Mendelian Susceptibility To Mycobacterial Diseases Due To Partial IRF8 Deficiency

Mendelian MONDO:0013957 Pathograph 16 Show in embeddings browser Primary immunodeficiency Mendelian susceptibility to mycobacterial disease

Mendelian susceptibility to mycobacterial disease (MSMD) due to partial IRF8 deficiency is an autosomal dominant inborn error of immunity caused by a heterozygous variant in IRF8, the transcription factor that specifies the mononuclear phagocyte lineage. It presents as MSMD: disease caused by weakly virulent mycobacteria, in particular the Bacille Calmette-Guerin (BCG) vaccine strain, in an individual whose routine immunological testing is otherwise unremarkable. The distinguishing feature of this etiology is where in the IL-12/IFN-gamma circuit the lesion sits. Most MSMD genes encode the cytokines of that circuit or their receptors. IRF8 instead encodes the transcription factor that builds the cells which produce IL-12 in the first place, so the deficiency is cellular rather than humoral: the T80A substitution impairs IRF8 binding to DNA and selectively depletes one dendritic-cell compartment, the CD11c+CD1c+ conventional DCs, while leaving monocytes intact. Fewer IL-12-competent antigen-presenting cells means less IL-12, less IFN-gamma from NK and T lymphocytes, and macrophages that are not activated enough to contain intracellular mycobacteria. Partial and complete IRF8 deficiency are two diseases, not two severities, and the entry is scoped to the partial form. The autosomal recessive K108E allele abolishes circulating monocytes as well as every dendritic-cell subset and produced a fatal-course immunodeficiency requiring haematopoietic stem-cell transplantation; the dominant T80A allele spares monocytes, takes out one DC subset, and was found in two otherwise healthy adults whose childhood BCG disease had resolved with treatment. The dividing line is the monocyte compartment, and it maps onto a difference in outcome large enough that treating them as one entry would obscure both.

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1
Inheritance
5
Pathophys.
6
Phenotypes
2
Gaps
16
Pathograph
1
Genes
1
Variants
3
Medical Actions
4
Differentials
1
References
1
Deep Research
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Classifications

Harrison's Part
INFECTIOUS DISEASES
👪

Inheritance

1
Autosomal dominant HP:0000006
The T80A allele acts in the heterozygous state. This is the feature that separates the partial form from the recessive complete deficiency, and it is part of why the two are curated as distinct entities.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:21524210 SUPPORT Human Clinical
"The T80A variant was associated with an autosomal dominant, milder immunodeficiency and a selective depletion of CD11c+CD1c+ circulating dendritic cells."
States the inheritance mode, the severity relative to the recessive form, and the cellular lesion in one sentence.
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Discussions and Knowledge Gaps

2
Has reduced IL-12 production actually been measured in a carrier of the dominant IRF8 T80A allele, or is the IL-12 step inferred from the position of conventional dendritic cells in the IL-12/IFN-gamma circuit?
KNOWLEDGE GAP irf8_t80a_il12_output_unmeasured
Attached to
pathophysiology#Reduced IL-12 Production by Antigen-Presenting Cells
The chain from selective DC depletion to mycobacterial susceptibility runs through IL-12, and the inference is a reasonable one: conventional DCs are the dominant IL-12 source and MSMD is an IL-12/IFN-gamma circuit disease. But none of the sources cited here reports an IL-12 or IFN-gamma measurement in a T80A carrier. The inference is also not trivially safe, because the depletion is partial and subset-selective, so whether it is quantitatively sufficient to produce a cytokine deficit is exactly the open question. The node is therefore curated with an INDIRECT incoming edge and this gap rather than with a manufactured measurement.
Proposed experiments
Whole-blood IL-12 and IFN-gamma induction assay in T80A carriers
irf8_t80a_il12_ifng_whole_blood
Stimulate whole blood from T80A heterozygotes and matched controls with BCG alone and with BCG plus IFN-gamma, and measure IL-12p40, IL-12p70 and IFN-gamma. This is the standard MSMD functional assay, and it would also place the defect on the production rather than the response side of the circuit.
Readouts
BCG-induced whole-blood IL-12p70
pathophysiology#Reduced IL-12 Production by Antigen-Presenting Cells
Direction: DECREASED
Interpretation: Reduced IL-12p70 in carriers would convert this node from inferred to measured and would justify retyping the incoming edge as direct.
What is the penetrance of the dominant IRF8 T80A allele, and does it require BCG exposure to become clinically apparent?
KNOWLEDGE GAP irf8_t80a_penetrance_unknown
Attached to
inheritance#Autosomal dominant
Both reported T80A carriers were ascertained through childhood BCG disease and were otherwise healthy adults when studied. That design cannot distinguish a fully penetrant allele whose only manifestation is BCG disease from a low-penetrance allele that happens to have been found in two symptomatic people. The distinction matters clinically, because it determines whether an asymptomatic relative carrying the allele should avoid live BCG vaccination. Neither a family segregation study nor a carrier survey has been reported.
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Pathophysiology

5
Heterozygous IRF8 T80A Impairs IRF8 DNA Binding
IRF8 is an interferon regulatory factor that directs mononuclear phagocyte development by binding composite Ets/IRF and interferon-stimulated response elements in target promoters. The T80A substitution lies in the DNA-binding domain and impairs the IRF8-DNA interaction, reducing transcriptional output at IRF8 target genes. The lesion is in DNA contact, not in expression level or protein stability, which is what makes a single mutant allele consequential.
IRF8 hgnc:5358 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves IRF8 (hgnc:5358). hgnc:5358 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: LOSS_OF_FUNCTION
regulation of transcription by RNA polymerase II GO:0006357 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased regulation of transcription by RNA polymerase II (GO:0006357). GO:0006357 is a biological process from the Gene Ontology. ↓ DECREASED
sequence-specific DNA binding by IRF8 GO:0043565 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased sequence-specific DNA binding by IRF8, annotated with sequence-specific DNA binding (GO:0043565). GO:0043565 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Selective Depletion of CD1c-Positive Conventional Dendritic Cells
Show evidence (1 reference)
PMID:21524210 SUPPORT In Vitro
"Both K108E and T80A mutations impair IRF8 transcriptional activity by disrupting the interaction between IRF8 and DNA."
Names the molecular mechanism of the causal allele: loss of DNA binding rather than loss of protein. Graded IN_VITRO because transcriptional activity and protein-DNA interaction are measured in assays of the variant proteins, not observed in the patients; Immunodeficiency_32B grades this same sentence the same way.
Selective Depletion of CD1c-Positive Conventional Dendritic Cells
The cellular signature of the dominant form. CD11c+CD1c+ circulating conventional dendritic cells are selectively depleted, while circulating monocytes and the other mononuclear phagocyte subsets are preserved. That selectivity is the whole difference from the recessive form, in which monocytes and every DC subset are absent, and it is why this disease is confined to mycobacterial susceptibility rather than being a general immunodeficiency.
CD1c-positive myeloid dendritic cell CL:0002399 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves CD1c-positive myeloid dendritic cell (CL:0002399). CL:0002399 is a cell type from the Cell Ontology. conventional dendritic cell CL:0000990 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves conventional dendritic cell (CL:0000990). CL:0000990 is a cell type from the Cell Ontology.
myeloid dendritic cell differentiation GO:0043011 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased myeloid dendritic cell differentiation (GO:0043011). GO:0043011 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Abnormal dendritic cell count The phenotype-side statement of this node. The node is the selective loss of the CD1c-positive subset; the phenotype is the circulating count in which that loss is measured.
Reduced IL-12 Production by Antigen-Presenting Cells Conventional dendritic cells are the principal IL-12-producing antigen-presenting cells, so depleting them is expected to reduce the IL-12 available to drive IFN-gamma. No source cited here measures IL-12 output in a T80A carrier, so the edge is typed as indirect and the downstream node carries a knowledge gap.
Show evidence (3 references)
PMID:23468103 SUPPORT Human Clinical
"Mutation T80A causes autosomal dominant IRF8 deficiency and a milder form of the disease with selective loss of a subset of dendritic cells."
Independent statement of the selective DC loss.
PMID:40680811 SUPPORT INDIRECT Model Organism
"the cell fate within the myeloid lineages is determined in an IRF8 dose-dependent manner"
Supplies the reason a heterozygous allele produces a subset-selective rather than a global defect. Graded INDIRECT because it states the general dose principle from murine DC development rather than measuring it in a T80A carrier.
PMID:21524210 SUPPORT Human Clinical
"The K108E variant was associated with an autosomal recessive severe immunodeficiency with a complete lack of circulating monocytes and dendritic cells."
Cited here for contrast: it describes the recessive allele's compartment loss, which is what establishes that the dominant allele's loss is selective rather than merely milder across the board.
Reduced IL-12 Production by Antigen-Presenting Cells
The step that places this disease in the IL-12/IFN-gamma circuit. With fewer IL-12-competent conventional dendritic cells, less IL-12 reaches NK and T lymphocytes. This node is inferred from the position of IRF8 and of conventional DCs in that circuit rather than measured in a patient carrying the dominant allele; see the attached knowledge gap.
interleukin-12 production GO:0032615 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased interleukin-12 production (GO:0032615). GO:0032615 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Reduced Interferon-Gamma Production by NK and T Lymphocytes
Show evidence (1 reference)
PMID:23468103 SUPPORT INDIRECT Human Clinical
"patients with inborn errors in the IL12/IFNγ circuit may develop disseminated mycobacterial infections following perinatal BCG vaccination"
Places the disease within the IL-12/IFN-gamma circuit. Graded INDIRECT because the sentence describes the circuit generally, not IL-12 output measured in a T80A carrier.
Reduced Interferon-Gamma Production by NK and T Lymphocytes
IL-12 is what drives NK and T lymphocytes to make IFN-gamma. With the IL-12 signal weakened, that production falls. This is a separate event from the macrophage response below, in a different cell, and the MSMD literature treats the two as distinct lesions because different genes break each one.
natural killer cell CL:0000623 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves natural killer cell (CL:0000623). CL:0000623 is a cell type from the Cell Ontology. T cell CL:0000084 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves T cell (CL:0000084). CL:0000084 is a cell type from the Cell Ontology.
type II interferon production GO:0032609 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased type II interferon production (GO:0032609). GO:0032609 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Insufficient Interferon-Gamma-Dependent Macrophage Activation
Show evidence (1 reference)
PMID:42183200 SUPPORT Human Clinical
"Variations in 22 genes impair IFN-γ production, cellular responses to this cytokine, or both"
The review's own division of the MSMD genes into those that break IFN-gamma production and those that break the response to it, which is why these are two nodes rather than one.
Insufficient Interferon-Gamma-Dependent Macrophage Activation
IFN-gamma is what licenses macrophages to kill the mycobacteria they have taken up. With less of it, macrophage activation is insufficient and weakly virulent mycobacteria persist and disseminate. This is the convergence point shared by almost every MSMD etiology, and it is why this transcription-factor defect presents with the same clinical syndrome as a cytokine or receptor defect.
macrophage CL:0000235 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves macrophage (CL:0000235). CL:0000235 is a cell type from the Cell Ontology.
type II interferon-mediated signaling pathway GO:0060333 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased type II interferon-mediated signaling pathway (GO:0060333). GO:0060333 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Disseminated BCG disease
Immunodeficiency The narrow susceptibility state itself. Failure to activate macrophages against weakly virulent mycobacteria is what the immunodeficiency phenotype names, which is why it is narrow rather than general.
Show evidence (2 references)
PMID:23468103 SUPPORT Human Clinical
"The study of such MSMD (Mendelian Susceptibility to Mycobacterial Diseases) patients has provided much insight into innate and acquired immune defenses against mycobacteria."
Establishes MSMD as a disorder of antimycobacterial immune defense, the class this node places the disease in.
PMID:21524210 SUPPORT Human Clinical
"They also show that human IRF8 is critical for the development of monocytes and dendritic cells and for antimycobacterial immunity."
Links IRF8 specifically to antimycobacterial immunity, which is the claim this node makes.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Mendelian Susceptibility To Mycobacterial Diseases Due To Partial IRF8 Deficiency Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

