Immunodeficiency 85 and Autoimmunity

Immunological MONDO:0030428 Pathograph 21 Show in embeddings browser Inborn Errors of Immunity Combined Immunodeficiency

An inborn error of immunity caused by a heterozygous missense variant in TOM1, an endosomal adaptor protein with no classical immunological function. The name records what makes it interesting: the same lesion produces immunodeficiency and autoimmunity together, in one patient, rather than one or the other. That combination is the entry's organising claim. TOM1 does not sit in a lymphocyte signalling pathway - it moves ubiquitinated cargo through the endolysosomal system and helps autophagosomes fuse with lysosomes. Losing that function starves immune effector responses of something they need while simultaneously removing a brake on inflammatory signalling, so the immune system is at once underpowered against infection and overactive against self. The evidence base is narrow, and in a specific way. Two related patients - a mother with relatively mild disease and her son, whose disease was aggressive and fatal - carry TOM1 p.Gly307Asp, and every functional experiment curated here was performed on their cells. A second, unrelated child with a different TOM1 variant (a splice change predicted to be dominant negative) has since been reported in an IPEX-like cohort, so the gene now has two families behind it while the variant still has one. The discovery paper's own caveat that unrelated cases are needed is curated on the gene entry rather than left in notes.

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1
Inheritance
6
Pathophys.
14
Phenotypes
2
Gaps
21
Pathograph
1
Genes
4
Medical Actions
3
References
1
Deep Research
👪

Inheritance

1
Autosomal dominant HP:0000006
A heterozygous variant transmitted from an affected mother to an affected son. The marked difference in severity between them - relatively mild disease in the mother, aggressive and fatal in the child - is what the discovery paper reads as evidence for additional genetic modifiers, and it means severity cannot be predicted from genotype in this disease.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:31263572 SUPPORT Human Clinical
"Clinically, the index patient presents with a relatively mild disease, whereas in the child the condition is aggressive and fatal."
The intrafamilial severity difference on which the modifier reading rests.
?

Discussions and Knowledge Gaps

2
Is TOM1 p.Gly307Asp causative of this syndrome, or is it a rare variant that co-segregated with the phenotype in the one family it has been reported in?
KNOWLEDGE GAP OPEN gap_single_family_causality
Attached to
genetic#TOM1 pathophysiology#TOM1 GAT-Domain Variant
Two claims are entangled here and have different amounts of evidence behind them, so the gap is about separating them rather than about a shortage of patients as such. TOM1 as a disease gene now has two unrelated families: the mother and son with p.Gly307Asp, and a subsequently reported child with a severe IPEX-like phenotype carrying a different, likely dominant-negative TOM1 splice variant. Two families with concordant immune dysregulation and different lesions in the same gene is a meaningfully stronger position than one. TOM1 p.Gly307Asp as *this* disease still rests on the original two related patients. Every functional experiment curated here was done on their cells, and the 2025 follow-up deepens that characterisation rather than adding cases. The functional work establishes that the variant has a specific, reproducible molecular effect - loss of the TOLLIP interaction, failure to restrain TOLLIP phosphoinositide binding, reduced myosin VI binding, autophagosome accumulation, excess inflammatory signalling. That is strong evidence the variant does something. It is weaker evidence that what it does is this disease, because a mother and son share far more than one variant, and the severity difference between them is itself attributed to unidentified modifiers. The 2025 authors state both halves in their own limitations paragraph, and this entry follows them: the second family is reported there, and so is the call for a larger cohort in the next sentence. The practical consequence is for variant interpretation. A GAT-domain TOM1 variant found in a new patient can now be read against a gene with two supporting families, but not against a case series for any particular allele, because there is none.
Proposed experiments
Targeted TOM1 screening in unexplained combined immunodeficiency with autoimmunity
unrelated_tom1_cohort
Screen TOM1 in existing cohorts of genetically unsolved inborn errors of immunity presenting with combined immunodeficiency and early-onset autoimmunity, and functionally test any GAT-domain variants for the TOLLIP-interaction and myosin VI binding defects that characterise p.Gly307Asp. The IPEX-like cohort that found the second family shows the approach works; what it did not do is test that patient's variant functionally, so a concordant functional phenotype in a third, unrelated carrier is what would settle this.
Show evidence (2 references)
PMID:40936361 SUPPORT Other
"However, since the initial report of these patients (Keskitalo et al., 2019), an unrelated child carrying a pathogenic TOM1 variant has been reported (Baxter et al., 2022), with a clinical phenotype resembling that of the TOM1 patients discussed here."
The second family, reported by the same paper that states the single-family limitation. This is the sentence that fixes the size of the gap.
PMID:33864888 SUPPORT Human Clinical
"Patient S15, with a severe IPE phenotype, is heterozygous for a TOM1 splice mutation that produces a stable product lacking the vesicular trafficking domain, so likely yielding a dominant negative effect"
The second family at first hand: a different TOM1 lesion, an unrelated patient, and an immune-dysregulation phenotype - which supports the gene while leaving p.Gly307Asp itself unreplicated.
Why did haematopoietic stem cell transplantation fail, and is the non-haematopoietic compartment the reason?
KNOWLEDGE GAP OPEN gap_why_hsct_failed
Attached to
treatments#Hematopoietic Stem Cell Transplantation pathophysiology#Impaired Lymphocyte Effector Function
HSCT replaces the haematopoietic compartment and nothing else. It is the standard curative approach for inborn errors of immunity precisely because most of them are diseases of haematopoietic lineages. The 2025 authors advance a specific answer, and it is worth stating as theirs rather than as this entry's reasoning. TOM1 is a ubiquitous trafficking adaptor rather than an immune-restricted gene; the signalling deficit in these patients was demonstrated in fibroblasts, a lineage a transplant does not replace; and they propose that persistent poorly-controlled innate signalling in those resident cells kept stimulating the replaced immune cells in a self-reinforcing loop, which they offer as a plausible explanation for the fatal lung disease. They state it at that strength - "potentially account for", "plausible explanation" - so it is a hypothesis with a mechanism, not a finding. What keeps it open is that three other explanations are live and the evidence does not separate them. The discovery paper records that the patient *rejected the allograft* within six months and the disease returned, which is a sufficient explanation for relapse on its own and is documented rather than inferred. Post-transplant pulmonary fibrosis is a recognised complication in its own right. And the fatal organ was already diseased before transplant, so its progression need not indicate anything about the graft at all. One patient cannot distinguish these, and the fibroblast finding shows the variant acts outside blood without showing that the lung disease is cell-autonomous. The stakes are practical: if the stromal contribution is real, transplant cannot be curative here and the caution the authors extend to other innate-immunity IEIs follows; if rejection is the whole story, it says nothing about the approach.
Proposed experiments
Lineage-restricted TOM1 models to separate haematopoietic from stromal contribution
tom1_lineage_restricted_models
Generate haematopoietic-restricted and mesenchymal-restricted TOM1 G307D models and compare lung and gut pathology, to test whether disease in those organs requires the variant in the resident tissue or is driven entirely by transplantable immune cells. A stromal requirement would explain the transplant outcome and change the therapeutic target. Note that the rejection observed in the index case cannot be modelled this way and would need separating from it clinically, in any future transplanted patient, by documenting chimerism alongside organ disease.
Show evidence (3 references)
PMID:40936361 SUPPORT Other
"the patient's fibroblasts have severely impaired regulation of innate immunity pathways, and although immune effector cells can be replaced by healthy ones with HSCT, cells in other tissues cannot"
The authors' proposed explanation, and the reason it is PARTIAL - it supplies a mechanism for why transplant would not be curative without testing it. Tagged OTHER because it is inference from their fibroblast data rather than a measurement in the transplanted patient.
PMID:40936361 SUPPORT Other
"Impaired inhibition of these pathways in TOM1 G307D patient fibroblasts likely caused a vicious circle, offering a plausible explanation for the severe lung inflammation and fibrosis to which the patient eventually succumbed."
The same hypothesis at its strongest statement, quoted with its own hedges intact - "likely", "plausible explanation".
PMID:31263572 SUPPORT Human Clinical
"Within 6 months, however, he rejected the allograft and the disease returned."
The competing explanation, and the only one that is documented rather than proposed. A rejected graft accounts for the return of disease without requiring any tissue-autonomous contribution.
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Pathophysiology

