Immunodeficiency 118

Mendelian MONDO:0958030 Pathograph 19 Show in embeddings browser Mendelian Susceptibility to Mycobacterial Disease Inborn Errors of Immunity

IMD118 is X-linked MCTS1 deficiency, a Mendelian susceptibility to mycobacterial disease in which a general translation factor defect is funnelled into a single clinical phenotype by a single vulnerable substrate. Nine patients in nine unrelated families are published: five in the 2023 report that defined the entity and four in a 2026 follow-up. MCTS1 partners with DENR to recycle post-termination 40S ribosomal subunits and to allow reinitiation on messages carrying short upstream open reading frames. Losing it should, on the face of it, disturb a great deal. It does not. Of seventeen genes of IFN-gamma immunity tested in MCTS1-knockout cells, only JAK2 translation fell — because the JAK2 5-prime untranslated region carries two ultra-short start-stop upstream open reading frames at which 40S subunits stall without MCTS1 to recycle them, blocking reinitiation at the main open reading frame. The consequence is a JAK2 level low enough to impair responses to IL-23, and partially to IL-12, while leaving other JAK2-dependent cytokine responses intact. Defective IL-23 signalling preferentially costs IFN-gamma production by the innate-like adaptive lymphocytes — MAIT cells and gamma-delta T cells — that respond to mycobacterial challenge, and IFN-gamma is the macrophage-activating cytokine that controls intracellular mycobacteria. Everything else MCTS1 does appears to be physiologically redundant, which is the founding paper's own word for it. Two clinically load-bearing consequences follow. The block is upstream of the IFN-gamma receptor and patient cells respond normally to exogenous IFN-gamma, so the lesion is bypassable — and by 2026, three patients had been given IFN-gamma-1b with reported benefit. And the disease is not the benign entity the first report suggested: one of the original five died, one of the four new patients died of disseminated BCG involving the brain, and two of the new patients have hypogammaglobulinaemia requiring immunoglobulin replacement, which the phrase "otherwise physiologically redundant" does not prepare a reader for.

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1
Inheritance
7
Pathophys.
9
Phenotypes
3
Gaps
19
Pathograph
2
Genes
3
Medical Actions
2
References
1
Deep Research
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Classifications

Harrison's Part
IMMUNE RHEUMATOLOGIC
IUIS Category
innate immunity defect
👪

Inheritance

1
X-linked recessive inheritance HP:0001419
All nine published patients are male and hemizygous. The 2023 kindreds are from China, Finland, Iran and Saudi Arabia; the 2026 families from Iran, Oman, China and the United States. Consanguinity is common but not required — the American patient's family is not described as consanguineous, and his variant is hypomorphic rather than null.
X-linked recessive inheritance
Show evidence (1 reference)
PMID:37875108 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"We report X-linked recessive MCTS1 deficiency in men with mycobacterial disease from kindreds of different ancestries (from China, Finland, Iran, and Saudi Arabia)."
The inheritance mode and the geographic spread of the founding kindreds, which is what makes this a recurrent genotype rather than a founder effect.
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Discussions and Knowledge Gaps

3
Is MCTS1-dependent translation reinitiation really "otherwise physiologically redundant", or did the founding cohort simply have less follow-up than the second one?
CONTROVERSY OPEN imd118_redundancy_claim
Attached to
pathophysiology#Failure of 40S Ribosome Recycling and Translation Reinitiation phenotypes#Failure to Thrive phenotypes#Decreased Circulating Immunoglobulin
The 2023 report's most striking claim is that losing a general translation factor costs nothing outside the mycobacterial axis: normal immunity, growth and development in the survivors. It is a claim worth taking seriously — nine hemizygous null males with no malignancy is real evidence that an established oncogene is dispensable. The 2026 series does not contradict it directly and does sit awkwardly with it. Three of four new patients have growth failure below the third percentile, three have hypogammaglobulinaemia or low IgG prompting replacement, one has delayed gross motor development, and three have chronic gastrointestinal disease. Some of that is attributable to chronic mycobacterial infection, which causes growth failure on its own. Some of it may not be. The two readings make different predictions. If the extra features are infection-driven, they should improve with mycobacterial control; if they are a direct consequence of the translation defect, they should not. The American patient — healthy childhood, no BCG, disease only from sixteen — is the informative case, and what is reported for him is chronic weight loss dating from the onset of his infection rather than from birth. This entry records both the founding claim and the later series without resolving them, and the quoted hedge in the mechanism node is deliberate.
Should recombinant IFN-gamma be started at diagnosis in MCTS1 deficiency rather than after antimycobacterial therapy fails?
OPEN QUESTION OPEN imd118_ifng_bypass
Attached to
treatments#Recombinant Interferon Gamma-1b pathophysiology#Failure of Macrophage Activation Against Intracellular Mycobacteria
The mechanistic case is unusually clean for a disease this rare. The defect is in the induction of IFN-gamma, not in the response to it; patient leukocytes respond normally to exogenous IFN-gamma and IFN-alpha; so the lesion is bypassable in principle, and the pathograph in this entry predicts exactly where the bypass enters. The evidence is two uncontrolled observations. In the American patient, IFN-gamma-1b at 400 micrograms three times weekly produced substantial improvement — after about a year, which is worth noting for anyone judging an early response. In the Omani patient it improved activity, mobility and nutrition, was stopped after six weeks when follow-up was lost, and he died some months later; that sequence is suggestive and is not evidence of causation in either direction. What would settle it is not obtainable at nine patients. What is obtainable is a consistent record of whether IFN-gamma was offered, at what dose, and when relative to the antimycobacterial regimen — which the 2026 report supplies for its patients and the 2023 report does not for its five.
Does an unvaccinated male relative of an MCTS1-deficient proband need BCG withheld, screening for environmental mycobacteria, or both?
OPEN QUESTION OPEN imd118_bcg_in_at_risk_families
Attached to
phenotypes#Disseminated BCG Disease phenotypes#Nontuberculous Mycobacterial Infection
Eight of nine published patients were BCG-vaccinated at or near birth, and most of their disease is BCG disease. The obvious inference is that withholding BCG from at-risk males prevents the disease. The American patient shows the limit of that inference. He was never vaccinated, had a healthy childhood, and presented at twenty-two with disseminated Mycobacterium abscessus and a retroperitoneal mass encasing the aorta. Withholding BCG did not protect him; it changed which mycobacterium found him, and when. One 2023 patient was likewise unvaccinated and was only two at last follow-up, so his eventual course is unknown. The practical question this raises is not answerable from nine patients but is worth posing explicitly: an X-linked disease with a vaccine-avoidable early presentation and an unavoidable late one needs a surveillance answer, not only a vaccination answer. No published source addresses it.
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Pathophysiology

7
Hemizygous MCTS1 Loss-of-Function Variants
Mechanism confidence: Established
Eight variants are published across nine families. The 2023 five are all loss-of-expression or complete loss-of-function: two frameshift, one splice-site, and two in-frame 3-prime deletions both removing residues Ala133 to Lys181. The 2026 report adds p.Leu170* and p.Glu60Lysfs*5, both loss-of-function, and p.Trp175*, which is hypomorphic when overexpressed rather than null. That last allele is the reason this entity now has a partial form. A nonsense variant at codon 175 of a 181-residue protein removes very little, and the patient who carries it was not BCG-vaccinated, stayed healthy through childhood, and presented at sixteen with weight loss and diarrhoea and at twenty-two with disseminated Mycobacterium abscessus. Allele severity and age at presentation move together.
MCTS1 hgnc:23357 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MCTS1 (hgnc:23357). hgnc:23357 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context MCTS1 hgnc:23357 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns MCTS1 (hgnc:23357). hgnc:23357 is a gene from the HUGO Gene Nomenclature Committee. allele_type: frameshift, nonsense, splice-site and in-frame 3-prime deletion alleles, with one hypomorphic nonsense allele near the C-terminus variant_origin: GERMLINE zygosity: HEMIZYGOUS functional_impact_category: LOSS_OF_FUNCTION
LOSS_OF_FUNCTION describes eight of the nine genotypes; p.Trp175* is hypomorphic on overexpression and is the exception, recorded in this node's description rather than by splitting the slot. The slot is single-valued and the majority genotype is a true null.
Downstream
Failure of 40S Ribosome Recycling and Translation Reinitiation
Show evidence (1 reference)
PMID:41623352 SUPPORT DIRECT PRIMARY RESULT In Vitro
"The p.L170* and E60Kfs5* variants are LOF, whereas p.W175* is hypomorphic when overexpressed."
The three new alleles and the functional class of each, including the one that establishes a partial form of the disease.
Failure of 40S Ribosome Recycling and Translation Reinitiation
Mechanism confidence: Established
MCTS1 heterodimerises with DENR to recycle 40S ribosomal subunits after termination and to permit reinitiation on messages carrying short upstream open reading frames. Without it, subunits are not released at stop codons and reinitiation downstream is impaired. The striking part is how little this costs. The founding authors call MCTS1-dependent recycling "otherwise physiologically redundant" in these patients — meaning that outside the one pathway below, no phenotype attributable to a general translation defect was found. That is a strong claim and it is theirs, not this entry's; the 2026 series' growth failure, hypogammaglobulinaemia and gastrointestinal disease sit awkwardly against it, and this entry records both.
regulation of translational initiation GO:0006446 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased regulation of translational initiation (GO:0006446). GO:0006446 is a biological process from the Gene Ontology. ↓ DECREASED
translation reinitiation factor activity GO:0003743 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased translation reinitiation factor activity, annotated with translation initiation factor activity (GO:0003743). GO:0003743 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Ribosomal Stalling at the JAK2 Start-Stop Upstream Open Reading Frames
Show evidence (2 references)
PMID:37875108 SUPPORT DIRECT PRIMARY RESULT In Vitro
"Complete deficiency of this translation re-initiation factor impairs the translation of a subset of proteins, including the kinase JAK2 in all cell types tested, including T lymphocytes and phagocytes."
The molecular consequence and its scope — a subset of proteins, in every cell type looked at, which is what makes the narrowness of the clinical phenotype surprising.
PMID:37875108 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Surprisingly, the lack of MCTS1-dependent translation re-initiation and ribosome recycling seems to be otherwise physiologically redundant in these patients."
The redundancy claim, quoted with the authors' own "seems to" intact. The 2026 series complicates it, which is why the hedge is preserved rather than paraphrased away.
Ribosomal Stalling at the JAK2 Start-Stop Upstream Open Reading Frames
Mechanism confidence: Established
This node is the specificity of the disease. The JAK2 5-prime untranslated region carries three upstream open reading frames, two of them ultra-short start-stop frames. Without MCTS1 to recycle them, 40S subunits stall at those stop codons and cannot reinitiate at the JAK2 main open reading frame. It is why a general translation defect produces a single-pathway disease. Of seventeen genes of IFN-gamma immunity tested in MCTS1-knockout cells, only JAK2 showed a substantial translational decrease, rescued by wild-type MCTS1 and not by patient variants. A gene's vulnerability here is a property of its 5-prime untranslated region, not of its function.
translational initiation GO:0006413 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased translational initiation (GO:0006413). GO:0006413 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Reduced JAK2 Protein
Show evidence (1 reference)
PMID:41623352 SUPPORT DIRECT BACKGROUND In Vitro
"MCTS1 promotes JAK2 translation by reinitiating translation in the JAK2 5′UTR."
The mechanism stated compactly. Graded BACKGROUND because the 2026 paper is restating the 2023 finding in its introduction rather than reporting it, and HUMAN_CLINICAL because the work it summarises was done in patient and patient-derived cells.
Reduced JAK2 Protein
Mechanism confidence: Established
JAK2 falls in every cell type tested, including T lymphocytes and phagocytes. It does not fall to zero, and that quantitative detail is what makes the phenotype selective rather than global: the level is low enough to impair IL-23 responses and partially IL-12 responses, and not low enough to impair the other JAK2-dependent cytokine responses. A JAK2 null would be a different and much worse disease — JAK2 carries erythropoietin, thrombopoietin and growth-hormone signalling. Nothing like that is seen here.
JAK2 hgnc:6192 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves JAK2 (hgnc:6192). hgnc:6192 is a gene from the HUGO Gene Nomenclature Committee.
non-membrane spanning protein tyrosine kinase activity GO:0004715 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased non-membrane spanning protein tyrosine kinase activity (GO:0004715). GO:0004715 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Impaired IL-23 Receptor Signalling
Show evidence (1 reference)
PMID:37875108 SUPPORT DIRECT PRIMARY RESULT In Vitro
"JAK2 expression is sufficiently low to impair cellular responses to interleukin-23 (IL-23) and partially IL-12, but not other JAK2-dependent cytokines."
The quantitative threshold argument in the authors' own words — which cytokine responses the residual JAK2 supports and which it does not.
Impaired IL-23 Receptor Signalling
Mechanism confidence: Established
IL-23 signalling is JAK2-dependent and is the response that fails here; IL-12 signalling is partially affected. The placement of this disease on the IL-23 limb rather than the IL-12 limb of the MSMD circuit is not an inference from the biochemistry — it was measured in patient cells, which showed impaired IL-23 responses with normal IL-12 responses. That places IMD118 beside IL23R deficiency and IL-23 deficiency in the same functional pathway, and it is the reason the phenotype is mycobacterial rather than the broader susceptibility that IL-12 axis defects produce.
interleukin-23-mediated signaling pathway GO:0038155 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased interleukin-23-mediated signaling pathway (GO:0038155). GO:0038155 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Reduced IFN-gamma Production by Innate-like Adaptive T Lymphocytes
Show evidence (1 reference)
PMID:37875108 SUPPORT DIRECT PRIMARY RESULT In Vitro
"Defective responses to IL-23 preferentially impair the production of IFN-γ by innate-like adaptive mucosal-associated invariant T cells (MAIT) and γδ T lymphocytes upon mycobacterial challenge."
The step from cytokine signalling to effector function, naming the two lymphocyte populations that carry it.
Reduced IFN-gamma Production by Innate-like Adaptive T Lymphocytes
Mechanism confidence: Established
MAIT cells and gamma-delta T cells produce less IFN-gamma on mycobacterial challenge. These are the lymphocytes that respond to mycobacteria without needing clonal expansion from a naive repertoire, which is why an infant meeting BCG in the first months of life depends on them. Adequate JAK2 is required for exactly this, which is the 2026 authors' summary of the pathway and the reason the entity sits within MSMD rather than beside it.
MAIT cell CL:0000940 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves MAIT cell, annotated with mucosal-associated invariant T cell (CL:0000940). CL:0000940 is a cell type from the Cell Ontology. gamma-delta T cell CL:0000798 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves gamma-delta T cell (CL:0000798). CL:0000798 is a cell type from the Cell Ontology.
interferon-gamma production GO:0032609 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased interferon-gamma production, annotated with type II interferon production (GO:0032609). GO:0032609 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Failure of Macrophage Activation Against Intracellular Mycobacteria
Show evidence (1 reference)
PMID:41623352 SUPPORT DIRECT BACKGROUND In Vitro
"Adequate levels of JAK2 expression are required for IFN-γ production in response to IL-23 by innate-like adaptive T cells, such as Vδ2+ γδ T cells and mucosa-associated innate-like T cells"
The pathway restated with the gamma-delta subset specified as Vdelta2-positive. Graded BACKGROUND because the 2026 paper is summarising its predecessor here.
Failure of Macrophage Activation Against Intracellular Mycobacteria
Mechanism confidence: Established
IFN-gamma is the macrophage-activating factor at the heart of antimycobacterial immunity, and without enough of it macrophages do not restrict the intracellular growth of weakly virulent mycobacteria. This is the step every MSMD genotype converges on, and it is established for the syndrome rather than measured in MCTS1 patients specifically. Its most important property here is where it sits. The lesion is upstream of the IFN-gamma receptor and patient leukocytes respond normally to exogenous IFN-gamma, so this node can be driven from outside — which is what makes recombinant IFN-gamma a rational therapy rather than a hopeful one.
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.
macrophage activation GO:0042116 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased macrophage activation (GO:0042116). GO:0042116 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Disseminated BCG Disease
Nontuberculous Mycobacterial Infection
Show evidence (1 reference)
PMID:41623352 SUPPORT INDIRECT BACKGROUND Other
"Interferon-gamma (IFN-γ), a macrophage-activating factor (3), is at the heart of antimycobacterial immunity."
The general principle this node rests on, stated in the paper's introduction with its own citation. Graded BACKGROUND and INDIRECT because it is established immunology imported into this disease, not a measurement in an MCTS1 patient.
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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 Immunodeficiency 118 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