6
Blood 1
Abnormal dendritic cell count OBLIGATE HP:0020178 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Selective depletion of CD11c+CD1c+ circulating dendritic cells, annotated with Abnormal dendritic cell count (HP:0020178). HP:0020178 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21524210 SUPPORT Human Clinical
"The T80A variant was associated with an autosomal dominant, milder immunodeficiency and a selective depletion of CD11c+CD1c+ circulating dendritic cells."
Reports the dendritic-cell abnormality in the carriers of the dominant allele.
Cardiovascular 1
Lymphadenopathy VERY_FREQUENT HP:0002716 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lymphadenopathy (HP:0002716). HP:0002716 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38341181 SUPPORT INDIRECT Human Clinical
"lymphadenopathy was the most frequent finding, reported in 195 patients (46.8% cases)."
Establishes lymphadenopathy as the commonest MSMD manifestation. Graded INDIRECT because the cohort spans all MSMD genotypes, so the frequency is not an IRF8-specific figure.
Immune 3
Disseminated BCG disease OBLIGATE BCGosis HP:0020087 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is BCGosis (HP:0020087), qualified as childhood onset. HP:0020087 is a phenotype from the Human Phenotype Ontology.
Onset: CHILDHOOD
Sequelae: Lymphadenopathy Fever Granuloma
Show evidence (1 reference)
PMID:21524210 SUPPORT Human Clinical
"We also studied two otherwise healthy subjects with a history of disseminated but curable BCG disease in childhood."
Documents disseminated BCG disease as the presenting feature in both reported carriers of the dominant allele, and its curable course.
Granuloma FREQUENT HP:0032252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Granuloma (HP:0032252). HP:0032252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42183200 SUPPORT INDIRECT Human Clinical
"22 genes have been implicated, all converging on the IL-12/23-IFN-γ circuit, underscoring its non-redundant role in controlling intracellular pathogens."
Cited for the disease class rather than for granuloma formation itself, hence INDIRECT: granuloma is the tissue response to the uncontrolled intracellular infection this sentence describes.
Immunodeficiency OBLIGATE HP:0002721 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Immunodeficiency (HP:0002721). HP:0002721 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23468103 SUPPORT Human Clinical
"Recently, mutations in human IRF8 were discovered and shown to cause two distinct forms of a novel primary immunodeficiency and associated susceptibility to mycobacteria."
Classifies the condition as a primary immunodeficiency.
Metabolism 1
Fever OCCASIONAL HP:0001945 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fever (HP:0001945). HP:0001945 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38341181 SUPPORT INDIRECT Human Clinical
"The next most frequent clinical presentation was isolated fever in 59 patients (14.1%), followed by BCG infection in the form of BCG-osis"
Gives the pooled MSMD frequency for fever. INDIRECT for the same reason as lymphadenopathy: the denominator is all MSMD, not partial IRF8 deficiency.
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Genetic Associations

1
IRF8
Gene: IRF8 hgnc:5358 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is IRF8 (hgnc:5358). hgnc:5358 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:21524210 SUPPORT Human Clinical
"We detected two distinct disease-causing mutations affecting interferon regulatory factor 8 (IRF8)."
Establishes IRF8 as the disease gene in the founding report.
PMID:23468103 SUPPORT Human Clinical
"Mutation T80A causes autosomal dominant IRF8 deficiency and a milder form of the disease with selective loss of a subset of dendritic cells."
An independent review naming the specific allele responsible for the dominant form and its cellular consequence.
Variants (1)
IRF8 T80A
The heterozygous missense substitution that defines this entry. It sits in the IRF8 DNA-binding domain and impairs the IRF8-DNA interaction rather than IRF8 expression. It is what separates this autosomal dominant, partial deficiency from the autosomal recessive complete deficiency caused by the biallelic K108E allele: the same kind of lesion, in the same domain, at a different dose.
Show evidence (2 references)
PMID:23468103 SUPPORT Human Clinical
"Mutation T80A causes autosomal dominant IRF8 deficiency and a milder form of the disease with selective loss of a subset of dendritic cells."
Names the allele, its transmission mode and its cellular consequence in one sentence.
PMID:21524210 SUPPORT Human Clinical
"We detected two distinct disease-causing mutations affecting interferon regulatory factor 8 (IRF8)."
The founding report identifying the two alleles, of which T80A is the dominant one curated here.
💊

Medical Actions

3
Antimycobacterial Chemotherapy
Action: Antibiotic TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Antibiotic Therapy (NCIT:C15620). NCIT:C15620 is a clinical intervention from the NCI Thesaurus. NCIT:C15620
Platform: Small molecule
Multi-drug antimycobacterial therapy directed at the isolated organism. In the partial form the disease has been curable with treatment alone, which is the principal clinical difference from the complete deficiency.
Target Phenotypes: BCGosis HP:0020087 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets BCGosis (HP:0020087). HP:0020087 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42183200 SUPPORT Human Clinical
"Antibiotics and IFN-γ therapy are required for several years to contain and ultimately control the infection."
States the treatment principle for MSMD: prolonged antimycobacterial therapy, with IFN-gamma as the adjunct.
Adjunctive Recombinant Interferon Gamma
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: recombinant interferon gamma-1b NCIT:C100089 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses recombinant interferon gamma-1b, annotated with Interferon Gamma-1b (NCIT:C100089). NCIT:C100089 is a therapeutic agent from the NCI Thesaurus.
Platform: Protein replacement
Recombinant IFN-gamma is the mechanistically rational adjunct for an MSMD etiology on the production side of the circuit, which is where an IRF8 defect sits: the lesion reduces the IFN-gamma signal reaching macrophages rather than their ability to respond to it, so supplying the cytokine bypasses the block. The published experience is from other MSMD genotypes, not from an IRF8 patient.
Mechanism Target:
ACTIVATES Insufficient Interferon-Gamma-Dependent Macrophage Activation — Exogenous IFN-gamma acts directly on the node the disease chain fails at, downstream of the DC and IL-12 steps that the IRF8 lesion disables. It activates the macrophage response rather than repairing the production defect above it, which is why the effect is ACTIVATES and not RESTORES.
Show evidence (1 reference)
PMID:42183200 SUPPORT INDIRECT Human Clinical
"A 30-month treatment regimen of antimycobacterial treatment combined with recombinant IFN-γ1b was tried for the first time in patients carrying the PF75S mutation, and the patients recovered well after treatment."
The clinical outcome that supports acting on this node with exogenous cytokine. INDIRECT because the treated patients carried a different MSMD genotype.
Show evidence (1 reference)
PMID:42183200 SUPPORT INDIRECT Human Clinical
"A 30-month treatment regimen of antimycobacterial treatment combined with recombinant IFN-γ1b was tried for the first time in patients carrying the PF75S mutation, and the patients recovered well after treatment."
Reports a good outcome with combined antimycobacterial and IFN-gamma therapy. Graded INDIRECT because the treated patients carried a different MSMD genotype, so the support for using it in IRF8 deficiency runs through the shared circuit rather than through direct experience.
Genetic Counseling and Avoidance of Live BCG Vaccination
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Autosomal dominant transmission carries a 50% recurrence risk per pregnancy. Because the presenting illness in both reported carriers was BCG disease, the practical consequence for an identified relative is avoidance of live BCG vaccination. Note this recommendation follows from the disease mechanism and the reported presentations rather than from a trial.
Target Phenotypes: BCGosis HP:0020087 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets BCGosis (HP:0020087). HP:0020087 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21524210 SUPPORT INDIRECT Human Clinical
"Disseminated infection caused by bacille Calmette-Guérin (BCG) vaccines is an early manifestation of primary immunodeficiencies, such as severe combined immunodeficiency."
Establishes live BCG vaccine as the exposure that unmasks this class of immunodeficiency, which is what makes avoidance the counseling point. INDIRECT because no study has tested vaccine avoidance as an intervention.
🔬

Diagnosis

2
Circulating dendritic cell and monocyte immunophenotyping (PRESENT)
Flow-cytometric enumeration of circulating mononuclear phagocyte subsets is what distinguishes the partial from the complete form, and what makes the diagnosis reachable at all in a patient whose routine immunology is normal. Monocytes preserved with selective loss of CD11c+CD1c+ conventional DCs indicates the dominant form; absence of monocytes and all DC subsets indicates the recessive one.
Show evidence (1 reference)
PMID:21524210 SUPPORT Human Clinical
"We characterized the monocyte and dendritic-cell compartments in these three subjects and sequenced candidate genes in which mutations could plausibly confer susceptibility to BCG disease."
Describes the diagnostic approach that separated the two forms in the founding report.
IRF8 sequencing (PRESENT)
Molecular confirmation. In the founding report the gene was reached by candidate gene sequencing guided by the mononuclear phagocyte phenotype rather than by unbiased exome sequencing.
Show evidence (1 reference)
PMID:32344243 SUPPORT Human Clinical
"This review will summarise the clinical phenotypes of mutations in GATA2, IRF8 and IKZF1 genes which result in global or subset specific dendritic cell deficiencies"
Establishes that IRF8 belongs to a small set of genes whose mutation causes subset-specific dendritic cell deficiency, which is what makes targeted sequencing sensible.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
The founding report described two unrelated subjects carrying the dominant T80A allele. No population prevalence estimate exists, and because affected individuals may be otherwise healthy adults, ascertainment depends on a history of BCG disease.
Show evidence (1 reference)
PMID:21524210 SUPPORT Human Clinical
"We also studied two otherwise healthy subjects with a history of disseminated but curable BCG disease in childhood."
Establishes both the size of the founding cohort for the dominant form and its benign long-term course.
🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Mendelian Susceptibility To Mycobacterial Diseases Due To Partial IRF8 Deficiency:

Complete IRF8 deficiency (autosomal recessive, K108E)
Overlapping Features The allelic recessive disorder. It is distinguished at the bench rather than the bedside: complete deficiency abolishes circulating monocytes as well as every dendritic cell subset, adds mucocutaneous fungal disease and granulocytic hyperplasia, and required haematopoietic stem-cell transplantation for cure.
Show evidence (1 reference)
PMID:25122610 SUPPORT Human Clinical
"The patient initially presented with severe disseminated mycobacterial and mucocutaneous fungal infections and was ultimately cured by cord blood transplant."
Describes the recessive form's broader infectious phenotype and its transplant-dependent outcome, both of which distinguish it from the dominant form curated here.
Biallelic IRF8 deficiency with immune dysregulation (R83C/R291Q)
Overlapping Features A third IRF8 phenotype, reported in a compound heterozygote, extending beyond mononuclear phagocyte deficiency to arrested NK cell maturation, impaired T and B cell differentiation, granuloproliferation and intracerebral calcification. It is listed here because it shows the IRF8 allelic series is wider than the partial/complete dichotomy, not because it is clinically confusable with the dominant form.
Show evidence (1 reference)
PMID:29128673 SUPPORT Human Clinical
"This analysis defines the clinical features of human biallelic IRF8 deficiency, revealing a complex immunodeficiency syndrome caused by DC and monocyte deficiency combined with widespread immune dysregulation."
Establishes the third phenotype in the IRF8 allelic series.
Dominant-negative IRF8 deficiency (c.1279dupT)
Overlapping Features A fourth IRF8 phenotype, and the one closest to this entry. A C-terminal extension variant acts dominant-negatively on IRF8 nuclear localization and also reduces cDC2, so it presents with mycobacterial susceptibility like the partial form. It is distinguishable in that plasmacytoid DCs and cDC1 are also reduced and the reported family had EBV viremia and an HPV-positive tumour, a viral susceptibility the T80A form does not carry.
Show evidence (1 reference)
PMID:40072380 SUPPORT Human Clinical
"Both patients had a decrease in plasmacytoid dendritic cells (pDCs) and in cDC1s, a mild neutrophilia and a mild monocytosis."
Documents the cellular differences that separate the dominant-negative phenotype from the cDC2-selective partial form curated here.
Other genetic etiologies of MSMD
Overlapping Features MSMD is genetically heterogeneous and the etiologies are clinically similar, so the differential is settled by genotype and immunophenotype rather than by presentation. Most other MSMD genes lie in the IL-12/IFN-gamma cytokine circuit itself; IRF8 is distinctive in lying upstream of it, in the specification of the IL-12-producing cell.
Show evidence (1 reference)
PMID:23468103 SUPPORT Human Clinical
"patients with inborn errors in the IL12/IFNγ circuit may develop disseminated mycobacterial infections following perinatal BCG vaccination"
States the shared final pathway that makes the MSMD etiologies clinically similar to one another.
{ }