6
TOM1 GAT-Domain Variant
The variant p.Gly307Asp lies in the GAT domain of TOM1, the domain through which TOM1 binds TOLLIP and ubiquitin. It is at a locus conserved across species and absent from gnomAD, and it does not abolish expression - wild-type and mutant TOM1 are expressed equally, so the lesion acts through protein-protein interactions rather than through absence of protein. Two interactions are measurably weakened, and they reach the same downstream failure by different routes: TOLLIP, which is the route this entry curates in detail, and myosin VI, which acts on autophagosome maturation directly. The node is kept to the variant itself so that both routes can hang off it.
Downstream
Loss of TOM1 Restraint on TOLLIP Phosphoinositide Binding The proximal biochemical consequence of the variant, measured in lipid-overlay and liposome-sedimentation assays with purified protein.
Autophagosome-Lysosome Fusion Failure A second, TOLLIP-independent route from the same variant. TOM1 and myosin VI act together in the last steps of autophagy, and loss of either causes autophagosomes to accumulate without maturing; the G307D variant binds myosin VI less well than wild-type TOM1. Curated as a parallel input rather than folded into the TOLLIP arm because the source treats it as an additional contributor, not a consequence of the TOLLIP defect.
Show evidence (6 references)
PMID:31263572 SUPPORT Human Clinical
"We report here a heterozygous TOM1 p.G307D missense mutation, detected by whole-exome sequencing, in two related patients presenting with early-onset autoimmunity, antibody deficiency, and features of combined immunodeficiency."
The variant, its zygosity, how it was found, and the phenotype it was found in.
PMID:31263572 SUPPORT In Vitro
"The mutant TOM1 failed to interact with TOLLIP, a protein required for IL-1 recycling, PAMP signaling and autophagosome maturation, further strengthening the link between the candidate mutation and patient pathophysiology."
The molecular consequence of the variant, and the three TOLLIP functions that make it immunologically consequential.
PMID:40936361 SUPPORT In Vitro
"The G307D variant impairs the ability of TOM1 to reduce TOLLIP phosphatidylinositol 3-phosphate binding, an important regulatory mechanism for cargo trafficking commitment for both proteins."
Resolves the interaction defect to a specific regulatory step, which is what makes this node a mechanism rather than an association.
+ 3 more references
Loss of TOM1 Restraint on TOLLIP Phosphoinositide Binding
The regulatory step the 2025 work resolves, and the reason this disease is a failure of one adaptor to regulate another rather than a simple loss of function. The phosphoinositide binding here is TOLLIP's, not TOM1's - a distinction worth stating because it is easy to attribute to the wrong protein. Purified TOM1 does not bind PtdIns3P-containing liposomes at all. What wild-type TOM1 does is *reduce* TOLLIP's affinity for PtdIns3P, releasing TOLLIP from the endosomal membrane and committing both proteins to cargo trafficking. TOM1 G307D is significantly less efficient at that inhibition, so TOLLIP remains committed to membrane PtdIns3P - which is why the molecular function below is annotated INCREASED rather than lost.
TOLLIP binding to phosphatidylinositol 3-phosphate, no longer restrained by TOM1 GO:0032266 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves increased TOLLIP binding to phosphatidylinositol 3-phosphate, no longer restrained by TOM1, annotated with phosphatidylinositol-3-phosphate binding (GO:0032266). GO:0032266 is a molecular function from the Gene Ontology. ↑ INCREASED
Downstream
Defective Endosomal Cargo Trafficking TOM1 and TOLLIP together commit ubiquitinated cargo to the endolysosomal route; TOLLIP retained on the endosomal membrane is where that commitment breaks.
Show evidence (3 references)
PMID:40936361 SUPPORT In Vitro
"However, TOM1 G307D was significantly less efficient in inhibiting TOLLIP phosphoinositide association (Fig. 2C), suggesting that some TOLLIP remains committed to membrane PtdIns3P."
The measurement this node rests on, and the direction of the effect - TOLLIP's PtdIns3P association is retained rather than released.
PMID:40936361 SUPPORT In Vitro
"Neither TOM1 nor TOM1 G307 were able to bind PtdIns3P-containing liposomes"
The negative control that fixes the attribution: the phosphoinositide binding annotated on this node belongs to TOLLIP, not to TOM1.
PMID:40936361 SUPPORT In Vitro
"In cells overexpressing TOM1 WT, colocalization of TOLLIP and EEA1 was significantly reduced, in keeping with previous data showing that TOM1 reduces TOLLIP binding to PtdIns3P. However, in cells overexpressing the G307D variant, TOLLIP and EEA1 colocalization was not reduced"
The same effect confirmed in cells rather than with purified protein, using early endosome colocalisation as the readout.
Defective Endosomal Cargo Trafficking
TOM1 is a multimodular adaptor that, with TOLLIP, clathrin and myosin VI, routes ubiquitinated proteins through endosomes to lysosomal degradation. This is the step at which a housekeeping function becomes an immunological one: the cargo includes immune receptors, and their recycling and disposal set the duration of the signals they carry.
endosomal transport GO:0016197 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased endosomal transport (GO:0016197). GO:0016197 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Autophagosome-Lysosome Fusion Failure Autophagosome maturation depends on the same adaptor machinery, so the trafficking defect surfaces as a fusion defect.
Show evidence (3 references)
PMID:40936361 SUPPORT In Vitro
"we show that the variant causes a defect in the interaction between TOM1 and TOLLIP, another adaptor protein involved in cargo trafficking and regulation of innate immunity."
Names cargo trafficking and innate-immune regulation as the two things this adaptor pair does, which is the pairing this node models.
PMID:31263572 SUPPORT Other
"The pathogenesis is linked to increased endoplasmic reticulum stress, inefficient autophagy, and impaired recycling of immune receptors."
The general mechanism by which endolysosomal defects cause monogenic autoimmune disease, into which this disorder is placed. Tagged OTHER because it is the review framing rather than a measurement in these patients.
PMID:31263572 SUPPORT In Vitro
"as increased IL-6 signaling and impaired CTLA-4 expression give monogenic autoimmune phenotypes similar to our patients.6,22 All tests were normal"
A negative result that constrains this node rather than supporting it directly. The obvious alternative explanation for the phenotype - a receptor the trafficking defect fails to put on the surface - was tested for CTLA4 and the IL-1 and IL-6 receptors and was not found. Curated because ruling that out is what leaves the defect at the level of degradative flux rather than of receptor display. The inline citation markers are part of the source sentence and are quoted as they appear.
Autophagosome-Lysosome Fusion Failure
The rate-limiting lesion, and the one measured directly in patient cells. Autophagosomes accumulate because they cannot fuse with lysosomes, and the cells respond abnormally to amino acid starvation - the stimulus that should drive autophagy hardest. Curating this as the central effector rather than as one consequence among several is a claim about direction: both arms below it are downstream of a single failure of degradative flux, which is what makes one variant produce two opposite-looking immune phenotypes.
autophagosome-lysosome fusion GO:0061909 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased autophagosome-lysosome fusion (GO:0061909). GO:0061909 is a biological process from the Gene Ontology. ↓ DECREASED autophagosome maturation GO:0097352 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased autophagosome maturation (GO:0097352). GO:0097352 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Excessive Inflammatory Pathway Activation Degradative flux terminates inflammatory signalling; when it fails, signalling persists. This is the autoimmune arm.
Impaired Lymphocyte Effector Function The immunodeficiency arm. Curated with unknown intermediates because the cited work establishes both the autophagy defect and the effector deficits in these patients but does not demonstrate the steps connecting them - which is exactly the part of this disease that is least understood.
Show evidence (3 references)
PMID:40936361 SUPPORT In Vitro
"Our experiments using TOM1 G307D patient cells suggested that the variant affects autophagy, seen as an aggravated response to amino acid starvation and accumulation of autophagosomes due to autophagosome-lysosome fusion defect."
The measurement this node rests on, in patient-derived cells rather than a model system.
PMID:31263572 SUPPORT In Vitro
"Consistent with previous knowledge on TOM1 protein function, we detected impaired autophagy and enhanced susceptibility to apoptosis in patient-derived cells."
Independent confirmation of impaired autophagy in patient cells, from the discovery study six years earlier, plus the apoptosis susceptibility that accompanies it.
PMID:31263572 SUPPORT Other
"TOM1 is an adaptor protein needed for the maturation of autophagosomes and their fusion with lysosomes."
The normal function whose loss this node describes.
Excessive Inflammatory Pathway Activation
Inflammatory pathways are excessively activated in patient cells. TOM1 and TOLLIP both normally restrain interleukin-1 receptor and NF-kB signalling, so losing the interaction removes a brake rather than pressing an accelerator - the autoimmunity here is disinhibition, not stimulation.
inflammatory response GO:0006954 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased inflammatory response (GO:0006954). GO:0006954 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Psoriasiform Dermatitis One of the organ-specific autoimmune manifestations. Indirect because no cited work traces the pathway from the cellular inflammatory phenotype to skin.
Oligoarthritis The presenting autoimmune feature in the index patient.
Interstitial Lung Disease The lung arm, which is also the arm that ultimately killed the more severely affected patient - after transplant, as pulmonary fibrosis.
Lymphocytic Interstitial Pneumonitis The specific form the lung disease took as it evolved in the severely affected patient. Curated separately from the general interstitial phenotype because only the son's disease is described as lymphocytic interstitial pneumonitis.
Autoimmune Enteropathy The gut arm, and the presenting manifestation in the severely affected patient at six months of age.
Chronic Diarrhea The clinical expression of the enteropathy.
Growth Failure Curated as downstream of the inflammatory arm because it accompanied autoimmune enteropathy in the severely affected patient, but no cited source establishes the mechanism, and chronic inflammation and enteropathic malabsorption are not distinguished by anything curated here.
Show evidence (2 references)
PMID:40936361 SUPPORT In Vitro
"In addition, inflammatory pathways showed excessive activation in TOM1 G307D patient cells."
The direct measurement in patient cells.
PMID:40936361 SUPPORT Other
"Previous experiments in mice and in vitro have shown that both TOM1 and its binding partner TOLLIP regulate the interleukin-1 receptor (IL-1R) and nuclear factor kappa B (NF-κB) signaling pathways, key mediators of inflammation and innate immunity, and that ablating TOM1 enhances the overall..."
The prior work establishing that these adaptors restrain rather than drive inflammatory signalling, which is what licenses the disinhibition reading in this node's description.
Impaired Lymphocyte Effector Function
The immunodeficiency arm. T cells secrete IFN-gamma and IL-17 poorly, patient fibroblasts show diminished STAT and ERK1/2 signalling, and the patients are hypogammaglobulinaemic with low dendritic cell, natural killer cell and switched memory B cell counts. The signalling deficit is worth noting for what it is not: it was measured in fibroblasts, a non-immune lineage. That the same variant blunts signalling outside the haematopoietic compartment is a fact this entry treats as load-bearing rather than incidental, for the reason set out in the transplant discussion below.
T cell CL:0000084 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves T cell (CL:0000084). CL:0000084 is a cell type from the Cell Ontology. B cell CL:0000236 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves B cell (CL:0000236). CL:0000236 is a cell type from the Cell Ontology.
Downstream
Recurrent Respiratory Infections The clinical expression of the antibody and cellular deficit.
Hypogammaglobulinemia The laboratory expression of the same deficit.
Reduced Natural Killer Cell Count One of the three cell-population deficits reported in both patients.
Decreased Dendritic Cell Count A second population deficit, and the one that reaches furthest upstream of the others - dendritic cells prime the responses the other lineages carry out.
Decreased Class-Switched Memory B Cells The B-cell-compartment correlate of the antibody deficiency.
Impaired Regulatory T Cell Function A regulatory rather than effector deficit, curated on this node because the source attributes it to the same MAPK and JAK-STAT signalling lesion. The known intermediate is that signalling defect; the edge is not direct.
Persistent EBV Viremia Failure to clear a virus whose control depends on the T and NK compartments this node describes. Marked with unknown intermediates because no cited work tests that link in these patients.
Show evidence (2 references)
PMID:31263572 SUPPORT In Vitro
"In addition, we noted diminished STAT and ERK1/2 signaling in patient fibroblasts, as well as poor IFN-γ and IL-17 secretion in T cells."
Both halves of this node, and the fibroblast observation the description flags.
PMID:40936361 SUPPORT Human Clinical
"Organ-specific symptoms were accompanied by hypogammaglobulinemia and low counts of dendritic, natural killer and switched memory B cells."
The cellular and humoral deficits, which is what makes this a combined immunodeficiency rather than an isolated antibody defect.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Immunodeficiency 85 and Autoimmunity 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

