Immunodeficiency 91 and Hyperinflammation

Mendelian MONDO:0030491 Pathograph 12 Show in embeddings browser primary immunodeficiency disease

An autosomal recessive inborn error of immunity caused by biallelic loss of ZNFX1, a cytosolic, interferon-inducible helicase that senses double-stranded nucleic acid. The disease is defined less by an inability to mount an immune response than by an inability to regulate one: patients meet infections that most children clear with an inflammatory episode that does not switch off, producing haemophagocytic lymphohistiocytosis (HLH) or HLH-like disease with hepatitis, cytopenias, seizures, and renal and pulmonary injury. Mortality in the founding cohort was high and death was usually from the inflammation rather than from the infection itself. Two things distinguish it from familial HLH, and both are curated here as evidence rather than as assertion. First, NK-cell degranulation and cytotoxicity are normal, so the mechanism is not the perforin-pathway defect that defines FHL. Second, the leukocytosis that accompanies these episodes is explicitly noted to be much less common in classical HLH.

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1
Inheritance
8
Pathophys.
2
Histopath.
20
Phenotypes
3
Gaps
12
Pathograph
1
Genes
3
Medical Actions
2
Differentials
2
Models
👪

Inheritance

1
Autosomal recessive HP:0000007
Homozygous and compound heterozygous loss-of-function ZNFX1 alleles, in consanguineous and non-consanguineous kindreds. No individual homozygous for a predicted loss-of-function ZNFX1 allele appears in public population databases, which is the population-genetic counterpart of the severity of the reported phenotype.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:33872655 SUPPORT Human Clinical
"Deleterious homozygous and compound heterozygous ZNFX1 variants were identified in all 13 patients."
Establishes the biallelic, recessive genetic architecture across all eight founding kindreds.
PMID:33876776 SUPPORT Human Clinical
"There are no subjects homozygous for pLOF variants in public databases."
Population-database absence of homozygous loss-of-function carriers, which supports the alleles being under strong negative selection rather than tolerated variation.
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Discussions and Knowledge Gaps

3
Are the viral-inflammatory phenotype and the monocytosis-mycobacterial phenotype of ZNFX1 deficiency one disease with variable expression, or two mechanistically distinct diseases at the same locus?
CONTROVERSY znfx1_two_phenotype_poles
Attached to
pathophysiology#Impaired Monocyte Homeostasis and Antimycobacterial Defence pathophysiology#Virally Triggered Hyperinflammatory Episode
The two founding reports appeared within weeks of each other and describe patients who look different. Vavassori's cohort had severe RNA and DNA viral infection with fatal HLH-like inflammation; Le Voyer's cohort had monocytosis and mycobacterial disease and explicitly did not have severe viral illness. This matters mechanistically, not just descriptively. If one disease, then any proposed mechanism has to explain both an inability to clear virus and an inability to contain mycobacteria, in patients with normal IFN-gamma production and normal responses to it. If two, then something - allele position, modifier genotype, or environmental exposure such as BCG vaccination practice - partitions them, and no published analysis has identified what. Both cohorts carried truncating alleles, so a simple severe-versus-hypomorph split does not obviously account for it. Ascertainment is a live alternative explanation: the cohorts were recruited through different clinical routes, one through inflammation and one through mycobacterial disease, and each may have under-detected the other's phenotype.
Proposed experiments
Cross-phenotype systematic assessment of a combined ZNFX1 cohort
exp_znfx1_cross_phenotype_cohort_assessment
Assemble the published patients and assess every individual for both phenotypes with the same protocol - viral clearance and ISG regulation on one side, monocyte counts and mycobacterial history on the other - rather than for the phenotype that prompted their referral. If ascertainment is the explanation, the poles should collapse.
Would support
pathophysiology#Loss of Cytosolic Double-Stranded Nucleic Acid Surveillance
Supporting outcome
  • Patients ascertained through mycobacterial disease are found to have subclinical ISG dysregulation and impaired monocyte viral clearance, and patients ascertained through HLH are found to have monocytosis, supporting one disease with ascertainment-driven apparent poles.
Refuting outcome
  • Each cohort is confirmed to lack the other's cellular phenotype under identical assays, supporting two mechanistically distinct diseases and requiring the pathograph to be split.
Mouse Znfx1 was characterised as a dsRNA sensor restricting RNA virus replication. Does that role explain the human disease, given that one of the two founding human cohorts had no severe viral illness at all?
HUMAN MODEL MISMATCH znfx1_mouse_sensor_vs_human_phenotype
Attached to
pathophysiology#Loss of Cytosolic Double-Stranded Nucleic Acid Surveillance animal_models#Znfx1-mutant mouse infected with LCMV
The murine antiviral-sensor result is what made ZNFX1 a credible candidate when the first patients were sequenced, and it fits the Vavassori cohort well. It fits the Le Voyer cohort poorly: those patients are susceptible to mycobacteria rather than to viruses, which is not what a dsRNA-sensor defect predicts. The mismatch is therefore not that the model fails to reproduce a human finding, but that the model may have anchored the field on one of two human phenotypes and made the other harder to explain. The NLRP3-restraint and AMPK-autophagy findings are both attempts to supply the missing function, and neither has been demonstrated in patient tissue.
Proposed experiments
Test NLRP3 derepression in patient-derived cells
exp_znfx1_patient_nlrp3_derepression
Measure NLRP3 inflammasome activation, caspase-1 cleavage and IL-1beta maturation in monocytes and macrophages from ZNFX1-deficient patients of both phenotypic poles, rather than in overexpression cell lines.
Would support
pathophysiology#Derepression of the NLRP3 Inflammasome
Supporting outcome
  • Patient macrophages show constitutive or lowered-threshold NLRP3 activation relative to controls, promoting the inflammasome edge from provisional to established.
Refuting outcome
  • Patient macrophages show normal NLRP3 activation thresholds, indicating that the cell-line finding does not transfer and that the hyperinflammation needs a different explanation.
Why do some patients deteriorate after the triggering virus has been cleared, or in the apparent absence of any infection?
KNOWLEDGE GAP znfx1_post_clearance_inflammation
Attached to
pathophysiology#Virally Triggered Hyperinflammatory Episode
A model in which inflammation is driven by failure to clear a pathogen predicts that inflammation stops when the pathogen does. The founding cohort reports otherwise in at least three patients. This is the strongest clinical argument that the disease has a genuine autoinflammatory component independent of pathogen load, and it is the observation that the NLRP3 mechanism would explain if it were confirmed in patients.
Proposed experiments
Serial cytokine and viral-load monitoring through an inflammatory episode
exp_znfx1_serial_cytokine_viral_load
Track viral load and IL-1-family and interferon-stimulated cytokine profiles in parallel through a full episode in the same patient, to establish whether inflammatory activity outlasts detectable virus.
Would support
pathophysiology#Derepression of the NLRP3 Inflammasome
Supporting outcome
  • Inflammatory cytokine levels remain elevated after viral clearance, supporting a pathogen-independent autoinflammatory driver.
Refuting outcome
  • Cytokine elevation tracks viral load closely, indicating that apparent post-clearance disease reflects undetected persistent infection rather than autonomous inflammation.
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Pathophysiology