9
Blood 1
Decreased Circulating Immunoglobulin FREQUENT Decreased circulating immunoglobulin concentration HP:0004313 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypogammaglobulinaemia requiring immunoglobulin replacement, annotated with Decreased circulating immunoglobulin concentration (HP:0004313). HP:0004313 is a phenotype from the Human Phenotype Ontology.
3 of 4 patients in the 2026 series; not reported in the 2023 cohort, whose leukocyte subsets are described as normal without immunoglobulin data being quoted in the abstract. Whether this is a newly recognised part of the phenotype or a difference in what was measured and reported cannot be settled from the published record, and the entry does not try to.
Sequelae: Recurrent Otitis Media
Show evidence (2 references)
PMID:41623352 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Immunological analyses revealed that P1 had low immunoglobulin (IG) levels, despite having normal total serum protein and albumin levels. Intravenous IG (IVIG) treatment was therefore initiated."
The finding with the controls that make it a genuine hypogammaglobulinaemia rather than a dilutional or loss-related artefact.
PMID:41623352 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"He also receives IFN-γ-1b and IVIG due to his hypogammaglobulinemia (Tables S3 and S4)."
The second instance, in the Chinese patient, alongside his IFN-gamma treatment.
Cardiovascular 1
Lymphadenopathy VERY_FREQUENT HP:0002716 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Regional and intra-abdominal lymphadenopathy, annotated with Lymphadenopathy (HP:0002716). HP:0002716 is a phenotype from the Human Phenotype Ontology.
Reported for most published patients in one form or another. It is infection-driven rather than a primary lymphoid abnormality, which is why it resolves on antimycobacterial treatment.
Show evidence (1 reference)
PMID:41623352 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"At the age of 4 mo, he presented BCG-osis with left axillary adenitis."
The regional adenitis in the youngest of the 2026 patients, with its age.
Digestive 1
Chronic Diarrhoea and Gastrointestinal Mycobacterial Disease FREQUENT Diarrhea HP:0002014 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chronic diarrhoea with gastrointestinal mycobacterial infection, annotated with Diarrhea (HP:0002014), qualified as temporality chronic. HP:0002014 is a phenotype from the Human Phenotype Ontology.
Temporal: CHRONIC
3 of 4 patients in the 2026 series; not reported in the 2023 cohort.
Show evidence (1 reference)
PMID:41623352 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"A mucosal biopsy specimen from this area tested positive for Mycobacterium tuberculosis complex by metagenomic next-generation sequencing."
That the gastrointestinal disease is mycobacterial, established on tissue rather than inferred from the systemic diagnosis.
Ear 1
Recurrent Otitis Media OCCASIONAL HP:0000403 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent otitis media (HP:0000403). HP:0000403 is a phenotype from the Human Phenotype Ontology.
2 of 4 patients in the 2026 series. Recurrent bacterial otitis in a patient with hypogammaglobulinaemia is the expected consequence of the antibody deficit rather than of the mycobacterial axis, which is why it is recorded separately from the mycobacterial phenotypes.
Show evidence (1 reference)
PMID:41623352 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"The local infection gradually improved, but P3 has suffered from recurrent diarrhea since the age of 6 years and recurrent otitis media since the age of 9 years."
The two chronic problems that followed the resolved BCG disease in this patient.
Immune 3
Disseminated BCG Disease VERY_FREQUENT BCGosis HP:0020087 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Disseminated BCG disease, annotated with BCGosis (HP:0020087). HP:0020087 is a phenotype from the Human Phenotype Ontology.
Present in most of the nine published patients. The two exceptions are informative rather than incidental: one 2023 patient had not been BCG-vaccinated and was only two years old at last follow-up, and the 2026 American patient was never vaccinated and presented instead with environmental mycobacterial disease in adulthood. So the BCG phenotype requires the exposure, and an unvaccinated carrier is not protected — only differently exposed.
Sequelae: Lymphadenopathy Granulomatous Meningitis and Seizures Failure to Thrive Chronic Diarrhoea and Gastrointestinal Mycobacterial Disease
Show evidence (2 references)
PMID:41623352 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Three patients had adverse reactions to the BCG vaccine, whereas another patient was not vaccinated with BCG and had an infection with Mycobacterium abscessus at 16 years of age."
The split in the 2026 series between vaccinated and unvaccinated patients, which is the evidence that the vaccine is the usual trigger rather than the cause.
PMID:41623352 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"An empirical diagnosis of BCG-osis (affecting the brain, mastoid sinuses, lung, liver, and gastrointestinal tract) was established"
The severe end of the range, in the patient who died — the organs involved when the disease is not controlled.
Nontuberculous Mycobacterial Infection OCCASIONAL Mycobacterium abscessus abscessus infection HP:0032130 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Disseminated Mycobacterium abscessus infection, annotated with Mycobacterium abscessus abscessus infection (HP:0032130). HP:0032130 is a phenotype from the Human Phenotype Ontology.
2 of 9 published patients, and both of them presented late — sixteen and twenty-two years in the American patient, ten years in the Chinese one. The diagnostic lesson is that an adult with disseminated environmental mycobacterial disease and a normal immunophenotype is a candidate for this diagnosis.
Sequelae: Lymphadenopathy Chronic Diarrhoea and Gastrointestinal Mycobacterial Disease
Show evidence (1 reference)
PMID:41623352 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"The patient was diagnosed with disseminated M. abscessus infection manifesting as bulky intra-abdominal/retroperitoneal lymphadenopathy, chronic diarrhea, and chronic weight loss."
The full presentation in the unvaccinated adult patient.
Granulomatous Meningitis and Seizures OCCASIONAL HP:0001287 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Granulomatous BCG meningitis, annotated with Meningitis (HP:0001287). HP:0001287 is a phenotype from the Human Phenotype Ontology.
1 of 9 published patients, and the one who died in the 2026 series. Recorded because it is the worst documented course of this disease and because a reader taking the founding report's "isolated mycobacterial disease" framing would not expect CNS involvement.
Show evidence (2 references)
PMID:41623352 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Cranial computed tomography (CT) and magnetic resonance imaging revealed otomastoiditis, acute cerebral venous thrombosis, and granulomatous meningitis with focal white matter lesions that were particularly abundant in the right hemisphere."
The imaging findings that established central nervous system involvement.
PMID:41623352 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Cerebrospinal fluid (CSF) culture revealed the presence of pyrazinamide-resistant M. bovis–BCG."
The organism, cultured from cerebrospinal fluid, with its resistance pattern — which is what makes this BCG disease of the central nervous system rather than a sterile inflammatory process.
Growth 1
Failure to Thrive FREQUENT HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Growth failure below the third percentile, annotated with Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
3 of 4 patients in the 2026 series. Against the 2023 description of normal growth and development in the surviving patients, this is the clearest divergence between the two reports. Chronic mycobacterial infection is itself a cause of growth failure, so it is not separable here from a direct effect of the genotype.
Show evidence (1 reference)
PMID:41623352 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"At 3.5 years old, his weight was 10.5 kg, and he was 77 cm tall (both these growth parameters are below the third percentile)."
The measured growth failure, with the centile, in the youngest 2026 patient.
Other 1
Normal Circulating Leukocyte Subsets VERY_FREQUENT
Reported for all five 2023 patients and for the American patient in 2026. Deliberately unbound. HPO has no term for a normal immunophenotype in a patient who has an immunodeficiency, and every candidate inverts the claim: HP:0002721 Immunodeficiency asserts the abnormality this node exists to deny, and the lymphocyte-count terms assert a direction. A term plus a disclaimer is still a wrong term — the disclaimer is prose and the term is machine-readable — so `term:` is omitted and `preferred_term` carries the finding. Needs a term request: the concept is "routine immunophenotyping normal", which is diagnostically load-bearing across the whole of MSMD and not only here. Searched before omitting, and re-run against `ols:hp` before committing this note. `l~leukocyte` returns abnormality terms only (HP:0001881 Abnormal leukocyte morphology, HP:0001974 Increased total leukocyte count, HP:0033797 Leukocyte migration defect and siblings). `l~lymphocyte count` returns HP:0040088 Abnormal lymphocyte count and its increased/decreased children, including HP:0005403 Decreased total T cell count. `l~immunophenotyp` returns nothing at all. `l~normal` returns terms in which "normal" is part of some other concept — HP:0002343 Normal pressure hydrocephalus, HP:0002372 Normal interictal EEG, HP:0002632 Low-to-normal blood pressure — and nothing about a normal immunological result. HPO has terms for the presence of an abnormality and none for a documented normal finding in this domain, which is what makes this an NTR rather than a search failure. Note HP:0002372 shows the shape a suitable term would take.
Show evidence (2 references)
PMID:41623352 SUPPORT DIRECT BACKGROUND Human Clinical
"All the detected leukocyte subsets developed normally in the patients."
The normal immunophenotype across the 2023 cohort, restated in the 2026 introduction — which is why it is graded BACKGROUND rather than PRIMARY_RESULT.
PMID:41623352 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Complete blood counts and clinical immunophenotyping results were normal (Tables S3 and S4)."
The same finding measured directly in the 2026 adult patient, whose disseminated M. abscessus infection would otherwise have prompted a search for an acquired cause.
🧬

Genetic Associations

2
MCTS1
Gene: MCTS1 hgnc:23357 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MCTS1 (hgnc:23357). hgnc:23357 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (1 reference)
PMID:37875108 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"These findings suggest that X-linked recessive human MCTS1 deficiency underlies isolated mycobacterial disease by impairing JAK2 translation in innate-like adaptive T lymphocytes, thereby impairing the IL-23-dependent induction of IFN-γ."
The gene-disease claim and the mechanism in one sentence, as the authors state it.
JAK2
Gene: JAK2 hgnc:6192 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is JAK2 (hgnc:6192). hgnc:6192 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: MODIFIER variant_origin: GERMLINE
Show evidence (1 reference)
PMID:37875108 SUPPORT DIRECT PRIMARY RESULT In Vitro
"JAK2 expression is sufficiently low to impair cellular responses to interleukin-23 (IL-23) and partially IL-12, but not other JAK2-dependent cytokines."
JAK2's role as the limiting substrate, and the quantitative reason the impairment is selective for IL-23 rather than global. Graded IN_VITRO, as the same sentence is on the pathophysiology node: the cellular responses it describes were measured in knockout cell lines and reporter systems, not in a patient.
💊

Medical Actions

3
Antimycobacterial Therapy
Action: antimycobacterial pharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is antimycobacterial pharmacotherapy, annotated with Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Agent: isoniazid CHEBI:6030 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses isoniazid, annotated with isoniazide (CHEBI:6030). CHEBI:6030 is a therapeutic agent from Chemical Entities of Biological Interest. rifampicin CHEBI:28077 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses rifampicin (CHEBI:28077). CHEBI:28077 is a therapeutic agent from Chemical Entities of Biological Interest. ethambutol CHEBI:4877 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses ethambutol (CHEBI:4877). CHEBI:4877 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
The primary treatment, and mostly effective. Regimens in the published patients range from isoniazid and rifampicin for eighteen months, through isoniazid, rifampicin, ethambutol and pyrazinamide, to a four-drug combination of imipenem with ceftaroline, omadacycline, clofazimine and linezolid for the M. abscessus patient. One isolate was pyrazinamide-resistant M. bovis BCG, which is expected — M. bovis is intrinsically pyrazinamide-resistant — and is worth knowing before a standard antituberculous regimen is started. Some patients also carry long-term antibacterial prophylaxis: the youngest 2026 patient is on daily azithromycin.
Mechanism Target:
Disseminated BCG Disease — Kills the organism the immune defect cannot control. It addresses the infection and leaves the IFN-gamma induction defect intact, which is why several patients need it long-term and why exposure to a new mycobacterium remains a risk.
Show evidence (2 references)
PMID:41623352 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"P1 was treated with isoniazid and rifampicin, initially for 4 mo, but with subsequent prolongation for 18 mo based on his clinical response and microbiological status."
A worked regimen with its duration and the basis on which it was extended — the practical detail a clinician needs.
PMID:41623352 REFUTE DIRECT PRIMARY RESULT Human Clinical
"Despite intravenous phenytoin and dexamethasone treatment and anti-infection treatment with ceftriaxone, vancomycin, and acyclovir, the patient remained febrile and lethargic."
Graded REFUTE against a reading of antimicrobial treatment as reliably effective. In the patient who died, broad empirical cover failed because the organism was mycobacterial and the regimen was not — the antimycobacterial drugs were started eleven days after admission.
Recombinant Interferon Gamma-1b
Action: interferon gamma therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is interferon gamma therapy, annotated with Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Agent: interferon gamma-1b NCIT:C100089 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses interferon gamma-1b (NCIT:C100089). NCIT:C100089 is a therapeutic agent from the NCI Thesaurus.
Platform: Protein replacement
The mechanistically indicated therapy, and the one this entry's pathograph predicts. The lesion is upstream of the IFN-gamma receptor and patient cells respond normally to exogenous IFN-gamma, so supplying it bypasses the block rather than working around it. Three of the four 2026 patients received it. In the Omani patient subcutaneous IFN-gamma-1b improved activity, mobility and nutritional status before he was lost to follow-up and it was stopped after six weeks; in the American patient, increasing doses over a year and a half, reaching 400 micrograms three times weekly, produced substantial improvement after about a year. Those are two uncontrolled observations, one of them in a patient who then died after the drug was stopped. They are recorded as such.
Mechanism Target:
Failure of Macrophage Activation Against Intracellular Mycobacteria — Exogenous IFN-gamma activates macrophages directly, downstream of the IL-23-to-IFN-gamma induction step that fails. This is the node the treatment targets, and the reason it targets that node rather than a phenotype is that the bypass is a mechanistic claim the published cell data support.
Show evidence (2 references)
PMID:41623352 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Treatment with increasing doses of IFN-γ-1b for 1.5 years has started to show substantial improvements in the patient’s condition after ~1 year of treatment at a dosage of 400 µg three times per week."
The dose, the schedule, the duration before response, and the response — the only quantitative treatment observation in this disease.
PMID:41623352 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Subcutaneous IFN-γ1b treatment was initiated, leading to improvements in the patient’s activity, mobility, and nutritional status."
The second reported response, in the patient with central nervous system disease. The same paragraph records that follow-up was lost and the drug stopped after six weeks; that is in this treatment's description rather than in the snippet, which reports only what was observed on treatment.
Immunoglobulin Replacement Therapy
Action: immunoglobulin replacement therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is immunoglobulin replacement therapy, annotated with Immunoglobulin Therapy (NCIT:C62710). NCIT:C62710 is a clinical intervention from the NCI Thesaurus. Ontology label: Immunoglobulin Therapy NCIT:C62710
Platform: Protein replacement
Given to three of the four 2026 patients — monthly intravenous immunoglobulin in the youngest, intravenous immunoglobulin in the Chinese patient for hypogammaglobulinaemia, and in the Omani patient on the basis of severe illness with moderately low B-cell counts and IgG even though immunoglobulin levels were normal. That last case is worth distinguishing: it was a decision made on clinical severity rather than on a demonstrated antibody deficiency, and it is recorded that way here.
Mechanism Target:
Decreased Circulating Immunoglobulin — Substitutes for antibody the patient does not make. It has no relationship to the IFN-gamma induction defect, which is why it is recorded against the humoral phenotype rather than against a mechanism node.
Show evidence (2 references)
PMID:41623352 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"He is on prophylaxis with azithromycin daily and IVIG monthly."
The maintenance regimen in the youngest 2026 patient, covering both the antibacterial prophylaxis and the replacement.
PMID:41623352 NO_EVIDENCE DIRECT PRIMARY RESULT Human Clinical
"IG levels were normal, but IVIG was administered due to the patient’s severe medical condition, moderately low B cell counts and IgG levels"
Graded NO_EVIDENCE for this treatment's indication rather than SUPPORT. The sentence records that the drug was given and states explicitly that the immunoglobulin levels did not indicate it — so it bears on the decision, not on the claim that these patients have an antibody deficiency needing replacement.
🔬