14
Blood 1
Hypogammaglobulinemia Decreased circulating immunoglobulin concentration HP:0004313 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased circulating immunoglobulin concentration (HP:0004313). HP:0004313 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40936361 SUPPORT Human Clinical
"Organ-specific symptoms were accompanied by hypogammaglobulinemia and low counts of dendritic, natural killer and switched memory B cells."
The phenotype in both patients, with the accompanying cellular deficits.
Digestive 1
Chronic Diarrhea HP:0002028 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chronic diarrhea (HP:0002028), qualified as temporality chronic. HP:0002028 is a phenotype from the Human Phenotype Ontology.
Temporal: CHRONIC
Show evidence (1 reference)
PMID:31263572 SUPPORT Human Clinical
"she developed chronic diarrhea with normal endoscopic findings"
The phenotype and the negative endoscopy that distinguishes it from the son's enteropathy.
Immune 1
Recurrent Respiratory Infections HP:0002205 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent respiratory infections (HP:0002205). HP:0002205 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31263572 SUPPORT Human Clinical
"The index patient suffered from recurrent respiratory tract infections and oligoarthritis since early teens, and later developed persistent low-copy EBV-viremia, as well as an antibody deficiency."
The index patient's course, naming this phenotype alongside the arthritis and the antibody deficiency.
Respiratory 1
Interstitial Lung Disease Abnormal pulmonary interstitial morphology HP:0006530 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal pulmonary interstitial morphology (HP:0006530). HP:0006530 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31263572 SUPPORT Human Clinical
"Her infant son developed hypogammaglobulinemia, autoimmune enteropathy, interstitial lung disease, profound growth failure, and treatment-resistant psoriasis vulgaris."
Names the interstitial lung disease.
Growth 1
Growth Failure Growth delay HP:0001510 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Growth delay (HP:0001510), qualified as severity severe. HP:0001510 is a phenotype from the Human Phenotype Ontology.
Severity: SEVERE
Show evidence (1 reference)
PMID:31263572 SUPPORT Human Clinical
"Her infant son developed hypogammaglobulinemia, autoimmune enteropathy, interstitial lung disease, profound growth failure, and treatment-resistant psoriasis vulgaris."
Names the growth failure among the severe phenotype.
Other 9
Oligoarthritis HP:0040313 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Oligoarthritis (HP:0040313). HP:0040313 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31263572 SUPPORT Human Clinical
"The index patient suffered from recurrent respiratory tract infections and oligoarthritis since early teens, and later developed persistent low-copy EBV-viremia, as well as an antibody deficiency."
Names the arthritis and its onset.
Psoriasiform Dermatitis HP:0003765 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Psoriasiform dermatitis (HP:0003765). HP:0003765 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31263572 SUPPORT Human Clinical
"Her infant son developed hypogammaglobulinemia, autoimmune enteropathy, interstitial lung disease, profound growth failure, and treatment-resistant psoriasis vulgaris."
The severe phenotype in full, which is the source for this and the three phenotypes below.
Lymphocytic Interstitial Pneumonitis Lymphocytic interstitial pneumonia HP:0006527 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lymphocytic interstitial pneumonia (HP:0006527). HP:0006527 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31263572 SUPPORT Human Clinical
"was subsequently diagnosed with autoimmune enteropathy and lung disease that later evolved to lymphocytic interstitial pneumonitis"
Names the specific pneumonitis and its evolution from the lung disease of infancy.
Autoimmune Enteropathy
Show evidence (2 references)
PMID:31263572 SUPPORT Human Clinical
"Her infant son developed hypogammaglobulinemia, autoimmune enteropathy, interstitial lung disease, profound growth failure, and treatment-resistant psoriasis vulgaris."
Names the enteropathy in the abstract's summary of the severe phenotype.
PMID:31263572 SUPPORT Human Clinical
"was evaluated for failure to thrive at age 6 months and was subsequently diagnosed with autoimmune enteropathy"
Establishes the age and the circumstance of the diagnosis, which is what makes it a presenting feature rather than a late complication.
Persistent EBV Viremia HP:0020072 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Persistent EBV viremia (HP:0020072). HP:0020072 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31263572 SUPPORT Human Clinical
"was noted to have persistent low-copy EBV viremia"
The phenotype, in the source's own qualification as low-copy.
Reduced Natural Killer Cell Count Reduced total natural killer cell count HP:0040218 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reduced total natural killer cell count (HP:0040218). HP:0040218 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31263572 SUPPORT Human Clinical
"Both patients had low numbers of dendritic cells, NK cells and switched memory B cells"
The measurement, in both patients rather than only the severely affected one.
Decreased Dendritic Cell Count Abnormal dendritic cell count HP:0020178 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased dendritic cell count, annotated with Abnormal dendritic cell count (HP:0020178). HP:0020178 is a phenotype from the Human Phenotype Ontology.
↓ DECREASED
Show evidence (1 reference)
PMID:31263572 SUPPORT Human Clinical
"Both patients had low numbers of dendritic cells, NK cells and switched memory B cells"
The measurement.
Decreased Class-Switched Memory B Cells
Show evidence (1 reference)
PMID:31263572 SUPPORT Human Clinical
"Both patients had low numbers of dendritic cells, NK cells and switched memory B cells"
The measurement, quoted in the source's own units - numbers, not proportions.
Impaired Regulatory T Cell Function
Show evidence (1 reference)
PMID:31263572 SUPPORT Human Clinical
"the regulatory T-cell function was impaired in the severely affected son"
The finding, and the fact that it is restricted to one of the two patients.
🧬