8
Biallelic ZNFX1 Loss of Function
Mechanism confidence: Established
The primary lesion is biallelic damage to ZNFX1, encoding a large interferon-stimulated helicase. Reported alleles include nonsense, frameshift and missense changes; the founding cohort carried 11 biallelic variants across eight kindreds, five truncating and six missense. Protein is undetectable in cells from patients carrying two truncating alleles, so for that allele class the functional consequence is absence of protein rather than a hypomorph.
ZNFX1 hgnc:29271 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ZNFX1 (hgnc:29271). hgnc:29271 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Loss of Cytosolic Double-Stranded Nucleic Acid Surveillance Absent or non-functional ZNFX1 removes the sensor itself, which is the proximate functional lesion.
Show evidence (2 references)
PMID:33872655 SUPPORT Human Clinical
"By using WES, we identified 11 biallelic ZNFX1 variants in 13 patients"
The allelic series in the founding cohort.
PMID:33872655 SUPPORT In Vitro
"ZNFX1 could not be detected in whole cell extracts of fibroblasts from 2 of the patients carrying biallelic stop codons"
Confirms at protein level that truncating alleles abolish ZNFX1, rather than producing a stable truncated product.
Loss of Cytosolic Double-Stranded Nucleic Acid Surveillance
Mechanism confidence: Established
ZNFX1 is an interferon-stimulated double-stranded RNA sensor that binds viral RNA and signals through the mitochondrial antiviral signalling protein MAVS, independently of the two other MAVS-associated sensors RIG-I and MDA5. Its expression is low in resting cells and is rapidly induced by viral infection and type I interferon, so the lesion is one of a stress-induced surveillance arm rather than of a constitutively required housekeeping pathway. In patient cells the protein is also recruited to, and can induce, cytoplasmic stress granules.
cellular response to exogenous double-stranded RNA GO:0071360 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves cellular response to exogenous double-stranded RNA, annotated with cellular response to exogenous dsRNA (GO:0071360), qualified as loss of function. GO:0071360 is a biological process from the Gene Ontology. ⇓ LOSS OF FUNCTION
double-stranded RNA binding GO:0003725 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves double-stranded RNA binding (GO:0003725), qualified as loss of function. GO:0003725 is a molecular function from the Gene Ontology. ⇓ LOSS OF FUNCTION
cytoplasmic stress granule GO:0010494 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves cytoplasmic stress granule (GO:0010494). GO:0010494 is a cellular component from the Gene Ontology.
Downstream
Dysregulated Interferon-Stimulated Gene Induction Losing the sensor deranges the transcriptional programme it normally shapes downstream of MAVS.
Derepression of the NLRP3 Inflammasome A second, non-sensing function of the same protein. Shown in cell lines and mice rather than in patient tissue, so the edge is graded provisional.
Impaired Monocyte Homeostasis and Antimycobacterial Defence The route from loss of the sensor to monocytosis and mycobacterial susceptibility is not established. The second founding cohort showed that it does not run through IFN-gamma, but did not identify what it does run through.
Show evidence (3 references)
PMID:33872655 SUPPORT In Vitro
"ZNFX1 binds to viral RNA and interacts with the mitochondrial antiviral signaling (MAVS) protein, promoting the expression of interferon-stimulated genes (ISGs)."
The molecular function lost, and the signalling adaptor it acts through.
PMID:33872655 SUPPORT In Vitro
"Low ZNFX1 protein expression was noted in fibroblasts under resting conditions, whereas a rapid upregulation was observed after 24 hours of stimulation"
Establishes ZNFX1 as an inducible rather than constitutive sensor, which is why the disease manifests as episodes triggered by infection.
PMID:33876776 SUPPORT In Vitro
"We find that this cytoplasmic protein can be recruited to or even induce stress granules."
Localises ZNFX1 to stress granules, the subcellular compartment the second group emphasises.
Dysregulated Interferon-Stimulated Gene Induction
Mechanism confidence: Established
The defect is dysregulation, not simple loss. Patient cells stimulated with intracellular double-stranded nucleic acid over-express interferon-stimulated genes, and the half-life of ISG mRNA is altered; baseline ISG expression in patient blood is higher than in controls. Yet the same cells respond poorly to soluble poly(I:C) and clear virus less well. Curating this node as "reduced interferon response" would misstate the finding: the pathology is an unbalanced response whose direction depends on how the nucleic acid is presented.
dermal fibroblast CL:0002551 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves dermal fibroblast, annotated with fibroblast of dermis (CL:0002551). CL:0002551 is a cell type from the Cell Ontology.
type I interferon-mediated signaling pathway GO:0060337 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves type I interferon-mediated signaling pathway (GO:0060337). GO:0060337 is a biological process from the Gene Ontology.
Downstream
Impaired Monocyte Clearance of Virus An unbalanced ISG programme leaves monocytes unable to complete an antiviral defence programme after nucleic-acid stimulation.
Show evidence (2 references)
PMID:33872655 SUPPORT In Vitro
"Stimulation of patient-derived primary cells with synthetic double-stranded nucleic acids was associated with a deregulated pattern of expression of ISGs and alterations in the half-life of the mRNA of ISGs and also associated with poorer clearance of viral infections by monocytes."
The core cellular phenotype, and the wording that justifies "deregulated" rather than "deficient" in this node's name.
PMID:33872655 SUPPORT In Vitro
"the baseline expression of ISGs seen in peripheral blood isolated from the patients"
Baseline ISG expression is raised rather than lowered, which is why this disease is discussed alongside the interferonopathies.
Derepression of the NLRP3 Inflammasome
Mechanism confidence: Provisional
Independently of its sensing role, ZNFX1 restrains the NLRP3 inflammasome by holding NLRP3 in the cytoplasm and preventing its accumulation on trans-Golgi-network vesicles in the resting state. Loss of that restraint releases caspase-1 activation and IL-1-family cytokine maturation. Two features make this the most attractive current explanation for the hyperinflammatory pole of the disease: it is a licensing defect rather than a signalling deficiency, and human pathogenic ZNFX1 variants fail to rescue it where wild-type ZNFX1 does. It is nonetheless graded provisional. The work is in cell lines and mice; no patient-derived tissue has been shown to carry a derepressed NLRP3 inflammasome, and no patient has been reported to respond to NLRP3-directed therapy in a way that would close the loop.
NLRP3 inflammasome complex assembly GO:0044546 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased NLRP3 inflammasome complex assembly (GO:0044546). GO:0044546 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Macrophage-Driven Cytokine Excess Unrestrained inflammasome activity yields caspase-1-dependent maturation of IL-1-family cytokines.
Show evidence (2 references)
PMID:39333773 SUPPORT In Vitro
"ZNFX1 retains NLRP3 in the cytoplasm and prevents its accumulation in the TGN38 + /TGN46+ vesicles in the resting state."
The proposed molecular mechanism of restraint that is lost in the disease.
PMID:39333773 SUPPORT In Vitro
"Expression of wild-type ZNFX1, but not of ZNFX1 with human pathogenic mutations, rescues the impairment of NLRP3 inflammasome inhibition."
Ties the mechanism specifically to the disease-causing alleles, which is what raises it above a general cell-biological observation.
Impaired Monocyte Clearance of Virus
Mechanism confidence: Established
After prestimulation with transfected poly(I:C), patient monocytes cleared vesicular stomatitis virus less efficiently than control monocytes. This is the cellular correlate of the clinical susceptibility to RNA and DNA viruses, and it locates the defect in a myeloid cell rather than in the lymphoid compartment.
monocyte CL:0000576 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves monocyte (CL:0000576). CL:0000576 is a cell type from the Cell Ontology.
defense response to virus GO:0051607 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased defense response to virus (GO:0051607). GO:0051607 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Virally Triggered Hyperinflammatory Episode Failure to clear the trigger sustains the stimulus that drives the inflammatory episode.
Show evidence (1 reference)
PMID:33872655 SUPPORT In Vitro
"the monocytes of P2.1 were less efficient in clearing VSV than the control monocytes were"
Direct functional demonstration of impaired viral clearance by patient monocytes.
Macrophage-Driven Cytokine Excess
Mechanism confidence: Provisional
Macrophages are the proposed effector of the inflammatory phase. In the Znfx1-mutant mouse, mutant macrophages infiltrate the liver more heavily after infection and produce more cytokine in vitro even without stimulation, which points at a cell-intrinsic hair-trigger rather than at a stronger upstream signal.
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.
Downstream
Virally Triggered Hyperinflammatory Episode Cytokine excess from activated macrophages is the proximate cause of the systemic episode.
Show evidence (1 reference)
PMID:41636200 SUPPORT Model Organism
"macrophages infiltrated the liver to a greater extent upon infection and produced greater levels of cytokines in vitro in the absence of stimulation, suggesting that these cells have a major role in driving inflammation"
Identifies the macrophage as the likely driver, and the unstimulated cytokine production is what makes it a cell-intrinsic claim.
Virally Triggered Hyperinflammatory Episode
Mechanism confidence: Established
The clinical event that defines the disease: a systemic inflammatory episode precipitated by infection, with cytopenia and hepatitis, meeting HLH criteria in half of the affected patients in the founding cohort. Two negative findings are load-bearing for the mechanism. NK-cell degranulation and cytotoxicity were normal in every patient with HLH, so this is not the cytotoxicity defect of familial HLH. And the episodes are accompanied by leukocytosis, which the authors note is much less common in classical HLH. Episodes are not always infection-locked: some patients progressed after the virus had been cleared, and some in the apparent absence of any infectious agent, which is difficult to reconcile with a purely trigger-driven model and is one reason the inflammasome arm is attractive.
Animal models
Znfx1-mutant mouse infected with LCMV Mouse recapitulates LCMV-infected Znfx1-mutant mice show hallmark features of HLH-like inflammation, with more pronounced T-cell expansion and Th1 polarisation than infected controls.
Show evidence (3 references)
PMID:33872655 SUPPORT Human Clinical
"Of the 12 patients with systemic inflammatory disease, 6 met the diagnostic criteria for hemophagocytic lymphohistiocytosis (HLH), including hemophagocytosis in bone marrow aspirates"
Frequency of formally defined HLH within the cohort.
PMID:33872655 SUPPORT Human Clinical
"Levels of natural killer cell degranulation and/or cytotoxicity were normal in all patients with HLH."
The specificity control that separates this disease mechanistically from familial HLH, where the cytotoxicity pathway is the lesion.
PMID:33872655 SUPPORT Human Clinical
"other patients showed progressive disease even after the virus had been cleared"
Evidence that the inflammatory programme can run on after the trigger is gone, which a purely infection-driven model does not predict.
Impaired Monocyte Homeostasis and Antimycobacterial Defence
Mechanism confidence: Provisional
The second pole of the disease, from the second founding cohort: intermittent monocytosis with mycobacterial disease, in patients with normal lymphocyte subsets who produce IFN-gamma normally and whose cells respond normally to it. That set of normal results is what makes the finding interesting - it places ZNFX1 outside the IFN-gamma circuit that explains most Mendelian susceptibility to mycobacterial disease, and leaves the effector mechanism unidentified.
monocyte CL:0000576 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves monocyte (CL:0000576). CL:0000576 is a cell type from the Cell Ontology.
Animal models
Znfx1-knockout mouse infected with Mycobacterium tuberculosis Mouse partially recapitulates Znfx1-knockout mice show increased mycobacterial burden and progressive lung injury, matching the direction of the human mycobacterial phenotype.
Show evidence (2 references)
PMID:33876776 SUPPORT Human Clinical
"Our results indicate that human ZNFX1 is associated with stress granules and essential for both monocyte homeostasis and protective immunity to mycobacteria."
The authors' summary claim for this arm of the phenotype.
PMID:33876776 SUPPORT Human Clinical
"Lymphocyte subsets are present at normal frequencies in these patients and produce IFN-γ normally."
Excludes the usual IFN-gamma-circuit explanations for mycobacterial susceptibility, which is why this arm is curated as mechanistically open.
✶

Histopathology

2
Hepatic necrosis with extramedullary hematopoiesis
Liver histology was heterogeneous and non-specific across patients: necrosis with extramedullary hematopoiesis in one, necrosis with lymphocytic infiltration in another, necrosis with nodular regenerative hyperplasia in a third, and centrilobular necrosis in a fourth. Necrosis is the common thread; nothing in the pattern is diagnostic, and the source says so.
Show evidence (1 reference)
PMID:33872655 SUPPORT Human Clinical
"Histologic assessment of the liver showed heterogeneous, nonspecific changes, such as necrosis and extramedullary hematopoiesis"
The hepatic histology, quoted with the authors' own "nonspecific" intact so the entry does not imply a diagnostic pattern.
Interstitial and cholesterol pneumonitis
Lung biopsy specimens from two patients showed interstitial pneumonitis and cholesterol pneumonitis respectively.
Show evidence (1 reference)
PMID:33872655 SUPPORT Human Clinical
"showed interstitial pneumonitis and cholesterol pneumonitis, respectively"
The pulmonary histology in the two biopsied patients.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Immunodeficiency 91 and Hyperinflammation 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