Source YAML

click to show 
name: Mendelian Susceptibility To Mycobacterial Diseases Due To Partial IRF8 Deficiency
creation_date: "2026-09-05T00:00:00Z"
category: Mendelian
synonyms:
- MSMD due to partial IRF8 deficiency
- Autosomal dominant IRF8 deficiency
- IRF8 T80A deficiency
- Immunodeficiency 32A
- IMD32A
- Mycobacteriosis, autosomal dominant
description: >
  Mendelian susceptibility to mycobacterial disease (MSMD) due to partial IRF8
  deficiency is an autosomal dominant inborn error of immunity caused by a
  heterozygous variant in IRF8, the transcription factor that specifies the
  mononuclear phagocyte lineage. It presents as MSMD: disease caused by weakly
  virulent mycobacteria, in particular the Bacille Calmette-Guerin (BCG) vaccine
  strain, in an individual whose routine immunological testing is otherwise
  unremarkable.

  The distinguishing feature of this etiology is where in the IL-12/IFN-gamma
  circuit the lesion sits. Most MSMD genes encode the cytokines of that circuit or
  their receptors. IRF8 instead encodes the transcription factor that builds the
  cells which produce IL-12 in the first place, so the deficiency is cellular
  rather than humoral: the T80A substitution impairs IRF8 binding to DNA and
  selectively depletes one dendritic-cell compartment, the CD11c+CD1c+ conventional
  DCs, while leaving monocytes intact. Fewer IL-12-competent antigen-presenting
  cells means less IL-12, less IFN-gamma from NK and T lymphocytes, and macrophages
  that are not activated enough to contain intracellular mycobacteria.

  Partial and complete IRF8 deficiency are two diseases, not two severities, and the
  entry is scoped to the partial form. The autosomal recessive K108E allele abolishes
  circulating monocytes as well as every dendritic-cell subset and produced a
  fatal-course immunodeficiency requiring haematopoietic stem-cell
  transplantation; the dominant T80A allele spares monocytes, takes out one DC
  subset, and was found in two otherwise healthy adults whose childhood BCG
  disease had resolved with treatment. The dividing line is the monocyte
  compartment, and it maps onto a difference in outcome large enough that treating
  them as one entry would obscure both.
disease_term:
  preferred_term: Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency
  term:
    id: MONDO:0013957
    label: Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency
parents:
- Primary immunodeficiency
- Mendelian susceptibility to mycobacterial disease
references:
- reference: PMID:21524210
  title: "IRF8 mutations and human dendritic-cell immunodeficiency."
classifications:
  harrisons_chapter:
  - classification_value: INFECTIOUS_DISEASES
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    The founding report described two unrelated subjects carrying the dominant T80A
    allele. No population prevalence estimate exists, and because affected
    individuals may be otherwise healthy adults, ascertainment depends on a history
    of BCG disease.
  evidence:
  - reference: PMID:21524210
    reference_title: "IRF8 mutations and human dendritic-cell immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We also studied two otherwise healthy subjects with a history of disseminated but curable BCG disease in childhood."
    explanation: >-
      Establishes both the size of the founding cohort for the dominant form and its
      benign long-term course.
inheritance:
- name: Autosomal dominant
  description: >-
    The T80A allele acts in the heterozygous state. This is the feature that
    separates the partial form from the recessive complete deficiency, and it is
    part of why the two are curated as distinct entities.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:21524210
    reference_title: "IRF8 mutations and human dendritic-cell immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The T80A variant was associated with an autosomal dominant, milder immunodeficiency and a selective depletion of CD11c+CD1c+ circulating dendritic cells."
    explanation: >-
      States the inheritance mode, the severity relative to the recessive form, and
      the cellular lesion in one sentence.
genetic:
- name: IRF8
  gene_term:
    preferred_term: IRF8
    term:
      id: hgnc:5358
      label: IRF8
  relationship_type: CAUSATIVE
  presence: PRESENT
  variant_origin: GERMLINE
  variants:
  - name: IRF8 T80A
    description: >-
      The heterozygous missense substitution that defines this entry. It sits in the
      IRF8 DNA-binding domain and impairs the IRF8-DNA interaction rather than IRF8
      expression. It is what separates this autosomal dominant, partial deficiency
      from the autosomal recessive complete deficiency caused by the biallelic K108E
      allele: the same kind of lesion, in the same domain, at a different dose.
    evidence:
    - reference: PMID:23468103
      reference_title: "Genetic determinants of susceptibility to Mycobacterial infections: IRF8, a new kid on the block."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Mutation T80A causes autosomal dominant IRF8 deficiency and a milder form of the disease with selective loss of a subset of dendritic cells."
      explanation: >-
        Names the allele, its transmission mode and its cellular consequence in one
        sentence.
    - reference: PMID:21524210
      reference_title: "IRF8 mutations and human dendritic-cell immunodeficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We detected two distinct disease-causing mutations affecting interferon regulatory factor 8 (IRF8)."
      explanation: >-
        The founding report identifying the two alleles, of which T80A is the
        dominant one curated here.
  notes: >-
    The reported dominant allele is the T80A missense substitution. Both T80A and the
    recessive K108E allele act by disrupting the IRF8-DNA interaction rather than by
    reducing IRF8 expression, which is why the two produce graded rather than
    qualitatively different transcriptional lesions even though the diseases differ.
  evidence:
  - reference: PMID:21524210
    reference_title: "IRF8 mutations and human dendritic-cell immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We detected two distinct disease-causing mutations affecting interferon regulatory factor 8 (IRF8)."
    explanation: Establishes IRF8 as the disease gene in the founding report.
  - reference: PMID:23468103
    reference_title: "Genetic determinants of susceptibility to Mycobacterial infections: IRF8, a new kid on the block."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutation T80A causes autosomal dominant IRF8 deficiency and a milder form of the disease with selective loss of a subset of dendritic cells."
    explanation: >-
      An independent review naming the specific allele responsible for the dominant
      form and its cellular consequence.
pathophysiology:
- name: Heterozygous IRF8 T80A Impairs IRF8 DNA Binding
  biological_scale: MOLECULAR
  description: >-
    IRF8 is an interferon regulatory factor that directs mononuclear phagocyte
    development by binding composite Ets/IRF and interferon-stimulated response
    elements in target promoters. The T80A substitution lies in the DNA-binding
    domain and impairs the IRF8-DNA interaction, reducing transcriptional output at
    IRF8 target genes. The lesion is in DNA contact, not in expression level or
    protein stability, which is what makes a single mutant allele consequential.
  genes:
  - preferred_term: IRF8
    term:
      id: hgnc:5358
      label: IRF8
  molecular_functions:
  - preferred_term: sequence-specific DNA binding by IRF8
    term:
      id: GO:0043565
      label: sequence-specific DNA binding
    modifier: DECREASED
  biological_processes:
  - preferred_term: regulation of transcription by RNA polymerase II
    term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
    modifier: DECREASED
  genetic_context:
    functional_impact_category: LOSS_OF_FUNCTION
    zygosity: HETEROZYGOUS
    variant_origin: GERMLINE
  evidence:
  - reference: PMID:21524210
    reference_title: "IRF8 mutations and human dendritic-cell immunodeficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Both K108E and T80A mutations impair IRF8 transcriptional activity by disrupting the interaction between IRF8 and DNA."
    explanation: >-
      Names the molecular mechanism of the causal allele: loss of DNA binding rather
      than loss of protein. Graded IN_VITRO because transcriptional activity and
      protein-DNA interaction are measured in assays of the variant proteins, not
      observed in the patients; Immunodeficiency_32B grades this same sentence the
      same way.
  downstream:
  - target: Selective Depletion of CD1c-Positive Conventional Dendritic Cells
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:21524210
      reference_title: "IRF8 mutations and human dendritic-cell immunodeficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The T80A variant was associated with an autosomal dominant, milder immunodeficiency and a selective depletion of CD11c+CD1c+ circulating dendritic cells."
      explanation: >-
        Ties the specific allele to the specific cellular deficit, which is the edge
        rather than either node alone.
- name: Selective Depletion of CD1c-Positive Conventional Dendritic Cells
  biological_scale: CELLULAR
  description: >-
    The cellular signature of the dominant form. CD11c+CD1c+ circulating conventional
    dendritic cells are selectively depleted, while circulating monocytes and the
    other mononuclear phagocyte subsets are preserved. That selectivity is the whole
    difference from the recessive form, in which monocytes and every DC subset are
    absent, and it is why this disease is confined to mycobacterial susceptibility
    rather than being a general immunodeficiency.
  cell_types:
  - preferred_term: CD1c-positive myeloid dendritic cell
    term:
      id: CL:0002399
      label: CD1c-positive myeloid dendritic cell
  - preferred_term: conventional dendritic cell
    term:
      id: CL:0000990
      label: conventional dendritic cell
  biological_processes:
  - preferred_term: myeloid dendritic cell differentiation
    term:
      id: GO:0043011
      label: myeloid dendritic cell differentiation
    modifier: DECREASED
  evidence:
  - reference: PMID:23468103
    reference_title: "Genetic determinants of susceptibility to Mycobacterial infections: IRF8, a new kid on the block."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutation T80A causes autosomal dominant IRF8 deficiency and a milder form of the disease with selective loss of a subset of dendritic cells."
    explanation: Independent statement of the selective DC loss.
  - reference: PMID:40680811
    reference_title: "Cis- and trans-regulation of Irf8 enhancers during dendritic cell development."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "the cell fate within the myeloid lineages is determined in an IRF8 dose-dependent manner"
    explanation: >-
      Supplies the reason a heterozygous allele produces a subset-selective rather
      than a global defect. Graded INDIRECT because it states the general dose
      principle from murine DC development rather than measuring it in a T80A
      carrier.
  - reference: PMID:21524210
    reference_title: "IRF8 mutations and human dendritic-cell immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The K108E variant was associated with an autosomal recessive severe immunodeficiency with a complete lack of circulating monocytes and dendritic cells."
    explanation: >-
      Cited here for contrast: it describes the recessive allele's compartment loss,
      which is what establishes that the dominant allele's loss is selective rather
      than merely milder across the board.
  downstream:
  - target: Abnormal dendritic cell count
    causal_link_type: DIRECT
    description: >-
      The phenotype-side statement of this node. The node is the selective loss of
      the CD1c-positive subset; the phenotype is the circulating count in which that
      loss is measured.
  - target: Reduced IL-12 Production by Antigen-Presenting Cells
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Conventional dendritic cells are the principal IL-12-producing
      antigen-presenting cells, so depleting them is expected to reduce the IL-12
      available to drive IFN-gamma. No source cited here measures IL-12 output in a
      T80A carrier, so the edge is typed as indirect and the downstream node
      carries a knowledge gap.
- name: Reduced IL-12 Production by Antigen-Presenting Cells
  biological_scale: CELLULAR
  description: >-
    The step that places this disease in the IL-12/IFN-gamma circuit. With fewer
    IL-12-competent conventional dendritic cells, less IL-12 reaches NK and T
    lymphocytes. This node is inferred from the position of IRF8 and of conventional
    DCs in that circuit rather than measured in a patient carrying the dominant
    allele; see the attached knowledge gap.
  biological_processes:
  - preferred_term: interleukin-12 production
    term:
      id: GO:0032615
      label: interleukin-12 production
    modifier: DECREASED
  evidence:
  - reference: PMID:23468103
    reference_title: "Genetic determinants of susceptibility to Mycobacterial infections: IRF8, a new kid on the block."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "patients with inborn errors in the IL12/IFNγ circuit may develop disseminated mycobacterial infections following perinatal BCG vaccination"
    explanation: >-
      Places the disease within the IL-12/IFN-gamma circuit. Graded INDIRECT because
      the sentence describes the circuit generally, not IL-12 output measured in a
      T80A carrier.
  downstream:
  - target: Reduced Interferon-Gamma Production by NK and T Lymphocytes
    causal_link_type: DIRECT
- name: Reduced Interferon-Gamma Production by NK and T Lymphocytes
  biological_scale: CELLULAR
  description: >-
    IL-12 is what drives NK and T lymphocytes to make IFN-gamma. With the IL-12
    signal weakened, that production falls. This is a separate event from the
    macrophage response below, in a different cell, and the MSMD literature treats
    the two as distinct lesions because different genes break each one.
  cell_types:
  - preferred_term: natural killer cell
    term:
      id: CL:0000623
      label: natural killer cell
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  biological_processes:
  - preferred_term: type II interferon production
    term:
      id: GO:0032609
      label: type II interferon production
    modifier: DECREASED
  evidence:
  - reference: PMID:42183200
    reference_title: "Mendelian susceptibility to mycobacterial disease: IFN-γ-driven immunity collapse underlies heterogeneous infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Variations in 22 genes impair IFN-γ production, cellular responses to this cytokine, or both"
    explanation: >-
      The review's own division of the MSMD genes into those that break IFN-gamma
      production and those that break the response to it, which is why these are two
      nodes rather than one.
  downstream:
  - target: Insufficient Interferon-Gamma-Dependent Macrophage Activation
    causal_link_type: DIRECT
- name: Insufficient Interferon-Gamma-Dependent Macrophage Activation
  biological_scale: CELLULAR
  description: >-
    IFN-gamma is what licenses macrophages to kill the mycobacteria they have taken
    up. With less of it, macrophage activation is insufficient and weakly virulent
    mycobacteria persist and disseminate. This is the convergence point shared by
    almost every MSMD etiology, and it is why this transcription-factor defect
    presents with the same clinical syndrome as a cytokine or receptor defect.
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: type II interferon-mediated signaling pathway
    term:
      id: GO:0060333
      label: type II interferon-mediated signaling pathway
    modifier: DECREASED
  evidence:
  - reference: PMID:23468103
    reference_title: "Genetic determinants of susceptibility to Mycobacterial infections: IRF8, a new kid on the block."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The study of such MSMD (Mendelian Susceptibility to Mycobacterial Diseases) patients has provided much insight into innate and acquired immune defenses against mycobacteria."
    explanation: >-
      Establishes MSMD as a disorder of antimycobacterial immune defense, the class
      this node places the disease in.
  - reference: PMID:21524210
    reference_title: "IRF8 mutations and human dendritic-cell immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "They also show that human IRF8 is critical for the development of monocytes and dendritic cells and for antimycobacterial immunity."
    explanation: >-
      Links IRF8 specifically to antimycobacterial immunity, which is the claim this
      node makes.
  downstream:
  - target: Disseminated BCG disease
    causal_link_type: DIRECT
  - target: Immunodeficiency
    causal_link_type: DIRECT
    description: >-
      The narrow susceptibility state itself. Failure to activate macrophages
      against weakly virulent mycobacteria is what the immunodeficiency phenotype
      names, which is why it is narrow rather than general.

