Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency

Summary

Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency (MONDO:0013957) is a disease caused by IRF8 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: IRF8 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 408
• Phenotypes (HPO): 3

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		2	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

3 HPO clinical features (Orphanet curated; top 3 by frequency):

HPO ID	Term	Frequency
HP:0001945	Fever	Very frequent (80-99%)
HP:0002716	Lymphadenopathy	Very frequent (80-99%)
HP:0010978	Abnormality of immune system physiology	Very frequent (80-99%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency
Mondo ID	MONDO:0013957
OMIM	614893
Orphanet	319600
DOID	DOID:0111986
UMLS	C3808589
MedGen	814919
GARD	0017463
Is cancer (heuristic)	no

Also known as: autosomal dominant mendelian susceptibility to mycobacterial diseases due to a partial deficiency caused by mutation in IRF8 · IMD32A · immunodeficiency 32A · immunodeficiency type 32A · IRF8 autosomal dominant mendelian susceptibility to mycobacterial diseases due to a partial deficiency · Mendelian susceptibility to mycobacterial diseases due to partial interferon regulatory factor 8 deficiency · MSMD due to partial interferon regulatory factor 8 deficiency · MSMD due to partial IRF8 deficiency

Data availability: 408 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease susceptibility › inherited disease susceptibility › inherited susceptibility to mycobacterial diseases › Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency

Related subtypes (13): immunodeficiency 27A, Mendelian susceptibility to mycobacterial diseases due to complete IL12B deficiency, Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency, Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency, autosomal dominant mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR1 deficiency, Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency, autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency, autosomal recessive Mendelian susceptibility to mycobacterial diseases due to complete IFNgammaR2 deficiency, autosomal dominant mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR2 deficiency, X-linked Mendelian susceptibility to mycobacterial diseases, Mendelian susceptibility to mycobacterial diseases due to complete IFNgammaR1 deficiency, Mendelian susceptibility to mycobacterial diseases due to a complete deficiency, Mendelian susceptibility to mycobacterial diseases due to a partial 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

408 retrieved; paginated sample, class counts are floors:

202 uncertain significance, 180 likely benign, 14 benign, 7 conflicting classifications of pathogenicity, 3 benign/likely benign, 1 pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
4819872	NM_002163.4(IRF8):c.1134_1144del (p.Ala381fs)	IRF8	Pathogenic	criteria provided, single submitter
56843	NM_002163.4(IRF8):c.238A>G (p.Thr80Ala)	IRF8	Likely pathogenic	criteria provided, single submitter
2054511	NM_002163.4(IRF8):c.712G>A (p.Gly238Ser)	IRF8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2151249	NM_002163.4(IRF8):c.376A>G (p.Thr126Ala)	IRF8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
475393	NM_002163.4(IRF8):c.602C>T (p.Ala201Val)	IRF8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
493195	NM_002163.4(IRF8):c.982T>G (p.Phe328Val)	IRF8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
542145	NM_002163.4(IRF8):c.1030G>A (p.Gly344Ser)	IRF8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
583095	NM_002163.4(IRF8):c.1279dup (p.Ter427LeuextTer?)	IRF8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
757443	NM_002163.4(IRF8):c.988+10G>A	IRF8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2424361	NC_000016.9:g.(?85936622)(86602447_?)dup	FENDRR	Uncertain significance	criteria provided, single submitter
1001095	NM_002163.4(IRF8):c.1082G>A (p.Arg361His)	IRF8	Uncertain significance	criteria provided, single submitter
1001633	NM_002163.4(IRF8):c.25C>T (p.Arg9Trp)	IRF8	Uncertain significance	criteria provided, single submitter
1003148	NM_002163.4(IRF8):c.752G>A (p.Arg251His)	IRF8	Uncertain significance	criteria provided, single submitter
1017927	NM_002163.4(IRF8):c.174G>A (p.Lys58=)	IRF8	Uncertain significance	criteria provided, single submitter
1024273	NC_000016.9:g.(?85936602)(85955242_?)dup	IRF8	Uncertain significance	criteria provided, single submitter
1038373	NM_002163.4(IRF8):c.485G>C (p.Ser162Thr)	IRF8	Uncertain significance	criteria provided, single submitter
1039492	NM_002163.4(IRF8):c.174+4A>G	IRF8	Uncertain significance	criteria provided, single submitter
1041491	NM_002163.4(IRF8):c.1180_1190del (p.Pro394fs)	IRF8	Uncertain significance	criteria provided, single submitter
1041891	NM_002163.4(IRF8):c.58A>G (p.Ser20Gly)	IRF8	Uncertain significance	criteria provided, single submitter
1042665	NM_002163.4(IRF8):c.398T>C (p.Val133Ala)	IRF8	Uncertain significance	criteria provided, single submitter
1051056	NM_002163.4(IRF8):c.536C>T (p.Ala179Val)	IRF8	Uncertain significance	criteria provided, single submitter
1051092	NM_002163.4(IRF8):c.850C>T (p.Arg284Trp)	IRF8	Uncertain significance	criteria provided, single submitter
1053677	NM_002163.4(IRF8):c.1135G>C (p.Glu379Gln)	IRF8	Uncertain significance	criteria provided, single submitter
1055542	NM_002163.4(IRF8):c.1018C>T (p.Arg340Trp)	IRF8	Uncertain significance	criteria provided, single submitter
1057123	NM_002163.4(IRF8):c.218C>T (p.Ala73Val)	IRF8	Uncertain significance	criteria provided, single submitter
1061796	NM_002163.4(IRF8):c.68A>G (p.Tyr23Cys)	IRF8	Uncertain significance	criteria provided, single submitter
1062197	NM_002163.4(IRF8):c.556G>A (p.Val186Met)	IRF8	Uncertain significance	criteria provided, single submitter
1346177	NM_002163.4(IRF8):c.601+1G>A	IRF8	Uncertain significance	criteria provided, single submitter
1356570	NM_002163.4(IRF8):c.418C>T (p.Arg140Cys)	IRF8	Uncertain significance	criteria provided, single submitter
1365636	NM_002163.4(IRF8):c.388_389delinsAA (p.Val130Lys)	IRF8	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 1 · 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
IRF8	Strong	Autosomal dominant	Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
IRF8	Orphanet:319600	Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
IRF8	HGNC:5358	ENSG00000140968	Q02556	Interferon regulatory factor 8	gencc,clinvar
FENDRR	HGNC:43894	ENSG00000268388		FOXF1 adjacent non-coding developmental regulatory RNA	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
IRF8	Interferon regulatory factor 8	Transcription factor that specifically binds to the upstream regulatory region of type I interferon (IFN) and IFN-inducible MHC class I genes (the interferon consensus sequence (ICS)).