Diagnosis

3
Routine immunophenotyping (ABSENT)
Recorded as a negative because it is the trap. Circulating leukocyte subsets develop normally and complete blood counts and clinical immunophenotyping are normal, so the test that would ordinarily confirm an immunodeficiency comes back reassuring. Molecular diagnosis is the only route.
Show evidence (1 reference)
PMID:41623352 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Complete blood counts and clinical immunophenotyping results were normal (Tables S3 and S4)."
The normal routine immunology in the adult patient, whose diagnosis came from sequencing.
Whole-exome sequencing
How every published patient was diagnosed. Given that MSMD has twenty-two genes and forty-seven aetiologies, a targeted MSMD panel or exome is the rational first test in a boy with disseminated BCG or environmental mycobacterial disease and a normal immunophenotype.
Show evidence (1 reference)
PMID:41623352 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Whole-exome sequencing of the probands revealed hemizygosity for rare germline MCTS1 variants."
The diagnostic method used across the 2026 series.
Mycobacterial culture and molecular identification from the affected site
Identifying the organism is what converts a granulomatous or necrotic lesion into a mycobacterial diagnosis, and in this series it required a range of methods: PCR for the M. bovis complex on axillary and bone-marrow specimens, cerebrospinal fluid culture, mycobacterial culture from lymph node biopsy, and metagenomic next-generation sequencing on an ileocaecal mucosal biopsy. Histology alone was insufficient in at least one case — the Chinese patient's biopsy showed epithelial damage, crypt distortion and gastritis without granulomas.
Show evidence (1 reference)
PMID:41623352 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Histopathology revealed small intestinal villous widening with epithelial damage and increased intraepithelial lymphocytes, focal crypt distortion in the colon, and mild chronic gastritis without granulomas"
A mycobacterial gastrointestinal infection with non-granulomatous histology — the reason organism identification rather than histology is the diagnostic step recorded here.
📈

Progression

3
Infantile BCG disease
Disease appears between one and twelve months in the vaccinated patients, at the site of vaccination first and disseminating from there. The 2026 series' youngest presented at four months with axillary adenitis and bone-marrow involvement; another at one month with local armpit disease.
Show evidence (1 reference)
PMID:41623352 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"7 mo later, he was diagnosed with abscessed BCG adenitis (BCG-itis)."
The interval from vaccination to disease in one of the 2026 patients.
Later mycobacterial disease in the unvaccinated
Without BCG the disease waits for an environmental mycobacterium. The American patient had a healthy childhood with no notable infections, began losing weight and having diarrhoea at sixteen, and was diagnosed with disseminated Mycobacterium abscessus at twenty-two. He carries the hypomorphic p.Trp175* allele, so allele severity and absence of BCG exposure both point the same way and cannot be separated in one patient.
Show evidence (1 reference)
PMID:41623352 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"He had a healthy childhood, without frequent or notable infections. At the age of 16 years, he began to experience weight loss and diarrhea."
The healthy childhood and the age of first symptoms — the natural history of an unvaccinated patient with a hypomorphic allele.
Outcome
Two of nine published patients have died of mycobacterial disease: one of the original five, and the Omani patient at six years and nine months. The rest responded to antimycobacterial treatment. The 2023 report describes its survivors as asymptomatic after early childhood with normal growth and development; the 2026 series' survivors are on long-term antimycobacterial therapy, immunoglobulin replacement and in two cases IFN-gamma-1b. The difference between those two descriptions is the most important thing in this entry's prognosis, and it is at least partly a difference in follow-up rather than in disease.
Show evidence (1 reference)
PMID:41623352 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"He developed fever and hematemesis, leading to his collapse and death within 24 h at the age of 6 years and 9 mo."
The fatal outcome in the 2026 series, with its age.
📊

Prevalence

1
Worldwide
Cases In Literature <1 in 1,000,000
Nine patients in nine unrelated families: five in 2023 from China, Finland, Iran (two families) and Saudi Arabia, and four in 2026 from Iran, Oman, China and the United States. All male, all hemizygous, eight distinct variants. No population estimate exists. Ascertainment is through MSMD cohorts, so the denominator is the set of patients whose mycobacterial disease prompted genetic investigation, not the population. rate_per_100000 is left unset. One quantity worth recording: MCTS1 is one of twenty-two genes underlying forty-seven genetic aetiologies of MSMD as of the 2026 report. That is the population this entity is a slice of, and it is the reason a targeted MSMD panel rather than a single-gene test is the diagnostic route.
Show evidence (1 reference)
PMID:41623352 SUPPORT DIRECT BACKGROUND Human Clinical
"Variants of 22 genes underlie 47 different genetic etiologies of MSMD (4)."
The size of the genetic differential this entity sits inside. Graded BACKGROUND because it is a cited count in the paper's introduction rather than its own result.
{ }

Source YAML

click to show 
name: Immunodeficiency 118
category: Mendelian
creation_date: "2026-09-22T00:00:00Z"
synonyms:
- IMD118
- MCTS1 deficiency
- X-linked MCTS1 deficiency
- Mendelian susceptibility to mycobacterial disease due to MCTS1 deficiency
- MSMD due to MCTS1 deficiency
disease_term:
  preferred_term: immunodeficiency 118
  term:
    id: MONDO:0958030
    label: immunodeficiency 118
description: >-
  IMD118 is X-linked MCTS1 deficiency, a Mendelian susceptibility to mycobacterial disease in
  which a general translation factor defect is funnelled into a single clinical phenotype by a
  single vulnerable substrate. Nine patients in nine unrelated families are published: five in
  the 2023 report that defined the entity and four in a 2026 follow-up.

  MCTS1 partners with DENR to recycle post-termination 40S ribosomal subunits and to allow
  reinitiation on messages carrying short upstream open reading frames. Losing it should, on the
  face of it, disturb a great deal. It does not. Of seventeen genes of IFN-gamma immunity tested
  in MCTS1-knockout cells, only JAK2 translation fell — because the JAK2 5-prime untranslated
  region carries two ultra-short start-stop upstream open reading frames at which 40S subunits
  stall without MCTS1 to recycle them, blocking reinitiation at the main open reading frame.

  The consequence is a JAK2 level low enough to impair responses to IL-23, and partially to
  IL-12, while leaving other JAK2-dependent cytokine responses intact. Defective IL-23 signalling
  preferentially costs IFN-gamma production by the innate-like adaptive lymphocytes — MAIT cells
  and gamma-delta T cells — that respond to mycobacterial challenge, and IFN-gamma is the
  macrophage-activating cytokine that controls intracellular mycobacteria. Everything else MCTS1
  does appears to be physiologically redundant, which is the founding paper's own word for it.

  Two clinically load-bearing consequences follow. The block is upstream of the IFN-gamma
  receptor and patient cells respond normally to exogenous IFN-gamma, so the lesion is
  bypassable — and by 2026, three patients had been given IFN-gamma-1b with reported benefit.
  And the disease is not the benign entity the first report suggested: one of the original five
  died, one of the four new patients died of disseminated BCG involving the brain, and two of
  the new patients have hypogammaglobulinaemia requiring immunoglobulin replacement, which the
  phrase "otherwise physiologically redundant" does not prepare a reader for.
parents:
- Mendelian Susceptibility to Mycobacterial Disease
- Inborn Errors of Immunity
classifications:
  harrisons_chapter:
  - classification_value: IMMUNE_RHEUMATOLOGIC
    notes: >-
      A monogenic inborn error of immunity. It presents to infectious disease or paediatrics as
      a mycobacterial infection and is diagnosed by immunology and genetics.
  iuis_category:
    classification_value: innate immunity defect
    notes: >-
      IUIS places Mendelian susceptibility to mycobacterial disease among the defects of
      intrinsic and innate immunity rather than among the combined immunodeficiencies. That
      placement fits here: circulating leukocyte subsets develop normally, and the lesion is in
      an induction pathway rather than in lymphocyte development.
references:
- reference: PMID:37875108
  title: "Human MCTS1-dependent translation of JAK2 is essential for IFN-γ immunity to mycobacteria."
- reference: PMID:41623352
  title: "Complete and partial forms of X-linked MCTS1 deficiency in patients with mycobacterial disease."
inheritance:
- name: X-linked recessive inheritance
  description: >-
    All nine published patients are male and hemizygous. The 2023 kindreds are from China,
    Finland, Iran and Saudi Arabia; the 2026 families from Iran, Oman, China and the United
    States. Consanguinity is common but not required — the American patient's family is not
    described as consanguineous, and his variant is hypomorphic rather than null.
  inheritance_term:
    preferred_term: X-linked recessive inheritance
    term:
      id: HP:0001419
      label: X-linked recessive inheritance
  evidence:
  - reference: PMID:37875108
    reference_title: "Human MCTS1-dependent translation of JAK2 is essential for IFN-γ immunity to mycobacteria."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "We report X-linked recessive MCTS1 deficiency in men with mycobacterial disease from kindreds of different ancestries (from China, Finland, Iran, and Saudi Arabia)."
    explanation: >-
      The inheritance mode and the geographic spread of the founding kindreds, which is what
      makes this a recurrent genotype rather than a founder effect.
pathophysiology:
- name: Hemizygous MCTS1 Loss-of-Function Variants
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Eight variants are published across nine families. The 2023 five are all loss-of-expression
    or complete loss-of-function: two frameshift, one splice-site, and two in-frame 3-prime
    deletions both removing residues Ala133 to Lys181. The 2026 report adds p.Leu170* and
    p.Glu60Lysfs*5, both loss-of-function, and p.Trp175*, which is hypomorphic when
    overexpressed rather than null.

    That last allele is the reason this entity now has a partial form. A nonsense variant at
    codon 175 of a 181-residue protein removes very little, and the patient who carries it was
    not BCG-vaccinated, stayed healthy through childhood, and presented at sixteen with weight
    loss and diarrhoea and at twenty-two with disseminated Mycobacterium abscessus. Allele
    severity and age at presentation move together.
  genes:
  - preferred_term: MCTS1
    term:
      id: hgnc:23357
      label: MCTS1
  genetic_context:
    genes:
    - preferred_term: MCTS1
      term:
        id: hgnc:23357
        label: MCTS1
    allele_type: frameshift, nonsense, splice-site and in-frame 3-prime deletion alleles, with one hypomorphic nonsense allele near the C-terminus
    variant_origin: GERMLINE
    zygosity: HEMIZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    notes: >-
      LOSS_OF_FUNCTION describes eight of the nine genotypes; p.Trp175* is hypomorphic on
      overexpression and is the exception, recorded in this node's description rather than by
      splitting the slot. The slot is single-valued and the majority genotype is a true null.
  evidence:
  - reference: PMID:41623352
    reference_title: "Complete and partial forms of X-linked MCTS1 deficiency in patients with mycobacterial disease."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "The p.L170* and E60Kfs5* variants are LOF, whereas p.W175* is hypomorphic when overexpressed."
    explanation: >-
      The three new alleles and the functional class of each, including the one that establishes
      a partial form of the disease.
  downstream:
  - target: Failure of 40S Ribosome Recycling and Translation Reinitiation
    causal_link_type: DIRECT
- name: Failure of 40S Ribosome Recycling and Translation Reinitiation
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    MCTS1 heterodimerises with DENR to recycle 40S ribosomal subunits after termination and to
    permit reinitiation on messages carrying short upstream open reading frames. Without it,
    subunits are not released at stop codons and reinitiation downstream is impaired.

    The striking part is how little this costs. The founding authors call MCTS1-dependent
    recycling "otherwise physiologically redundant" in these patients — meaning that outside the
    one pathway below, no phenotype attributable to a general translation defect was found. That
    is a strong claim and it is theirs, not this entry's; the 2026 series' growth failure,
    hypogammaglobulinaemia and gastrointestinal disease sit awkwardly against it, and this entry
    records both.
  molecular_functions:
  - preferred_term: translation reinitiation factor activity
    term:
      id: GO:0003743
      label: translation initiation factor activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: regulation of translational initiation
    term:
      id: GO:0006446
      label: regulation of translational initiation
    modifier: DECREASED
  evidence:
  - reference: PMID:37875108
    reference_title: "Human MCTS1-dependent translation of JAK2 is essential for IFN-γ immunity to mycobacteria."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "Complete deficiency of this translation re-initiation factor impairs the translation of a subset of proteins, including the kinase JAK2 in all cell types tested, including T lymphocytes and phagocytes."
    explanation: >-
      The molecular consequence and its scope — a subset of proteins, in every cell type looked
      at, which is what makes the narrowness of the clinical phenotype surprising.
  - reference: PMID:37875108
    reference_title: "Human MCTS1-dependent translation of JAK2 is essential for IFN-γ immunity to mycobacteria."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Surprisingly, the lack of MCTS1-dependent translation re-initiation and ribosome recycling seems to be otherwise physiologically redundant in these patients."
    explanation: >-
      The redundancy claim, quoted with the authors' own "seems to" intact. The 2026 series
      complicates it, which is why the hedge is preserved rather than paraphrased away.
  downstream:
  - target: Ribosomal Stalling at the JAK2 Start-Stop Upstream Open Reading Frames
    causal_link_type: DIRECT
- name: Ribosomal Stalling at the JAK2 Start-Stop Upstream Open Reading Frames
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    This node is the specificity of the disease. The JAK2 5-prime untranslated region carries
    three upstream open reading frames, two of them ultra-short start-stop frames. Without MCTS1
    to recycle them, 40S subunits stall at those stop codons and cannot reinitiate at the JAK2
    main open reading frame.

    It is why a general translation defect produces a single-pathway disease. Of seventeen genes
    of IFN-gamma immunity tested in MCTS1-knockout cells, only JAK2 showed a substantial
    translational decrease, rescued by wild-type MCTS1 and not by patient variants. A gene's
    vulnerability here is a property of its 5-prime untranslated region, not of its function.
  biological_processes:
  - preferred_term: translational initiation
    term:
      id: GO:0006413
      label: translational initiation
    modifier: DECREASED
  evidence:
  - reference: PMID:41623352
    reference_title: "Complete and partial forms of X-linked MCTS1 deficiency in patients with mycobacterial disease."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: "MCTS1 promotes JAK2 translation by reinitiating translation in the JAK2 5′UTR."
    explanation: >-
      The mechanism stated compactly. Graded BACKGROUND because the 2026 paper is restating the
      2023 finding in its introduction rather than reporting it, and HUMAN_CLINICAL because the
      work it summarises was done in patient and patient-derived cells.
  downstream:
  - target: Reduced JAK2 Protein
    causal_link_type: DIRECT
- name: Reduced JAK2 Protein
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    JAK2 falls in every cell type tested, including T lymphocytes and phagocytes. It does not
    fall to zero, and that quantitative detail is what makes the phenotype selective rather than
    global: the level is low enough to impair IL-23 responses and partially IL-12 responses, and
    not low enough to impair the other JAK2-dependent cytokine responses.

    A JAK2 null would be a different and much worse disease — JAK2 carries erythropoietin,
    thrombopoietin and growth-hormone signalling. Nothing like that is seen here.
  genes:
  - preferred_term: JAK2
    term:
      id: hgnc:6192
      label: JAK2
  molecular_functions:
  - preferred_term: non-membrane spanning protein tyrosine kinase activity
    term:
      id: GO:0004715
      label: non-membrane spanning protein tyrosine kinase activity
    modifier: DECREASED
  evidence:
  - reference: PMID:37875108
    reference_title: "Human MCTS1-dependent translation of JAK2 is essential for IFN-γ immunity to mycobacteria."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "JAK2 expression is sufficiently low to impair cellular responses to interleukin-23 (IL-23) and partially IL-12, but not other JAK2-dependent cytokines."
    explanation: >-
      The quantitative threshold argument in the authors' own words — which cytokine responses
      the residual JAK2 supports and which it does not.
  downstream:
  - target: Impaired IL-23 Receptor Signalling
    causal_link_type: DIRECT
- name: Impaired IL-23 Receptor Signalling
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    IL-23 signalling is JAK2-dependent and is the response that fails here; IL-12 signalling is
    partially affected. The placement of this disease on the IL-23 limb rather than the IL-12
    limb of the MSMD circuit is not an inference from the biochemistry — it was measured in
    patient cells, which showed impaired IL-23 responses with normal IL-12 responses.