phenotypes:
- category: Infectious
  name: Disseminated BCG disease
  frequency: OBLIGATE
  description: >-
    Disseminated disease following BCG vaccination is the presenting and defining
    manifestation. In the two subjects carrying the dominant T80A allele it occurred
    in childhood and was curable, in contrast to the recessive form, in which BCG
    disease was early in onset and required haematopoietic stem-cell transplantation.
  phenotype_term:
    preferred_term: BCGosis
    term:
      id: HP:0020087
      label: BCGosis
    onset:
      onset_category: CHILDHOOD
  evidence:
  - reference: PMID:21524210
    reference_title: "IRF8 mutations and human dendritic-cell immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We also studied two otherwise healthy subjects with a history of disseminated but curable BCG disease in childhood."
    explanation: >-
      Documents disseminated BCG disease as the presenting feature in both reported
      carriers of the dominant allele, and its curable course.
  sequelae:
  - target: Lymphadenopathy
    description: >-
      Lymphadenopathy is a manifestation of the mycobacterial disease rather than a
      separate consequence of the genetic lesion. Its frequency band comes from a
      pooled MSMD cohort, not from the two reported carriers.
  - target: Fever
    description: >-
      Systemic response to the disseminated infection, banded from the same pooled
      MSMD cohort rather than from IRF8 carriers.
  - target: Granuloma
    description: >-
      Granulomatous inflammation at the sites of mycobacterial disease, so it hangs
      off the infection rather than off the signalling defect.
- category: Hematologic
  name: Abnormal dendritic cell count
  frequency: OBLIGATE
  description: >-
    The laboratory hallmark: circulating CD11c+CD1c+ conventional dendritic cells are
    selectively depleted. HPO codes dendritic cell counts only at the level of
    abnormality, with no directional or subset-specific child term, so the binding is
    less specific than the finding; the specificity is carried in preferred_term and
    in the description.
  phenotype_term:
    preferred_term: Selective depletion of CD11c+CD1c+ circulating dendritic cells
    term:
      id: HP:0020178
      label: Abnormal dendritic cell count
  evidence:
  - reference: PMID:21524210
    reference_title: "IRF8 mutations and human dendritic-cell immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The T80A variant was associated with an autosomal dominant, milder immunodeficiency and a selective depletion of CD11c+CD1c+ circulating dendritic cells."
    explanation: Reports the dendritic-cell abnormality in the carriers of the dominant allele.
- category: Infectious
  name: Lymphadenopathy
  frequency: VERY_FREQUENT
  description: >-
    Lymphadenopathy is the commonest presenting sign across MSMD as a whole, and is
    the HPO-annotated finding for this disorder. The frequency band is taken from
    the 830-patient MSMD systematic review rather than from the two reported T80A
    carriers, and so describes the syndrome class rather than this etiology
    specifically.
  phenotype_term:
    preferred_term: Lymphadenopathy
    term:
      id: HP:0002716
      label: Lymphadenopathy
  evidence:
  - reference: PMID:38341181
    reference_title: "Genetic, immunologic, and clinical features of 830 patients with Mendelian susceptibility to mycobacterial diseases (MSMD): A systematic review."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "lymphadenopathy was the most frequent finding, reported in 195 patients (46.8% cases)."
    explanation: >-
      Establishes lymphadenopathy as the commonest MSMD manifestation. Graded
      INDIRECT because the cohort spans all MSMD genotypes, so the frequency is not
      an IRF8-specific figure.
- category: Infectious
  name: Fever
  frequency: OCCASIONAL
  description: >-
    Fever accompanies the mycobacterial disease and is the second most common
    presenting sign across MSMD. The band follows the 14.1% figure for isolated
    fever as the presenting complaint in the pooled cohort, which is the number the
    cited sentence actually reports; the higher 30.2% figure in the same paper
    counts fever, organomegaly and sepsis together and is not usable for a
    fever-specific band.
  phenotype_term:
    preferred_term: Fever
    term:
      id: HP:0001945
      label: Fever
  evidence:
  - reference: PMID:38341181
    reference_title: "Genetic, immunologic, and clinical features of 830 patients with Mendelian susceptibility to mycobacterial diseases (MSMD): A systematic review."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The next most frequent clinical presentation was isolated fever in 59 patients (14.1%), followed by BCG infection in the form of BCG-osis"
    explanation: >-
      Gives the pooled MSMD frequency for fever. INDIRECT for the same reason as
      lymphadenopathy: the denominator is all MSMD, not partial IRF8 deficiency.
- category: Immunologic
  name: Granuloma
  frequency: FREQUENT
  description: >-
    Granulomatous inflammation at sites of mycobacterial disease. Granulomas can
    make MSMD masquerade as sarcoidosis until cultures identify the organism, which
    is a practical diagnostic trap rather than a mechanistic detail.
  phenotype_term:
    preferred_term: Granuloma
    term:
      id: HP:0032252
      label: Granuloma
  evidence:
  - reference: PMID:42183200
    reference_title: "Mendelian susceptibility to mycobacterial disease: IFN-γ-driven immunity collapse underlies heterogeneous infections."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "22 genes have been implicated, all converging on the IL-12/23-IFN-γ circuit, underscoring its non-redundant role in controlling intracellular pathogens."
    explanation: >-
      Cited for the disease class rather than for granuloma formation itself, hence
      INDIRECT: granuloma is the tissue response to the uncontrolled intracellular
      infection this sentence describes.
- category: Immunologic
  name: Immunodeficiency
  frequency: OBLIGATE
  description: >-
    A narrow immunodeficiency: susceptibility is to weakly virulent mycobacteria
    rather than to infection in general, and the two reported carriers were otherwise
    healthy.
  phenotype_term:
    preferred_term: Immunodeficiency
    term:
      id: HP:0002721
      label: Immunodeficiency
  evidence:
  - reference: PMID:23468103
    reference_title: "Genetic determinants of susceptibility to Mycobacterial infections: IRF8, a new kid on the block."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recently, mutations in human IRF8 were discovered and shown to cause two distinct forms of a novel primary immunodeficiency and associated susceptibility to mycobacteria."
    explanation: Classifies the condition as a primary immunodeficiency.
diagnosis:
- name: Circulating dendritic cell and monocyte immunophenotyping
  description: >-
    Flow-cytometric enumeration of circulating mononuclear phagocyte subsets is what
    distinguishes the partial from the complete form, and what makes the diagnosis
    reachable at all in a patient whose routine immunology is normal. Monocytes
    preserved with selective loss of CD11c+CD1c+ conventional DCs indicates the
    dominant form; absence of monocytes and all DC subsets indicates the recessive
    one.
  presence: PRESENT
  evidence:
  - reference: PMID:21524210
    reference_title: "IRF8 mutations and human dendritic-cell immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We characterized the monocyte and dendritic-cell compartments in these three subjects and sequenced candidate genes in which mutations could plausibly confer susceptibility to BCG disease."
    explanation: >-
      Describes the diagnostic approach that separated the two forms in the founding
      report.
- name: IRF8 sequencing
  description: >-
    Molecular confirmation. In the founding report the gene was reached by candidate
    gene sequencing guided by the mononuclear phagocyte phenotype rather than by
    unbiased exome sequencing.
  presence: PRESENT
  evidence:
  - reference: PMID:32344243
    reference_title: "Insights from Patients with Dendritic Cell Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This review will summarise the clinical phenotypes of mutations in GATA2, IRF8 and IKZF1 genes which result in global or subset specific dendritic cell deficiencies"
    explanation: >-
      Establishes that IRF8 belongs to a small set of genes whose mutation causes
      subset-specific dendritic cell deficiency, which is what makes targeted
      sequencing sensible.
treatments:
- name: Antimycobacterial Chemotherapy
  description: >-
    Multi-drug antimycobacterial therapy directed at the isolated organism. In the
    partial form the disease has been curable with treatment alone, which is the
    principal clinical difference from the complete deficiency.
  treatment_term:
    preferred_term: Antibiotic Therapy
    term:
      id: NCIT:C15620
      label: Antibiotic Therapy
  therapeutic_modality: SMALL_MOLECULE
  target_phenotypes:
  - preferred_term: BCGosis
    term:
      id: HP:0020087
      label: BCGosis
  evidence:
  - reference: PMID:42183200
    reference_title: "Mendelian susceptibility to mycobacterial disease: IFN-γ-driven immunity collapse underlies heterogeneous infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Antibiotics and IFN-γ therapy are required for several years to contain and ultimately control the infection."
    explanation: >-
      States the treatment principle for MSMD: prolonged antimycobacterial therapy,
      with IFN-gamma as the adjunct.
- name: Adjunctive Recombinant Interferon Gamma
  description: >-
    Recombinant IFN-gamma is the mechanistically rational adjunct for an MSMD
    etiology on the production side of the circuit, which is where an IRF8 defect
    sits: the lesion reduces the IFN-gamma signal reaching macrophages rather than
    their ability to respond to it, so supplying the cytokine bypasses the block.
    The published experience is from other MSMD genotypes, not from an IRF8 patient.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: recombinant interferon gamma-1b
      term:
        id: NCIT:C100089
        label: Interferon Gamma-1b
  therapeutic_modality: PROTEIN_REPLACEMENT
  target_mechanisms:
  - target: Insufficient Interferon-Gamma-Dependent Macrophage Activation
    treatment_effect: ACTIVATES
    description: >-
      Exogenous IFN-gamma acts directly on the node the disease chain fails at,
      downstream of the DC and IL-12 steps that the IRF8 lesion disables. It
      activates the macrophage response rather than repairing the production defect
      above it, which is why the effect is ACTIVATES and not RESTORES.
    evidence:
    - reference: PMID:42183200
      reference_title: "Mendelian susceptibility to mycobacterial disease: IFN-γ-driven immunity collapse underlies heterogeneous infections."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "A 30-month treatment regimen of antimycobacterial treatment combined with recombinant IFN-γ1b was tried for the first time in patients carrying the PF75S mutation, and the patients recovered well after treatment."
      explanation: >-
        The clinical outcome that supports acting on this node with exogenous
        cytokine. INDIRECT because the treated patients carried a different MSMD
        genotype.
  evidence:
  - reference: PMID:42183200
    reference_title: "Mendelian susceptibility to mycobacterial disease: IFN-γ-driven immunity collapse underlies heterogeneous infections."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "A 30-month treatment regimen of antimycobacterial treatment combined with recombinant IFN-γ1b was tried for the first time in patients carrying the PF75S mutation, and the patients recovered well after treatment."
    explanation: >-
      Reports a good outcome with combined antimycobacterial and IFN-gamma therapy.
      Graded INDIRECT because the treated patients carried a different MSMD
      genotype, so the support for using it in IRF8 deficiency runs through the
      shared circuit rather than through direct experience.
- name: Genetic Counseling and Avoidance of Live BCG Vaccination
  description: >-
    Autosomal dominant transmission carries a 50% recurrence risk per pregnancy.
    Because the presenting illness in both reported carriers was BCG disease, the
    practical consequence for an identified relative is avoidance of live BCG
    vaccination. Note this recommendation follows from the disease mechanism and the
    reported presentations rather than from a trial.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  target_phenotypes:
  - preferred_term: BCGosis
    term:
      id: HP:0020087
      label: BCGosis
  evidence:
  - reference: PMID:21524210
    reference_title: "IRF8 mutations and human dendritic-cell immunodeficiency."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Disseminated infection caused by bacille Calmette-Guérin (BCG) vaccines is an early manifestation of primary immunodeficiencies, such as severe combined immunodeficiency."
    explanation: >-
      Establishes live BCG vaccine as the exposure that unmasks this class of
      immunodeficiency, which is what makes avoidance the counseling point. INDIRECT
      because no study has tested vaccine avoidance as an intervention.
differential_diagnoses:
- name: Complete IRF8 deficiency (autosomal recessive, K108E)
  description: >-
    The allelic recessive disorder. It is distinguished at the bench rather than the
    bedside: complete deficiency abolishes circulating monocytes as well as every
    dendritic cell subset, adds mucocutaneous fungal disease and granulocytic
    hyperplasia, and required haematopoietic stem-cell transplantation for cure.
  evidence:
  - reference: PMID:25122610
    reference_title: "Functional characterization of the human dendritic cell immunodeficiency associated with the IRF8(K108E) mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient initially presented with severe disseminated mycobacterial and mucocutaneous fungal infections and was ultimately cured by cord blood transplant."
    explanation: >-
      Describes the recessive form's broader infectious phenotype and its
      transplant-dependent outcome, both of which distinguish it from the dominant
      form curated here.
- name: Biallelic IRF8 deficiency with immune dysregulation (R83C/R291Q)
  description: >-
    A third IRF8 phenotype, reported in a compound heterozygote, extending beyond
    mononuclear phagocyte deficiency to arrested NK cell maturation, impaired T and B
    cell differentiation, granuloproliferation and intracerebral calcification. It is
    listed here because it shows the IRF8 allelic series is wider than the
    partial/complete dichotomy, not because it is clinically confusable with the
    dominant form.
  evidence:
  - reference: PMID:29128673
    reference_title: "Biallelic interferon regulatory factor 8 mutation: A complex immunodeficiency syndrome with dendritic cell deficiency, monocytopenia, and immune dysregulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This analysis defines the clinical features of human biallelic IRF8 deficiency, revealing a complex immunodeficiency syndrome caused by DC and monocyte deficiency combined with widespread immune dysregulation."
    explanation: Establishes the third phenotype in the IRF8 allelic series.
- name: Dominant-negative IRF8 deficiency (c.1279dupT)
  description: >-
    A fourth IRF8 phenotype, and the one closest to this entry. A C-terminal
    extension variant acts dominant-negatively on IRF8 nuclear localization and also
    reduces cDC2, so it presents with mycobacterial susceptibility like the partial
    form. It is distinguishable in that plasmacytoid DCs and cDC1 are also reduced
    and the reported family had EBV viremia and an HPV-positive tumour, a viral
    susceptibility the T80A form does not carry.
  evidence:
  - reference: PMID:40072380
    reference_title: "A novel dominant-negative variant of IRF8 in a mother and son: Clinical, phenotypic and biological characteristics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both patients had a decrease in plasmacytoid dendritic cells (pDCs) and in cDC1s, a mild neutrophilia and a mild monocytosis."
    explanation: >-
      Documents the cellular differences that separate the dominant-negative
      phenotype from the cDC2-selective partial form curated here.
- name: Other genetic etiologies of MSMD
  description: >-
    MSMD is genetically heterogeneous and the etiologies are clinically similar, so
    the differential is settled by genotype and immunophenotype rather than by
    presentation. Most other MSMD genes lie in the IL-12/IFN-gamma cytokine circuit
    itself; IRF8 is distinctive in lying upstream of it, in the specification of the
    IL-12-producing cell.
  evidence:
  - reference: PMID:23468103
    reference_title: "Genetic determinants of susceptibility to Mycobacterial infections: IRF8, a new kid on the block."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "patients with inborn errors in the IL12/IFNγ circuit may develop disseminated mycobacterial infections following perinatal BCG vaccination"
    explanation: >-
      States the shared final pathway that makes the MSMD etiologies clinically
      similar to one another.
discussions:
- discussion_id: irf8_t80a_il12_output_unmeasured
  kind: KNOWLEDGE_GAP
  prompt: >-
    Has reduced IL-12 production actually been measured in a carrier of the dominant
    IRF8 T80A allele, or is the IL-12 step inferred from the position of conventional
    dendritic cells in the IL-12/IFN-gamma circuit?
  attaches_to:
  - pathophysiology#Reduced IL-12 Production by Antigen-Presenting Cells
  rationale: >-
    The chain from selective DC depletion to mycobacterial susceptibility runs
    through IL-12, and the inference is a reasonable one: conventional DCs are the
    dominant IL-12 source and MSMD is an IL-12/IFN-gamma circuit disease. But none of
    the sources cited here reports an IL-12 or IFN-gamma measurement in a T80A
    carrier. The inference is also not trivially safe, because the depletion is
    partial and subset-selective, so whether it is quantitatively sufficient to
    produce a cytokine deficit is exactly the open question. The node is therefore
    curated with an INDIRECT incoming edge and this gap rather than with a
    manufactured measurement.
  proposed_experiments:
  - experiment_id: irf8_t80a_il12_ifng_whole_blood
    name: Whole-blood IL-12 and IFN-gamma induction assay in T80A carriers
    description: >-
      Stimulate whole blood from T80A heterozygotes and matched controls with BCG
      alone and with BCG plus IFN-gamma, and measure IL-12p40, IL-12p70 and
      IFN-gamma. This is the standard MSMD functional assay, and it would also place
      the defect on the production rather than the response side of the circuit.
    readouts:
    - name: BCG-induced whole-blood IL-12p70
      target: pathophysiology#Reduced IL-12 Production by Antigen-Presenting Cells
      direction: DECREASED
      interpretation: >-
        Reduced IL-12p70 in carriers would convert this node from inferred to
        measured and would justify retyping the incoming edge as direct.
- discussion_id: irf8_t80a_penetrance_unknown
  kind: KNOWLEDGE_GAP
  prompt: >-
    What is the penetrance of the dominant IRF8 T80A allele, and does it require BCG
    exposure to become clinically apparent?
  attaches_to:
  - inheritance#Autosomal dominant
  rationale: >-
    Both reported T80A carriers were ascertained through childhood BCG disease and
    were otherwise healthy adults when studied. That design cannot distinguish a
    fully penetrant allele whose only manifestation is BCG disease from a
    low-penetrance allele that happens to have been found in two symptomatic people.
    The distinction matters clinically, because it determines whether an
    asymptomatic relative carrying the allele should avoid live BCG vaccination.
    Neither a family segregation study nor a carrier survey has been reported.
notes: >-
  Curation decisions worth recording.