20
Blood 7
Hemophagocytosis HP:0012156 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hemophagocytosis (HP:0012156). HP:0012156 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33872655 SUPPORT Human Clinical
"6 met the diagnostic criteria for hemophagocytic lymphohistiocytosis (HLH), including hemophagocytosis in bone marrow aspirates"
Documents marrow hemophagocytosis in the cohort.
Increased Monocyte Count Increased total monocyte count HP:0012311 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Monocytosis, annotated with Increased total monocyte count (HP:0012311). HP:0012311 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33876776 SUPPORT Human Clinical
"We report four patients from two unrelated kindreds with intermittent monocytosis and mycobacterial disease"
Establishes monocytosis as a defining feature of the second cohort.
Thrombocytopenia HP:0001873 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thrombocytopenia (HP:0001873). HP:0001873 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33872655 SUPPORT Human Clinical
"The cytopenia was characterized by anemia in 1 individual and anemia with thrombocytopenia in 12 individuals."
Frequency and pattern of the cytopenia.
Anemia HP:0001903 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anemia (HP:0001903). HP:0001903 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33872655 SUPPORT Human Clinical
"The cytopenia was characterized by anemia in 1 individual and anemia with thrombocytopenia in 12 individuals."
Anemia was present in all cytopenic patients in the cohort.
Pulmonary Hemorrhage HP:0040223 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pulmonary hemorrhage (HP:0040223). HP:0040223 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33872655 SUPPORT Human Clinical
"A total of 6 patients had pulmonary hemorrhage."
Frequency of pulmonary hemorrhage in the cohort.
Leukocytosis FREQUENT Increased total leukocyte count HP:0001974 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Leukocytosis, annotated with Increased total leukocyte count (HP:0001974). HP:0001974 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33872655 SUPPORT Human Clinical
"In 8 individuals, anemia and anemia with thrombocytopenia were combined with a high leukocyte count"
The count of patients with leukocytosis alongside their cytopenia.
PMID:33872655 SUPPORT Human Clinical
"with the latter being much less common in classical HLH"
The comparison that makes leukocytosis discriminating rather than incidental.
Coagulopathy FREQUENT Abnormality of the coagulation cascade HP:0003256 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Coagulopathy, annotated with Abnormality of the coagulation cascade (HP:0003256). HP:0003256 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33872655 SUPPORT Human Clinical
"elevated serum lactate dehydrogenase levels (n = 10), coagulopathy (n = 7)"
Coagulopathy and its count within the hepatic-disease group.
Digestive 2
Hepatomegaly VERY_FREQUENT HP:0002240 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatomegaly (HP:0002240). HP:0002240 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33872655 SUPPORT Human Clinical
"as evidenced by elevated serum liver enzyme levels (n = 12 patients), hepatomegaly (n = 13)"
Names hepatomegaly and its count directly. An earlier version of this item quoted the liver-enzyme clause from the same sentence, which evidenced a different finding.
Acute Liver Failure OCCASIONAL Acute hepatic failure HP:0006554 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Acute hepatic failure (HP:0006554). HP:0006554 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33872655 SUPPORT Human Clinical
"A total of 3 patients met the criteria for acute liver failure"
The count of patients reaching formal acute-liver-failure criteria.
Genitourinary 2
Nephrotic Syndrome HP:0000100 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nephrotic syndrome (HP:0000100). HP:0000100 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33872655 SUPPORT Human Clinical
"We variously observed hemolytic uremic syndrome (P2.1), membranoproliferative glomerulonephritis (P6.1), nephrotic syndrome"
Enumerates the renal presentations observed, including nephrotic syndrome.
Hemolytic Uremic Syndrome HP:0005575 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hemolytic-uremic syndrome (HP:0005575). HP:0005575 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33872655 SUPPORT Human Clinical
"We variously observed hemolytic uremic syndrome (P2.1)"
Names hemolytic uremic syndrome in a specific patient. The thrombotic microangiopathy sentence quoted here previously supports the TMA claim in the description but never says HUS.
PMID:33872655 SUPPORT Human Clinical
"There was evidence of renal involvement in 12 patients, including histologically proven thrombotic microangiopathy (TMA)"
The histologically proven thrombotic microangiopathy that underlies the renal presentations, kept as a separate item for the separate claim.
Immune 3
Acute Respiratory Distress Syndrome HP:0033677 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Acute respiratory distress syndrome (HP:0033677). HP:0033677 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33872655 SUPPORT Human Clinical
"Acute respiratory distress syndrome occurred in 7 patients and was mostly associated with viral infections."
Frequency and trigger association for ARDS in the cohort.
Recurrent Viral Infections HP:0004429 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent viral infections (HP:0004429). HP:0004429 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33872655 SUPPORT Human Clinical
"The patients were abnormally susceptible to viral infections"
The susceptibility claim itself, stated directly by the source.
PMID:33872655 SUPPORT Human Clinical
"It is noteworthy that live virus vaccines also caused severe vaccine strain infections in 2 patients"
Documents vaccine-strain disease, which matters clinically and shows the susceptibility extends to attenuated organisms.
Recurrent Mycobacterial Infections HP:0011274 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent mycobacterial infections (HP:0011274). HP:0011274 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33876776 SUPPORT Human Clinical
"mycobacterial disease, including bacillus Calmette-Guérin-osis and disseminated tuberculosis"
The specific mycobacterial presentations reported.
Metabolism 1
Elevated Hepatic Transaminases Elevated circulating hepatic transaminase concentration HP:0002910 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated circulating hepatic transaminase concentration (HP:0002910). HP:0002910 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33872655 SUPPORT Human Clinical
"A total of 14 patients had hepatic disease, as evidenced by elevated serum liver enzyme levels"
The laboratory evidence used to define hepatic disease in the cohort.
Musculoskeletal 1
Cerebral Calcification OCCASIONAL HP:0002514 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebral calcification (HP:0002514). HP:0002514 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33872655 SUPPORT Human Clinical
"Neuroimaging showed evidence of multiple focal calcifications in 3 patients"
The imaging finding and its count.
Nervous System 3
Seizures HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33872655 SUPPORT Human Clinical
"Neurologic involvement was observed in 10 patients, 7 of whom experienced recurrent seizures."
Frequency of seizures within the cohort.
Developmental Regression HP:0002376 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Developmental regression (HP:0002376). HP:0002376 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33872655 SUPPORT Human Clinical
"A total of 3 patients showed developmental regression"
Documents regression as distinct from static delay.
Cerebral White Matter Abnormalities FREQUENT Abnormal cerebral white matter morphology HP:0002500 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal cerebral white matter morphology (HP:0002500). HP:0002500 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33872655 SUPPORT Human Clinical
"ischemic lesions (diffusion restriction on magnetic resonance imaging) in 4 patients"
The ischemic component of the neuroimaging findings, with its count.
Respiratory 1
Interstitial Pneumonitis HP:0006515 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Interstitial pneumonitis (HP:0006515). HP:0006515 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37291413 SUPPORT Human Clinical
"a patient with a ZNFX1 mutation who presented with HLH-like disease and was found to have interstitial pneumonitis, peripheral monocytosis, renal disease, and B cell compartment abnormalities"
A single well-characterised case establishing interstitial pneumonitis in this disease.
🧬

Genetic Associations

1
ZNFX1
Gene: ZNFX1 hgnc:29271 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ZNFX1 (hgnc:29271). hgnc:29271 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:33872655 SUPPORT Human Clinical
"In all of the patients, ZNFX1 was the only candidate gene that segregated with the disease."
Segregation evidence for causality in the founding cohort.
PMID:33876776 SUPPORT Human Clinical
"The patients are homozygous for ZNFX1 variants (p.S959* and p.E1606Rfs*10) predicted to be loss of function (pLOF)."
Independent identification of biallelic loss-of-function alleles in a separate cohort.
💊

Medical Actions

3
Allogeneic Hematopoietic Stem Cell Transplantation
Action: allogeneic hematopoietic stem cell transplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is allogeneic hematopoietic stem cell transplantation, annotated with Hematopoietic Cell Transplantation (NCIT:C15431). NCIT:C15431 is a clinical intervention from the NCI Thesaurus. Ontology label: Hematopoietic Cell Transplantation NCIT:C15431
Platform: Cell therapy
The only reported intervention that has altered the course of the disease. One patient transplanted at age 3 was in good health five years later, and his cerebral white-matter changes stabilised and then regressed after transplant - which is the most direct evidence available that the neurological injury is driven by the haematopoietic compartment rather than being an independent, cell-autonomous consequence of ZNFX1 loss in brain. This rests on a single transplanted patient. It is a strong mechanistic hint and a weak efficacy claim, and it should not be quoted as an established indication.
Mechanism Target:
INHIBITS Macrophage-Driven Cytokine Excess — Replacing the haematopoietic compartment replaces the ZNFX1-deficient myeloid cells that drive the inflammatory episodes.
Show evidence (1 reference)
PMID:33872655 SUPPORT Human Clinical
"Brain magnetic resonance imaging of this patient showed that the white matter changes present at the age of 32 months had stabilized at the age of 42 months"
Post-transplant stabilisation of the imaging abnormality, the observation that ties the neurological injury to the transplantable compartment.
Show evidence (2 references)
PMID:33872655 SUPPORT Human Clinical
"One patient (P4.2) underwent allogeneic hematopoietic stem cell transplantation (HSCT) at the age of 3 years. Five years later, he is in good health but still has a significant developmental delay."
The single reported transplant and its outcome, including the residual deficit, which the description reports rather than smoothing over.
PMID:33872655 SUPPORT Human Clinical
"In 1 patient, HSCT arrested the HLH-like episodes and was followed by improvements in neurologic development."
The authors' own statement of what transplant achieved, which is stronger than the outcome description alone: it names the inflammatory episodes as the thing that stopped.
Ruxolitinib
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: ruxolitinib CHEBI:66919 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses ruxolitinib (CHEBI:66919). CHEBI:66919 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
A JAK inhibitor, given to one patient on the rationale that the disease is an interferon-driven inflammatory state. The reported effect was beneficial but transient. Curated because a transient response is mechanistically informative - it is consistent with JAK-STAT signalling carrying part but not all of the inflammatory drive - and because omitting a therapy that was tried and partly failed would misrepresent the therapeutic landscape.
Show evidence (1 reference)
PMID:33872655 SUPPORT Human Clinical
"The Janus kinase inhibitor ruxolitinib was administered to 1 patient (P5.2); it had a beneficial but transient effect."
The single reported use and its explicitly transient benefit.
Anakinra
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: anakinra NCIT:C38717 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses anakinra (NCIT:C38717). NCIT:C38717 is a therapeutic agent from the NCI Thesaurus.
Platform: Peptide
IL-1 receptor antagonist, used with corticosteroids in one fatal case of CMV-triggered HLH. It is included because the NLRP3 arm of the mechanism predicts that IL-1 blockade should help, and the one reported attempt did not prevent death - a result worth recording before that prediction is treated as established.
Show evidence (1 reference)
PMID:41202491 NO_EVIDENCE Human Clinical
"Despite intensive supportive care and immunomodulation with anakinra and corticosteroids, the patient progressed to irreversible organ failure and died from respiratory failure."
Cited to record that IL-1 blockade was tried and did not rescue this patient. Graded NO_EVIDENCE because a single fatal case neither establishes nor refutes efficacy.
🔬

Biochemical Markers

1
Serum lactate dehydrogenase
Show evidence (1 reference)
PMID:33872655 SUPPORT Human Clinical
"elevated serum lactate dehydrogenase levels (n = 10)"
The analyte, its direction, and its count in the cohort.
🔬

Diagnosis

2
Genomic screening for ZNFX1 in severe viral infection with HLH
The founding cohort's own recommendation is that ZNFX1 be included in genomic screens for patients presenting with severe viral infection and HLH. Recorded because the disease has no biochemical or functional screening test - NK degranulation and cytotoxicity, the assays that would ordinarily triage a child with HLH, are normal here, so a normal cytotoxicity result does not exclude this diagnosis and sequencing is the route to it.
Show evidence (1 reference)
PMID:33872655 SUPPORT Human Clinical
"We recommend that (1) variants in ZNFX1 be included in genomic screens for patients experiencing severe viral infections and HLH"
The authors' explicit diagnostic recommendation.
HLH diagnostic criteria
Six of the 12 patients with systemic inflammatory disease met formal HLH diagnostic criteria, including marrow hemophagocytosis. The remainder had HLH-like disease that did not meet criteria, so the criteria identify a subset of the inflammatory phenotype rather than defining it.
Show evidence (1 reference)
PMID:33872655 SUPPORT Human Clinical
"Of the 12 patients with systemic inflammatory disease, 6 met the diagnostic criteria for hemophagocytic lymphohistiocytosis (HLH), including hemophagocytosis in bone marrow aspirates"
The proportion meeting formal criteria, which is what makes "HLH-like" the right descriptor for the disease as a whole.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
Fewer than 30 patients had been reported by 2023, in a small number of largely consanguineous kindreds. No population-based estimate exists, and the figure below is a count of published cases, not a rate.
Show evidence (1 reference)
PMID:37291413 SUPPORT Human Clinical
"Recently, NFX1-type zinc finger-containing 1 (ZNFX1) mutations have been described in 28 patients from 17 families with a type I IFN inborn error of immunity ... These patients are reported to have recurrent viral and mycobacterial infections as well as monocytosis, thrombocytopenia,..."
The paper summarizes 28 patients from 17 families with ZNFX1-related inborn errors of immunity and describes infection and hyperinflammatory manifestations. This is a literature count, not a population prevalence.
⚖️