Genetic Associations

1
TOM1 (A heterozygous missense variant, p.Gly307Asp, in the GAT domain. Typed CAUSATIVE because OMIM has assigned the phenotype a number (619510) and the 2025 functional work resolves the variant's effect to a specific molecular step, but the caveat belongs in the same breath: p.Gly307Asp itself has been reported in one family only, and the discovery paper says in its own abstract that unrelated cases are needed before the genotype-phenotype relationship is firm. The gene is better supported than the variant. An unrelated child with a severe IPEX-like phenotype was subsequently found to carry a different TOM1 lesion - a splice variant yielding a stable product lacking the vesicular trafficking domain, and so likely dominant negative - in a cohort study of FOXP3-negative IPEX-like disease. That second family raises confidence that TOM1 is a disease gene without adding anything to the case for this variant, which is the distinction the knowledge gap below turns on.)
Gene: TOM1 hgnc:11982 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TOM1 (hgnc:11982). hgnc:11982 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:31263572 SUPPORT Human Clinical
"In sum, we report here an identification of a novel gene, TOM1, associating with early-onset autoimmunity, antibody deficiency, and features of combined immunodeficiency."
The gene-disease claim, quoted in the source's own careful register - "associating with" rather than "causing".
PMID:31263572 SUPPORT Human Clinical
"Other patient cases from unrelated families are needed to firmly establish a causal relationship between the genotype and the phenotype."
PARTIAL because it is the source qualifying its own gene-disease claim. Curated here rather than only in notes, so the limitation travels with the gene entry.
💊