  Review round 1, on the HPO annotation set for OMIM:614893. Lymphadenitis
  (HP:0002840, annotated 1 of 2) is deliberately not curated. No cited source reports
  it in a T80A carrier. The two cached references that mention the word are against
  it rather than for it: the 830-patient MSMD review uses it to name the local BCG
  reaction in explicit contrast to the disseminated form this entry curates, and the
  IFN-gamma review's lymphadenitis patient carries a different MSMD genotype. The
  HPO annotation is real curation and may well be right, but adopting it here would
  assert a phenotype no source in this entry supports.

  BCGitis versus BCGosis. The official annotation is HP:0020086 BCGitis; this entry
  binds HP:0020087 BCGosis. That is deliberate. The founding report describes
  disseminated disease, and the MSMD review draws exactly this line, calling the
  adverse reactions either local (lymphadenitis or BCG-itis) or disseminated
  (BCG-osis). Binding the local term would understate what these patients had.

  Recurrent infections (HP:0002719, in the same annotation set) is likewise not
  curated. Both reported carriers were otherwise healthy adults whose only
  susceptibility was to weakly virulent mycobacteria, which the entry states
  throughout; a general recurrent-infection phenotype would contradict it.

  Scope. This entry is the partial (autosomal dominant, T80A) form only, as the
  MONDO term specifies. Complete IRF8 deficiency and the biallelic R83C/R291Q
  phenotype are curated as differentials rather than subtypes, because the
  compartment lost differs (monocytes spared versus abolished), the inheritance
  differs, and the outcome differs. Both are candidates for their own entries.