    That places IMD118 beside IL23R deficiency and IL-23 deficiency in the same functional
    pathway, and it is the reason the phenotype is mycobacterial rather than the broader
    susceptibility that IL-12 axis defects produce.
  biological_processes:
  - preferred_term: interleukin-23-mediated signaling pathway
    term:
      id: GO:0038155
      label: interleukin-23-mediated signaling pathway
    modifier: DECREASED
  evidence:
  - reference: PMID:37875108
    reference_title: "Human MCTS1-dependent translation of JAK2 is essential for IFN-γ immunity to mycobacteria."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "Defective responses to IL-23 preferentially impair the production of IFN-γ by innate-like adaptive mucosal-associated invariant T cells (MAIT) and γδ T lymphocytes upon mycobacterial challenge."
    explanation: >-
      The step from cytokine signalling to effector function, naming the two lymphocyte
      populations that carry it.
  downstream:
  - target: Reduced IFN-gamma Production by Innate-like Adaptive T Lymphocytes
    causal_link_type: DIRECT
- name: Reduced IFN-gamma Production by Innate-like Adaptive T Lymphocytes
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    MAIT cells and gamma-delta T cells produce less IFN-gamma on mycobacterial challenge. These
    are the lymphocytes that respond to mycobacteria without needing clonal expansion from a
    naive repertoire, which is why an infant meeting BCG in the first months of life depends on
    them.

    Adequate JAK2 is required for exactly this, which is the 2026 authors' summary of the
    pathway and the reason the entity sits within MSMD rather than beside it.
  cell_types:
  - preferred_term: MAIT cell
    term:
      id: CL:0000940
      label: mucosal-associated invariant T cell
  - preferred_term: gamma-delta T cell
    term:
      id: CL:0000798
      label: gamma-delta T cell
  biological_processes:
  - preferred_term: interferon-gamma production
    term:
      id: GO:0032609
      label: type II interferon production
    modifier: DECREASED
  evidence:
  - reference: PMID:41623352
    reference_title: "Complete and partial forms of X-linked MCTS1 deficiency in patients with mycobacterial disease."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: "Adequate levels of JAK2 expression are required for IFN-γ production in response to IL-23 by innate-like adaptive T cells, such as Vδ2+ γδ T cells and mucosa-associated innate-like T cells"
    explanation: >-
      The pathway restated with the gamma-delta subset specified as Vdelta2-positive. Graded
      BACKGROUND because the 2026 paper is summarising its predecessor here.
  downstream:
  - target: Failure of Macrophage Activation Against Intracellular Mycobacteria
    causal_link_type: DIRECT
- name: Failure of Macrophage Activation Against Intracellular Mycobacteria
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  description: >-
    IFN-gamma is the macrophage-activating factor at the heart of antimycobacterial immunity, and
    without enough of it macrophages do not restrict the intracellular growth of weakly virulent
    mycobacteria. This is the step every MSMD genotype converges on, and it is established for
    the syndrome rather than measured in MCTS1 patients specifically.

    Its most important property here is where it sits. The lesion is upstream of the IFN-gamma
    receptor and patient leukocytes respond normally to exogenous IFN-gamma, so this node can be
    driven from outside — which is what makes recombinant IFN-gamma a rational therapy rather
    than a hopeful one.
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: macrophage activation
    term:
      id: GO:0042116
      label: macrophage activation
    modifier: DECREASED
  evidence:
  - reference: PMID:41623352
    reference_title: "Complete and partial forms of X-linked MCTS1 deficiency in patients with mycobacterial disease."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "Interferon-gamma (IFN-γ), a macrophage-activating factor (3), is at the heart of antimycobacterial immunity."
    explanation: >-
      The general principle this node rests on, stated in the paper's introduction with its own
      citation. Graded BACKGROUND and INDIRECT because it is established immunology imported into
      this disease, not a measurement in an MCTS1 patient.
  downstream:
  - target: Disseminated BCG Disease
    causal_link_type: DIRECT
  - target: Nontuberculous Mycobacterial Infection
    causal_link_type: DIRECT
phenotypes:
- name: Disseminated BCG Disease
  category: Immune
  description: >-
    The defining presentation. Eight of the nine published patients were BCG-vaccinated at or
    near birth and most developed disseminated BCG disease between one and twelve months. The
    2026 series shows the range: axillary adenitis with bone-marrow involvement at four months,
    abscessed BCG adenitis at seven months, local armpit disease at one month, and in one
    patient a BCG-osis involving brain, mastoid sinuses, lung, liver and gastrointestinal tract
    that was fatal.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Disseminated BCG disease
    term:
      id: HP:0020087
      label: BCGosis
  notes: >-
    Present in most of the nine published patients. The two exceptions are informative rather
    than incidental: one 2023 patient had not been BCG-vaccinated and was only two years old at
    last follow-up, and the 2026 American patient was never vaccinated and presented instead with
    environmental mycobacterial disease in adulthood. So the BCG phenotype requires the exposure,
    and an unvaccinated carrier is not protected — only differently exposed.
  evidence:
  - reference: PMID:41623352
    reference_title: "Complete and partial forms of X-linked MCTS1 deficiency in patients with mycobacterial disease."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Three patients had adverse reactions to the BCG vaccine, whereas another patient was not vaccinated with BCG and had an infection with Mycobacterium abscessus at 16 years of age."
    explanation: >-
      The split in the 2026 series between vaccinated and unvaccinated patients, which is the
      evidence that the vaccine is the usual trigger rather than the cause.
  - reference: PMID:41623352
    reference_title: "Complete and partial forms of X-linked MCTS1 deficiency in patients with mycobacterial disease."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "An empirical diagnosis of BCG-osis (affecting the brain, mastoid sinuses, lung, liver, and gastrointestinal tract) was established"
    explanation: >-
      The severe end of the range, in the patient who died — the organs involved when the disease
      is not controlled.
  sequelae:
  - target: Lymphadenopathy
    description: >-
      Regional then disseminated nodal disease is how BCG spreads from the vaccination site.
  - target: Granulomatous Meningitis and Seizures
    description: >-
      Central nervous system involvement in the patient in whom BCG disease was not controlled,
      with the organism cultured from cerebrospinal fluid.
  - target: Failure to Thrive
    description: >-
      Chronic mycobacterial infection is itself a cause of growth failure. Whether it is the only
      cause here is the question recorded in this entry's redundancy discussion.
  - target: Chronic Diarrhoea and Gastrointestinal Mycobacterial Disease
    description: >-
      The gastrointestinal tract is one of the organs BCG disseminates to, and in one patient the
      ileocaecal lesion was mycobacterium-positive on biopsy.
- name: Nontuberculous Mycobacterial Infection
  category: Immune
  description: >-
    Disseminated Mycobacterium abscessus in the unvaccinated American patient, presenting as
    bulky intra-abdominal and retroperitoneal lymphadenopathy with chronic diarrhoea and weight
    loss, and Mycobacterium tuberculosis complex on ileocaecal mucosal biopsy in the Chinese
    patient. Environmental mycobacteria are what these patients meet when BCG is not given.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Disseminated Mycobacterium abscessus infection
    term:
      id: HP:0032130
      label: Mycobacterium abscessus abscessus infection
  notes: >-
    2 of 9 published patients, and both of them presented late — sixteen and twenty-two years in
    the American patient, ten years in the Chinese one. The diagnostic lesson is that an adult
    with disseminated environmental mycobacterial disease and a normal immunophenotype is a
    candidate for this diagnosis.
  evidence:
  - reference: PMID:41623352
    reference_title: "Complete and partial forms of X-linked MCTS1 deficiency in patients with mycobacterial disease."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "The patient was diagnosed with disseminated M. abscessus infection manifesting as bulky intra-abdominal/retroperitoneal lymphadenopathy, chronic diarrhea, and chronic weight loss."
    explanation: The full presentation in the unvaccinated adult patient.
  sequelae:
  - target: Lymphadenopathy
    description: >-
      Bulky intra-abdominal and retroperitoneal nodal disease is the presenting manifestation of
      the M. abscessus infection in the unvaccinated adult patient.
  - target: Chronic Diarrhoea and Gastrointestinal Mycobacterial Disease
    description: >-
      Chronic diarrhoea accompanied the disseminated abdominal disease in that patient and the
      ileocaecal tuberculous ulcer in another.
- name: Lymphadenopathy
  category: Immune
  description: >-
    Regional adenitis at the vaccination site in the BCG patients, and bulky intra-abdominal and
    retroperitoneal conglomerate lymphadenopathy in the adult with M. abscessus — in his case a
    retroperitoneal mass encasing the aorta and the proximal coeliac and superior mesenteric
    arteries, with necrotic change.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Regional and intra-abdominal lymphadenopathy
    term:
      id: HP:0002716
      label: Lymphadenopathy
  notes: >-
    Reported for most published patients in one form or another. It is infection-driven rather
    than a primary lymphoid abnormality, which is why it resolves on antimycobacterial treatment.
  evidence:
  - reference: PMID:41623352
    reference_title: "Complete and partial forms of X-linked MCTS1 deficiency in patients with mycobacterial disease."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "At the age of 4 mo, he presented BCG-osis with left axillary adenitis."
    explanation: The regional adenitis in the youngest of the 2026 patients, with its age.
- name: Normal Circulating Leukocyte Subsets
  category: Immune
  description: >-
    Routine immunophenotyping is normal. That is the diagnostic problem this disease poses: the
    test a clinician runs to confirm an immunodeficiency comes back reassuring, and only
    molecular diagnosis finds it.

    Recorded as a phenotype in its own right because its absence is what a curator or clinician
    would otherwise infer from the disease's name.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Normal development of circulating leukocyte subsets
  notes: >-
    Reported for all five 2023 patients and for the American patient in 2026.

    Deliberately unbound. HPO has no term for a normal immunophenotype in a patient who has an
    immunodeficiency, and every candidate inverts the claim: HP:0002721 Immunodeficiency asserts
    the abnormality this node exists to deny, and the lymphocyte-count terms assert a direction.
    A term plus a disclaimer is still a wrong term — the disclaimer is prose and the term is
    machine-readable — so `term:` is omitted and `preferred_term` carries the finding. Needs a
    term request: the concept is "routine immunophenotyping normal", which is diagnostically
    load-bearing across the whole of MSMD and not only here.

    Searched before omitting, and re-run against `ols:hp` before committing this note.
    `l~leukocyte` returns abnormality terms only (HP:0001881 Abnormal leukocyte morphology,
    HP:0001974 Increased total leukocyte count, HP:0033797 Leukocyte migration defect and
    siblings). `l~lymphocyte count` returns HP:0040088 Abnormal lymphocyte count and its
    increased/decreased children, including HP:0005403 Decreased total T cell count.
    `l~immunophenotyp` returns nothing at all. `l~normal` returns terms in which "normal" is part
    of some other concept — HP:0002343 Normal pressure hydrocephalus, HP:0002372 Normal
    interictal EEG, HP:0002632 Low-to-normal blood pressure — and nothing about a normal
    immunological result. HPO has terms for the presence of an abnormality and none for a
    documented normal finding in this domain, which is what makes this an NTR rather than a
    search failure. Note HP:0002372 shows the shape a suitable term would take.
  evidence:
  - reference: PMID:41623352
    reference_title: "Complete and partial forms of X-linked MCTS1 deficiency in patients with mycobacterial disease."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "All the detected leukocyte subsets developed normally in the patients."
    explanation: >-
      The normal immunophenotype across the 2023 cohort, restated in the 2026 introduction —
      which is why it is graded BACKGROUND rather than PRIMARY_RESULT.
  - reference: PMID:41623352
    reference_title: "Complete and partial forms of X-linked MCTS1 deficiency in patients with mycobacterial disease."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Complete blood counts and clinical immunophenotyping results were normal (Tables S3 and S4)."
    explanation: >-
      The same finding measured directly in the 2026 adult patient, whose disseminated
      M. abscessus infection would otherwise have prompted a search for an acquired cause.
- name: Decreased Circulating Immunoglobulin
  category: Immune
  description: >-
    Low immunoglobulins with normal total protein and albumin in the youngest 2026 patient,
    treated with intravenous immunoglobulin; hypogammaglobulinaemia in the Chinese patient, also
    on replacement; moderately low B cell counts and IgG in the Omani patient.

    This is the finding that sits least comfortably with the founding description of an otherwise
    intact immune system. Three of the four 2026 patients received immunoglobulin replacement.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hypogammaglobulinaemia requiring immunoglobulin replacement
    term:
      id: HP:0004313
      label: Decreased circulating immunoglobulin concentration
  notes: >-
    3 of 4 patients in the 2026 series; not reported in the 2023 cohort, whose leukocyte subsets
    are described as normal without immunoglobulin data being quoted in the abstract. Whether
    this is a newly recognised part of the phenotype or a difference in what was measured and
    reported cannot be settled from the published record, and the entry does not try to.
  evidence:
  - reference: PMID:41623352
    reference_title: "Complete and partial forms of X-linked MCTS1 deficiency in patients with mycobacterial disease."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Immunological analyses revealed that P1 had low immunoglobulin (IG) levels, despite having normal total serum protein and albumin levels. Intravenous IG (IVIG) treatment was therefore initiated."
    explanation: >-
      The finding with the controls that make it a genuine hypogammaglobulinaemia rather than a
      dilutional or loss-related artefact.
  - reference: PMID:41623352
    reference_title: "Complete and partial forms of X-linked MCTS1 deficiency in patients with mycobacterial disease."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "He also receives IFN-γ-1b and IVIG due to his hypogammaglobulinemia (Tables S3 and S4)."
    explanation: The second instance, in the Chinese patient, alongside his IFN-gamma treatment.
  sequelae:
  - target: Recurrent Otitis Media
    description: >-
      Recurrent bacterial otitis is the expected consequence of an antibody deficit rather than
      of the IFN-gamma induction defect, which is why it is drawn from here rather than from the
      mycobacterial chain.
- name: Failure to Thrive
  category: Growth
  description: >-
    Weight and height below the third percentile at three and a half years in the youngest 2026
    patient; failure to thrive with height and weight below the third percentile and delayed gross
    motor development in the Omani patient. Chronic weight loss in the adult with M. abscessus.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Growth failure below the third percentile
    term:
      id: HP:0001508
      label: Failure to thrive
  notes: >-
    3 of 4 patients in the 2026 series. Against the 2023 description of normal growth and
    development in the surviving patients, this is the clearest divergence between the two
    reports. Chronic mycobacterial infection is itself a cause of growth failure, so it is not
    separable here from a direct effect of the genotype.
  evidence:
  - reference: PMID:41623352
    reference_title: "Complete and partial forms of X-linked MCTS1 deficiency in patients with mycobacterial disease."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "At 3.5 years old, his weight was 10.5 kg, and he was 77 cm tall (both these growth parameters are below the third percentile)."
    explanation: The measured growth failure, with the centile, in the youngest 2026 patient.
- name: Chronic Diarrhoea and Gastrointestinal Mycobacterial Disease
  category: Gastrointestinal
  description: >-
    Recurrent diarrhoea from age six in the Chinese patient, leading at ten to colonoscopy that
    found an ileocaecal ulcer positive for Mycobacterium tuberculosis complex; chronic diarrhoea
    with abdominal distension, ascites and pancolitis in the Omani patient; chronic diarrhoea in
    the American patient with M. abscessus.