Medical Actions

4
mTOR Inhibitor Therapy
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: everolimus CHEBI:68478 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses everolimus (CHEBI:68478). CHEBI:68478 is a therapeutic agent from Chemical Entities of Biological Interest.
Everolimus was given to the severely affected patient on an explicit mechanistic rationale: rapalogs induce autophagy, and this is a disease of impaired autophagy. It made him worse, with flares of eczema and respiratory distress that settled once the drug was stopped. The 2025 work supplies the reason, and it turns the failure into a mechanistic result rather than an idiosyncratic reaction. The block in this disease is at autophagosome-lysosome *fusion*, not at autophagosome *formation*. An mTOR inhibitor pushes harder on formation, upstream of a step that cannot clear, so autophagosomes accumulate further and flux does not improve. The corresponding in vitro observation is that rapamycin failed to raise autophagosome numbers in patient lymphocytes at all. The authors state the clinical implication as caution rather than contraindication, and this entry does not strengthen it.
Mechanism Target:
MODULATES Autophagosome-Lysosome Fusion Failure — MODULATES rather than ACTIVATES or RESTORES, deliberately. The drug does not act on fusion; it acts on autophagy induction upstream of the fusion block, and the observed consequence at this node was aggravation rather than correction. Curating it as ACTIVATES would assert a therapeutic effect on this node that the sources say did not occur.
Show evidence (1 reference)
PMID:40936361 SUPPORT Other
"it is reasonable to assume that treatment with an mTOR inhibitor led to the exacerbation of symptoms by further increasing autophagosome formation without alleviating the defect in autophagosome-lysosome fusion and thus aggravating accumulation of autophagosomes"
The mechanistic link between the drug and this node, in the authors' own hedged register - "it is reasonable to assume", which is why this is a proposed explanation rather than a measured drug effect. Tagged OTHER for that reason.
Show evidence (3 references)
PMID:31263572 REFUTE Human Clinical
"Rapamycin and other rapalogs are potent inducers of autophagy, and in an attempt to control autoimmunity we treated patient 2 with everolimus. Contrary to our expectations, this led to flares of eczema and respiratory distress, symptoms that quickly stabilized once the drug was stopped."
REFUTE because it is evidence against the treatment in this disease. The rationale, the outcome, and the dechallenge are all in one sentence, which is what makes the harm attributable to the drug rather than to the disease course.
PMID:31263572 REFUTE In Vitro
"In vitro, rapamycin treatment on patient lymphocytes failed to increase the number of autophagosomes"
The corresponding negative result in patient cells: the drug did not do the thing it was given to do.
PMID:40936361 SUPPORT Other
"our data suggesting a disturbance in autophagosome-lysosome fusion warrants caution in using mTOR inhibitors in the treatment of patients with TOM1 variants"
The authors' own statement of the clinical implication, at the strength they state it - caution, not contraindication.
Proposed Targeted Immunomodulation (IL-1 Antagonism or JAK Inhibition)
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: interleukin-1 beta antagonist Relation: this treatment uses this therapeutic agent This treatment uses interleukin-1 beta antagonist. JAK inhibitor NCIT:C172200 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses JAK inhibitor (NCIT:C172200). NCIT:C172200 is a therapeutic agent from the NCI Thesaurus.
Suggested by the 2025 authors on the strength of the mechanism they describe: the inflammatory arm of this disease runs through IL-1 receptor and NF-kB signalling that TOM1 and TOLLIP normally restrain, and the signalling deficits measured in patient cells involve the JAK-STAT pathway. No patient has received either. This entry curates the proposal, not a treatment effect, and the distinction matters more than usual here: the last mechanistically reasoned therapy in this disease made the patient worse.
Show evidence (1 reference)
PMID:40936361 SUPPORT Other
"With our current understanding of the TOM1 G307D variant, either IL-1β antagonists or JAK inhibitors could be potential treatment options."
PARTIAL because the source supports these being candidate options and nothing more - there is no administration, no outcome, and no trial. Tagged OTHER because it is an author inference from mechanism rather than clinical or experimental evidence.
Hematopoietic Stem Cell Transplantation
Action: hematopoietic stem cell transplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is 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
Attempted in the severely affected patient after several immunomodulating drugs failed. He rejected the allograft within six months, the disease returned, and he died of progressive pulmonary fibrosis. The two sources give different intervals for the death and the entry does not silently pick one. The 2019 discovery paper, which describes the clinical course in detail, says he died one year after the transplant; the 2025 paper says six months post-HSCT. Both are quoted below. Curated because a failed treatment is a finding, not an absence of one. The 2025 paper frames its own contribution partly in these terms - as insight into the caveats of immunomodulatory and stem cell therapy in this disease - and an entry that listed HSCT without its outcome would mislead in the direction that matters most.
Show evidence (3 references)
PMID:40936361 REFUTE Human Clinical
"Attempts to alleviate the severe autoimmunity with several immunomodulating drugs failed, and the younger patient, with a more severe phenotype, underwent hematopoietic stem cell transplantation (HSCT) but died 6 months post-HSCT owing to lung fibrosis."
REFUTE because this is evidence against the treatment in this disease, in the only patient in whom it has been reported. It also records the failure of immunomodulation that preceded it.
PMID:40936361 SUPPORT Other
"Our study also provides insights into the caveats of immunomodulatory and stem cell therapies in patients with TOM1 pathogenic variants."
The authors' own framing of the therapeutic implication, which is why this treatment is curated with its caveat rather than omitted.
PMID:31263572 REFUTE Human Clinical
"recently underwent allogeneic stem cell transplant, with a temporary resolution of autoimmune symptoms. Within 6 months, however, he rejected the allograft and the disease returned. He died one year after the transplant for progressive pulmonary fibrosis."
The discovery paper's account of the same transplant, and the only source that records graft rejection. It also gives a different interval to death - one year, against the 2025 paper's six months - which is why the description names both.
Immunoglobulin Replacement Therapy
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Both patients received immunoglobulin replacement for the antibody deficiency. In the index patient the intravenous route was started at diagnosis and discontinued for adverse effects, and she is now on the subcutaneous route; her son received it from infancy alongside tacrolimus and methotrexate. Curated as supportive rather than disease-modifying: it replaces the product of the failing compartment and does not act on any mechanism node, so it carries no target_mechanisms.
Show evidence (1 reference)
PMID:31263572 SUPPORT Human Clinical
"Intravenous immunoglobulin replacement was initiated but soon discontinued due to adverse effects."
The index patient's course on replacement therapy, including the intolerance that moved her to the subcutaneous route.
{ }

Source YAML

click to show 
name: Immunodeficiency 85 and Autoimmunity
creation_date: "2026-08-22T04:00:00Z"
category: Immunological
disease_term:
  preferred_term: immunodeficiency 85 and autoimmunity
  term:
    id: MONDO:0030428
    label: immunodeficiency 85 and autoimmunity
description: >-
  An inborn error of immunity caused by a heterozygous missense variant in TOM1, an
  endosomal adaptor protein with no classical immunological function. The name records
  what makes it interesting: the same lesion produces immunodeficiency and autoimmunity
  together, in one patient, rather than one or the other.

  That combination is the entry's organising claim. TOM1 does not sit in a lymphocyte
  signalling pathway - it moves ubiquitinated cargo through the endolysosomal system and
  helps autophagosomes fuse with lysosomes. Losing that function starves immune effector
  responses of something they need while simultaneously removing a brake on inflammatory
  signalling, so the immune system is at once underpowered against infection and
  overactive against self.

  The evidence base is narrow, and in a specific way. Two related patients - a mother with
  relatively mild disease and her son, whose disease was aggressive and fatal - carry TOM1
  p.Gly307Asp, and every functional experiment curated here was performed on their cells.
  A second, unrelated child with a different TOM1 variant (a splice change predicted to be
  dominant negative) has since been reported in an IPEX-like cohort, so the gene now has
  two families behind it while the variant still has one. The discovery paper's own caveat
  that unrelated cases are needed is curated on the gene entry rather than left in notes.

parents:
- Inborn Errors of Immunity
- Combined Immunodeficiency

pathophysiology:

- name: TOM1 GAT-Domain Variant
  role: trigger
  biological_scale: MOLECULAR
  description: >-
    The variant p.Gly307Asp lies in the GAT domain of TOM1, the domain through which TOM1
    binds TOLLIP and ubiquitin. It is at a locus conserved across species and absent from
    gnomAD, and it does not abolish expression - wild-type and mutant TOM1 are expressed
    equally, so the lesion acts through protein-protein interactions rather than through
    absence of protein.