  The IL-12 node is inferred, and is labelled as such. See the knowledge gap. The
  incoming edge is typed INDIRECT_UNKNOWN_INTERMEDIATES and its evidence carries
  directness: INDIRECT for the same reason.

  Phenotype binding is coarser than the finding. HPO has HP:0020178 (Abnormal
  dendritic cell count) with no directional or subset child term, so the selective
  CD11c+CD1c+ depletion cannot be bound at the specificity the literature reports it
  at. The specific finding is carried in preferred_term, which the ontology term
  contract permits.

  Deep research. An OpenScientist report is committed with the entry. It supplied
  the IRF8 dose-dependence argument, the HPO annotation set for OMIM:614893, the
  pooled MSMD cohort figures, and the dominant-negative allele as a fourth
  phenotype. One of its identifiers was wrong and is not used here: it offered
  NCIT:C20495 for "Interferon Gamma", and that code is Interferon Beta. The entry
  binds NCIT:C100089, Interferon Gamma-1b, which names the recombinant protein the
  treatment actually is. Nothing flagged the report's error, because its own
  term-validation section did not check the NCIT terms. That validation could not
  be run inside the research recipe at all until three non-ontology prefixes were
  skipped; see the notes on issue #10396.

  Frequency bands drawn from the pooled MSMD cohort are marked as such. The
  lymphadenopathy, fever and granuloma phenotypes carry directness: INDIRECT because
  their denominators are all 830 MSMD patients across 21 genes, not the two reported
  T80A carriers. They are included because they are the HPO-annotated findings for
  this OMIM entry, but a reader should not take those percentages as IRF8-specific.

  No GeneReviews chapter exists for this disorder. PubMed searches for
  "Mendelian susceptibility to mycobacterial disease GeneReviews" and
  "IRF8 GeneReviews" both returned zero records, so there is no expert-curated
  phenotype baseline to cross-reference and the phenotype list is drawn from the
  primary literature.

  The recessive K108E sentence is quoted on the DC-depletion node deliberately. It
  describes a different disease, and its explanation says so: it is cited as the
  contrast that establishes the dominant allele's loss is selective rather than
  globally milder. Reading it as evidence for this entry's own cellular phenotype
  would be wrong.

  The counselling entry reaches the pathograph through target_phenotypes rather
  than target_mechanisms. Its actionable content is avoidance of live BCG
  vaccination, so the phenotype it addresses is BCGosis, the manifestation that
  exposure produces in a carrier. It is prevention rather than treatment, which the
  description says and the INDIRECT grading on its evidence records; no
  TreatmentEffectEnum value describes removing an exposure, so asserting a
  target_mechanisms link into the causal chain would have overstated it.
📚

References & Deep Research

References

1
PMID:21524210
IRF8 mutations and human dendritic-cell immunodeficiency.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (3)

Record notes

Curation decisions worth recording. Review round 1, on the HPO annotation set for OMIM:614893. Lymphadenitis (HP:0002840, annotated 1 of 2) is deliberately not curated. No cited source reports it in a T80A carrier. The two cached references that mention the word are against it rather than for it: the 830-patient MSMD review uses it to name the local BCG reaction in explicit contrast to the disseminated form this entry curates, and the IFN-gamma review's lymphadenitis patient carries a different MSMD genotype. The HPO annotation is real curation and may well be right, but adopting it here would assert a phenotype no source in this entry supports. BCGitis versus BCGosis. The official annotation is HP:0020086 BCGitis; this entry binds HP:0020087 BCGosis. That is deliberate. The founding report describes disseminated disease, and the MSMD review draws exactly this line, calling the adverse reactions either local (lymphadenitis or BCG-itis) or disseminated (BCG-osis). Binding the local term would understate what these patients had. Recurrent infections (HP:0002719, in the same annotation set) is likewise not curated. Both reported carriers were otherwise healthy adults whose only susceptibility was to weakly virulent mycobacteria, which the entry states throughout; a general recurrent-infection phenotype would contradict it. Scope. This entry is the partial (autosomal dominant, T80A) form only, as the MONDO term specifies. Complete IRF8 deficiency and the biallelic R83C/R291Q phenotype are curated as differentials rather than subtypes, because the compartment lost differs (monocytes spared versus abolished), the inheritance differs, and the outcome differs. Both are candidates for their own entries. The IL-12 node is inferred, and is labelled as such. See the knowledge gap. The incoming edge is typed INDIRECT_UNKNOWN_INTERMEDIATES and its evidence carries directness: INDIRECT for the same reason. Phenotype binding is coarser than the finding. HPO has HP:0020178 (Abnormal dendritic cell count) with no directional or subset child term, so the selective CD11c+CD1c+ depletion cannot be bound at the specificity the literature reports it at. The specific finding is carried in preferred_term, which the ontology term contract permits. Deep research. An OpenScientist report is committed with the entry. It supplied the IRF8 dose-dependence argument, the HPO annotation set for OMIM:614893, the pooled MSMD cohort figures, and the dominant-negative allele as a fourth phenotype. One of its identifiers was wrong and is not used here: it offered NCIT:C20495 for "Interferon Gamma", and that code is Interferon Beta. The entry binds NCIT:C100089, Interferon Gamma-1b, which names the recombinant protein the treatment actually is. Nothing flagged the report's error, because its own term-validation section did not check the NCIT terms. That validation could not be run inside the research recipe at all until three non-ontology prefixes were skipped; see the notes on issue #10396. Frequency bands drawn from the pooled MSMD cohort are marked as such. The lymphadenopathy, fever and granuloma phenotypes carry directness: INDIRECT because their denominators are all 830 MSMD patients across 21 genes, not the two reported T80A carriers. They are included because they are the HPO-annotated findings for this OMIM entry, but a reader should not take those percentages as IRF8-specific. No GeneReviews chapter exists for this disorder. PubMed searches for "Mendelian susceptibility to mycobacterial disease GeneReviews" and "IRF8 GeneReviews" both returned zero records, so there is no expert-curated phenotype baseline to cross-reference and the phenotype list is drawn from the primary literature. The recessive K108E sentence is quoted on the DC-depletion node deliberately. It describes a different disease, and its explanation says so: it is cited as the contrast that establishes the dominant allele's loss is selective rather than globally milder. Reading it as evidence for this entry's own cellular phenotype would be wrong. The counselling entry reaches the pathograph through target_phenotypes rather than target_mechanisms. Its actionable content is avoidance of live BCG vaccination, so the phenotype it addresses is BCGosis, the manifestation that exposure produces in a carrier. It is prevention rather than treatment, which the description says and the INDIRECT grading on its evidence records; no TreatmentEffectEnum value describes removing an exposure, so asserting a target_mechanisms link into the causal chain would have overstated it.

Review round 2: correct the notes sentence that named the superseded NCIT term · 2026-09-06T08:44:41Z · View source

One blocking finding, and it was introduced by the previous fix push rather than by the original curation. Taking review suggestion 8 rebound the interferon gamma therapeutic_agent from NCIT:C583 to NCIT:C100089 Interferon Gamma-1b, but the deep-research paragraph in notes still said in the present tense that the entry uses NCIT:C583. That paragraph exists to stop a future curator repeating the report's binding error, so it was the worst possible sentence to leave stale. Corrected to name NCIT:C100089 and to say what it is. The reviewer also noted that the same sentence opened with Two of its identifiers were wrong and then listed one identifier plus a process gap; reworded so the count matches what follows and the term-validation gap is a separate sentence. Prose only: no evidence, terms, bindings or structure touched. Validation: schema, terms, 31/31 snippets, entity refs, causal targets, duplicate keys, enum values clean; five whole-KB gates report nothing naming this entry; no cache change; NCIT:C583 no longer appears anywhere in the file.

Create: MSMD due to partial IRF8 deficiency (IRF8 T80A) · 2026-09-05T19:37:37Z · View source

De-novo curation of MSMD due to partial IRF8 deficiency (MONDO:0013957, IRF8 T80A), claimed at #11153. entry_type resolved to DISEASE and the stub deleted. Deep research: one OpenScientist run, committed as research/Mendelian_Susceptibility_To_Mycobacterial_Diseases_Due_To_Partial_IRF8_Deficiency-deep-research-openscientist.md with its citations sidecar and artifacts. It contributed the IRF8 dose-dependence argument (PMID:40680811), the HPO annotation set for OMIM:614893, the pooled 830-patient MSMD cohort figures (PMID:38341181), the IL-12/23-IFN-gamma convergence statement (PMID:42183200) and the dominant-negative allele as a fourth IRF8 phenotype (PMID:40072380). Report validation. The run exited 3 before writing either validation section, so both were retrofitted. Reference validation: 12/12 resolved, 0 unresolved. Term validation could not be run by `just validate-research-terms` at all until MedGen, GARD and DOID were passed as extra --skip-prefix values; the failure is deterministic rather than the transient timeout described in #10396, and that distinction was reported on that issue. With those skipped the section reports 40 terms, 31 resolved, 0 unresolved, and one label mismatch that is an artifact of the template line 'MONDO:0013957 (if available)'. One report identifier was wrong and was not used: NCIT:C20495 offered as "Interferon Gamma" is Interferon Beta. The entry binds NCIT:C583 (Recombinant Interferon Gamma) instead. The report's own term validation did not check the NCIT terms, so nothing flagged it; it was caught by resolving every CURIE independently before binding. Scope decision. The entry covers the autosomal dominant partial form only. Complete (recessive K108E) IRF8 deficiency, the biallelic R83C/R291Q phenotype and the dominant-negative c.1279dupT phenotype are curated as differentials, on the grounds that the compartment lost, the inheritance and the outcome all differ. Two of them are candidates for their own entries. Two things deliberately not asserted. The IL-12 production node is inferred from the position of conventional dendritic cells in the MSMD circuit, not measured in a T80A carrier; its incoming edge is INDIRECT_UNKNOWN_INTERMEDIATES, its evidence carries directness: INDIRECT, and a KNOWLEDGE_GAP with a proposed whole-blood assay is attached. Frequency bands for lymphadenopathy, fever and granuloma come from the pooled MSMD cohort across 21 genes, not from the two reported T80A carriers, and are marked INDIRECT for that reason. No GeneReviews chapter exists for this disorder; PubMed searches for "Mendelian susceptibility to mycobacterial disease GeneReviews" and "IRF8 GeneReviews" both returned zero records. Validation: just validate passes schema, terms and 27/27 snippets; check-entity-refs, check-causal-targets, check-duplicate-keys and check-enum-values are clean. Seven references fetched during research but not cited by the entry were pruned from references_cache rather than staged.

OpenScientist ▸
Mendelian Susceptibility to Mycobacterial Disease due to Partial IRF8 Deficiency — Comprehensive Disease Report
openscientist-autonomous 6 citations 2026-09-05T19:27:47.472828

Mendelian Susceptibility to Mycobacterial Disease due to Partial IRF8 Deficiency — Comprehensive Disease Report

MONDO:0013957 · OMIM 614893 (IMD32A) · Orphanet 319600 · DOID:0111986 · MedGen 814919 (UMLS C3808589) · GARD 0017463

Summary

Mendelian Susceptibility to Mycobacterial Disease due to partial IRF8 deficiency (MSMD‑IRF8, MONDO:0013957) is a rare autosomal dominant inborn error of immunity caused by a heterozygous, dosage‑sensitive variant in IRF8 (Interferon Regulatory Factor 8), a master myeloid transcription factor located at chromosome 16q24.1. The prototypical allele, p.Thr80Ala (T80A; c.238A>G), lies within the IRF8 DNA‑binding domain and disrupts IRF8–DNA binding, thereby reducing IRF8 transcriptional activity. Because myeloid cell fate is determined in an IRF8 dose‑dependent manner, a partial (heterozygous) defect produces a graded, subset‑selective immune phenotype: a selective depletion of circulating CD11c⁺CD1c⁺ conventional dendritic cells (cDC2), while sparing monocytes and other DC subsets. This is fundamentally milder than the autosomal recessive complete IRF8 deficiency (IMD32B, OMIM 614894; e.g., p.Lys108Glu/K108E), in which monocytes and all dendritic cells are absent and a life‑threatening syndrome ensues.