Clinical Burden

High
Eleven of the 15 patients in the founding cohort died in childhood, seven of them before three months of age, with a median age at death of 1.1 years. Death was usually from the inflammatory episode rather than from the infection that triggered it: inflammatory episodes with hepatitis and cytopenia were fatal in seven cases.
Show evidence (2 references)
PMID:33872655 SUPPORT Human Clinical
"The mortality rate was high: 11 of the 15 patients died during childhood, with 7 deaths occurring before patients reached the age of 3 months"
The mortality figures underlying the HIGH burden level.
PMID:33872655 SUPPORT Human Clinical
"Inflammatory episodes with hepatitis and cytopenia were fatal in 7 cases"
Identifies the inflammatory episode rather than the infection as the usual proximate cause of death, which is the claim the pathophysiology makes.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Immunodeficiency 91 and Hyperinflammation:

Familial hemophagocytic lymphohistiocytosis
Overlapping Features The differential that matters most, because ZNFX1 disease presents as HLH and the two are separated by mechanism rather than by presentation. Familial HLH is caused by variants in six genes that directly impair perforin-mediated cytotoxicity. ZNFX1 patients have normal NK-cell degranulation and cytotoxicity, so the pathway that defines familial HLH is intact in them.
Distinguishing Features
  • Normal NK-cell degranulation and cytotoxicity in ZNFX1 deficiency, versus impaired perforin-mediated cytotoxicity in familial HLH.
  • Leukocytosis accompanying the inflammatory episodes, which is much less common in classical HLH.
Show evidence (2 references)
PMID:33872655 SUPPORT Human Clinical
"To date, variants in 6 different genes (PRF1, UNC13D, STXBP2, STX11, RAB27A, and LYST) are known to directly affect perforin-mediated cytotoxicity and thereby cause HLH."
Names the familial HLH genes and the pathway that defines them.
PMID:33872655 SUPPORT Human Clinical
"Levels of natural killer cell degranulation and/or cytotoxicity were normal in all patients with HLH."
The measurement that separates ZNFX1 deficiency from familial HLH in an individual patient.
Other genetic causes of HLH and HLH-like disease
Overlapping Features A second tier of genes is linked to HLH and HLH-like disease without acting through perforin-mediated cytotoxicity. The founding paper places ZNFX1 in this group explicitly, which is the nosological claim this entry inherits.
Show evidence (1 reference)
PMID:33872655 SUPPORT Human Clinical
"have been linked to HLH and HLH-like disease"
Establishes the second, non-cytotoxicity tier of HLH genes.
🐁

Animal Models

2
Znfx1-mutant mouse infected with LCMV
A mouse model built specifically to reproduce the HLH-like arm of the human disease, using lymphocytic choriomeningitis virus as the trigger. It is the first model to pair the genotype with a viral challenge rather than characterising the knockout at rest.
Species
Mouse
Genotype
Znfx1mut
Publication
PMID:41636200
Pathograph links
Virally Triggered Hyperinflammatory Episode recapitulates fidelity: moderate LCMV-infected Znfx1-mutant mice show hallmark features of HLH-like inflammation, with more pronounced T-cell expansion and Th1 polarisation than infected controls.
Limitations: LCMV is not among the viruses that trigger episodes in patients, so the trigger is a laboratory surrogate rather than the human exposure. The model reproduces the inflammatory phenotype but has not been shown to reproduce the renal, pulmonary or neurological injury that dominates the human disease, and the mouse Znfx1 literature describes it primarily as an antiviral dsRNA sensor - a role the second human cohort does not support.
Readouts
Hepatic macrophage infiltration after LCMV infection
Direction: INCREASED
Interpretation: Identifies the macrophage as the infiltrating effector cell in the inflamed organ that is also most affected in patients.
Show evidence (1 reference)
PMID:41636200 SUPPORT Model Organism
"Znfx1mut macrophages infiltrated the liver to a greater extent upon infection"
The histological readout of macrophage-driven hepatic inflammation.
T cell expansion and Th1 polarisation
Direction: INCREASED
Interpretation: Shows the lymphoid arm is also engaged, which matters because the human disease is not a lymphocyte-cytotoxicity defect.
Show evidence (1 reference)
PMID:41636200 SUPPORT Model Organism
"Immunophenotyping revealed more pronounced T cell expansion and type-1 helper (Th1) polarization in LCMV-infected Znfx1mut mice."
The immunophenotyping readout defining the model's inflammatory signature.
Show evidence (1 reference)
PMID:41636200 SUPPORT Model Organism
"This novel murine model of HLH-like inflammation mirrors key aspects of the immune dysregulation observed in patients"
The authors' own claim for the model's fidelity to the human disease.
Znfx1-knockout mouse infected with Mycobacterium tuberculosis
A separate model addressing the mycobacterial pole of the disease. It offers a candidate mechanism the human work does not: ZNFX1 stabilises the mRNA encoding an AMPK catalytic subunit, and its loss impairs autophagic control of M. tuberculosis in macrophages.
Species
Mouse
Genotype
Znfx1 knockout
Publication
PMID:38016036
Pathograph links
Impaired Monocyte Homeostasis and Antimycobacterial Defence partially recapitulates fidelity: low Znfx1-knockout mice show increased mycobacterial burden and progressive lung injury, matching the direction of the human mycobacterial phenotype.
Limitations: The model reproduces susceptibility but not the defining human feature of this arm, which is monocytosis; and the proposed AMPK-autophagy mechanism has not been tested in patient cells. Human patients presented with BCG-osis and disseminated tuberculosis rather than with the chronic pulmonary disease modelled here. Fidelity is graded LOW for that reason rather than because the murine work is weak.
Readouts
Pulmonary M. tuberculosis burden
Direction: INCREASED
Interpretation: Confirms the direction of the susceptibility phenotype in vivo.
Show evidence (1 reference)
PMID:38016036 SUPPORT Model Organism
"reduced phagocytosis, suppressed macrophage activation, increased M. tuberculosis burden, progressive lung tissue injury, and chronic inflammation in M. tuberculosis-infected mice"
The in vivo outcome measures for the knockout under mycobacterial challenge.
Show evidence (1 reference)
PMID:38016036 SUPPORT Model Organism
"ZNFX1 critically maintained AMPK-regulated autophagic flux by stabilizing protein kinase AMP-activated catalytic subunit alpha 2 mRNA"
The proposed molecular mechanism linking ZNFX1 loss to defective antimycobacterial autophagy.
{ }

Source YAML

click to show 
name: Immunodeficiency 91 and Hyperinflammation
creation_date: "2026-08-30T02:45:00Z"
category: Mendelian
disease_term:
  preferred_term: immunodeficiency 91 and hyperinflammation
  term:
    id: MONDO:0030491
    label: immunodeficiency 91 and hyperinflammation
description: >-
  An autosomal recessive inborn error of immunity caused by biallelic loss of
  ZNFX1, a cytosolic, interferon-inducible helicase that senses double-stranded
  nucleic acid. The disease is defined less by an inability to mount an immune
  response than by an inability to regulate one: patients meet infections that
  most children clear with an inflammatory episode that does not switch off,
  producing haemophagocytic lymphohistiocytosis (HLH) or HLH-like disease with
  hepatitis, cytopenias, seizures, and renal and pulmonary injury. Mortality in
  the founding cohort was high and death was usually from the inflammation
  rather than from the infection itself.

  Two things distinguish it from familial HLH, and both are curated here as
  evidence rather than as assertion. First, NK-cell degranulation and
  cytotoxicity are normal, so the mechanism is not the perforin-pathway defect
  that defines FHL. Second, the leukocytosis that accompanies these episodes is
  explicitly noted to be much less common in classical HLH.
synonyms:
- IMD91
- ZNFX1 deficiency
- immunodeficiency 91 with hyperinflammation and immune dysregulation
parents:
- primary immunodeficiency disease
notes: >-
  Nosological scope, and the single most important thing to know before
  extending this entry. ZNFX1 deficiency was reported twice in 2021, by two
  groups, with substantially different phenotypes, and the disagreement is not
  resolved.

  Vavassori et al. (PMID:33872655) described 15 patients whose disease is
  dominated by severe infection with RNA and DNA viruses and by virally
  triggered HLH-like inflammation, with 11 deaths in childhood. Le Voyer et al.
  (PMID:33876776) described four patients whose disease is dominated by
  intermittent monocytosis and mycobacterial disease - BCG-osis and disseminated
  tuberculosis - and who, in the authors' own words, "do not suffer from severe
  viral illnesses".