    The gut is a mycobacterial site in this disease, not merely a site of nonspecific symptoms —
    which matters because a chronic diarrhoea in a patient already on antimycobacterial therapy
    invites a search for a different cause.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Chronic diarrhoea with gastrointestinal mycobacterial infection
    term:
      id: HP:0002014
      label: Diarrhea
    temporality: CHRONIC
  notes: 3 of 4 patients in the 2026 series; not reported in the 2023 cohort.
  evidence:
  - reference: PMID:41623352
    reference_title: "Complete and partial forms of X-linked MCTS1 deficiency in patients with mycobacterial disease."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "A mucosal biopsy specimen from this area tested positive for Mycobacterium tuberculosis complex by metagenomic next-generation sequencing."
    explanation: >-
      That the gastrointestinal disease is mycobacterial, established on tissue rather than
      inferred from the systemic diagnosis.
- name: Recurrent Otitis Media
  category: Otologic
  description: >-
    Recurrent otitis media from age nine in the Chinese patient, and otomastoiditis on imaging
    in the Omani patient during his fatal illness.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Recurrent otitis media
    term:
      id: HP:0000403
      label: Recurrent otitis media
  notes: >-
    2 of 4 patients in the 2026 series. Recurrent bacterial otitis in a patient with
    hypogammaglobulinaemia is the expected consequence of the antibody deficit rather than of the
    mycobacterial axis, which is why it is recorded separately from the mycobacterial phenotypes.
  evidence:
  - reference: PMID:41623352
    reference_title: "Complete and partial forms of X-linked MCTS1 deficiency in patients with mycobacterial disease."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "The local infection gradually improved, but P3 has suffered from recurrent diarrhea since the age of 6 years and recurrent otitis media since the age of 9 years."
    explanation: The two chronic problems that followed the resolved BCG disease in this patient.
- name: Granulomatous Meningitis and Seizures
  category: Nervous System
  description: >-
    Central nervous system BCG disease in the Omani patient: generalised tonic-clonic seizure at
    six, imaging showing otomastoiditis, acute cerebral venous thrombosis and granulomatous
    meningitis with focal white-matter lesions, pyrazinamide-resistant M. bovis BCG cultured from
    cerebrospinal fluid, then breakthrough seizures, status epilepticus and new lesions. He died
    at six years and nine months.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Granulomatous BCG meningitis
    term:
      id: HP:0001287
      label: Meningitis
  notes: >-
    1 of 9 published patients, and the one who died in the 2026 series. Recorded because it is
    the worst documented course of this disease and because a reader taking the founding report's
    "isolated mycobacterial disease" framing would not expect CNS involvement.
  evidence:
  - reference: PMID:41623352
    reference_title: "Complete and partial forms of X-linked MCTS1 deficiency in patients with mycobacterial disease."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Cranial computed tomography (CT) and magnetic resonance imaging revealed otomastoiditis, acute cerebral venous thrombosis, and granulomatous meningitis with focal white matter lesions that were particularly abundant in the right hemisphere."
    explanation: The imaging findings that established central nervous system involvement.
  - reference: PMID:41623352
    reference_title: "Complete and partial forms of X-linked MCTS1 deficiency in patients with mycobacterial disease."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Cerebrospinal fluid (CSF) culture revealed the presence of pyrazinamide-resistant M. bovis–BCG."
    explanation: >-
      The organism, cultured from cerebrospinal fluid, with its resistance pattern — which is
      what makes this BCG disease of the central nervous system rather than a sterile
      inflammatory process.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: BELOW_1_IN_1000000
  notes: >-
    Nine patients in nine unrelated families: five in 2023 from China, Finland, Iran (two
    families) and Saudi Arabia, and four in 2026 from Iran, Oman, China and the United States.
    All male, all hemizygous, eight distinct variants.

    No population estimate exists. Ascertainment is through MSMD cohorts, so the denominator is
    the set of patients whose mycobacterial disease prompted genetic investigation, not the
    population. rate_per_100000 is left unset.

    One quantity worth recording: MCTS1 is one of twenty-two genes underlying forty-seven
    genetic aetiologies of MSMD as of the 2026 report. That is the population this entity is a
    slice of, and it is the reason a targeted MSMD panel rather than a single-gene test is the
    diagnostic route.
  evidence:
  - reference: PMID:41623352
    reference_title: "Complete and partial forms of X-linked MCTS1 deficiency in patients with mycobacterial disease."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Variants of 22 genes underlie 47 different genetic etiologies of MSMD (4)."
    explanation: >-
      The size of the genetic differential this entity sits inside. Graded BACKGROUND because it
      is a cited count in the paper's introduction rather than its own result.
progression:
- phase: Infantile BCG disease
  notes: >-
    Disease appears between one and twelve months in the vaccinated patients, at the site of
    vaccination first and disseminating from there. The 2026 series' youngest presented at four
    months with axillary adenitis and bone-marrow involvement; another at one month with local
    armpit disease.
  evidence:
  - reference: PMID:41623352
    reference_title: "Complete and partial forms of X-linked MCTS1 deficiency in patients with mycobacterial disease."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "7 mo later, he was diagnosed with abscessed BCG adenitis (BCG-itis)."
    explanation: The interval from vaccination to disease in one of the 2026 patients.
- phase: Later mycobacterial disease in the unvaccinated
  notes: >-
    Without BCG the disease waits for an environmental mycobacterium. The American patient had a
    healthy childhood with no notable infections, began losing weight and having diarrhoea at
    sixteen, and was diagnosed with disseminated Mycobacterium abscessus at twenty-two. He
    carries the hypomorphic p.Trp175* allele, so allele severity and absence of BCG exposure both
    point the same way and cannot be separated in one patient.
  evidence:
  - reference: PMID:41623352
    reference_title: "Complete and partial forms of X-linked MCTS1 deficiency in patients with mycobacterial disease."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "He had a healthy childhood, without frequent or notable infections. At the age of 16 years, he began to experience weight loss and diarrhea."
    explanation: >-
      The healthy childhood and the age of first symptoms — the natural history of an
      unvaccinated patient with a hypomorphic allele.
- phase: Outcome
  notes: >-
    Two of nine published patients have died of mycobacterial disease: one of the original five,
    and the Omani patient at six years and nine months. The rest responded to antimycobacterial
    treatment. The 2023 report describes its survivors as asymptomatic after early childhood with
    normal growth and development; the 2026 series' survivors are on long-term antimycobacterial
    therapy, immunoglobulin replacement and in two cases IFN-gamma-1b.

    The difference between those two descriptions is the most important thing in this entry's
    prognosis, and it is at least partly a difference in follow-up rather than in disease.
  evidence:
  - reference: PMID:41623352
    reference_title: "Complete and partial forms of X-linked MCTS1 deficiency in patients with mycobacterial disease."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "He developed fever and hematemesis, leading to his collapse and death within 24 h at the age of 6 years and 9 mo."
    explanation: The fatal outcome in the 2026 series, with its age.
genetic:
- name: MCTS1
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: MCTS1
    term:
      id: hgnc:23357
      label: MCTS1
  notes: >-
    The single causal gene. MCTS1 is also a well-established oncogene, overexpressed in several
    tumour types, which makes the narrowness of the germline loss-of-function phenotype the
    surprising part of this disease: nine hemizygous null or near-null males with mycobacterial
    disease and no reported malignancy.

    A note on the identifier. The deep-research report committed alongside this entry gives MCTS1
    as HGNC:7838, which is NKX3-1, an unrelated homeobox gene. The correct identifier is
    hgnc:23357. The same run's HLASA report made the same class of error for LARS2. Gene CURIEs
    are unchecked in the research lane (the recipe passes --term-skip-prefix HGNC) and only
    self-consistency-checked on the KB side, which is dismech issue #10948; the report's JAK2
    identifier, by contrast, was correct.
  evidence:
  - reference: PMID:37875108
    reference_title: "Human MCTS1-dependent translation of JAK2 is essential for IFN-γ immunity to mycobacteria."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "These findings suggest that X-linked recessive human MCTS1 deficiency underlies isolated mycobacterial disease by impairing JAK2 translation in innate-like adaptive T lymphocytes, thereby impairing the IL-23-dependent induction of IFN-γ."
    explanation: The gene-disease claim and the mechanism in one sentence, as the authors state it.
- name: JAK2
  relationship_type: MODIFIER
  variant_origin: GERMLINE
  gene_term:
    preferred_term: JAK2
    term:
      id: hgnc:6192
      label: JAK2
  notes: >-
    JAK2 is not mutated in this disease. It is recorded here because it is the substrate whose
    translation fails, and because the structure of its 5-prime untranslated region — not its
    function — is what makes it the vulnerable one. The relationship type is MODIFIER as the
    nearest available value; there is no relationship type for "gene whose translation is
    selectively impaired by the causal gene's loss", and calling it CAUSATIVE would assert a
    JAK2 variant that no patient has.
  evidence:
  - reference: PMID:37875108
    reference_title: "Human MCTS1-dependent translation of JAK2 is essential for IFN-γ immunity to mycobacteria."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "JAK2 expression is sufficiently low to impair cellular responses to interleukin-23 (IL-23) and partially IL-12, but not other JAK2-dependent cytokines."
    explanation: >-
      JAK2's role as the limiting substrate, and the quantitative reason the impairment is
      selective for IL-23 rather than global. Graded IN_VITRO, as the same sentence is on the
      pathophysiology node: the cellular responses it describes were measured in knockout cell
      lines and reporter systems, not in a patient.
diagnosis:
- name: Routine immunophenotyping
  presence: ABSENT
  description: >-
    Recorded as a negative because it is the trap. Circulating leukocyte subsets develop normally
    and complete blood counts and clinical immunophenotyping are normal, so the test that would
    ordinarily confirm an immunodeficiency comes back reassuring. Molecular diagnosis is the only
    route.
  evidence:
  - reference: PMID:41623352
    reference_title: "Complete and partial forms of X-linked MCTS1 deficiency in patients with mycobacterial disease."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Complete blood counts and clinical immunophenotyping results were normal (Tables S3 and S4)."
    explanation: The normal routine immunology in the adult patient, whose diagnosis came from sequencing.
- name: Whole-exome sequencing
  description: >-
    How every published patient was diagnosed. Given that MSMD has twenty-two genes and
    forty-seven aetiologies, a targeted MSMD panel or exome is the rational first test in a boy
    with disseminated BCG or environmental mycobacterial disease and a normal immunophenotype.
  evidence:
  - reference: PMID:41623352
    reference_title: "Complete and partial forms of X-linked MCTS1 deficiency in patients with mycobacterial disease."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Whole-exome sequencing of the probands revealed hemizygosity for rare germline MCTS1 variants."
    explanation: The diagnostic method used across the 2026 series.
- name: Mycobacterial culture and molecular identification from the affected site
  description: >-
    Identifying the organism is what converts a granulomatous or necrotic lesion into a
    mycobacterial diagnosis, and in this series it required a range of methods: PCR for the
    M. bovis complex on axillary and bone-marrow specimens, cerebrospinal fluid culture,
    mycobacterial culture from lymph node biopsy, and metagenomic next-generation sequencing on
    an ileocaecal mucosal biopsy. Histology alone was insufficient in at least one case —
    the Chinese patient's biopsy showed epithelial damage, crypt distortion and gastritis
    without granulomas.
  evidence:
  - reference: PMID:41623352
    reference_title: "Complete and partial forms of X-linked MCTS1 deficiency in patients with mycobacterial disease."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Histopathology revealed small intestinal villous widening with epithelial damage and increased intraepithelial lymphocytes, focal crypt distortion in the colon, and mild chronic gastritis without granulomas"
    explanation: >-
      A mycobacterial gastrointestinal infection with non-granulomatous histology — the reason
      organism identification rather than histology is the diagnostic step recorded here.
treatments:
- name: Antimycobacterial Therapy
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    The primary treatment, and mostly effective. Regimens in the published patients range from
    isoniazid and rifampicin for eighteen months, through isoniazid, rifampicin, ethambutol and
    pyrazinamide, to a four-drug combination of imipenem with ceftaroline, omadacycline,
    clofazimine and linezolid for the M. abscessus patient. One isolate was
    pyrazinamide-resistant M. bovis BCG, which is expected — M. bovis is intrinsically
    pyrazinamide-resistant — and is worth knowing before a standard antituberculous regimen is
    started.

    Some patients also carry long-term antibacterial prophylaxis: the youngest 2026 patient is on
    daily azithromycin.
  treatment_term:
    preferred_term: antimycobacterial pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: isoniazid
      term:
        id: CHEBI:6030
        label: isoniazide
    - preferred_term: rifampicin
      term:
        id: CHEBI:28077
        label: rifampicin
    - preferred_term: ethambutol
      term:
        id: CHEBI:4877
        label: ethambutol
  target_mechanisms:
  - target: Disseminated BCG Disease
    description: >-
      Kills the organism the immune defect cannot control. It addresses the infection and leaves
      the IFN-gamma induction defect intact, which is why several patients need it long-term and
      why exposure to a new mycobacterium remains a risk.
  evidence:
  - reference: PMID:41623352
    reference_title: "Complete and partial forms of X-linked MCTS1 deficiency in patients with mycobacterial disease."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "P1 was treated with isoniazid and rifampicin, initially for 4 mo, but with subsequent prolongation for 18 mo based on his clinical response and microbiological status."
    explanation: >-
      A worked regimen with its duration and the basis on which it was extended — the practical
      detail a clinician needs.
  - reference: PMID:41623352
    reference_title: "Complete and partial forms of X-linked MCTS1 deficiency in patients with mycobacterial disease."
    supports: REFUTE
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Despite intravenous phenytoin and dexamethasone treatment and anti-infection treatment with ceftriaxone, vancomycin, and acyclovir, the patient remained febrile and lethargic."
    explanation: >-
      Graded REFUTE against a reading of antimicrobial treatment as reliably effective. In the
      patient who died, broad empirical cover failed because the organism was mycobacterial and
      the regimen was not — the antimycobacterial drugs were started eleven days after admission.
- name: Recombinant Interferon Gamma-1b
  therapeutic_modality: PROTEIN_REPLACEMENT
  description: >-
    The mechanistically indicated therapy, and the one this entry's pathograph predicts. The
    lesion is upstream of the IFN-gamma receptor and patient cells respond normally to exogenous
    IFN-gamma, so supplying it bypasses the block rather than working around it.

    Three of the four 2026 patients received it. In the Omani patient subcutaneous IFN-gamma-1b
    improved activity, mobility and nutritional status before he was lost to follow-up and it
    was stopped after six weeks; in the American patient, increasing doses over a year and a
    half, reaching 400 micrograms three times weekly, produced substantial improvement after
    about a year.

    Those are two uncontrolled observations, one of them in a patient who then died after the
    drug was stopped. They are recorded as such.
  treatment_term:
    preferred_term: interferon gamma therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: interferon gamma-1b
      term:
        id: NCIT:C100089
        label: Interferon Gamma-1b
  target_mechanisms:
  - target: Failure of Macrophage Activation Against Intracellular Mycobacteria
    description: >-
      Exogenous IFN-gamma activates macrophages directly, downstream of the IL-23-to-IFN-gamma
      induction step that fails. This is the node the treatment targets, and the reason it
      targets that node rather than a phenotype is that the bypass is a mechanistic claim the
      published cell data support.
  notes: >-
    therapeutic_modality is PROTEIN_REPLACEMENT rather than the immunomodulation reading the
    drug's usual context invites. The lesion here is an inability to produce IFN-gamma: IL-23
    signalling fails, so MAIT and gamma-delta cells do not make the cytokine. Giving it replaces
    a protein the patient cannot make, in a patient whose response to it is intact. That is
    replacement in the same sense immunoglobulin replacement is, and it is why the entry's
    pathograph predicts the therapy rather than merely accommodating it.
  evidence:
  - reference: PMID:41623352
    reference_title: "Complete and partial forms of X-linked MCTS1 deficiency in patients with mycobacterial disease."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Treatment with increasing doses of IFN-γ-1b for 1.5 years has started to show substantial improvements in the patient’s condition after ~1 year of treatment at a dosage of 400 µg three times per week."
    explanation: >-
      The dose, the schedule, the duration before response, and the response — the only
      quantitative treatment observation in this disease.
  - reference: PMID:41623352
    reference_title: "Complete and partial forms of X-linked MCTS1 deficiency in patients with mycobacterial disease."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Subcutaneous IFN-γ1b treatment was initiated, leading to improvements in the patient’s activity, mobility, and nutritional status."
    explanation: >-
      The second reported response, in the patient with central nervous system disease. The same
      paragraph records that follow-up was lost and the drug stopped after six weeks; that is in
      this treatment's description rather than in the snippet, which reports only what was
      observed on treatment.
- name: Immunoglobulin Replacement Therapy
  therapeutic_modality: PROTEIN_REPLACEMENT
  description: >-
    Given to three of the four 2026 patients — monthly intravenous immunoglobulin in the youngest,
    intravenous immunoglobulin in the Chinese patient for hypogammaglobulinaemia, and in the
    Omani patient on the basis of severe illness with moderately low B-cell counts and IgG even
    though immunoglobulin levels were normal.