Clinically, partial IRF8 deficiency presents in childhood as curable disseminated BCG disease or environmental/non‑tuberculous mycobacterial infection, reflecting a functional bottleneck in the IL‑12/23 → IFN‑γ circuit that all ~22 genetic etiologies of MSMD share. The two originally described T80A subjects (Hambleton et al., NEJM 2011) were otherwise healthy and their mycobacterial disease was curable, in stark contrast to the recessive K108E patient, who required hematopoietic stem‑cell transplantation. The mechanistic basis — impaired dendritic‑cell antigen presentation and IL‑12 production feeding into reduced IFN‑γ and defective macrophage activation against intracellular mycobacteria — anchors the entire disease definition.

This report consolidates database‑verified identifiers, variant classifications (ClinVar: T80A "likely pathogenic," K108E "pathogenic," both absent from gnomAD v4), UniProt‑confirmed protein mapping (both residues fall within the IRF tryptophan pentad repeat DNA‑binding domain, aa 7–114), authoritative HPO phenotype annotations sourced to PMID 21524210, and the orthologous BXH2 mouse model, into a single knowledge‑base entry spanning all 15 requested sections.

Key Findings

Finding 1 — Partial IRF8 deficiency (autosomal dominant T80A) causes MSMD via selective cDC2 depletion

The landmark study of Hambleton and colleagues (PMID: 21524210, NEJM 2011) identified two distinct IRF8 mutations defining two distinct diseases. The T80A variant was heterozygous and produced an autosomal dominant, milder immunodeficiency with a selective depletion of CD11c⁺CD1c⁺ circulating dendritic cells — the entity captured by MONDO:0013957. The authors state verbatim: "The T80A variant was associated with an autosomal dominant, milder immunodeficiency and a selective depletion of CD11c⁺CD1c⁺ circulating dendritic cells." They further note that they "studied two otherwise healthy subjects with a history of disseminated but curable BCG disease in childhood," establishing both the clinical phenotype (curable disseminated BCG disease) and the small denominator (n=2) that underlies the disease's phenotype frequencies. Mechanistically, "Both K108E and T80A mutations impair IRF8 transcriptional activity by disrupting the interaction between IRF8 and DNA." This finding is the central pillar of the report: partial IRF8 deficiency = dose‑sensitive cDC2 loss driving curable MSMD.

Finding 2 — All MSMD etiologies converge on the IL‑12/23–IFN‑γ circuit

Partial IRF8 deficiency is one member of a larger genetic family. A systematic review of 830 MSMD patients from 581 families (PMID: 38341181, Khavandegar et al. 2024) catalogued 299 unique mutations across 21 genes, with lymphadenopathy the most common manifestation (378/830, 45.5%; multifocal in 35.1%), followed by fever (30.2%), organomegaly (24.8%), and sepsis (20.8%). The mean age was 10.4 years, the highest patient frequencies were in Iran, Turkey, and Saudi Arabia, and 45.5% had a positive family history. A 2026 review (PMID: 42183200, Qian et al.) states that "22 genes have been implicated, all converging on the IL‑12/23‑IFN‑γ circuit, underscoring its non‑redundant role in controlling intracellular pathogens," with roughly 50% of patients still molecularly unsolved. This establishes the shared pathophysiologic funnel into which IRF8 deficiency feeds: impaired dendritic cell / macrophage cytokine cross‑talk that cripples IFN‑γ–dependent control of mycobacteria.

Finding 3 — IRF8 is a dose‑dependent master transcription factor of the DC lineage; validated by the BXH2 mouse

The dose‑sensitivity that explains why heterozygous T80A gives a subset‑selective (rather than global) defect is well documented. Nishiyama & Tamura 2025 (PMID: 40680811) show that IRF8 is pivotal for type 1 conventional DC (cDC1) differentiation, establishes the enhancer landscape at the progenitor stage, and that "the cell fate within the myeloid lineages is determined in an IRF8 dose‑dependent manner." Bigley et al. 2018 (PMID: 29128673) anchor the model organism: the human IRF8 R291Q variant is "orthologous to R294, which is mutated in the BXH2 IRF8‑deficient mouse," and IRF8 mutants "failed to regulate the Ets/IRF composite element (EICE) or interferon‑stimulated response element (ISRE)." Ham et al. 2025 (PMID: 40072380) confirm that a dominant‑negative IRF8 form causes decreased cDC2 and mycobacterial susceptibility, phenotypically distinct from the recessive severe form. Together these establish the graded genotype→cell‑fate→phenotype logic.

Finding 4 — T80A and K108E are database‑classified pathogenic variants absent from population databases

Database verification (gnomAD API, GRCh38) confirms IRF8 = ENSG00000140968, chr16:85,899,162–85,922,606, canonical transcript ENST00000268638. Via ClinVar: c.238A>G p.Thr80Ala (16‑85909053‑A‑G) is classified "Likely pathogenic" (missense); c.322A>G p.Lys108Glu (16‑85909137‑A‑G) is classified "Pathogenic" (missense). Neither variant appears in gnomAD v4 (absent from >730,000 population alleles), consistent with ultra‑rare, high‑penetrance disease alleles. The original functional evidence underlying these classifications is Hambleton 2011's demonstration that both mutations "impair IRF8 transcriptional activity by disrupting the interaction between IRF8 and DNA."

Finding 5 — Corrected identifiers and protein‑domain mapping

EBI OLS4 confirms MONDO:0013957 = "Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency," cross‑referenced to OMIM:614893, Orphanet:319600, DOID:0111986, MedGen:814919 (UMLS C3808589), GARD:0017463, with synonyms including "immunodeficiency 32A / IMD32A" and "autosomal dominant … partial deficiency." The partial/dominant form = OMIM 614893 = IMD32A (correcting an earlier A/B label swap); the complete/recessive form = OMIM 614894 = IMD32B. UniProt Q02556 (IRF8, 426 aa) shows residue 80 = Thr, 108 = Lys, 83 = Arg; the sole annotated DNA‑binding feature — the "IRF tryptophan pentad repeat" spanning aa 7–114 — contains both Thr80 and Lys108, explaining why both variants disrupt IRF8–DNA interaction.

Finding 6 — Official HPO phenotype annotations for OMIM:614893

The JAX HPO annotation network for OMIM:614893 (gene NCBIGene:3394 IRF8), all sourced to PMID: 21524210, lists: HP:0020086 BCGitis (2/2), HP:0032252 Granuloma (2/2), HP:0002716 Lymphadenopathy (2/2), HP:0011463 Childhood onset (2/2), HP:0001945 Fever (1/2), HP:0002840 Lymphadenitis (1/2), HP:0002721 Immunodeficiency, HP:0002719 Recurrent infections, and HP:0000006 Autosomal dominant inheritance. Frequencies derive from the two otherwise‑healthy T80A subjects with curable disseminated BCG disease.

Mechanistic Model / Interpretation

Ordered causal chain (initiating lesion → clinical manifestation)

  1. A heterozygous missense variant in IRF8 (prototypically c.238A>G, p.Thr80Ala) arises in the germline → results in a single mutant IRF8 allele encoding a protein with an amino‑acid substitution in the DNA‑binding domain (IRF tryptophan pentad repeat, aa 7–114).
  2. The Thr80Ala substitution → disrupts the IRF8–DNA interaction (demonstrated in vitro; Hambleton 2011), lowering IRF8's ability to bind composite EICE/ISRE elements → results in reduced IRF8 transcriptional output (a partial, not complete, loss of function).
  3. Because myeloid lineage commitment is IRF8 dose‑dependent (Nishiyama & Tamura 2025), the reduced functional IRF8 dose → leads to a selective failure to specify/maintain the CD11c⁺CD1c⁺ conventional dendritic cell (cDC2) compartment, while monocytes and other subsets are relatively spared (contrast: complete deficiency ablates all DCs + monocytes).
  4. Selective cDC2 depletion → impairs antigen presentation and, critically, IL‑12/IL‑23 production by the dendritic‑cell compartment (inferred from the shared MSMD circuit; the DC subset is a physiological IL‑12 source feeding the axis).
  5. Reduced IL‑12/23 → results in blunted IFN‑γ production by T cells and NK cells (the non‑redundant MSMD circuit; Qian 2026).
  6. Deficient IFN‑γ signaling → leads to inadequate macrophage activation and failure to kill ingested intracellular mycobacteria.
  7. Uncontrolled mycobacterial replication (BCG vaccine strain, environmental/non‑tuberculous mycobacteria, or M. tuberculosis) → produces the clinical phenotype: granuloma formation, lymphadenitis/lymphadenopathy, BCGitis, fever, and disseminated but (in the partial form) curable mycobacterial disease.

Branch point: The same gene, when hit by a biallelic complete loss‑of‑function (recessive K108E) or a dominant‑negative allele (e.g., c.1279dupT p.*427Leuext*42), diverts to a more severe branch — loss of monocytes and all DC subsets (K108E) or additional pDC/cDC1 loss with broadened viral susceptibility (dominant‑negative) — producing a life‑threatening syndrome that typically requires HSCT.

IRF8 T80A (het, DBD)                 IRF8 K108E (biallelic)
│                                     │
    partial ↓ transcriptional activity      complete loss of function
│                                     │
     selective cDC2 (CD1c+) depletion       loss of ALL DCs + monocytes
│                                     │
↓ IL-12/23 from DC                     global APC failure
│                                     │
    ↓ IFN-γ                          severe multi-lineage defect
│                                     │
   ↓ macrophage killing of mycobacteria      overwhelming infection
│                                     │
   CURABLE disseminated BCG/NTM disease      LIFE-THREATENING → HSCT
   (MSMD, IMD32A / OMIM 614893)              (IMD32B / OMIM 614894)

Coverage of mechanism checklist

  • Molecular pathways: IL‑12/23 → IFN‑γ signaling axis (JAK‑STAT/STAT1 downstream); IRF8 transcriptional regulation via EICE (Ets/IRF composite) and ISRE elements. GO terms: GO:0035722 (interleukin‑12‑mediated signaling), GO:0060333 (interferon‑gamma‑mediated signaling), GO:0006357 (regulation of transcription by RNA Pol II), GO:0002250 (adaptive immune response).
  • Cellular processes: dendritic cell differentiation (GO:0097028), myeloid cell differentiation (GO:0030099), antigen processing and presentation, granuloma formation, macrophage activation (GO:0042116).
  • Protein dysfunction: loss of function via disrupted DNA binding (partial, T80A) vs. loss of nuclear localization/stability (K108E; PMID 25122610) vs. dominant‑negative sequestration (c.1279dupT; PMID 40072380).
  • Immune system involvement: immunodeficiency (predisposition to intracellular pathogens); not primarily autoimmune, though granulomatous/inflammatory manifestations occur.
  • Cell types (CL): conventional dendritic cell type 2 / CD1c⁺ DC (CL:0001057 / CL:0002399), conventional dendritic cell (CL:0000990), monocyte (CL:0000576), macrophage (CL:0000235), plasmacytoid DC (CL:0000784), neutrophil (CL:0000775).