  This entry curates both poles rather than merging them into a single
  phenotype list or silently preferring the larger cohort. The `discussions`
  block records what is genuinely open about the relationship between them.
  A curator adding new patients should say which pole they resemble, and should
  not import mycobacterial findings into the viral-inflammatory arm or vice
  versa - the two cohorts differ in ancestry, ascertainment route, and the
  variants reported, and no published analysis has yet shown that the
  difference is allelic.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Homozygous and compound heterozygous loss-of-function ZNFX1 alleles, in
    consanguineous and non-consanguineous kindreds. No individual homozygous for
    a predicted loss-of-function ZNFX1 allele appears in public population
    databases, which is the population-genetic counterpart of the severity of
    the reported phenotype.
  evidence:
  - reference: PMID:33872655
    reference_title: Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Deleterious homozygous and compound heterozygous ZNFX1 variants were identified in all 13 patients."
    explanation: Establishes the biallelic, recessive genetic architecture across all eight founding kindreds.
  - reference: PMID:33876776
    reference_title: Inherited deficiency of stress granule ZNFX1 in patients with monocytosis and mycobacterial disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There are no subjects homozygous for pLOF variants in public databases."
    explanation: >-
      Population-database absence of homozygous loss-of-function carriers, which
      supports the alleles being under strong negative selection rather than
      tolerated variation.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Fewer than 30 patients had been reported by 2023, in a small number of
    largely consanguineous kindreds. No population-based estimate exists, and
    the figure below is a count of published cases, not a rate.
  evidence:
  - reference: PMID:37291413
    reference_title: ZNFX1 Deficiency in a Child with Interstitial Pneumonitis and Peripheral Monocytosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recently, NFX1-type zinc finger-containing 1 (ZNFX1) mutations have been described in 28
      patients from 17 families with a type I IFN inborn error of immunity ... These patients are
      reported to have recurrent viral and mycobacterial infections as well as monocytosis,
      thrombocytopenia, hepatosplenomegaly, and hemophagocytic lymphohistiocytosis (HLH) or HLH-like
      manifestations.
    explanation: >-
      The paper summarizes 28 patients from 17 families with ZNFX1-related inborn errors of immunity
      and describes infection and hyperinflammatory manifestations. This is a literature count, not
      a population prevalence.
pathophysiology:
- name: Biallelic ZNFX1 Loss of Function
  biological_scale: MOLECULAR
  description: >-
    The primary lesion is biallelic damage to ZNFX1, encoding a large
    interferon-stimulated helicase. Reported alleles include nonsense,
    frameshift and missense changes; the founding cohort carried 11 biallelic
    variants across eight kindreds, five truncating and six missense. Protein is
    undetectable in cells from patients carrying two truncating alleles, so for
    that allele class the functional consequence is absence of protein rather
    than a hypomorph.
  genes:
  - preferred_term: ZNFX1
    term:
      id: hgnc:29271
      label: ZNFX1
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:33872655
    reference_title: Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By using WES, we identified 11 biallelic ZNFX1 variants in 13 patients"
    explanation: The allelic series in the founding cohort.
  - reference: PMID:33872655
    reference_title: Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "ZNFX1 could not be detected in whole cell extracts of fibroblasts from 2 of the patients carrying biallelic stop codons"
    explanation: >-
      Confirms at protein level that truncating alleles abolish ZNFX1, rather
      than producing a stable truncated product.
  downstream:
  - target: Loss of Cytosolic Double-Stranded Nucleic Acid Surveillance
    causal_link_type: DIRECT
    description: >-
      Absent or non-functional ZNFX1 removes the sensor itself, which is the
      proximate functional lesion.
- name: Loss of Cytosolic Double-Stranded Nucleic Acid Surveillance
  biological_scale: MOLECULAR
  description: >-
    ZNFX1 is an interferon-stimulated double-stranded RNA sensor that binds
    viral RNA and signals through the mitochondrial antiviral signalling protein
    MAVS, independently of the two other MAVS-associated sensors RIG-I and MDA5.
    Its expression is low in resting cells and is rapidly induced by viral
    infection and type I interferon, so the lesion is one of a stress-induced
    surveillance arm rather than of a constitutively required housekeeping
    pathway. In patient cells the protein is also recruited to, and can induce,
    cytoplasmic stress granules.
  biological_processes:
  - preferred_term: cellular response to exogenous double-stranded RNA
    modifier: LOSS_OF_FUNCTION
    term:
      id: GO:0071360
      label: cellular response to exogenous dsRNA
  molecular_functions:
  - preferred_term: double-stranded RNA binding
    modifier: LOSS_OF_FUNCTION
    term:
      id: GO:0003725
      label: double-stranded RNA binding
  cellular_components:
  - preferred_term: cytoplasmic stress granule
    term:
      id: GO:0010494
      label: cytoplasmic stress granule
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:33872655
    reference_title: Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "ZNFX1 binds to viral RNA and interacts with the mitochondrial antiviral signaling (MAVS) protein, promoting the expression of interferon-stimulated genes (ISGs)."
    explanation: The molecular function lost, and the signalling adaptor it acts through.
  - reference: PMID:33872655
    reference_title: Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Low ZNFX1 protein expression was noted in fibroblasts under resting conditions, whereas a rapid upregulation was observed after 24 hours of stimulation"
    explanation: >-
      Establishes ZNFX1 as an inducible rather than constitutive sensor, which
      is why the disease manifests as episodes triggered by infection.
  - reference: PMID:33876776
    reference_title: Inherited deficiency of stress granule ZNFX1 in patients with monocytosis and mycobacterial disease.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We find that this cytoplasmic protein can be recruited to or even induce stress granules."
    explanation: Localises ZNFX1 to stress granules, the subcellular compartment the second group emphasises.
  downstream:
  - target: Dysregulated Interferon-Stimulated Gene Induction
    causal_link_type: DIRECT
    description: >-
      Losing the sensor deranges the transcriptional programme it normally
      shapes downstream of MAVS.
  - target: Derepression of the NLRP3 Inflammasome
    causal_link_type: DIRECT
    description: >-
      A second, non-sensing function of the same protein. Shown in cell lines
      and mice rather than in patient tissue, so the edge is graded provisional.
  - target: Impaired Monocyte Homeostasis and Antimycobacterial Defence
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The route from loss of the sensor to monocytosis and mycobacterial
      susceptibility is not established. The second founding cohort showed that
      it does not run through IFN-gamma, but did not identify what it does run
      through.
- name: Dysregulated Interferon-Stimulated Gene Induction
  biological_scale: CELLULAR
  description: >-
    The defect is dysregulation, not simple loss. Patient cells stimulated with
    intracellular double-stranded nucleic acid over-express interferon-stimulated
    genes, and the half-life of ISG mRNA is altered; baseline ISG expression in
    patient blood is higher than in controls. Yet the same cells respond poorly
    to soluble poly(I:C) and clear virus less well. Curating this node as
    "reduced interferon response" would misstate the finding: the pathology is
    an unbalanced response whose direction depends on how the nucleic acid is
    presented.
  biological_processes:
  - preferred_term: type I interferon-mediated signaling pathway
    term:
      id: GO:0060337
      label: type I interferon-mediated signaling pathway
  cell_types:
  - preferred_term: dermal fibroblast
    term:
      id: CL:0002551
      label: fibroblast of dermis
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:33872655
    reference_title: Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Stimulation of patient-derived primary cells with synthetic double-stranded nucleic acids was associated with a deregulated pattern of expression of ISGs and alterations in the half-life of the mRNA of ISGs and also associated with poorer clearance of viral infections by monocytes."
    explanation: >-
      The core cellular phenotype, and the wording that justifies "deregulated"
      rather than "deficient" in this node's name.
  - reference: PMID:33872655
    reference_title: Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "the baseline expression of ISGs seen in peripheral blood isolated from the patients"
    explanation: >-
      Baseline ISG expression is raised rather than lowered, which is why this
      disease is discussed alongside the interferonopathies.
  downstream:
  - target: Impaired Monocyte Clearance of Virus
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      An unbalanced ISG programme leaves monocytes unable to complete an
      antiviral defence programme after nucleic-acid stimulation.
- name: Derepression of the NLRP3 Inflammasome
  biological_scale: MOLECULAR
  description: >-
    Independently of its sensing role, ZNFX1 restrains the NLRP3 inflammasome by
    holding NLRP3 in the cytoplasm and preventing its accumulation on
    trans-Golgi-network vesicles in the resting state. Loss of that restraint
    releases caspase-1 activation and IL-1-family cytokine maturation. Two
    features make this the most attractive current explanation for the
    hyperinflammatory pole of the disease: it is a licensing defect rather than
    a signalling deficiency, and human pathogenic ZNFX1 variants fail to rescue
    it where wild-type ZNFX1 does.

    It is nonetheless graded provisional. The work is in cell lines and mice; no
    patient-derived tissue has been shown to carry a derepressed NLRP3
    inflammasome, and no patient has been reported to respond to NLRP3-directed
    therapy in a way that would close the loop.
  biological_processes:
  - preferred_term: NLRP3 inflammasome complex assembly
    modifier: INCREASED
    term:
      id: GO:0044546
      label: NLRP3 inflammasome complex assembly
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:39333773
    reference_title: The human disease-associated gene ZNFX1 controls inflammation through inhibition of the NLRP3 inflammasome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "ZNFX1 retains NLRP3 in the cytoplasm and prevents its accumulation in the TGN38 + /TGN46+ vesicles in the resting state."
    explanation: The proposed molecular mechanism of restraint that is lost in the disease.
  - reference: PMID:39333773
    reference_title: The human disease-associated gene ZNFX1 controls inflammation through inhibition of the NLRP3 inflammasome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Expression of wild-type ZNFX1, but not of ZNFX1 with human pathogenic mutations, rescues the impairment of NLRP3 inflammasome inhibition."
    explanation: >-
      Ties the mechanism specifically to the disease-causing alleles, which is
      what raises it above a general cell-biological observation.
  downstream:
  - target: Macrophage-Driven Cytokine Excess
    causal_link_type: DIRECT
    description: >-
      Unrestrained inflammasome activity yields caspase-1-dependent maturation
      of IL-1-family cytokines.
- name: Impaired Monocyte Clearance of Virus
  biological_scale: CELLULAR
  description: >-
    After prestimulation with transfected poly(I:C), patient monocytes cleared
    vesicular stomatitis virus less efficiently than control monocytes. This is
    the cellular correlate of the clinical susceptibility to RNA and DNA viruses,
    and it locates the defect in a myeloid cell rather than in the lymphoid
    compartment.
  cell_types:
  - preferred_term: monocyte
    term:
      id: CL:0000576
      label: monocyte
  biological_processes:
  - preferred_term: defense response to virus
    modifier: DECREASED
    term:
      id: GO:0051607
      label: defense response to virus
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:33872655
    reference_title: Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "the monocytes of P2.1 were less efficient in clearing VSV than the control monocytes were"
    explanation: Direct functional demonstration of impaired viral clearance by patient monocytes.
  downstream:
  - target: Virally Triggered Hyperinflammatory Episode
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Failure to clear the trigger sustains the stimulus that drives the
      inflammatory episode.
- name: Macrophage-Driven Cytokine Excess
  biological_scale: CELLULAR
  description: >-
    Macrophages are the proposed effector of the inflammatory phase. In the
    Znfx1-mutant mouse, mutant macrophages infiltrate the liver more heavily
    after infection and produce more cytokine in vitro even without stimulation,
    which points at a cell-intrinsic hair-trigger rather than at a stronger
    upstream signal.
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:41636200
    reference_title: A Novel Murine Model of Hemophagocytic Lymphohistiocytosis-Like Inflammation in ZNFX1 Deficiency.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "macrophages infiltrated the liver to a greater extent upon infection and produced greater levels of cytokines in vitro in the absence of stimulation, suggesting that these cells have a major role in driving inflammation"
    explanation: >-
      Identifies the macrophage as the likely driver, and the unstimulated
      cytokine production is what makes it a cell-intrinsic claim.
  downstream:
  - target: Virally Triggered Hyperinflammatory Episode
    causal_link_type: DIRECT
    description: Cytokine excess from activated macrophages is the proximate cause of the systemic episode.
- name: Virally Triggered Hyperinflammatory Episode
  biological_scale: ORGANISM
  description: >-
    The clinical event that defines the disease: a systemic inflammatory episode
    precipitated by infection, with cytopenia and hepatitis, meeting HLH criteria
    in half of the affected patients in the founding cohort. Two negative
    findings are load-bearing for the mechanism. NK-cell degranulation and
    cytotoxicity were normal in every patient with HLH, so this is not the
    cytotoxicity defect of familial HLH. And the episodes are accompanied by
    leukocytosis, which the authors note is much less common in classical HLH.