    Two interactions are measurably weakened, and they reach the same downstream failure by
    different routes: TOLLIP, which is the route this entry curates in detail, and myosin
    VI, which acts on autophagosome maturation directly. The node is kept to the variant
    itself so that both routes can hang off it.
  evidence:
  - reference: PMID:31263572
    reference_title: "Dominant TOM1 mutation associated with combined immunodeficiency and autoimmune disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report here a heterozygous TOM1 p.G307D missense mutation, detected by
      whole-exome sequencing, in two related patients presenting with early-onset
      autoimmunity, antibody deficiency, and features of combined immunodeficiency.
    explanation: >-
      The variant, its zygosity, how it was found, and the phenotype it was found in.
  - reference: PMID:31263572
    reference_title: "Dominant TOM1 mutation associated with combined immunodeficiency and autoimmune disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The mutant TOM1 failed to interact with TOLLIP, a protein required for IL-1
      recycling, PAMP signaling and autophagosome maturation, further strengthening the
      link between the candidate mutation and patient pathophysiology.
    explanation: >-
      The molecular consequence of the variant, and the three TOLLIP functions that make
      it immunologically consequential.
  - reference: PMID:40936361
    reference_title: "A TOM1 variant impairs interaction with TOLLIP, autophagosome-lysosome fusion and regulation of innate immunity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The G307D variant impairs the ability of TOM1 to reduce TOLLIP phosphatidylinositol
      3-phosphate binding, an important regulatory mechanism for cargo trafficking
      commitment for both proteins.
    explanation: >-
      Resolves the interaction defect to a specific regulatory step, which is what makes
      this node a mechanism rather than an association.
  - reference: PMID:40936361
    reference_title: "A TOM1 variant impairs interaction with TOLLIP, autophagosome-lysosome fusion and regulation of innate immunity."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      The variant is in the GAT domain of TOM1, in a locus highly conserved among species,
      and absent from databases including gnomAD.
    explanation: >-
      The variant-level evidence for pathogenicity - domain, conservation, population
      absence. Tagged COMPUTATIONAL because it is database and alignment evidence rather
      than an experiment.
  - reference: PMID:31263572
    reference_title: "Dominant TOM1 mutation associated with combined immunodeficiency and autoimmune disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The expression of WT and mutant TOM1 were identical
    explanation: >-
      Establishes that the variant acts through protein-protein interactions rather than by
      reducing the amount of TOM1, which is what makes the two interaction defects below
      the mechanism rather than a correlate of it.
  - reference: PMID:40936361
    reference_title: "A TOM1 variant impairs interaction with TOLLIP, autophagosome-lysosome fusion and regulation of innate immunity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      we observed that TOM1 G307 interaction with myosin VI was reduced compared to that
      for TOM1 WT, which likely also contributes to the impairment in autophagy seen in
      patient cells
    explanation: >-
      The second interaction defect, and the source's own hedged attribution of an
      additional contribution to the autophagy phenotype - which is why the myosin VI edge
      is curated as a parallel input rather than as the main route.
  downstream:
  - target: Loss of TOM1 Restraint on TOLLIP Phosphoinositide Binding
    causal_link_type: DIRECT
    description: >-
      The proximal biochemical consequence of the variant, measured in lipid-overlay and
      liposome-sedimentation assays with purified protein.
  - target: Autophagosome-Lysosome Fusion Failure
    causal_link_type: DIRECT
    description: >-
      A second, TOLLIP-independent route from the same variant. TOM1 and myosin VI act
      together in the last steps of autophagy, and loss of either causes autophagosomes to
      accumulate without maturing; the G307D variant binds myosin VI less well than
      wild-type TOM1. Curated as a parallel input rather than folded into the TOLLIP arm
      because the source treats it as an additional contributor, not a consequence of the
      TOLLIP defect.

- name: Loss of TOM1 Restraint on TOLLIP Phosphoinositide Binding
  role: amplifier
  biological_scale: MOLECULAR
  description: >-
    The regulatory step the 2025 work resolves, and the reason this disease is a failure of
    one adaptor to regulate another rather than a simple loss of function.

    The phosphoinositide binding here is TOLLIP's, not TOM1's - a distinction worth stating
    because it is easy to attribute to the wrong protein. Purified TOM1 does not bind
    PtdIns3P-containing liposomes at all. What wild-type TOM1 does is *reduce* TOLLIP's
    affinity for PtdIns3P, releasing TOLLIP from the endosomal membrane and committing both
    proteins to cargo trafficking. TOM1 G307D is significantly less efficient at that
    inhibition, so TOLLIP remains committed to membrane PtdIns3P - which is why the
    molecular function below is annotated INCREASED rather than lost.
  molecular_functions:
  - preferred_term: TOLLIP binding to phosphatidylinositol 3-phosphate, no longer restrained by TOM1
    term:
      id: GO:0032266
      label: phosphatidylinositol-3-phosphate binding
    modifier: INCREASED
  evidence:
  - reference: PMID:40936361
    reference_title: "A TOM1 variant impairs interaction with TOLLIP, autophagosome-lysosome fusion and regulation of innate immunity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      However, TOM1 G307D was significantly less efficient in inhibiting TOLLIP
      phosphoinositide association (Fig. 2C), suggesting that some TOLLIP remains committed
      to membrane PtdIns3P.
    explanation: >-
      The measurement this node rests on, and the direction of the effect - TOLLIP's
      PtdIns3P association is retained rather than released.
  - reference: PMID:40936361
    reference_title: "A TOM1 variant impairs interaction with TOLLIP, autophagosome-lysosome fusion and regulation of innate immunity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Neither TOM1 nor TOM1 G307 were able to bind PtdIns3P-containing liposomes
    explanation: >-
      The negative control that fixes the attribution: the phosphoinositide binding
      annotated on this node belongs to TOLLIP, not to TOM1.
  - reference: PMID:40936361
    reference_title: "A TOM1 variant impairs interaction with TOLLIP, autophagosome-lysosome fusion and regulation of innate immunity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In cells overexpressing TOM1 WT, colocalization of TOLLIP and EEA1 was significantly
      reduced, in keeping with previous data showing that TOM1 reduces TOLLIP binding to
      PtdIns3P. However, in cells overexpressing the G307D variant, TOLLIP and EEA1
      colocalization was not reduced
    explanation: >-
      The same effect confirmed in cells rather than with purified protein, using early
      endosome colocalisation as the readout.
  downstream:
  - target: Defective Endosomal Cargo Trafficking
    causal_link_type: DIRECT
    description: >-
      TOM1 and TOLLIP together commit ubiquitinated cargo to the endolysosomal route;
      TOLLIP retained on the endosomal membrane is where that commitment breaks.

- name: Defective Endosomal Cargo Trafficking
  role: amplifier
  biological_scale: CELLULAR
  description: >-
    TOM1 is a multimodular adaptor that, with TOLLIP, clathrin and myosin VI, routes
    ubiquitinated proteins through endosomes to lysosomal degradation. This is the step at
    which a housekeeping function becomes an immunological one: the cargo includes immune
    receptors, and their recycling and disposal set the duration of the signals they carry.
  biological_processes:
  - preferred_term: endosomal transport
    term:
      id: GO:0016197
      label: endosomal transport
    modifier: DECREASED
  evidence:
  - reference: PMID:40936361
    reference_title: "A TOM1 variant impairs interaction with TOLLIP, autophagosome-lysosome fusion and regulation of innate immunity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      we show that the variant causes a defect in the interaction between TOM1 and TOLLIP,
      another adaptor protein involved in cargo trafficking and regulation of innate
      immunity.
    explanation: >-
      Names cargo trafficking and innate-immune regulation as the two things this adaptor
      pair does, which is the pairing this node models.
  - reference: PMID:31263572
    reference_title: "Dominant TOM1 mutation associated with combined immunodeficiency and autoimmune disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The pathogenesis is linked to increased endoplasmic reticulum stress, inefficient
      autophagy, and impaired recycling of immune receptors.
    explanation: >-
      The general mechanism by which endolysosomal defects cause monogenic autoimmune
      disease, into which this disorder is placed. Tagged OTHER because it is the review
      framing rather than a measurement in these patients.
  - reference: PMID:31263572
    reference_title: "Dominant TOM1 mutation associated with combined immunodeficiency and autoimmune disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      as increased IL-6 signaling and impaired CTLA-4 expression give monogenic autoimmune
      phenotypes similar to our patients.6,22 All tests were normal
    explanation: >-
      A negative result that constrains this node rather than supporting it directly. The
      obvious alternative explanation for the phenotype - a receptor the trafficking defect
      fails to put on the surface - was tested for CTLA4 and the IL-1 and IL-6 receptors
      and was not found. Curated because ruling that out is what leaves the defect at the
      level of degradative flux rather than of receptor display. The inline citation markers
      are part of the source sentence and are quoted as they appear.
  downstream:
  - target: Autophagosome-Lysosome Fusion Failure
    causal_link_type: DIRECT
    description: >-
      Autophagosome maturation depends on the same adaptor machinery, so the trafficking
      defect surfaces as a fusion defect.