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
IRF8	Other/Unknown	no		Interferon_reg_fact_DNA-bd_dom, SMAD_FHA_dom_sf, SMAD-like_dom_sf
FENDRR	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
leukocyte	1
monocyte	1
mononuclear cell	1
lower esophagus muscularis layer	1
muscle layer of sigmoid colon	1
right lung	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
IRF8	265	broad	marker	monocyte, mononuclear cell, leukocyte
FENDRR	188	broad	marker	right lung, muscle layer of sigmoid colon, lower esophagus muscularis layer

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IRF8	3,554
FENDRR	0

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
IRF8	Q02556	75.54

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 2 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Interferon alpha/beta signaling	1	152.3×	0.014	IRF8
Interferon gamma signaling	1	125.5×	0.014	IRF8
Interferon Signaling	1	120.2×	0.014	IRF8
Cytokine Signaling in Immune system	1	40.8×	0.031	IRF8
Immune System	1	13.0×	0.077	IRF8

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
plasmacytoid dendritic cell differentiation	1	8426.0×	0.002	IRF8
follicular B cell differentiation	1	4213.0×	0.002	IRF8
germinal center B cell differentiation	1	1685.2×	0.003	IRF8
regulation of type I interferon production	1	1685.2×	0.003	IRF8
dendritic cell differentiation	1	1053.2×	0.004	IRF8
myeloid cell differentiation	1	648.1×	0.005	IRF8
defense response to protozoan	1	601.9×	0.005	IRF8
immune system process	1	391.9×	0.006	IRF8
positive regulation of interleukin-12 production	1	391.9×	0.006	IRF8
phagocytosis	1	240.7×	0.008	IRF8
positive regulation of type II interferon production	1	224.7×	0.008	IRF8
cellular response to type II interferon	1	208.1×	0.008	IRF8
autophagy	1	110.1×	0.013	IRF8
defense response to bacterium	1	108.0×	0.013	IRF8
cellular response to lipopolysaccharide	1	98.0×	0.014	IRF8
positive regulation of apoptotic process	1	56.7×	0.022	IRF8
immune response	1	47.1×	0.025	IRF8
negative regulation of transcription by RNA polymerase II	1	17.7×	0.063	IRF8
positive regulation of transcription by RNA polymerase II	1	14.9×	0.071	IRF8
regulation of transcription by RNA polymerase II	1	11.7×	0.086	IRF8

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 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
IRF8	0	0
FENDRR	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	2	IRF8, FENDRR

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)
IRF8	0	—
FENDRR	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.