    Episodes are not always infection-locked: some patients progressed after the
    virus had been cleared, and some in the apparent absence of any infectious
    agent, which is difficult to reconcile with a purely trigger-driven model and
    is one reason the inflammasome arm is attractive.
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:33872655
    reference_title: Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of the 12 patients with systemic inflammatory disease, 6 met the diagnostic criteria for hemophagocytic lymphohistiocytosis (HLH), including hemophagocytosis in bone marrow aspirates"
    explanation: Frequency of formally defined HLH within the cohort.
  - reference: PMID:33872655
    reference_title: Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Levels of natural killer cell degranulation and/or cytotoxicity were normal in all patients with HLH."
    explanation: >-
      The specificity control that separates this disease mechanistically from
      familial HLH, where the cytotoxicity pathway is the lesion.
  - reference: PMID:33872655
    reference_title: Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "other patients showed progressive disease even after the virus had been cleared"
    explanation: >-
      Evidence that the inflammatory programme can run on after the trigger is
      gone, which a purely infection-driven model does not predict.
- name: Impaired Monocyte Homeostasis and Antimycobacterial Defence
  biological_scale: CELLULAR
  description: >-
    The second pole of the disease, from the second founding cohort:
    intermittent monocytosis with mycobacterial disease, in patients with normal
    lymphocyte subsets who produce IFN-gamma normally and whose cells respond
    normally to it. That set of normal results is what makes the finding
    interesting - it places ZNFX1 outside the IFN-gamma circuit that explains
    most Mendelian susceptibility to mycobacterial disease, and leaves the
    effector mechanism unidentified.
  cell_types:
  - preferred_term: monocyte
    term:
      id: CL:0000576
      label: monocyte
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:33876776
    reference_title: Inherited deficiency of stress granule ZNFX1 in patients with monocytosis and mycobacterial disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our results indicate that human ZNFX1 is associated with stress granules and essential for both monocyte homeostasis and protective immunity to mycobacteria."
    explanation: The authors' summary claim for this arm of the phenotype.
  - reference: PMID:33876776
    reference_title: Inherited deficiency of stress granule ZNFX1 in patients with monocytosis and mycobacterial disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lymphocyte subsets are present at normal frequencies in these patients and produce IFN-γ normally."
    explanation: >-
      Excludes the usual IFN-gamma-circuit explanations for mycobacterial
      susceptibility, which is why this arm is curated as mechanistically open.
genetic:
- name: ZNFX1
  gene_term:
    preferred_term: ZNFX1
    term:
      id: hgnc:29271
      label: ZNFX1
  relationship_type: CAUSATIVE
  notes: >-
    ZNFX1 encodes a large multidomain helicase with an ATP-binding site, a DEAD
    helicase box, six zinc fingers and a coiled-coil region; the helicase domain
    is homologous to the RNA helicase Aquarius. Reported disease alleles are
    distributed across the protein and include both truncating and missense
    changes.

    Both founding cohorts identified ZNFX1 as the only candidate segregating
    with disease in their kindreds, by independent whole-exome studies in
    different populations. That independent convergence, rather than any single
    functional assay, is the strongest argument for causality here.
  evidence:
  - reference: PMID:33872655
    reference_title: Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In all of the patients, ZNFX1 was the only candidate gene that segregated with the disease."
    explanation: Segregation evidence for causality in the founding cohort.
  - reference: PMID:33876776
    reference_title: Inherited deficiency of stress granule ZNFX1 in patients with monocytosis and mycobacterial disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patients are homozygous for ZNFX1 variants (p.S959* and p.E1606Rfs*10) predicted to be loss of function (pLOF)."
    explanation: Independent identification of biallelic loss-of-function alleles in a separate cohort.
phenotypes:
- category: Hematologic
  name: Hemophagocytosis
  description: >-
    Hemophagocytosis in bone marrow aspirates, as part of formally diagnosed HLH
    in 6 of the 12 patients with systemic inflammatory disease in the founding
    cohort.
  phenotype_term:
    preferred_term: Hemophagocytosis
    term:
      id: HP:0012156
      label: Hemophagocytosis
  evidence:
  - reference: PMID:33872655
    reference_title: Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "6 met the diagnostic criteria for hemophagocytic lymphohistiocytosis (HLH), including hemophagocytosis in bone marrow aspirates"
    explanation: Documents marrow hemophagocytosis in the cohort.
- category: Hematologic
  name: Increased Monocyte Count
  description: >-
    Intermittent monocytosis is the presenting haematological abnormality in the
    mycobacterial pole of the disease, and is also reported in single cases from
    the inflammatory pole.
  phenotype_term:
    preferred_term: Monocytosis
    term:
      id: HP:0012311
      label: Increased total monocyte count
  evidence:
  - reference: PMID:33876776
    reference_title: Inherited deficiency of stress granule ZNFX1 in patients with monocytosis and mycobacterial disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report four patients from two unrelated kindreds with intermittent monocytosis and mycobacterial disease"
    explanation: Establishes monocytosis as a defining feature of the second cohort.
- category: Hematologic
  name: Thrombocytopenia
  description: Anemia with thrombocytopenia was the usual cytopenia pattern during inflammatory episodes.
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
  evidence:
  - reference: PMID:33872655
    reference_title: Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The cytopenia was characterized by anemia in 1 individual and anemia with thrombocytopenia in 12 individuals."
    explanation: Frequency and pattern of the cytopenia.
- category: Hematologic
  name: Anemia
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  evidence:
  - reference: PMID:33872655
    reference_title: Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The cytopenia was characterized by anemia in 1 individual and anemia with thrombocytopenia in 12 individuals."
    explanation: Anemia was present in all cytopenic patients in the cohort.
- category: Hepatic
  name: Hepatomegaly
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:33872655
    reference_title: Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "as evidenced by elevated serum liver enzyme levels (n = 12 patients), hepatomegaly (n = 13)"
    explanation: >-
      Names hepatomegaly and its count directly. An earlier version of this item
      quoted the liver-enzyme clause from the same sentence, which evidenced a
      different finding.
- category: Hepatic
  name: Elevated Hepatic Transaminases
  phenotype_term:
    preferred_term: Elevated circulating hepatic transaminase concentration
    term:
      id: HP:0002910
      label: Elevated circulating hepatic transaminase concentration
  evidence:
  - reference: PMID:33872655
    reference_title: Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A total of 14 patients had hepatic disease, as evidenced by elevated serum liver enzyme levels"
    explanation: The laboratory evidence used to define hepatic disease in the cohort.
- category: Neurologic
  name: Seizures
  description: >-
    Recurrent seizures in 7 of 10 patients with neurological involvement; in
    three the seizures occurred during an HLH episode, which is one reason the
    neurological disease is difficult to separate from the systemic inflammation.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:33872655
    reference_title: Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neurologic involvement was observed in 10 patients, 7 of whom experienced recurrent seizures."
    explanation: Frequency of seizures within the cohort.
- category: Neurologic
  name: Developmental Regression
  phenotype_term:
    preferred_term: Developmental regression
    term:
      id: HP:0002376
      label: Developmental regression
  evidence:
  - reference: PMID:33872655
    reference_title: Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A total of 3 patients showed developmental regression"
    explanation: Documents regression as distinct from static delay.
- category: Respiratory
  name: Acute Respiratory Distress Syndrome
  phenotype_term:
    preferred_term: Acute respiratory distress syndrome
    term:
      id: HP:0033677
      label: Acute respiratory distress syndrome
  evidence:
  - reference: PMID:33872655
    reference_title: Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Acute respiratory distress syndrome occurred in 7 patients and was mostly associated with viral infections."
    explanation: Frequency and trigger association for ARDS in the cohort.
- category: Respiratory
  name: Pulmonary Hemorrhage
  phenotype_term:
    preferred_term: Pulmonary hemorrhage
    term:
      id: HP:0040223
      label: Pulmonary hemorrhage
  evidence:
  - reference: PMID:33872655
    reference_title: Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A total of 6 patients had pulmonary hemorrhage."
    explanation: Frequency of pulmonary hemorrhage in the cohort.
- category: Respiratory
  name: Interstitial Pneumonitis
  phenotype_term:
    preferred_term: Interstitial pneumonitis
    term:
      id: HP:0006515
      label: Interstitial pneumonitis
  evidence:
  - reference: PMID:37291413
    reference_title: ZNFX1 Deficiency in a Child with Interstitial Pneumonitis and Peripheral Monocytosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a patient with a ZNFX1 mutation who presented with HLH-like disease and was found to have interstitial pneumonitis, peripheral monocytosis, renal disease, and B cell compartment abnormalities"
    explanation: A single well-characterised case establishing interstitial pneumonitis in this disease.
- category: Renal
  name: Nephrotic Syndrome
  phenotype_term:
    preferred_term: Nephrotic syndrome
    term:
      id: HP:0000100
      label: Nephrotic syndrome
  evidence:
  - reference: PMID:33872655
    reference_title: Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We variously observed hemolytic uremic syndrome (P2.1), membranoproliferative glomerulonephritis (P6.1), nephrotic syndrome"
    explanation: Enumerates the renal presentations observed, including nephrotic syndrome.
- category: Renal
  name: Hemolytic Uremic Syndrome
  description: >-
    Histologically proven thrombotic microangiopathy in three patients, one of
    whom presented as hemolytic uremic syndrome. The authors are careful that
    peripheral destruction from thrombotic microangiopathy may contribute to the
    cytopenia, but judge HLH the dominant cause.
  phenotype_term:
    preferred_term: Hemolytic-uremic syndrome
    term:
      id: HP:0005575
      label: Hemolytic-uremic syndrome
  evidence:
  - reference: PMID:33872655
    reference_title: Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We variously observed hemolytic uremic syndrome (P2.1)"
    explanation: >-
      Names hemolytic uremic syndrome in a specific patient. The thrombotic
      microangiopathy sentence quoted here previously supports the TMA claim in
      the description but never says HUS.
  - reference: PMID:33872655
    reference_title: Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There was evidence of renal involvement in 12 patients, including histologically proven thrombotic microangiopathy (TMA)"
    explanation: >-
      The histologically proven thrombotic microangiopathy that underlies the
      renal presentations, kept as a separate item for the separate claim.
- category: Hematologic
  name: Leukocytosis
  description: >-
    A high leukocyte count with neutrophilia and lymphocytosis accompanied the
    cytopenia in 8 of 15 patients. This is the feature the entry's
    pathophysiology leans on as a discriminator from classical HLH, where
    leukocytosis is much less common, so it is curated as a phenotype rather
    than left in prose.
  phenotype_term:
    preferred_term: Leukocytosis
    term:
      id: HP:0001974
      label: Increased total leukocyte count
  frequency: FREQUENT
  evidence:
  - reference: PMID:33872655
    reference_title: Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 8 individuals, anemia and anemia with thrombocytopenia were combined with a high leukocyte count"
    explanation: The count of patients with leukocytosis alongside their cytopenia.
  - reference: PMID:33872655
    reference_title: Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with the latter being much less common in classical HLH"
    explanation: >-
      The comparison that makes leukocytosis discriminating rather than
      incidental.
- category: Hepatic
  name: Coagulopathy
  phenotype_term:
    preferred_term: Coagulopathy
    term:
      id: HP:0003256
      label: Abnormality of the coagulation cascade
  frequency: FREQUENT
  evidence:
  - reference: PMID:33872655
    reference_title: Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "elevated serum lactate dehydrogenase levels (n = 10), coagulopathy (n = 7)"
    explanation: Coagulopathy and its count within the hepatic-disease group.
- category: Hepatic
  name: Acute Liver Failure
  description: >-
    Three of 15 patients met formal criteria for acute liver failure, which is
    the severe end of the hepatic involvement rather than a separate process.
  phenotype_term:
    preferred_term: Acute hepatic failure
    term:
      id: HP:0006554
      label: Acute hepatic failure
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:33872655
    reference_title: Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A total of 3 patients met the criteria for acute liver failure"
    explanation: The count of patients reaching formal acute-liver-failure criteria.
- category: Neurologic
  name: Cerebral Calcification
  phenotype_term:
    preferred_term: Cerebral calcification
    term:
      id: HP:0002514
      label: Cerebral calcification
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:33872655
    reference_title: Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neuroimaging showed evidence of multiple focal calcifications in 3 patients"
    explanation: The imaging finding and its count.
- category: Neurologic
  name: Cerebral White Matter Abnormalities
  description: >-
    T2 hyperintense lesions in five patients and ischemic lesions with diffusion
    restriction in four. In the one transplanted patient the white-matter changes
    stabilised and then regressed after HSCT, which is why this phenotype is
    mechanistically informative rather than merely descriptive.
  phenotype_term:
    preferred_term: Abnormal cerebral white matter morphology
    term:
      id: HP:0002500
      label: Abnormal cerebral white matter morphology
  frequency: FREQUENT
  evidence:
  - reference: PMID:33872655
    reference_title: Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ischemic lesions (diffusion restriction on magnetic resonance imaging) in 4 patients"
    explanation: The ischemic component of the neuroimaging findings, with its count.
- category: Infectious
  name: Recurrent Viral Infections
  description: >-
    Severe infection with both RNA viruses (influenza A and B, parainfluenza,
    respiratory syncytial virus, norovirus, rotavirus) and DNA viruses (HHV-6,
    adenovirus, cytomegalovirus). Live viral vaccines caused severe vaccine-strain
    infection in two patients, which is a practical point of some weight.
  phenotype_term:
    preferred_term: Recurrent viral infections
    term:
      id: HP:0004429
      label: Recurrent viral infections
  evidence:
  - reference: PMID:33872655
    reference_title: Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patients were abnormally susceptible to viral infections"
    explanation: The susceptibility claim itself, stated directly by the source.
  - reference: PMID:33872655
    reference_title: Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is noteworthy that live virus vaccines also caused severe vaccine strain infections in 2 patients"
    explanation: >-
      Documents vaccine-strain disease, which matters clinically and shows the
      susceptibility extends to attenuated organisms.
- category: Infectious
  name: Recurrent Mycobacterial Infections
  description: >-
    BCG-osis and disseminated tuberculosis in the second founding cohort. This
    phenotype is reported in patients who did not have severe viral illness, and
    should not be assumed to co-occur with the viral-inflammatory phenotype.
  phenotype_term:
    preferred_term: Recurrent mycobacterial infections
    term:
      id: HP:0011274
      label: Recurrent mycobacterial infections
  evidence:
  - reference: PMID:33876776
    reference_title: Inherited deficiency of stress granule ZNFX1 in patients with monocytosis and mycobacterial disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mycobacterial disease, including bacillus Calmette-Guérin-osis and disseminated tuberculosis"
    explanation: The specific mycobacterial presentations reported.
clinical_burden:
  burden_level: HIGH
  rationale: >-
    Eleven of the 15 patients in the founding cohort died in childhood, seven of
    them before three months of age, with a median age at death of 1.1 years.
    Death was usually from the inflammatory episode rather than from the
    infection that triggered it: inflammatory episodes with hepatitis and
    cytopenia were fatal in seven cases.
  evidence:
  - reference: PMID:33872655
    reference_title: Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mortality rate was high: 11 of the 15 patients died during childhood, with 7 deaths occurring before patients reached the age of 3 months"
    explanation: The mortality figures underlying the HIGH burden level.
  - reference: PMID:33872655
    reference_title: Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Inflammatory episodes with hepatitis and cytopenia were fatal in 7 cases"
    explanation: >-
      Identifies the inflammatory episode rather than the infection as the usual
      proximate cause of death, which is the claim the pathophysiology makes.