- name: Autophagosome-Lysosome Fusion Failure
  role: central_effector
  biological_scale: CELLULAR
  description: >-
    The rate-limiting lesion, and the one measured directly in patient cells.
    Autophagosomes accumulate because they cannot fuse with lysosomes, and the cells
    respond abnormally to amino acid starvation - the stimulus that should drive autophagy
    hardest.

    Curating this as the central effector rather than as one consequence among several is
    a claim about direction: both arms below it are downstream of a single failure of
    degradative flux, which is what makes one variant produce two opposite-looking immune
    phenotypes.
  biological_processes:
  - preferred_term: autophagosome-lysosome fusion
    term:
      id: GO:0061909
      label: autophagosome-lysosome fusion
    modifier: DECREASED
  - preferred_term: autophagosome maturation
    term:
      id: GO:0097352
      label: autophagosome maturation
    modifier: DECREASED
  evidence:
  - reference: PMID:40936361
    reference_title: "A TOM1 variant impairs interaction with TOLLIP, autophagosome-lysosome fusion and regulation of innate immunity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Our experiments using TOM1 G307D patient cells suggested that the variant affects
      autophagy, seen as an aggravated response to amino acid starvation and accumulation
      of autophagosomes due to autophagosome-lysosome fusion defect.
    explanation: >-
      The measurement this node rests on, in patient-derived cells rather than a model
      system.
  - reference: PMID:31263572
    reference_title: "Dominant TOM1 mutation associated with combined immunodeficiency and autoimmune disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Consistent with previous knowledge on TOM1 protein function, we detected impaired
      autophagy and enhanced susceptibility to apoptosis in patient-derived cells.
    explanation: >-
      Independent confirmation of impaired autophagy in patient cells, from the discovery
      study six years earlier, plus the apoptosis susceptibility that accompanies it.
  - reference: PMID:31263572
    reference_title: "Dominant TOM1 mutation associated with combined immunodeficiency and autoimmune disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      TOM1 is an adaptor protein needed for the maturation of autophagosomes and their
      fusion with lysosomes.
    explanation: >-
      The normal function whose loss this node describes.
  downstream:
  - target: Excessive Inflammatory Pathway Activation
    causal_link_type: DIRECT
    description: >-
      Degradative flux terminates inflammatory signalling; when it fails, signalling
      persists. This is the autoimmune arm.
  - target: Impaired Lymphocyte Effector Function
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The immunodeficiency arm. Curated with unknown intermediates because the cited work
      establishes both the autophagy defect and the effector deficits in these patients
      but does not demonstrate the steps connecting them - which is exactly the part of
      this disease that is least understood.

- name: Excessive Inflammatory Pathway Activation
  role: consequence
  biological_scale: CELLULAR
  description: >-
    Inflammatory pathways are excessively activated in patient cells. TOM1 and TOLLIP both
    normally restrain interleukin-1 receptor and NF-kB signalling, so losing the
    interaction removes a brake rather than pressing an accelerator - the autoimmunity here
    is disinhibition, not stimulation.
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  evidence:
  - reference: PMID:40936361
    reference_title: "A TOM1 variant impairs interaction with TOLLIP, autophagosome-lysosome fusion and regulation of innate immunity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In addition, inflammatory pathways showed excessive activation in TOM1 G307D patient
      cells.
    explanation: >-
      The direct measurement in patient cells.
  - reference: PMID:40936361
    reference_title: "A TOM1 variant impairs interaction with TOLLIP, autophagosome-lysosome fusion and regulation of innate immunity."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Previous experiments in mice and in vitro have shown that both TOM1 and its binding
      partner TOLLIP regulate the interleukin-1 receptor (IL-1R) and nuclear factor kappa B
      (NF-κB) signaling pathways, key mediators of inflammation and innate immunity, and
      that ablating TOM1 enhances the overall proinflammatory milieu
    explanation: >-
      The prior work establishing that these adaptors restrain rather than drive
      inflammatory signalling, which is what licenses the disinhibition reading in this
      node's description.
  downstream:
  - target: Psoriasiform Dermatitis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      One of the organ-specific autoimmune manifestations. Indirect because no cited work
      traces the pathway from the cellular inflammatory phenotype to skin.
  - target: Oligoarthritis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The presenting autoimmune feature in the index patient.
  - target: Interstitial Lung Disease
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The lung arm, which is also the arm that ultimately killed the more severely
      affected patient - after transplant, as pulmonary fibrosis.
  - target: Lymphocytic Interstitial Pneumonitis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The specific form the lung disease took as it evolved in the severely affected
      patient. Curated separately from the general interstitial phenotype because only the
      son's disease is described as lymphocytic interstitial pneumonitis.
  - target: Autoimmune Enteropathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The gut arm, and the presenting manifestation in the severely affected patient at
      six months of age.
  - target: Chronic Diarrhea
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The clinical expression of the enteropathy.
  - target: Growth Failure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Curated as downstream of the inflammatory arm because it accompanied autoimmune
      enteropathy in the severely affected patient, but no cited source establishes the
      mechanism, and chronic inflammation and enteropathic malabsorption are not
      distinguished by anything curated here.

- name: Impaired Lymphocyte Effector Function
  role: consequence
  biological_scale: CELLULAR
  description: >-
    The immunodeficiency arm. T cells secrete IFN-gamma and IL-17 poorly, patient
    fibroblasts show diminished STAT and ERK1/2 signalling, and the patients are
    hypogammaglobulinaemic with low dendritic cell, natural killer cell and switched memory
    B cell counts.

    The signalling deficit is worth noting for what it is not: it was measured in
    fibroblasts, a non-immune lineage. That the same variant blunts signalling outside the
    haematopoietic compartment is a fact this entry treats as load-bearing rather than
    incidental, for the reason set out in the transplant discussion below.
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  evidence:
  - reference: PMID:31263572
    reference_title: "Dominant TOM1 mutation associated with combined immunodeficiency and autoimmune disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In addition, we noted diminished STAT and ERK1/2 signaling in patient fibroblasts, as
      well as poor IFN-γ and IL-17 secretion in T cells.
    explanation: >-
      Both halves of this node, and the fibroblast observation the description flags.
  - reference: PMID:40936361
    reference_title: "A TOM1 variant impairs interaction with TOLLIP, autophagosome-lysosome fusion and regulation of innate immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Organ-specific symptoms were accompanied by hypogammaglobulinemia and low counts of
      dendritic, natural killer and switched memory B cells.
    explanation: >-
      The cellular and humoral deficits, which is what makes this a combined
      immunodeficiency rather than an isolated antibody defect.
  downstream:
  - target: Recurrent Respiratory Infections
    causal_link_type: DIRECT
    description: >-
      The clinical expression of the antibody and cellular deficit.
  - target: Hypogammaglobulinemia
    causal_link_type: DIRECT
    description: >-
      The laboratory expression of the same deficit.
  - target: Reduced Natural Killer Cell Count
    causal_link_type: DIRECT
    description: >-
      One of the three cell-population deficits reported in both patients.
  - target: Decreased Dendritic Cell Count
    causal_link_type: DIRECT
    description: >-
      A second population deficit, and the one that reaches furthest upstream of the
      others - dendritic cells prime the responses the other lineages carry out.
  - target: Decreased Class-Switched Memory B Cells
    causal_link_type: DIRECT
    description: >-
      The B-cell-compartment correlate of the antibody deficiency.
  - target: Impaired Regulatory T Cell Function
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      A regulatory rather than effector deficit, curated on this node because the source
      attributes it to the same MAPK and JAK-STAT signalling lesion. The known intermediate
      is that signalling defect; the edge is not direct.
  - target: Persistent EBV Viremia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Failure to clear a virus whose control depends on the T and NK compartments this node
      describes. Marked with unknown intermediates because no cited work tests that link in
      these patients.

phenotypes:

- category: Immunological
  name: Recurrent Respiratory Infections
  description: >-
    The presenting infectious susceptibility, from early teens in the index patient.
  phenotype_term:
    preferred_term: Recurrent respiratory infections
    term:
      id: HP:0002205
      label: Recurrent respiratory infections
  evidence:
  - reference: PMID:31263572
    reference_title: "Dominant TOM1 mutation associated with combined immunodeficiency and autoimmune disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The index patient suffered from recurrent respiratory tract infections and
      oligoarthritis since early teens, and later developed persistent low-copy EBV-viremia,
      as well as an antibody deficiency.
    explanation: >-
      The index patient's course, naming this phenotype alongside the arthritis and the
      antibody deficiency.