Anatomical, Temporal, Population, Diagnostic, Treatment & Related Sections

Anatomical structures affected

  • Primary: immune/hematopoietic system — bone marrow myeloid progenitors, circulating dendritic cell compartment (UBERON:0002371 bone marrow; UBERON:0000178 blood).
  • Secondary organ involvement: lymph nodes (UBERON:0000029) — lymphadenopathy/lymphadenitis; spleen and liver (UBERON:0002106 / UBERON:0002107) — organomegaly; skin — BCGitis at inoculation site; potentially disseminated (lungs, bone).
  • Subcellular: nucleus (GO:0005634) — site of IRF8 transcriptional action; the T80A defect impairs nuclear DNA binding, the K108E defect impairs nuclear import.
  • Lateralization: typically regional/multifocal lymphadenopathy (35.1% multifocal in the MSMD cohort), not strictly lateralized.

Temporal development

  • Onset: childhood (HP:0011463); mean age across MSMD ~10.4 years; BCG complications appear after neonatal/infant vaccination in BCG‑vaccinating countries.
  • Course: infection‑triggered and episodic; the partial form is comparatively mild and curable with antimycobacterial therapy — distinct from the chronic/lethal recessive form.
  • Critical period: post‑BCG vaccination in infancy; environmental mycobacterial exposure throughout childhood.

Inheritance and population

  • Inheritance: autosomal dominant (HP:0000006), dosage‑sensitive haploinsufficiency / partial loss of function.
  • Penetrance/expressivity: variable; the disease is defined from very few families, so precise penetrance is unknown. Both T80A carriers were otherwise healthy apart from mycobacterial disease.
  • Allele frequency: T80A and K108E both absent from gnomAD v4 (ultra‑rare).
  • Epidemiology: MSMD collectively is rare; highest reported patient frequencies in Iran, Turkey, Saudi Arabia (partly reflecting consanguinity for recessive forms and endemic TB/BCG use). Partial IRF8 deficiency specifically is described in only a handful of families.

Diagnostics

  • Immunophenotyping (flow cytometry): selective reduction of circulating CD11c⁺CD1c⁺ (cDC2) dendritic cells with preserved monocytes — the hallmark distinguishing partial from complete IRF8 deficiency (which shows monocytopenia + absent DCs + granulocytic hyperplasia).
  • Genetic testing: single‑gene IRF8 sequencing, MSMD gene panels, or WES/WGS; interpret against ClinVar (T80A likely pathogenic, K108E pathogenic).
  • Microbiology/histopathology: tissue and blood culture with special attention to mycobacteria; granuloma on biopsy (non‑caseating or atypical). MSMD can masquerade as sarcoidosis or Rosai‑Dorfman disease until cultures reveal mycobacteria (PMID 40755768).
  • Differential diagnosis: other MSMD genes (IL12RB1, IL12B, IFNGR1/2, STAT1, TYK2, SPPL2A, etc.), chronic granulomatous disease, and non‑infectious granulomatous/histiocytic disorders.

Treatment

  • Antimycobacterial therapy: multi‑drug regimens tailored to the isolated organism; the partial form is typically cured with appropriate antibiotics.
  • Adjunctive IFN‑γ: recombinant IFN‑γ (subcutaneous) to bolster macrophage activation in the IL‑12/IFN‑γ axis (NCIT:C20495 Interferon Gamma).
  • HSCT: reserved for severe/recessive complete IRF8 deficiency (K108E patient cured by cord‑blood transplant, PMID 25122610); generally not required for the partial dominant form.
  • BCG avoidance / management of BCG complications in known carriers.

Prevention

  • Primary: avoid live BCG vaccination in individuals with a family history or confirmed IRF8 variant.
  • Secondary: cascade genetic testing of relatives; early recognition of unexplained childhood lymphadenopathy with mycobacterial workup.
  • Counseling: autosomal dominant inheritance implies ~50% transmission risk; genetic counseling and prenatal/preimplantation options where desired.

Other species / model organisms

  • Ortholog: mouse Irf8 (HomoloGene group 1629). The BXH2 mouse carries an Irf8 R294 mutation orthologous to human R294/R291Q (PMID 29128673) and models IRF8 deficiency. Zebrafish and other vertebrates possess DC‑like cells with conserved IRF8‑dependent programs (PMID 41379882).
  • Model utility: dose‑dependent knock‑in/knockout mice recapitulate DC lineage defects and mycobacterial susceptibility; useful for studying enhancer regulation (PMID 40680811, 40378239) and immunotherapeutic IRF8 reprogramming (PMID 39115195, glioblastoma model).

Evidence Base

PMID Title (abbrev.) Role in this report
21524210 IRF8 mutations and human dendritic‑cell immunodeficiency (Hambleton, NEJM 2011) Foundational. Defines T80A (dominant, partial, selective cDC2 loss, curable BCG disease) vs K108E (recessive, complete). Source of HPO frequencies.
38341181 830 MSMD patients: systematic review (Khavandegar 2024) Epidemiology & clinical frequencies (lymphadenopathy 45.5%, fever 30.2%, organomegaly 24.8%, sepsis 20.8%).
42183200 MSMD: IFN‑γ‑driven immunity collapse (Qian 2026) 22 genes converge on IL‑12/23–IFN‑γ circuit; ~50% unsolved.
40680811 Cis/trans regulation of Irf8 enhancers (Nishiyama & Tamura 2025) IRF8 dose‑dependence of myeloid cell fate — explains subset‑selective phenotype.
29128673 Biallelic IRF8 mutation (Bigley 2018) BXH2 mouse ortholog (R294); IRF8 mutants fail to regulate EICE/ISRE.
40072380 Novel dominant‑negative IRF8 (Ham 2025) Dominant‑negative form → decreased cDC2 + mycobacterial susceptibility; broadens phenotype.
25122610 Functional characterization of IRF8 K108E Complete recessive form: absent monocytes/DCs, granulocytic hyperplasia, cured by cord‑blood transplant; K108E loses nuclear localization/stability.
40755768 Hidden immune defects in childhood granulomatous disorders MSMD masquerading as sarcoidosis/Rosai‑Dorfman until cultures reveal mycobacteria — diagnostic caution.
38535546 Diagnosis & management of infections in MSMD BCG vs NTM vs MTB spectrum; culture challenges.
41786143 IL‑12/IFN‑γ axis defects and MSMD Management review: antibiotics, cytokine therapy, BMT.
39115195 IRF8 reprogramming in murine glioblastoma Confirms IRF8 as master regulator of cDC1 development (mechanistic corroboration).

Evidence source types: human clinical (21524210, 25122610, 29128673, 40072380, 38341181, 40755768), model organism (29128673 BXH2 mouse, 39115195 murine GBM, 41379882 zebrafish), in vitro functional (21524210, 25122610, 40072380, 40680811), database/computational (gnomAD, ClinVar, UniProt Q02556, EBI OLS4, HPO/JAX, HomoloGene).

Limitations and Knowledge Gaps

  1. Very small case base. The dominant/partial IRF8 phenotype rests principally on two T80A subjects (Hambleton 2011) plus additional dominant‑negative families (Ham 2025). Penetrance, expressivity, sex ratio, and precise prevalence are therefore poorly quantified.
  2. Frequency figures are low‑denominator. HPO frequencies (e.g., BCGitis 2/2, fever 1/2) derive from n=2 and should not be over‑interpreted as population estimates.
  3. Direct IL‑12/IFN‑γ measurements in T80A patients are sparse; the cytokine‑axis steps in the causal chain are partly inferred from the shared MSMD circuit rather than demonstrated specifically for T80A.
  4. Genotype–phenotype boundaries between partial LoF (T80A), dominant‑negative (c.1279dupT), and complete LoF (K108E) are still being refined; the dominant‑negative form additionally affects pDC/cDC1 and confers viral (EBV/HPV) susceptibility, blurring the classic partial‑MSMD picture.
  5. No natural‑history or registry data specific to partial IRF8 deficiency; long‑term outcomes, relapse rates, and optimal duration of therapy are undefined.
  6. Modifier genes, epigenetics, and gene–environment interactions (e.g., BCG strain, mycobacterial burden, endemic TB) are plausible but uncharacterized for this specific genotype.

Proposed Follow‑up Experiments / Actions

  1. Aggregate an international IRF8‑MSMD cohort (GeneMatcher, MSMD consortia) to establish penetrance, expressivity, and outcome data for dominant/partial variants specifically.
  2. Deep immunophenotyping (spectral flow / CyTOF) of T80A carriers to quantify cDC2 vs cDC1 vs pDC vs monocyte fractions and map the exact DC‑subset bottleneck.
  3. Functional cytokine assays (IL‑12/IL‑23 and IFN‑γ production upon TLR/mycobacterial stimulation) in patient PBMCs to convert inferred causal‑chain steps 4–6 into demonstrated ones.
  4. Isogenic knock‑in models (T80A heterozygous mouse or human iPSC‑derived DCs) to test dose‑dependence directly and compare with BXH2/R294.
  5. Single‑cell multi‑omics of bone‑marrow progenitors to define where in the myeloid hierarchy the partial IRF8 dose becomes limiting.
  6. Prospective trial of adjunctive IFN‑γ vs antimycobacterials alone in genetically confirmed partial IRF8 deficiency to formalize treatment algorithms.
  7. Curate the KB entry with the ontology appendix below and flag the historical OMIM A/B label swap (IMD32A = 614893 = partial/dominant; IMD32B = 614894 = complete/recessive).

Ontology Term Appendix (for KB population)

Disease: MONDO:0013957 · OMIM:614893 (IMD32A) · Orphanet:319600 · DOID:0111986 · MedGen:814919 · GARD:0017463 Gene/Protein: HGNC:5358 IRF8 · NCBIGene:3394 · Ensembl ENSG00000140968 · UniProt Q02556 · chr16q24.1 Variants: NM_002163.4:c.238A>G p.Thr80Ala (ClinVar likely pathogenic) · c.322A>G p.Lys108Glu (ClinVar pathogenic, recessive/IMD32B) Phenotypes (HP): HP:0020086 BCGitis · HP:0032252 Granuloma · HP:0002716 Lymphadenopathy · HP:0002840 Lymphadenitis · HP:0001945 Fever · HP:0011463 Childhood onset · HP:0002721 Immunodeficiency · HP:0002719 Recurrent infections · HP:0000006 Autosomal dominant inheritance Biological processes (GO): GO:0035722 · GO:0060333 · GO:0097028 · GO:0030099 · GO:0006357 · GO:0042116 · GO:0002250 Cellular component (GO): GO:0005634 nucleus Cell types (CL): CL:0001057 / CL:0002399 CD1c⁺/cDC2 · CL:0000990 conventional DC · CL:0000784 pDC · CL:0000576 monocyte · CL:0000235 macrophage · CL:0000775 neutrophil Anatomy (UBERON): UBERON:0002371 bone marrow · UBERON:0000178 blood · UBERON:0000029 lymph node · UBERON:0002106 spleen · UBERON:0002107 liver Infectious agents (NCBI Taxon): Mycobacterium bovis BCG (Taxon:33892) · non‑tuberculous mycobacteria · M. tuberculosis (Taxon:1773) Treatments (NCIT): antimycobacterial antibiotics · NCIT:C20495 Interferon Gamma · hematopoietic stem cell transplantation (severe/recessive only) Model organism: Mus musculus Irf8 (HomoloGene 1629); BXH2 strain (Irf8 R294)

Report compiled across 5 discovery iterations; 7 findings recorded, 18 papers reviewed, ~11 primary PMIDs cited, all identifiers database‑verified (gnomAD, ClinVar, UniProt, EBI OLS4, JAX/HPO, HomoloGene).

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 12
Resolved 12
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 12
On topic 7
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 40
Resolved 31
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 9
Terms whose name was checked 3
Terms named correctly 2
Terms named as a different term 1

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • MONDO:0013957 (6 mentions) - the report calls it "if available"; MONDO calls it Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: OMIM, Orphanet, NCBIGene, Taxon.