diagnosis:
- name: Genomic screening for ZNFX1 in severe viral infection with HLH
  description: >-
    The founding cohort's own recommendation is that ZNFX1 be included in
    genomic screens for patients presenting with severe viral infection and HLH.
    Recorded because the disease has no biochemical or functional screening
    test - NK degranulation and cytotoxicity, the assays that would ordinarily
    triage a child with HLH, are normal here, so a normal cytotoxicity result
    does not exclude this diagnosis and sequencing is the route to it.
  evidence:
  - reference: PMID:33872655
    reference_title: Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We recommend that (1) variants in ZNFX1 be included in genomic screens for patients experiencing severe viral infections and HLH"
    explanation: The authors' explicit diagnostic recommendation.
- name: HLH diagnostic criteria
  description: >-
    Six of the 12 patients with systemic inflammatory disease met formal HLH
    diagnostic criteria, including marrow hemophagocytosis. The remainder had
    HLH-like disease that did not meet criteria, so the criteria identify a
    subset of the inflammatory phenotype rather than defining it.
  evidence:
  - reference: PMID:33872655
    reference_title: Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of the 12 patients with systemic inflammatory disease, 6 met the diagnostic criteria for hemophagocytic lymphohistiocytosis (HLH), including hemophagocytosis in bone marrow aspirates"
    explanation: >-
      The proportion meeting formal criteria, which is what makes "HLH-like" the
      right descriptor for the disease as a whole.

biochemical:
- name: Serum lactate dehydrogenase
  notes: >-
    Elevated in 10 of the 15 patients as part of the hepatic-disease picture.
    Recorded as an observed laboratory abnormality; no reference interval is
    given by the source and none is asserted here.
  evidence:
  - reference: PMID:33872655
    reference_title: Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "elevated serum lactate dehydrogenase levels (n = 10)"
    explanation: The analyte, its direction, and its count in the cohort.

histopathology:
- name: Hepatic necrosis with extramedullary hematopoiesis
  description: >-
    Liver histology was heterogeneous and non-specific across patients: necrosis
    with extramedullary hematopoiesis in one, necrosis with lymphocytic
    infiltration in another, necrosis with nodular regenerative hyperplasia in a
    third, and centrilobular necrosis in a fourth. Necrosis is the common thread;
    nothing in the pattern is diagnostic, and the source says so.
  context: Liver biopsy and autopsy material from four patients in the founding cohort.
  evidence:
  - reference: PMID:33872655
    reference_title: Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Histologic assessment of the liver showed heterogeneous, nonspecific changes, such as necrosis and extramedullary hematopoiesis"
    explanation: >-
      The hepatic histology, quoted with the authors' own "nonspecific" intact so
      the entry does not imply a diagnostic pattern.
- name: Interstitial and cholesterol pneumonitis
  description: >-
    Lung biopsy specimens from two patients showed interstitial pneumonitis and
    cholesterol pneumonitis respectively.
  context: Lung biopsy from two patients in the founding cohort.
  evidence:
  - reference: PMID:33872655
    reference_title: Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "showed interstitial pneumonitis and cholesterol pneumonitis, respectively"
    explanation: The pulmonary histology in the two biopsied patients.

differential_diagnoses:
- name: Familial hemophagocytic lymphohistiocytosis
  description: >-
    The differential that matters most, because ZNFX1 disease presents as HLH
    and the two are separated by mechanism rather than by presentation. Familial
    HLH is caused by variants in six genes that directly impair
    perforin-mediated cytotoxicity. ZNFX1 patients have normal NK-cell
    degranulation and cytotoxicity, so the pathway that defines familial HLH is
    intact in them.
  distinguishing_features:
  - >-
    Normal NK-cell degranulation and cytotoxicity in ZNFX1 deficiency, versus
    impaired perforin-mediated cytotoxicity in familial HLH.
  - >-
    Leukocytosis accompanying the inflammatory episodes, which is much less
    common in classical HLH.
  evidence:
  - reference: PMID:33872655
    reference_title: Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To date, variants in 6 different genes (PRF1, UNC13D, STXBP2, STX11, RAB27A, and LYST) are known to directly affect perforin-mediated cytotoxicity and thereby cause HLH."
    explanation: Names the familial HLH genes and the pathway that defines them.
  - reference: PMID:33872655
    reference_title: Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Levels of natural killer cell degranulation and/or cytotoxicity were normal in all patients with HLH."
    explanation: >-
      The measurement that separates ZNFX1 deficiency from familial HLH in an
      individual patient.
- name: Other genetic causes of HLH and HLH-like disease
  description: >-
    A second tier of genes is linked to HLH and HLH-like disease without acting
    through perforin-mediated cytotoxicity. The founding paper places ZNFX1 in
    this group explicitly, which is the nosological claim this entry inherits.
  evidence:
  - reference: PMID:33872655
    reference_title: Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "have been linked to HLH and HLH-like disease"
    explanation: Establishes the second, non-cytotoxicity tier of HLH genes.

treatments:
- name: Allogeneic Hematopoietic Stem Cell Transplantation
  therapeutic_modality: CELL_THERAPY
  description: >-
    The only reported intervention that has altered the course of the disease.
    One patient transplanted at age 3 was in good health five years later, and
    his cerebral white-matter changes stabilised and then regressed after
    transplant - which is the most direct evidence available that the
    neurological injury is driven by the haematopoietic compartment rather than
    being an independent, cell-autonomous consequence of ZNFX1 loss in brain.