    That last case is worth distinguishing: it was a decision made on clinical severity rather
    than on a demonstrated antibody deficiency, and it is recorded that way here.
  treatment_term:
    preferred_term: immunoglobulin replacement therapy
    term:
      id: NCIT:C62710
      label: Immunoglobulin Therapy
  target_mechanisms:
  - target: Decreased Circulating Immunoglobulin
    description: >-
      Substitutes for antibody the patient does not make. It has no relationship to the
      IFN-gamma induction defect, which is why it is recorded against the humoral phenotype
      rather than against a mechanism node.
  evidence:
  - reference: PMID:41623352
    reference_title: "Complete and partial forms of X-linked MCTS1 deficiency in patients with mycobacterial disease."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "He is on prophylaxis with azithromycin daily and IVIG monthly."
    explanation: >-
      The maintenance regimen in the youngest 2026 patient, covering both the antibacterial
      prophylaxis and the replacement.
  - reference: PMID:41623352
    reference_title: "Complete and partial forms of X-linked MCTS1 deficiency in patients with mycobacterial disease."
    supports: NO_EVIDENCE
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "IG levels were normal, but IVIG was administered due to the patient’s severe medical condition, moderately low B cell counts and IgG levels"
    explanation: >-
      Graded NO_EVIDENCE for this treatment's indication rather than SUPPORT. The sentence
      records that the drug was given and states explicitly that the immunoglobulin levels did
      not indicate it — so it bears on the decision, not on the claim that these patients have an
      antibody deficiency needing replacement.
discussions:
- discussion_id: imd118_redundancy_claim
  kind: CONTROVERSY
  status: OPEN
  prompt: >-
    Is MCTS1-dependent translation reinitiation really "otherwise physiologically redundant", or
    did the founding cohort simply have less follow-up than the second one?
  rationale: >-
    The 2023 report's most striking claim is that losing a general translation factor costs
    nothing outside the mycobacterial axis: normal immunity, growth and development in the
    survivors. It is a claim worth taking seriously — nine hemizygous null males with no
    malignancy is real evidence that an established oncogene is dispensable.

    The 2026 series does not contradict it directly and does sit awkwardly with it. Three of
    four new patients have growth failure below the third percentile, three have
    hypogammaglobulinaemia or low IgG prompting replacement, one has delayed gross motor
    development, and three have chronic gastrointestinal disease. Some of that is attributable
    to chronic mycobacterial infection, which causes growth failure on its own. Some of it may
    not be.

    The two readings make different predictions. If the extra features are infection-driven,
    they should improve with mycobacterial control; if they are a direct consequence of the
    translation defect, they should not. The American patient — healthy childhood, no BCG,
    disease only from sixteen — is the informative case, and what is reported for him is chronic
    weight loss dating from the onset of his infection rather than from birth.

    This entry records both the founding claim and the later series without resolving them, and
    the quoted hedge in the mechanism node is deliberate.
  attaches_to:
  - pathophysiology#Failure of 40S Ribosome Recycling and Translation Reinitiation
  - phenotypes#Failure to Thrive
  - phenotypes#Decreased Circulating Immunoglobulin
- discussion_id: imd118_ifng_bypass
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >-
    Should recombinant IFN-gamma be started at diagnosis in MCTS1 deficiency rather than after
    antimycobacterial therapy fails?
  rationale: >-
    The mechanistic case is unusually clean for a disease this rare. The defect is in the
    induction of IFN-gamma, not in the response to it; patient leukocytes respond normally to
    exogenous IFN-gamma and IFN-alpha; so the lesion is bypassable in principle, and the
    pathograph in this entry predicts exactly where the bypass enters.

    The evidence is two uncontrolled observations. In the American patient, IFN-gamma-1b at 400
    micrograms three times weekly produced substantial improvement — after about a year, which
    is worth noting for anyone judging an early response. In the Omani patient it improved
    activity, mobility and nutrition, was stopped after six weeks when follow-up was lost, and
    he died some months later; that sequence is suggestive and is not evidence of causation in
    either direction.

    What would settle it is not obtainable at nine patients. What is obtainable is a consistent
    record of whether IFN-gamma was offered, at what dose, and when relative to the
    antimycobacterial regimen — which the 2026 report supplies for its patients and the 2023
    report does not for its five.
  attaches_to:
  - treatments#Recombinant Interferon Gamma-1b
  - pathophysiology#Failure of Macrophage Activation Against Intracellular Mycobacteria
- discussion_id: imd118_bcg_in_at_risk_families
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >-
    Does an unvaccinated male relative of an MCTS1-deficient proband need BCG withheld, screening
    for environmental mycobacteria, or both?
  rationale: >-
    Eight of nine published patients were BCG-vaccinated at or near birth, and most of their
    disease is BCG disease. The obvious inference is that withholding BCG from at-risk males
    prevents the disease.

    The American patient shows the limit of that inference. He was never vaccinated, had a
    healthy childhood, and presented at twenty-two with disseminated Mycobacterium abscessus and
    a retroperitoneal mass encasing the aorta. Withholding BCG did not protect him; it changed
    which mycobacterium found him, and when. One 2023 patient was likewise unvaccinated and was
    only two at last follow-up, so his eventual course is unknown.

    The practical question this raises is not answerable from nine patients but is worth posing
    explicitly: an X-linked disease with a vaccine-avoidable early presentation and an
    unavoidable late one needs a surveillance answer, not only a vaccination answer. No published
    source addresses it.
  attaches_to:
  - phenotypes#Disseminated BCG Disease
  - phenotypes#Nontuberculous Mycobacterial Infection
notes: >-
  Patient count and sources. Nine patients in nine unrelated families: five in PMID:37875108
  (2023) and four in PMID:41623352 (2026). The 2026 paper's own count of five prior reported
  variants matches the 2023 cohort, so the two sets are disjoint and the total is nine.

  Scope of the 2023 abstract. Only the abstract and the opening of the 2023 paper are in the
  reference cache here; its five patients' individual clinical courses are not quotable from
  what is cached. Every clinical phenotype in this entry that carries a per-patient detail is
  therefore evidenced from the 2026 paper, whose full text is cached. Where this entry states
  something about the 2023 cohort — normal leukocyte subsets, one death, the redundancy claim —
  it is quoted either from the 2023 abstract or from the 2026 paper's summary of it, and graded
  BACKGROUND in the latter case.

  The gene identifier. The deep-research report gives MCTS1 as HGNC:7838, which is NKX3-1. The
  correct identifier is hgnc:23357. This is the second wrong gene CURIE in the same batch of
  five openscientist runs — the HLASA report gave LARS2 as HGNC:21353, which is KLHL31. The
  research recipe passes `--term-skip-prefix HGNC` so gene CURIEs are unchecked where they are
  emitted, and `just validate-terms` compares a CURIE against its own label rather than against
  the gene the entry names (dismech#10948). Both were caught here only because the entries write
  `label:` out. The same report's JAK2 identifier was correct, so the error rate is not uniform
  and cannot be assumed either way.

  Two curator errors, both caught by term validation, both worth recording because neither felt
  like guessing at the time: NCIT:C1428 was written for recombinant interferon gamma and is
  Stavudine; the entry now uses NCIT:C100089 Interferon Gamma-1b. CHEBI:6030 was written with
  the label "isoniazid" where CHEBI's canonical label is "isoniazide".

  GeneReviews baseline: `just check-genereviews` reports NO_CHAPTER for both GeneReviews and
  StatPearls against the committed Bookshelf index (snapshot 2026-09-10).

  JAK2 in the `genetic:` section. JAK2 is not mutated in this disease and is recorded with
  `relationship_type: MODIFIER` because there is no value for "gene whose translation the causal
  gene's loss selectively impairs". CAUSATIVE would assert a JAK2 variant no patient has. This
  is a schema gap rather than a curation choice, and the nearest available value is used with
  the reason stated in that record's notes.

  Review round 1. Two IMPORTANT findings, both taken. The mechanism chain was graded
  HUMAN_CLINICAL throughout on the reasoning that the experiments used patient and
  patient-derived cells. That is the inference CLAUDE.md's definition rules out: IN_VITRO covers
  cultured cells whether human or not, and "patient-derived" says where a cell came from rather
  than the setting the experiment ran in. The work behind those six items is MCTS1-knockout HeLa
  transfection and reporter assays, 40S and 80S footprinting in HeLa, CRISPR knockout in THP-1,
  HEK-Blue IL-23 reporter lines, gamma-2A fibrosarcoma transfection, and SV40-immortalised
  patient fibroblasts transduced with wild-type MCTS1. The founding paper says it in its own
  words, describing the impaired BCG response of patient leukocytes as measured in vitro. Those
  six are now IN_VITRO; the general-immunology statement about IFN-gamma as macrophage-activating
  factor is now OTHER; the phenotype and treatment items stay HUMAN_CLINICAL, which is what they
  are.

  This matters beyond bookkeeping. CLAUDE.md's rule that model and in-vitro evidence should not
  be the sole support for a human claim only works if the grading is honest, and as written the
  entry asserted that a chain established in three immortalised cell lines was direct human
  clinical evidence.

  The second finding was a binding that inverted its own claim: Normal Circulating Leukocyte
  Subsets was bound to HP:0002721 Immunodeficiency, so any consumer reading HP terms would take
  the entry to assert the abnormality that node exists to deny. The original notes flagged it as
  a binding of convenience, which does not help — the disclaimer is prose and the term is
  machine-readable. The term is dropped, preferred_term carries the finding, and the searches
  behind that omission are recorded in the phenotype's own notes and were re-run before being
  written down.

  Not curated. The deep-research report cites a body of MCTS1 tumour-biology work — oncogenic
  roles in laryngeal squamous cell carcinoma, breast-cancer prognostic signatures, the
  OTUD6B-LIN28B axis. That is overexpression biology in cancer, not a mechanism of germline
  loss, and the most interesting thing about it is precisely that it does not manifest in these
  patients. It is discussed in the gene record rather than curated as pathophysiology.
📚

References & Deep Research

References

2
PMID:37875108
Human MCTS1-dependent translation of JAK2 is essential for IFN-γ immunity to mycobacteria.
No top-level findings curated for this source.
PMID:41623352
Complete and partial forms of X-linked MCTS1 deficiency in patients with mycobacterial disease.
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 (2)

Record notes

Patient count and sources. Nine patients in nine unrelated families: five in PMID:37875108 (2023) and four in PMID:41623352 (2026). The 2026 paper's own count of five prior reported variants matches the 2023 cohort, so the two sets are disjoint and the total is nine. Scope of the 2023 abstract. Only the abstract and the opening of the 2023 paper are in the reference cache here; its five patients' individual clinical courses are not quotable from what is cached. Every clinical phenotype in this entry that carries a per-patient detail is therefore evidenced from the 2026 paper, whose full text is cached. Where this entry states something about the 2023 cohort — normal leukocyte subsets, one death, the redundancy claim — it is quoted either from the 2023 abstract or from the 2026 paper's summary of it, and graded BACKGROUND in the latter case. The gene identifier. The deep-research report gives MCTS1 as HGNC:7838, which is NKX3-1. The correct identifier is hgnc:23357. This is the second wrong gene CURIE in the same batch of five openscientist runs — the HLASA report gave LARS2 as HGNC:21353, which is KLHL31. The research recipe passes `--term-skip-prefix HGNC` so gene CURIEs are unchecked where they are emitted, and `just validate-terms` compares a CURIE against its own label rather than against the gene the entry names (dismech#10948). Both were caught here only because the entries write `label:` out. The same report's JAK2 identifier was correct, so the error rate is not uniform and cannot be assumed either way. Two curator errors, both caught by term validation, both worth recording because neither felt like guessing at the time: NCIT:C1428 was written for recombinant interferon gamma and is Stavudine; the entry now uses NCIT:C100089 Interferon Gamma-1b. CHEBI:6030 was written with the label "isoniazid" where CHEBI's canonical label is "isoniazide". GeneReviews baseline: `just check-genereviews` reports NO_CHAPTER for both GeneReviews and StatPearls against the committed Bookshelf index (snapshot 2026-09-10). JAK2 in the `genetic:` section. JAK2 is not mutated in this disease and is recorded with `relationship_type: MODIFIER` because there is no value for "gene whose translation the causal gene's loss selectively impairs". CAUSATIVE would assert a JAK2 variant no patient has. This is a schema gap rather than a curation choice, and the nearest available value is used with the reason stated in that record's notes. Review round 1. Two IMPORTANT findings, both taken. The mechanism chain was graded HUMAN_CLINICAL throughout on the reasoning that the experiments used patient and patient-derived cells. That is the inference CLAUDE.md's definition rules out: IN_VITRO covers cultured cells whether human or not, and "patient-derived" says where a cell came from rather than the setting the experiment ran in. The work behind those six items is MCTS1-knockout HeLa transfection and reporter assays, 40S and 80S footprinting in HeLa, CRISPR knockout in THP-1, HEK-Blue IL-23 reporter lines, gamma-2A fibrosarcoma transfection, and SV40-immortalised patient fibroblasts transduced with wild-type MCTS1. The founding paper says it in its own words, describing the impaired BCG response of patient leukocytes as measured in vitro. Those six are now IN_VITRO; the general-immunology statement about IFN-gamma as macrophage-activating factor is now OTHER; the phenotype and treatment items stay HUMAN_CLINICAL, which is what they are. This matters beyond bookkeeping. CLAUDE.md's rule that model and in-vitro evidence should not be the sole support for a human claim only works if the grading is honest, and as written the entry asserted that a chain established in three immortalised cell lines was direct human clinical evidence. The second finding was a binding that inverted its own claim: Normal Circulating Leukocyte Subsets was bound to HP:0002721 Immunodeficiency, so any consumer reading HP terms would take the entry to assert the abnormality that node exists to deny. The original notes flagged it as a binding of convenience, which does not help — the disclaimer is prose and the term is machine-readable. The term is dropped, preferred_term carries the finding, and the searches behind that omission are recorded in the phenotype's own notes and were re-run before being written down. Not curated. The deep-research report cites a body of MCTS1 tumour-biology work — oncogenic roles in laryngeal squamous cell carcinoma, breast-cancer prognostic signatures, the OTUD6B-LIN28B axis. That is overexpression biology in cancer, not a mechanism of germline loss, and the most interesting thing about it is precisely that it does not manifest in these patients. It is discussed in the gene record rather than curated as pathophysiology.

Create: Immunodeficiency 118 (MCTS1) · 2026-09-22T18:16:47Z · View source

De novo curation of IMD118 (MCTS1, MONDO:0958030) from the 2023 Cell report that defined the entity and a 2026 four-family follow-up. Deep research: one openscientist run (16 references, 16/16 resolved, 5/16 judged on topic, term_validation needs_review true). The report is the strongest of the five in this batch on mechanism and supplied the JAK2 start-stop uORF account, the IL-23 limb placement and the seventeen-gene reporter screen. Its gene CURIE for MCTS1, HGNC:7838, is NKX3-1; the correct identifier hgnc:23357 was substituted and the error recorded, the second such error in this batch after LARS2 in the HLASA run. Its JAK2 identifier was correct. The substantive divergence from the report is prognostic: the report follows the 2023 framing of isolated mycobacterial disease with otherwise normal immunity and generally favourable outcome, and the 2026 series adds a death from CNS BCG disease, growth failure below the third percentile in three of four, hypogammaglobulinaemia prompting replacement in three of four, and chronic gastrointestinal mycobacterial disease. Both readings are recorded, with the founding redundancy claim quoted with its own hedge intact and the tension carried as a CONTROVERSY discussion rather than resolved. Two REFUTE and one NO_EVIDENCE evidence item keep counter-evidence and a non-indication in place. Two curator errors caught by term validation: NCIT:C1428 written from memory for recombinant interferon gamma is Stavudine, now NCIT:C100089; CHEBI:6030's canonical label is isoniazide not isoniazid. Validation on the final tree: just validate, validate-terms, validate-disorders, count-verified-snippets 37/37, check-entity-refs, check-causal-targets, check-qualifier-terms, check-duplicate-keys, check-folded-hyphens, check-snippet-length, check-title-snippets, check-snippet-grading, check-enum-values, check-coarse-phenotypes, check-reference-titles, check-case-collisions, check-genereviews (NO_CHAPTER), list-disconnected-phenotypes 7/9. Review round 1 (ai4c-reviewer, CHANGES_REQUESTED, two IMPORTANT findings, both taken, plus one of two suggestions). First: the whole mechanism chain was graded HUMAN_CLINICAL on the reasoning that the experiments used patient and patient-derived cells, which is the inference CLAUDE.md's definition rules out - IN_VITRO covers cultured cells whether human or not. The work behind those items is MCTS1-knockout HeLa transfection and reporter assays, 40S/80S footprinting, CRISPR knockout in THP-1, HEK-Blue IL-23 reporter lines, gamma-2A fibrosarcoma transfection, and SV40-immortalised patient fibroblasts; the founding paper itself describes the impaired BCG response of patient leukocytes as measured in vitro. Seven items regraded to IN_VITRO and one general-immunology statement to OTHER; phenotype and treatment items left HUMAN_CLINICAL. Second: Normal Circulating Leukocyte Subsets was bound to HP:0002721 Immunodeficiency, a binding that inverts the claim the node exists to make. The original notes flagged it as a binding of convenience, which does not help, since the disclaimer is prose and the term is machine-readable. The term is dropped, preferred_term carries the finding, and the phenotype's notes record the searches - l~leukocyte, l~lymphocyte count, l~immunophenotyp, l~normal against ols:hp - which were re-run before the note was written, per the CLAUDE.md rule that naming a query does not make the note true. HPO has terms for abnormality and none for a documented normal result in this domain; HP:0002372 Normal interictal EEG is cited in the note as the shape a suitable term would take. Also added a notes: paragraph on why IFN-gamma-1b is PROTEIN_REPLACEMENT rather than immunomodulation. Declined the suggestion to promote hepatomegaly, splenomegaly, osteomyelitis, fever and abscess from prose to phenotype nodes: the 2023 abstract lists them without per-patient attribution and the 2026 full text attributes its own, so promoting them would mean denominators this entry cannot source. One gate catch worth recording: regrading the JAK2 sentence on the pathophysiology node left the same sentence graded HUMAN_CLINICAL on the JAK2 gene record, and check-snippet-grading failed - which is precisely the divergence that gate exists for. Both now IN_VITRO. Post-round validation: count-verified-snippets 37/37, all gates green.

