasome mediated degradation	1	92.8×	0.028	PSMD2
Regulation of ornithine decarboxylase (ODC)	1	90.6×	0.028	PSMD2
Vpu mediated degradation of CD4	1	88.5×	0.028	PSMD2
Autodegradation of the E3 ubiquitin ligase COP1	1	88.5×	0.028	PSMD2
Ubiquitin-dependent degradation of Cyclin D	1	88.5×	0.028	PSMD2
Maturation of spike protein	1	88.5×	0.028	RPN1
Cross-presentation of soluble exogenous antigens (endosomes)	1	84.6×	0.028	PSMD2
Vif-mediated degradation of APOBEC3G	1	84.6×	0.028	PSMD2
AUF1 (hnRNP D0) binds and destabilizes mRNA	1	82.8×	0.028	PSMD2
Degradation of AXIN	1	82.8×	0.028	PSMD2
FBXL7 down-regulates AURKA during mitotic entry and in early mitosis	1	82.8×	0.028	PSMD2
GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2	1	82.8×	0.028	PSMD2
Hh mutants are degraded by ERAD	1	81.0×	0.028	PSMD2
SCF-beta-TrCP mediated degradation of Emi1	1	79.3×	0.028	PSMD2
Degradation of DVL	1	79.3×	0.028	PSMD2
Negative regulation of NOTCH4 signaling	1	79.3×	0.028	PSMD2
GSK3B-mediated proteasomal degradation of PD-L1(CD274)	1	79.3×	0.028	PSMD2
Regulation of RUNX3 expression and activity	1	77.7×	0.028	PSMD2
Somitogenesis	1	77.7×	0.028	PSMD2
NIK–>noncanonical NF-kB signaling	1	76.1×	0.028	PSMD2
SPOP-mediated proteasomal degradation of PD-L1(CD274)	1	76.1×	0.028	PSMD2
Degradation of GLI1 by the proteasome	1	74.6×	0.028	PSMD2
Degradation of GLI2 by the proteasome	1	74.6×	0.028	PSMD2
GLI3 is processed to GLI3R by the proteasome	1	74.6×	0.028	PSMD2
Defective CFTR causes cystic fibrosis	1	73.2×	0.028	PSMD2

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
semicircular canal development	1	4213.0×	0.007	GATA2
regulation of forebrain neuron differentiation	1	4213.0×	0.007	GATA2
regulation of primitive erythrocyte differentiation	1	2106.5×	0.007	GATA2
eosinophil fate commitment	1	2106.5×	0.007	GATA2
ventral spinal cord interneuron differentiation	1	1404.3×	0.007	GATA2
cell differentiation in hindbrain	1	1404.3×	0.007	GATA2
negative regulation of hematopoietic progenitor cell differentiation	1	1053.2×	0.008	GATA2
GABAergic neuron differentiation	1	842.6×	0.008	GATA2
commitment of neuronal cell to specific neuron type in forebrain	1	702.2×	0.008	GATA2
thyroid-stimulating hormone-secreting cell differentiation	1	702.2×	0.008	GATA2
negative regulation of brown fat cell differentiation	1	702.2×	0.008	GATA2
glandular epithelial cell maturation	1	601.9×	0.008	GATA2
response to lipid	1	601.9×	0.008	GATA2
negative regulation of macrophage differentiation	1	526.6×	0.008	GATA2
vascular wound healing	1	468.1×	0.008	GATA2
negative regulation of inclusion body assembly	1	421.3×	0.008	DNAJB8
positive regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis	1	421.3×	0.008	GATA2
positive regulation of mast cell degranulation	1	383.0×	0.008	GATA2
negative regulation of neural precursor cell proliferation	1	383.0×	0.008	GATA2
positive regulation of megakaryocyte differentiation	1	351.1×	0.009	GATA2
positive regulation of phagocytosis, engulfment	1	324.1×	0.009	GATA2
negative regulation of neuroblast proliferation	1	300.9×	0.009	GATA2
urogenital system development	1	247.8×	0.010	GATA2
cell fate determination	1	234.1×	0.010	GATA2
definitive hemopoiesis	1	234.1×	0.010	GATA2
regulation of protein catabolic process	1	210.7×	0.011	PSMD2
central nervous system neuron development	1	200.6×	0.011	GATA2
neuron maturation	1	200.6×	0.011	GATA2
embryonic placenta development	1	191.5×	0.011	GATA2
positive regulation of cell migration involved in sprouting angiogenesis	1	183.2×	0.011	GATA2

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 5 evidence-associated genes (60%) 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
PSMD2	BORTEZOMIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PSMD2	2	4
GATA2	0	0
RPN1	0	0
ABTB1	0	0
DNAJB8	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BORTEZOMIB	4	PSMD2
CARFILZOMIB	4	PSMD2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PSMD2	27	Binding:27
RPN1	8	Binding:8
GATA2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RPN1	2.4.99.18	dolichyl-diphosphooligosaccharide-protein glycotransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

2 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)
BORTEZOMIB	4	PSMD2
CARFILZOMIB	4	PSMD2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PSMD2
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	RPN1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	GATA2, ABTB1, DNAJB8

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)
GATA2	1	—
RPN1	8	—
ABTB1	0	—
DNAJB8	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.