    This rests on a single transplanted patient. It is a strong mechanistic hint
    and a weak efficacy claim, and it should not be quoted as an established
    indication.
  treatment_term:
    preferred_term: allogeneic hematopoietic stem cell transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  target_mechanisms:
  - target: Macrophage-Driven Cytokine Excess
    treatment_effect: INHIBITS
    description: >-
      Replacing the haematopoietic compartment replaces the ZNFX1-deficient
      myeloid cells that drive the inflammatory episodes.
    evidence:
    - reference: PMID:33872655
      reference_title: Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Brain magnetic resonance imaging of this patient showed that the white matter changes present at the age of 32 months had stabilized at the age of 42 months"
      explanation: >-
        Post-transplant stabilisation of the imaging abnormality, the observation
        that ties the neurological injury to the transplantable compartment.
  evidence:
  - reference: PMID:33872655
    reference_title: Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One patient (P4.2) underwent allogeneic hematopoietic stem cell transplantation (HSCT) at the age of 3 years. Five years later, he is in good health but still has a significant developmental delay."
    explanation: >-
      The single reported transplant and its outcome, including the residual
      deficit, which the description reports rather than smoothing over.
  - reference: PMID:33872655
    reference_title: Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 1 patient, HSCT arrested the HLH-like episodes and was followed by improvements in neurologic development."
    explanation: >-
      The authors' own statement of what transplant achieved, which is stronger
      than the outcome description alone: it names the inflammatory episodes as
      the thing that stopped.
- name: Ruxolitinib
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    A JAK inhibitor, given to one patient on the rationale that the disease is an
    interferon-driven inflammatory state. The reported effect was beneficial but
    transient. Curated because a transient response is mechanistically
    informative - it is consistent with JAK-STAT signalling carrying part but
    not all of the inflammatory drive - and because omitting a therapy that was
    tried and partly failed would misrepresent the therapeutic landscape.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: ruxolitinib
      term:
        id: CHEBI:66919
        label: ruxolitinib
  evidence:
  - reference: PMID:33872655
    reference_title: Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The Janus kinase inhibitor ruxolitinib was administered to 1 patient (P5.2); it had a beneficial but transient effect."
    explanation: The single reported use and its explicitly transient benefit.
- name: Anakinra
  therapeutic_modality: PEPTIDE
  description: >-
    IL-1 receptor antagonist, used with corticosteroids in one fatal case of
    CMV-triggered HLH. It is included because the NLRP3 arm of the mechanism
    predicts that IL-1 blockade should help, and the one reported attempt did
    not prevent death - a result worth recording before that prediction is
    treated as established.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: anakinra
      term:
        id: NCIT:C38717
        label: Anakinra
  evidence:
  - reference: PMID:41202491
    reference_title: ZNFX1 deficiency presenting as recurrent HLH triggered by CMV infection.
    supports: NO_EVIDENCE
    evidence_source: HUMAN_CLINICAL
    snippet: "Despite intensive supportive care and immunomodulation with anakinra and corticosteroids, the patient progressed to irreversible organ failure and died from respiratory failure."
    explanation: >-
      Cited to record that IL-1 blockade was tried and did not rescue this
      patient. Graded NO_EVIDENCE because a single fatal case neither
      establishes nor refutes efficacy.
animal_models:
- name: Znfx1-mutant mouse infected with LCMV
  species: Mouse
  genotype: Znfx1mut
  publication: PMID:41636200
  description: >-
    A mouse model built specifically to reproduce the HLH-like arm of the human
    disease, using lymphocytic choriomeningitis virus as the trigger. It is the
    first model to pair the genotype with a viral challenge rather than
    characterising the knockout at rest.
  modeled_mechanisms:
  - target: Virally Triggered Hyperinflammatory Episode
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      LCMV-infected Znfx1-mutant mice show hallmark features of HLH-like
      inflammation, with more pronounced T-cell expansion and Th1 polarisation
      than infected controls.
    limitations: >-
      LCMV is not among the viruses that trigger episodes in patients, so the
      trigger is a laboratory surrogate rather than the human exposure. The model
      reproduces the inflammatory phenotype but has not been shown to reproduce
      the renal, pulmonary or neurological injury that dominates the human
      disease, and the mouse Znfx1 literature describes it primarily as an
      antiviral dsRNA sensor - a role the second human cohort does not support.
    readouts:
    - name: Hepatic macrophage infiltration after LCMV infection
      target: Virally Triggered Hyperinflammatory Episode
      direction: INCREASED
      interpretation: >-
        Identifies the macrophage as the infiltrating effector cell in the
        inflamed organ that is also most affected in patients.
      evidence:
      - reference: PMID:41636200
        reference_title: A Novel Murine Model of Hemophagocytic Lymphohistiocytosis-Like Inflammation in ZNFX1 Deficiency.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Znfx1mut macrophages infiltrated the liver to a greater extent upon infection"
        explanation: The histological readout of macrophage-driven hepatic inflammation.
    - name: T cell expansion and Th1 polarisation
      target: Virally Triggered Hyperinflammatory Episode
      direction: INCREASED
      interpretation: >-
        Shows the lymphoid arm is also engaged, which matters because the human
        disease is not a lymphocyte-cytotoxicity defect.
      evidence:
      - reference: PMID:41636200
        reference_title: A Novel Murine Model of Hemophagocytic Lymphohistiocytosis-Like Inflammation in ZNFX1 Deficiency.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Immunophenotyping revealed more pronounced T cell expansion and type-1 helper (Th1) polarization in LCMV-infected Znfx1mut mice."
        explanation: The immunophenotyping readout defining the model's inflammatory signature.
    evidence:
    - reference: PMID:41636200
      reference_title: A Novel Murine Model of Hemophagocytic Lymphohistiocytosis-Like Inflammation in ZNFX1 Deficiency.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "This novel murine model of HLH-like inflammation mirrors key aspects of the immune dysregulation observed in patients"
      explanation: The authors' own claim for the model's fidelity to the human disease.
- name: Znfx1-knockout mouse infected with Mycobacterium tuberculosis
  species: Mouse
  genotype: Znfx1 knockout
  publication: PMID:38016036
  description: >-
    A separate model addressing the mycobacterial pole of the disease. It offers
    a candidate mechanism the human work does not: ZNFX1 stabilises the mRNA
    encoding an AMPK catalytic subunit, and its loss impairs autophagic control
    of M. tuberculosis in macrophages.
  modeled_mechanisms:
  - target: Impaired Monocyte Homeostasis and Antimycobacterial Defence
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      Znfx1-knockout mice show increased mycobacterial burden and progressive
      lung injury, matching the direction of the human mycobacterial phenotype.
    limitations: >-
      The model reproduces susceptibility but not the defining human feature of
      this arm, which is monocytosis; and the proposed AMPK-autophagy mechanism
      has not been tested in patient cells. Human patients presented with BCG-osis
      and disseminated tuberculosis rather than with the chronic pulmonary disease
      modelled here. Fidelity is graded LOW for that reason rather than because
      the murine work is weak.
    readouts:
    - name: Pulmonary M. tuberculosis burden
      target: Impaired Monocyte Homeostasis and Antimycobacterial Defence
      direction: INCREASED
      interpretation: Confirms the direction of the susceptibility phenotype in vivo.
      evidence:
      - reference: PMID:38016036
        reference_title: ZNFX1 promotes AMPK-mediated autophagy against Mycobacterium tuberculosis by stabilizing Prkaa2 mRNA.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "reduced phagocytosis, suppressed macrophage activation, increased M. tuberculosis burden, progressive lung tissue injury, and chronic inflammation in M. tuberculosis-infected mice"
        explanation: The in vivo outcome measures for the knockout under mycobacterial challenge.
    evidence:
    - reference: PMID:38016036
      reference_title: ZNFX1 promotes AMPK-mediated autophagy against Mycobacterium tuberculosis by stabilizing Prkaa2 mRNA.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "ZNFX1 critically maintained AMPK-regulated autophagic flux by stabilizing protein kinase AMP-activated catalytic subunit alpha 2 mRNA"
      explanation: >-
        The proposed molecular mechanism linking ZNFX1 loss to defective
        antimycobacterial autophagy.
discussions:
- discussion_id: znfx1_two_phenotype_poles
  kind: CONTROVERSY
  prompt: >-
    Are the viral-inflammatory phenotype and the monocytosis-mycobacterial
    phenotype of ZNFX1 deficiency one disease with variable expression, or two
    mechanistically distinct diseases at the same locus?
  attaches_to:
  - pathophysiology#Impaired Monocyte Homeostasis and Antimycobacterial Defence
  - pathophysiology#Virally Triggered Hyperinflammatory Episode
  rationale: >-
    The two founding reports appeared within weeks of each other and describe
    patients who look different. Vavassori's cohort had severe RNA and DNA viral
    infection with fatal HLH-like inflammation; Le Voyer's cohort had monocytosis
    and mycobacterial disease and explicitly did not have severe viral illness.

    This matters mechanistically, not just descriptively. If one disease, then
    any proposed mechanism has to explain both an inability to clear virus and
    an inability to contain mycobacteria, in patients with normal IFN-gamma
    production and normal responses to it. If two, then something - allele
    position, modifier genotype, or environmental exposure such as BCG
    vaccination practice - partitions them, and no published analysis has
    identified what.

    Both cohorts carried truncating alleles, so a simple severe-versus-hypomorph
    split does not obviously account for it. Ascertainment is a live alternative
    explanation: the cohorts were recruited through different clinical routes,
    one through inflammation and one through mycobacterial disease, and each may
    have under-detected the other's phenotype.
  proposed_experiments:
  - experiment_id: exp_znfx1_cross_phenotype_cohort_assessment
    name: Cross-phenotype systematic assessment of a combined ZNFX1 cohort
    description: >-
      Assemble the published patients and assess every individual for both
      phenotypes with the same protocol - viral clearance and ISG regulation on
      one side, monocyte counts and mycobacterial history on the other - rather
      than for the phenotype that prompted their referral. If ascertainment is
      the explanation, the poles should collapse.
    would_support:
    - pathophysiology#Loss of Cytosolic Double-Stranded Nucleic Acid Surveillance
    supporting_outcome:
    - >-
      Patients ascertained through mycobacterial disease are found to have
      subclinical ISG dysregulation and impaired monocyte viral clearance, and
      patients ascertained through HLH are found to have monocytosis, supporting
      one disease with ascertainment-driven apparent poles.
    refuting_outcome:
    - >-
      Each cohort is confirmed to lack the other's cellular phenotype under
      identical assays, supporting two mechanistically distinct diseases and
      requiring the pathograph to be split.
- discussion_id: znfx1_mouse_sensor_vs_human_phenotype
  kind: HUMAN_MODEL_MISMATCH
  prompt: >-
    Mouse Znfx1 was characterised as a dsRNA sensor restricting RNA virus
    replication. Does that role explain the human disease, given that one of the
    two founding human cohorts had no severe viral illness at all?
  attaches_to:
  - pathophysiology#Loss of Cytosolic Double-Stranded Nucleic Acid Surveillance
  - animal_models#Znfx1-mutant mouse infected with LCMV
  rationale: >-
    The murine antiviral-sensor result is what made ZNFX1 a credible candidate
    when the first patients were sequenced, and it fits the Vavassori cohort
    well. It fits the Le Voyer cohort poorly: those patients are susceptible to
    mycobacteria rather than to viruses, which is not what a dsRNA-sensor defect
    predicts.

    The mismatch is therefore not that the model fails to reproduce a human
    finding, but that the model may have anchored the field on one of two human
    phenotypes and made the other harder to explain. The NLRP3-restraint and
    AMPK-autophagy findings are both attempts to supply the missing function,
    and neither has been demonstrated in patient tissue.
  proposed_experiments:
  - experiment_id: exp_znfx1_patient_nlrp3_derepression
    name: Test NLRP3 derepression in patient-derived cells
    description: >-
      Measure NLRP3 inflammasome activation, caspase-1 cleavage and IL-1beta
      maturation in monocytes and macrophages from ZNFX1-deficient patients of
      both phenotypic poles, rather than in overexpression cell lines.
    would_support:
    - pathophysiology#Derepression of the NLRP3 Inflammasome
    supporting_outcome:
    - >-
      Patient macrophages show constitutive or lowered-threshold NLRP3
      activation relative to controls, promoting the inflammasome edge from
      provisional to established.
    refuting_outcome:
    - >-
      Patient macrophages show normal NLRP3 activation thresholds, indicating
      that the cell-line finding does not transfer and that the hyperinflammation
      needs a different explanation.
- discussion_id: znfx1_post_clearance_inflammation
  kind: KNOWLEDGE_GAP
  prompt: >-
    Why do some patients deteriorate after the triggering virus has been
    cleared, or in the apparent absence of any infection?
  attaches_to:
  - pathophysiology#Virally Triggered Hyperinflammatory Episode
  rationale: >-
    A model in which inflammation is driven by failure to clear a pathogen
    predicts that inflammation stops when the pathogen does. The founding cohort
    reports otherwise in at least three patients. This is the strongest clinical
    argument that the disease has a genuine autoinflammatory component
    independent of pathogen load, and it is the observation that the NLRP3
    mechanism would explain if it were confirmed in patients.
  proposed_experiments:
  - experiment_id: exp_znfx1_serial_cytokine_viral_load
    name: Serial cytokine and viral-load monitoring through an inflammatory episode
    description: >-
      Track viral load and IL-1-family and interferon-stimulated cytokine
      profiles in parallel through a full episode in the same patient, to
      establish whether inflammatory activity outlasts detectable virus.
    would_support:
    - pathophysiology#Derepression of the NLRP3 Inflammasome
    supporting_outcome:
    - >-
      Inflammatory cytokine levels remain elevated after viral clearance,
      supporting a pathogen-independent autoinflammatory driver.
    refuting_outcome:
    - >-
      Cytokine elevation tracks viral load closely, indicating that apparent
      post-clearance disease reflects undetected persistent infection rather
      than autonomous inflammation.