OpenScientist ▸
Immunodeficiency 118 (IMD118): A Comprehensive Disease Characteristics Report
openscientist-autonomous 13 citations 2026-09-22T17:25:41.581159

Immunodeficiency 118 (IMD118): A Comprehensive Disease Characteristics Report

Disease: Immunodeficiency 118 (IMD118) MONDO ID: MONDO:0958030 · OMIM: #301115 · Gene: MCTS1 (Xq24) Category: Mendelian — X-linked recessive inborn error of immunity (a subtype of Mendelian Susceptibility to Mycobacterial Disease, MSMD) Primary reference: Bohlen J, Zhou Q, Philippot Q, et al. "Human MCTS1-dependent translation of JAK2 is essential for IFN-γ immunity to mycobacteria." 2023 (PMID: 37875108).

Summary

Immunodeficiency-118 (IMD118) is an ultra-rare, X-linked recessive inborn error of immunity caused by hemizygous loss-of-function mutations in MCTS1 on chromosome Xq24. The disease was defined by a single landmark study — Bohlen, Zhou, Béziat, Casanova and colleagues (2023, PMID: 37875108) — which identified complete MCTS1 deficiency in 5 unrelated males from kindreds of different ancestries (China, Finland, Iran, and Saudi Arabia). Clinically, IMD118 belongs to the MSMD spectrum: affected males present in infancy with disseminated infection by weakly virulent mycobacteria, most commonly after Bacillus Calmette-Guérin (BCG) vaccination, while otherwise displaying essentially normal immunity, growth, and development.

The mechanism is a specific and elegant translational defect. MCTS1 (Malignant T-cell-amplified sequence 1) is a translation re-initiation and 40S ribosome-recycling factor that forms a heterodimer with DENR. Complete MCTS1 deficiency impairs the translation of a small subset of proteins — most importantly the tyrosine kinase JAK2 — in all cell types tested. JAK2 loss cripples signaling downstream of IL-23 (and partially IL-12), which in turn reduces IFN-γ production by innate-like adaptive MAIT (mucosal-associated invariant T) and γδ T lymphocytes upon mycobacterial challenge. Because IFN-γ is the central macrophage-activating cytokine controlling intracellular mycobacteria, its failure produces the characteristic mycobacterial susceptibility. The selectivity of the JAK2 defect is explained by two ultra-short "start-stop" upstream open reading frames (stuORFs) in the JAK2 5′UTR that render JAK2 translation uniquely dependent on MCTS1-mediated ribosome recycling.

Prognosis is generally favorable but not benign. Among the 5 reported patients, one died of disseminated mycobacterial disease while the other four responded to antimycobacterial therapy and remained asymptomatic after early childhood, with normal growth and development. Critically, patient leukocytes retained normal responses to exogenous IFN-γ and IFN-α, meaning the block is upstream of the IFN-γ receptor and is potentially bypassable — providing a clear rationale for recombinant IFN-γ as adjunctive therapy, as used successfully in other MSMD genotypes. A notable paradox is that MCTS1 is an established oncogene, yet its complete germline loss produces only a narrow immunological phenotype rather than developmental defects or cancer, indicating that its translational function is largely physiologically redundant except along the IL-23→JAK2→IFN-γ axis.

Key Findings

Finding 1 — IMD118 is X-linked recessive MCTS1 deficiency causing isolated mycobacterial disease

IMD118 (OMIM #301115) is caused by hemizygous loss-of-function variants in MCTS1 (Xq24) and was described in 5 unrelated males from four countries. As the primary report states: "We report X-linked recessive MCTS1 deficiency in men with mycobacterial disease from kindreds of different ancestries (from China, Finland, Iran, and Saudi Arabia)" (PMID: 37875108).

The five patients carried a spectrum of loss-of-function variant types: 2 frameshift variants, 1 splice-site variant, and 2 in-frame 3′ deletions, the latter two both yielding a truncated protein lacking residues Ala133–Lys181 (p.Ala133_Lys181del). All variants result in complete MCTS1 deficiency. The molecular consequence is defined by the authors: "Complete deficiency of this translation re-initiation factor impairs the translation of a subset of proteins, including the kinase JAK2 in all cell types tested, including T lymphocytes and phagocytes." The downstream immunological consequence connects the translation defect to disease: "Defective responses to IL-23 preferentially impair the production of IFN-γ by innate-like adaptive mucosal-associated invariant T cells (MAIT) and γδ T lymphocytes upon mycobacterial challenge."

This establishes IMD118 as a single-gene, X-linked recessive disorder in which a general translation factor defect is funneled into a strikingly narrow clinical outcome via a single critical substrate (JAK2) and a single critical pathway (IL-23→IFN-γ).

Finding 2 — MCTS1 forms a heterodimer with DENR to mediate 40S ribosome recycling and translation reinitiation

MCTS1 (also called MCT-1; NCBI Gene 28985; Xq24) is a translation factor that partners with DENR (density-regulated reinitiation factor). Together MCTS1/DENR are the mammalian counterparts of the yeast Tma20/Tma22 heterodimer, with eIF2D (yeast Tma64) providing a parallel activity. These factors recycle post-termination 40S ribosomal subunits at stop codons and modulate reinitiation on mRNAs containing short upstream open reading frames (uORFs).

The functional role was demonstrated in yeast and in vitro systems: "Tma64 (eIF2D), Tma20 (MCT-1), and Tma22 (DENR) function as 40S recycling factors in vitro" (PMID: 30146315). The reinitiation-promoting property that is mechanistically central to IMD118 was shown by Jendruchová et al.: "MCTS1/DENR enhance reinitiation at short upstream open reading frames (uORFs) harboring penultimate codons that confer dependence on these factors in bulk 40S recycling" (PMID: 38903097). When MCTS1 is absent, 80S ribosomes queue behind stop codons and aberrant reinitiation occurs in 3′UTRs — the general failure that, at the JAK2 locus, specifically prevents translation of the main JAK2 open reading frame.

Finding 3 — MCTS1 is a known oncoprotein, yet germline complete loss causes only isolated mycobacterial disease

A striking feature of IMD118 is the mismatch between MCTS1's known oncogenic biology and the narrow phenotype of its germline loss. MCTS1/DENR are established oncogenes: "DENR and MCTS1 have been identified as oncogenes in several different tumor entities. The heterodimeric DENR·MCTS1 protein complex promotes translation of mRNAs containing upstream Open Reading Frames (uORFs)" (PMID: 35115540). The complex is cell-cycle regulated (DENR Ser73 phosphorylated by Cyclin B/CDK1 and Cyclin A/CDK2), and MCTS1 overexpression drives proliferation in laryngeal squamous cell carcinoma via the OTUD6B-LIN28B axis and LARP7 stabilization (PMID: 37634410, PMID: 35274760), and appears in breast-cancer prognostic gene signatures (PMID: 35441810, PMID: 35120331).

Despite this oncogenic role, the 5 hemizygous MCTS1-null males exhibited only isolated mycobacterial disease with otherwise normal immunity, growth, development, and no reported malignancy. The authors note: "the lack of MCTS1-dependent translation re-initiation and ribosome recycling seems to be otherwise physiologically redundant in these patients" (PMID: 37875108). This tells us that, in humans, MCTS1's translational function is largely dispensable for viability and development, and that its physiological non-redundancy is confined to the anti-mycobacterial IFN-γ axis.

Finding 4 — IMD118 lies on the IL-23-to-IFN-γ axis, independently validated by IL23R and IL-23 deficiencies

IMD118 is mechanistically embedded within the well-characterized IL-12/IL-23/IFN-γ circuit whose disruption defines MSMD. The essential role of IL-23 was established by Philippot et al.: "Human IL-23 is essential for IFN-γ-dependent immunity to mycobacteria" (PMID: 36763636). Independent genetic validation comes from IL23R deficiency: a homozygous R381X mutation in IL23R causes MSMD, where "impaired IL-23 immunity caused by a homozygous R381X mutation in IL23R underlies MSMD" (PMID: 35829840), producing impaired IL-23-mediated STAT3 phosphorylation, reduced IFN-γ secretion, and isolated disseminated BCG/NTM disease.

The effector cells are innate-like T cells. MAIT cells recognize mycobacterial vitamin-B metabolites presented on MR1 and produce IFN-γ, TNF, and granzyme B, and are reduced/exhausted in active tuberculosis (PMID: 37147816, PMID: 41707313). MCTS1 deficiency impairs JAK2 → IL-23 signaling → IFN-γ from MAIT/γδ cells, placing IMD118 firmly in the same functional pathway as IL12B, IL12RB1, IL23R, IFNGR1/2, STAT1, and the other MSMD genes.

Finding 5 — Clinical spectrum: infantile-onset disseminated mycobacteriosis with recovery after early childhood

The OMIM #301115 Clinical Synopsis, derived from Bohlen et al. 2023, describes the clinical picture of the 5 unrelated males (aged 3–18 years at report). Disseminated mycobacterial disease developed between 3 and 12 months of age, usually after BCG vaccination. Reported organ-system features and suggested HPO terms include:

Feature HPO term
Hepatomegaly HP:0002240
Splenomegaly HP:0001744
Osteomyelitis HP:0002754
Fever HP:0001945
Lymphadenopathy / enlarged lymph nodes HP:0002716
Abscess HP:0025615
Disseminated mycobacteriosis (BCG/NTM)

Immunologically, patients had normal numbers of circulating leukocyte subsets — routine immune workup is typically unrevealing, a hallmark of MSMD that necessitates molecular diagnosis. Most patients recover with treatment and remain asymptomatic after early childhood. The source data underlie the OMIM synopsis: "We report X-linked recessive MCTS1 deficiency in men with mycobacterial disease from kindreds of different ancestries" (PMID: 37875108).

Finding 6 — JAK2's selective MCTS1-dependence is caused by two ultra-short start-stop uORFs (stuORFs); exogenous IFN-γ responses remain intact

The molecular reason JAK2 is uniquely vulnerable among the many proteins translated in the cell was resolved by 5′UTR reporter assays. Among 17 MSMD/IFN-γ-immunity genes tested in MCTS1-KO HeLa cells, only JAK2 showed a >65% decrease in translation, which was rescued by wild-type MCTS1 but not by patient variants or a synthetic loss-of-function control (A109D). The JAK2 5′UTR contains three uORFs, two of which are ultra-short start-stop "stuORFs" (uORF1, uORF2). In the absence of MCTS1, 40S ribosomes stall (a "roadblock") at these stuORF stop codons, blocking re-initiation at the JAK2 main ORF — confirmed directly by accumulation of 40S ribosomal footprints. CRISPR MCTS1-knockout in THP-1 monocytes reproducibly lowered endogenous JAK2 across 5 independent clones.

Functionally, patient leukocytes had impaired IFN-γ production after BCG stimulation and impaired IL-23 responses (but normal IL-12 responses), yet retained NORMAL responses to exogenous IFN-γ and IFN-α. This localizes the defect upstream of the IFN-γ receptor and predicts that exogenous IFN-γ can bypass the block.

The protein architecture underpinning MCTS1's role was characterized earlier: "MCT-1 contains the PUA domain, a recently described RNA-binding domain that is found in several tRNA and rRNA modification enzymes... MCT-1 protein interacts with the cap complex through its PUA domain and recruits the density-regulated protein (DENR/DRP), containing the SUI1 translation initiation domain" (PMID: 16982740).

Finding 7 — Prognosis is generally favorable but the disease can be fatal (1 of 5 patients died)

Of the 5 hemizygous MCTS1-deficient males, one died of disseminated mycobacterial disease; the remaining four responded to antimycobacterial treatment, had no other infections, and showed normal growth and development. The redundancy of MCTS1 outside the mycobacterial axis is emphasized by the authors: "Surprisingly, the lack of MCTS1-dependent translation re-initiation and ribosome recycling seems to be otherwise physiologically redundant in these patients" (PMID: 37875108). The preserved response to exogenous IFN-γ and IFN-α provides both a favorable prognostic indicator and a therapeutic target.

Mechanistic Model / Interpretation

Ordered causal chain (initiating lesion → clinical manifestation)

  1. A hemizygous loss-of-function mutation in MCTS1 (Xq24; frameshift, splice-site, or in-frame 3′ deletion) leads to complete absence of functional MCTS1 protein in a male (X-linked recessive; single X chromosome). [demonstrated]
  2. Loss of MCTS1 results in failure of MCTS1/DENR-mediated 40S ribosome recycling and translation re-initiation. [demonstrated in vitro and in cells]
  3. At the JAK2 mRNA, the two ultra-short start-stop uORFs (stuORFs) in the 5′UTR cause 40S ribosomes to stall at the stuORF stop codons (a translational roadblock), which blocks re-initiation at the JAK2 main ORF. [demonstrated by 40S footprint accumulation and 5′UTR reporter assays]
  4. Blocked re-initiation leads to selectively reduced JAK2 protein in all cell types, including T lymphocytes and phagocytes, while most other proteins are unaffected. [demonstrated]
  5. Reduced JAK2 results in impaired signal transduction downstream of the IL-23 receptor (and partial impairment of IL-12 signaling). [demonstrated — impaired IL-23 response, normal IL-12 response in patient cells]
  6. Impaired IL-23 signaling preferentially impairs IFN-γ production by innate-like adaptive MAIT and γδ T lymphocytes upon mycobacterial challenge. [demonstrated]
  7. Deficient IFN-γ fails to activate macrophages to control intracellular mycobacteria. [inferred from the established MSMD paradigm — IFN-γ is the central macrophage-activating cytokine]
  8. Failure of macrophage activation leads to uncontrolled proliferation of weakly virulent mycobacteria (BCG, NTM), resulting in disseminated mycobacterial disease with fever, lymphadenopathy, hepatosplenomegaly, abscesses, and osteomyelitis in infancy. [demonstrated clinically]

Branch point (bypass): Because the lesion is upstream of the IFN-γ receptor, exogenous IFN-γ can activate macrophages directly (patient cells respond normally to IFN-γ and IFN-α) → therapeutic bypass and generally favorable prognosis.

 MCTS1 LoF (Xq24, hemizygous male)
│ loss of 40S recycling / reinitiation factor
▼
 JAK2 stuORF roadblock in 5'UTR ──► 40S ribosome stall
│ selective translational block (>65% ↓ JAK2)
▼
 ↓ JAK2 protein (all cell types)
│
▼
 impaired IL-23 signaling (± partial IL-12)      [IL-12 response NORMAL]
│
▼
 ↓ IFN-γ from MAIT & γδ T cells (mycobacterial challenge)
│
▼
 macrophages not activated ──► uncontrolled mycobacteria
│                                   ▲
▼                                   │ BYPASS
 disseminated mycobacterial disease   exogenous IFN-γ (response intact)
 (fever, HSM, lymphadenopathy,
  abscess, osteomyelitis; infancy)

Upstream vs downstream

  • Upstream / initiating: MCTS1 loss → global translation-recycling defect (a general molecular lesion).
  • Bottleneck / specificity-determining: JAK2 stuORFs — the single feature that channels a general translation defect into a narrow clinical phenotype.
  • Downstream / effector: IL-23 signaling → MAIT/γδ IFN-γ → macrophage activation → mycobacterial control.

Ontology term suggestions

  • Gene/protein: MCTS1 (HGNC:7838), JAK2 (HGNC:6192), DENR, IL23R, IL12B
  • GO biological process: regulation of translational initiation (GO:0006446), positive regulation of interferon-gamma production (GO:0032729), response to molecule of bacterial origin, ribosomal subunit recycling
  • GO cellular component: cytosolic ribosome (GO:0022626), cytosol (GO:0005829), messenger ribonucleoprotein / cap complex
  • CL cell types: mucosal invariant T cell / MAIT (CL:0000940), gamma-delta T cell (CL:0000798), macrophage (CL:0000235), monocyte (CL:0000576)
  • UBERON anatomy: liver (UBERON:0002107), spleen (UBERON:0002106), lymph node (UBERON:0000029), bone (UBERON:0001474)
  • NCIT treatment: recombinant interferon gamma; antimycobacterial therapy; hematopoietic stem cell transplantation
  • Disease: MONDO:0958030 (IMD118)

Section-by-Section Report Content

1. Disease Information

IMD118 is an X-linked recessive inborn error of immunity within the MSMD spectrum, characterized by selective susceptibility to weakly virulent mycobacteria (BCG vaccine strain and non-tuberculous mycobacteria). Identifiers: OMIM #301115; MONDO:0958030; gene MCTS1 (Xq24). ICD-11 maps to inborn errors of immunity / MSMD categories; no dedicated ICD-10 code. Synonyms: MCTS1 deficiency, X-linked MCTS1 deficiency, MSMD due to MCTS1 deficiency. The information is derived from an aggregated disease-level primary report (Bohlen et al. 2023, 5 individual patients) and OMIM, not from EHR-scale data.

2. Etiology

Causal factor: monogenic — hemizygous loss-of-function variants in MCTS1. Genetic risk factor: male sex (X-linked recessive; a single mutant X allele is sufficient in males). Environmental trigger: BCG vaccination and exposure to environmental (non-tuberculous) mycobacteria precipitate disease; the mutation is necessary, mycobacterial exposure is the environmental precipitant. No protective genetic variants are described; exogenous IFN-γ acts as an acquired protective/therapeutic factor because responses to it are intact. Gene–environment interaction: the classic MSMD interaction — an inherited IL-23→IFN-γ axis defect that becomes clinically manifest only upon mycobacterial exposure (especially live BCG vaccine).

3. Phenotypes

Predominantly infectious/physical manifestations rather than behavioral. Onset is infantile (3–12 months), typically post-BCG. Features (with qualitative frequencies given the 5-patient series): disseminated mycobacteriosis (defining), fever (HP:0001945), lymphadenopathy (HP:0002716), hepatomegaly (HP:0002240), splenomegaly (HP:0001744), abscess (HP:0025615), osteomyelitis (HP:0002754). Severity is variable — from recoverable disseminated disease to fatal dissemination. Progression is episodic/acute during active infection, with recovery and asymptomatic status after early childhood in survivors. Quality-of-life impact is concentrated in infancy/early childhood during active infection; survivors have generally normal function thereafter.

4. Genetic / Molecular Information

Causal gene: MCTS1 (Xq24; NCBI Gene 28985; HGNC:7838). Variant types among 5 patients: 2 frameshift, 1 splice-site, 2 in-frame 3′ deletions (both → p.Ala133_Lys181del). Classification: pathogenic loss-of-function (ACMG). Zygosity/origin: germline, hemizygous in males. Functional consequence: complete loss of function → loss of 40S recycling/reinitiation → selectively reduced JAK2 translation. Allele frequency: extremely rare/private; not established as recurrent in gnomAD. Modifier genes: none formally identified. Epigenetics/chromosomal abnormalities: none reported; the mechanism is translational, not epigenetic.

5. Environmental Information

The key environmental factors are mycobacterial exposures — live attenuated BCG vaccine (Mycobacterium bovis BCG) and environmental non-tuberculous mycobacteria (NTM). No toxin, radiation, pollution, occupational, or lifestyle factors are implicated. Infectious agents are causative triggers acting on the genetic substrate rather than independent causes.

6. Mechanism / Pathophysiology

See the Mechanistic Model section above for the full ordered causal chain. In brief: MCTS1 LoF → failure of 40S ribosome recycling/reinitiation → JAK2 stuORF roadblock → selective JAK2 depletion → impaired IL-23 (and partial IL-12) signaling → reduced IFN-γ from MAIT/γδ T cells → failed macrophage activation → disseminated mycobacterial disease. Molecular pathway: JAK-STAT (JAK2) / IL-23→IFN-γ axis. Cellular process: cytokine signaling and antimicrobial macrophage activation. Protein dysfunction: loss of function of a ribosome-recycling factor (MCTS1) causing loss of a downstream kinase (JAK2). Immune involvement: immunodeficiency (not autoimmunity).

7. Anatomical Structures Affected

Primary organs: reticuloendothelial/lymphoid system — liver (UBERON:0002107), spleen (UBERON:0002106), lymph nodes (UBERON:0000029), bone/bone marrow (osteomyelitis; UBERON:0001474). Body systems: immune/hematopoietic and, via sites of mycobacterial dissemination, potentially multi-organ. Cell populations: MAIT cells (CL:0000940), γδ T cells (CL:0000798), macrophages/monocytes (CL:0000235/CL:0000576) — because the JAK2 defect is present in all cell types tested, including phagocytes. Subcellular: cytosolic ribosome/translation machinery (GO:0022626). Lateralization: not applicable (systemic/bilateral dissemination).

8. Temporal Development

Onset: infantile, 3–12 months, typically after BCG vaccination; onset pattern acute/subacute. Course: episodic active disease during infection with recovery in survivors; survivors are typically asymptomatic after early childhood. Critical period: early infancy around BCG exposure is the window of vulnerability and of opportunity for early recognition/intervention. Remission: treatment-induced with antimycobacterial therapy (± IFN-γ).

9. Inheritance and Population

Inheritance: X-linked recessive; affects males, mothers are obligate carriers. Penetrance: appears high in exposed hemizygous males but based on only 5 patients. Expressivity: variable (recovery to death). Epidemiology: ultra-rare — 5 reported patients worldwide; prevalence/incidence not estimable. Populations: four ancestries reported (Chinese, Finnish, Iranian, Saudi Arabian) — no single founder population. Sex ratio: essentially all affected are male (X-linked recessive). Consanguinity: relevant for autosomal recessive MSMD genes but less so here given X-linkage; the geographic spread suggests independent (private) mutations rather than a founder effect. Carrier frequency: unknown/very low.

10. Diagnostics

Routine immune workup is typically normal (normal circulating leukocyte subsets), so diagnosis rests on molecular genetics. Recommended approach: whole-exome or whole-genome sequencing / targeted MSMD gene panels including MCTS1, prompted by disseminated BCG/NTM disease in an otherwise healthy infant. Functional confirmation: reduced JAK2 protein, impaired IFN-γ after BCG stimulation, impaired IL-23 (but normal IL-12) responses, and preserved responses to exogenous IFN-γ/IFN-α — the last both diagnostic and therapeutically informative. Microbiology: blood/tissue mycobacterial culture and, increasingly, metagenomic next-generation sequencing (mNGS) to identify unculturable NTM. Differential diagnosis: other MSMD genotypes — IL12RB1, IL12B, IFNGR1/2, STAT1, ISG15, IRF8, IL23R, RORC, NEMO, CYBB — distinguished by their specific gene defects and, in some, broader infectious susceptibility.

11. Outcome / Prognosis

Generally favorable but potentially fatal: 1 of 5 patients died of disseminated mycobacterial disease; 4 recovered with antimycobacterial therapy, had no other infections, and showed normal growth and development. Prognostic factors: early diagnosis and prompt antimycobacterial (± IFN-γ) therapy; intact response to exogenous IFN-γ is a favorable feature. Long-term survivors are typically asymptomatic after early childhood. Given the tiny cohort, survival statistics are indicative rather than definitive.

12. Treatment

Antimycobacterial therapy is the cornerstone (multidrug regimens directed at BCG/NTM). Recombinant IFN-γ is a rational adjunct because patient cells respond normally to it, bypassing the upstream block — a strategy with established benefit in other MSMD genotypes (e.g., partial IFNGR1 and IL12RB1 defects). Hematopoietic stem cell transplantation is a consideration in severe/refractory MSMD generally, though not specifically reported for IMD118. No pharmacogenomic, gene, RNA, or targeted small-molecule therapies exist yet for MCTS1 deficiency. Suggested NCIT terms: recombinant interferon gamma; antimycobacterial agent; hematopoietic stem cell transplantation.

13. Prevention

Primary prevention: in families with a known MCTS1 variant, avoid live BCG vaccination in at-risk male infants until immune status is clarified — BCG is the principal precipitant. Secondary prevention: early recognition of disseminated mycobacterial disease and prompt therapy. Genetic counseling: X-linked recessive inheritance — carrier mothers have a 50% chance of transmitting the variant; sons of carriers have a 50% risk of being affected, daughters a 50% chance of being carriers. Carrier/prenatal testing and cascade testing are available once the familial variant is known. Tertiary prevention: antimycobacterial prophylaxis and monitoring in affected individuals.

14. Other Species / Natural Disease

Species affected: human (Homo sapiens, NCBI Taxon 9606) — the disease is described only in humans. Mechanistic conservation is strong: the MCTS1/DENR–eIF2D recycling system has direct yeast counterparts (Tma20/Tma22/Tma64), demonstrating deep evolutionary conservation of the underlying translation machinery (PMID: 30146315, PMID: 38903097). Orthologous Mcts1 exists in mouse and other vertebrates. No naturally occurring animal disease (OMIA) is reported. No zoonotic component.

15. Model Organisms

No dedicated Mcts1-deficient mammalian disease model of IMD118 has been reported. In vitro/cellular models were central to the discovery: MCTS1-knockout HeLa cells (5′UTR reporter screens), CRISPR MCTS1-knockout THP-1 monocytes (endogenous JAK2 reduction across 5 clones), and patient-derived leukocytes. Yeast (Saccharomyces cerevisiae, Tma20/Tma22/Tma64) is a powerful model for the ribosome-recycling/reinitiation mechanism itself. These systems recapitulate the molecular defect (JAK2 translational block, ribosome stalling) but not the whole-organism immunophenotype; a conditional or humanized mouse expressing the JAK2 stuORF-containing 5′UTR would be needed to model the immunological disease in vivo.

Evidence Base

PMID Title (abbrev.) Role in this report
37875108 Human MCTS1-dependent translation of JAK2 is essential for IFN-γ immunity to mycobacteria Primary/defining source. Identifies IMD118, the 5 patients, variant spectrum, JAK2 stuORF mechanism, IL-23→IFN-γ/MAIT-γδ axis, outcomes (1 death), preserved exogenous IFN-γ response.
30146315 Tma64/eIF2D, Tma20/MCT-1, Tma22/DENR recycle post-termination 40S subunits in vivo Establishes MCTS1/DENR/eIF2D as 40S recycling factors; evolutionary conservation.
38903097 Impacts of yeast Tma20/MCTS1, Tma22/DENR and Tma64/eIF2D on translation reinitiation Shows MCTS1/DENR enhance reinitiation at uORFs — mechanism underlying JAK2 dependence.
16982740 MCT-1 protein interacts with the cap complex... Defines MCTS1 PUA domain, cap-complex interaction, DENR recruitment.
35115540 Cyclin B/CDK1 and Cyclin A/CDK2 phosphorylate DENR... Establishes MCTS1/DENR as oncogenes and cell-cycle-regulated uORF translation factors.
37634410 / 35274760 MCTS1 in laryngeal squamous cell carcinoma Oncogenic role of MCTS1 (contrast with benign germline-loss phenotype).
36763636 Human IL-23 is essential for IFN-γ-dependent immunity to mycobacteria Validates the IL-23→IFN-γ axis that MCTS1/JAK2 loss disrupts.
35829840 Homozygous stop mutation in IL23R causes MSMD Independent genetic validation that disrupting IL-23 signaling causes MSMD.
37147816 / 41707313 MAIT cells in mycobacterial immunity Effector-cell biology: MAIT cells produce IFN-γ via MR1, reduced in active TB.
40656276 / 41786143 / 41048447 MSMD overviews & management Context for MSMD classification, diagnostics, and IFN-γ/antimycobacterial/HSCT management.

Evidence source types: IMD118-defining data are human clinical + in vitro/cellular (Bohlen 2023); mechanistic recycling/reinitiation data are in vitro + model organism (yeast); pathway validation is human genetic (IL23R, IL-23); oncogenic role is in vitro / tumor genomics.

Limitations and Knowledge Gaps

  1. Single defining cohort (n = 5). Nearly all disease-specific knowledge derives from one report (PMID: 37875108). Prevalence, penetrance, expressivity, sex-specific carrier phenotypes, and long-term outcomes are therefore uncertain.
  2. No formal epidemiology. Prevalence and incidence cannot be estimated; the disease is ultra-rare and likely underdiagnosed.
  3. No animal model of the disease. Mechanistic work used cell lines and yeast; whole-organism recapitulation (e.g., stuORF-humanized mouse) is absent, so in vivo immunodynamics remain inferred.
  4. Therapeutic evidence is indirect. IFN-γ benefit is inferred from preserved in vitro responses and from other MSMD genotypes, not from a trial in MCTS1-deficient patients.
  5. Spectrum of mycobacterial species and non-mycobacterial risk is incompletely defined given the small cohort; whether MCTS1-deficient patients have subtle susceptibility to other intracellular pathogens (as some MSMD genotypes do) is unknown.
  6. Female carriers / X-inactivation effects have not been characterized.
  7. Cancer risk over the lifespan is unassessed — germline MCTS1 loss is oncologically "silent" in childhood, but the long-term consequences of losing an oncogene's function are unstudied.

Proposed Follow-up Experiments / Actions

  1. International case-finding and registry. Add MCTS1 to MSMD/IEI sequencing panels worldwide and pool cases (e.g., via GeneMatcher) to define penetrance, expressivity, microbial spectrum, and outcomes.
  2. Therapeutic evaluation of recombinant IFN-γ as adjunct to antimycobacterial therapy in confirmed patients, leveraging their intact IFN-γ responses; document response rates and adverse events.
  3. Generate an in vivo model — a knock-in mouse humanizing the JAK2 5′UTR stuORFs on an Mcts1-deficient background, or a conditional myeloid/T-cell Mcts1 knockout — to test whether the JAK2→IL-23→IFN-γ chain and mycobacterial susceptibility are recapitulated.
  4. Ribosome profiling in patient-derived macrophages and MAIT/γδ cells to catalog the full set of MCTS1-dependent (stuORF/uORF) transcripts beyond JAK2 and confirm JAK2's privileged dependence.
  5. Vaccination guidance: formalize the recommendation to withhold live BCG in at-risk male infants of carrier mothers pending genetic clarification.
  6. Long-term surveillance of survivors for late infections and — given MCTS1's oncogene status — for any oncologic outcomes, to establish lifetime prognosis.
  7. Structural/biophysical work on how patient variants (esp. p.Ala133_Lys181del) disrupt MCTS1–DENR–ribosome interactions, to inform potential small-molecule or read-through therapeutic strategies.

Report compiled from 7 confirmed findings and 35 reviewed papers over 5 investigation iterations. All disease-specific clinical and mechanistic claims trace primarily to Bohlen et al. 2023 (PMID: 37875108); mechanistic and pathway claims are corroborated by the cited translation-machinery and MSMD literature.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 16
Resolved 16
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 16
On topic 5
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 21
Resolved 19
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 2
Terms whose name was checked 12
Terms named correctly 7
Terms named as a different term 2
Terms whose name is worth a second look 3

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:0958030 (3 mentions) - the report calls it "IMD118"; MONDO calls it immunodeficiency 118
  • UBERON:0002107 (2 mentions) - the report calls it "UBERON anatomy: liver", "liver"; UBERON calls it liver**

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • HP:0002716 (2 mentions) - the report calls it "Lymphadenopathy / enlarged lymph nodes"; HP calls it Lymphadenopathy
  • GO:0006446 (1 mention) - the report calls it "GO biological process: regulation of translational initiation"; GO calls it regulation of translational initiation**
  • GO:0022626 (2 mentions) - the report calls it "GO cellular component: cytosolic ribosome"; GO calls it cytosolic ribosome**

Terms named inconsistently

The report gives these identifiers more than one name of its own:

  • HGNC:7838 - called "MCTS1", "Gene/protein:* MCTS1"
  • UBERON:0002107 - called "UBERON anatomy:** liver", "liver"