- category: Immunological
  name: Hypogammaglobulinemia
  description: >-
    Low immunoglobulin in both patients. In the index case IgG was 3.0 g/l with IgA 0.15
    and IgM 0.17 at age 16; immunoglobulin replacement was started, stopped for adverse
    effects, and later restarted subcutaneously.
  phenotype_term:
    preferred_term: Decreased circulating immunoglobulin concentration
    term:
      id: HP:0004313
      label: Decreased circulating immunoglobulin concentration
  evidence:
  - reference: PMID:40936361
    reference_title: "A TOM1 variant impairs interaction with TOLLIP, autophagosome-lysosome fusion and regulation of innate immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Organ-specific symptoms were accompanied by hypogammaglobulinemia and low counts of
      dendritic, natural killer and switched memory B cells.
    explanation: >-
      The phenotype in both patients, with the accompanying cellular deficits.

- category: Musculoskeletal
  name: Oligoarthritis
  description: >-
    Seronegative oligoarthritis, diagnosed at 16 in the index patient. Seronegativity is
    worth recording: the autoimmunity here is not defined by a classical autoantibody.
  phenotype_term:
    preferred_term: Oligoarthritis
    term:
      id: HP:0040313
      label: Oligoarthritis
  evidence:
  - reference: PMID:31263572
    reference_title: "Dominant TOM1 mutation associated with combined immunodeficiency and autoimmune disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The index patient suffered from recurrent respiratory tract infections and
      oligoarthritis since early teens, and later developed persistent low-copy EBV-viremia,
      as well as an antibody deficiency.
    explanation: >-
      Names the arthritis and its onset.

- category: Dermatological
  name: Psoriasiform Dermatitis
  description: >-
    Treatment-resistant psoriasis vulgaris in the severely affected patient. The
    treatment-resistance is the notable part and recurs across this disease's
    manifestations.
  phenotype_term:
    preferred_term: Psoriasiform dermatitis
    term:
      id: HP:0003765
      label: Psoriasiform dermatitis
  evidence:
  - reference: PMID:31263572
    reference_title: "Dominant TOM1 mutation associated with combined immunodeficiency and autoimmune disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Her infant son developed hypogammaglobulinemia, autoimmune enteropathy, interstitial
      lung disease, profound growth failure, and treatment-resistant psoriasis vulgaris.
    explanation: >-
      The severe phenotype in full, which is the source for this and the three phenotypes
      below.

- category: Respiratory
  name: Interstitial Lung Disease
  description: >-
    Interstitial lung disease in the severely affected patient, and the organ that
    ultimately caused death - as progressive pulmonary fibrosis after transplant. The two
    sources give different intervals for that death; see the transplant treatment entry.
  phenotype_term:
    preferred_term: Abnormal pulmonary interstitial morphology
    term:
      id: HP:0006530
      label: Abnormal pulmonary interstitial morphology
  evidence:
  - reference: PMID:31263572
    reference_title: "Dominant TOM1 mutation associated with combined immunodeficiency and autoimmune disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Her infant son developed hypogammaglobulinemia, autoimmune enteropathy, interstitial
      lung disease, profound growth failure, and treatment-resistant psoriasis vulgaris.
    explanation: >-
      Names the interstitial lung disease.

- category: Growth
  name: Growth Failure
  description: >-
    Profound growth failure, recorded at -4.5 SD in the severely affected patient, against
    normal growth in his mother. The same variant, the same family, opposite ends of the
    growth phenotype.
  phenotype_term:
    preferred_term: Growth delay
    term:
      id: HP:0001510
      label: Growth delay
    severity: SEVERE
  evidence:
  - reference: PMID:31263572
    reference_title: "Dominant TOM1 mutation associated with combined immunodeficiency and autoimmune disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Her infant son developed hypogammaglobulinemia, autoimmune enteropathy, interstitial
      lung disease, profound growth failure, and treatment-resistant psoriasis vulgaris.
    explanation: >-
      Names the growth failure among the severe phenotype.

- category: Respiratory
  name: Lymphocytic Interstitial Pneumonitis
  description: >-
    The form the lung disease took as it evolved in the severely affected patient, from
    the lung disease diagnosed alongside his enteropathy in infancy. Curated separately
    from the general interstitial phenotype because only his disease is described this
    specifically; his mother's lung involvement is not.
  phenotype_term:
    preferred_term: Lymphocytic interstitial pneumonia
    term:
      id: HP:0006527
      label: Lymphocytic interstitial pneumonia
  evidence:
  - reference: PMID:31263572
    reference_title: "Dominant TOM1 mutation associated with combined immunodeficiency and autoimmune disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      was subsequently diagnosed with autoimmune enteropathy and lung disease that later
      evolved to lymphocytic interstitial pneumonitis
    explanation: >-
      Names the specific pneumonitis and its evolution from the lung disease of infancy.

- category: Gastrointestinal
  name: Autoimmune Enteropathy
  description: >-
    Diagnosed in the severely affected patient during the evaluation for failure to thrive
    at six months of age, making it one of the two presenting features of his disease.

    Deliberately left unbound. HPO has no term for autoimmune enteropathy: the nearest
    candidates are Protein-losing enteropathy (HP:0002243), which asserts a mechanism not
    reported here, Abnormal intestine morphology (HP:0002242), which loses the autoimmune
    character entirely, and Autoimmunity (HP:0002960), which loses the organ. The claim is
    carried by the name, description and evidence instead.
  evidence:
  - reference: PMID:31263572
    reference_title: "Dominant TOM1 mutation associated with combined immunodeficiency and autoimmune disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Her infant son developed hypogammaglobulinemia, autoimmune enteropathy, interstitial
      lung disease, profound growth failure, and treatment-resistant psoriasis vulgaris.
    explanation: >-
      Names the enteropathy in the abstract's summary of the severe phenotype.
  - reference: PMID:31263572
    reference_title: "Dominant TOM1 mutation associated with combined immunodeficiency and autoimmune disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      was evaluated for failure to thrive at age 6 months and was subsequently diagnosed
      with autoimmune enteropathy
    explanation: >-
      Establishes the age and the circumstance of the diagnosis, which is what makes it a
      presenting feature rather than a late complication.

- category: Gastrointestinal
  name: Chronic Diarrhea
  description: >-
    In the mildly affected mother, from her early thirties, with normal endoscopic
    findings. Worth recording as a distinct phenotype rather than as part of the son's
    enteropathy: the gut is affected in both patients, but only one has an enteropathy
    diagnosis and only the other has a normal endoscopy.
  phenotype_term:
    preferred_term: Chronic diarrhea
    term:
      id: HP:0002028
      label: Chronic diarrhea
    temporality: CHRONIC
  evidence:
  - reference: PMID:31263572
    reference_title: "Dominant TOM1 mutation associated with combined immunodeficiency and autoimmune disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      she developed chronic diarrhea with normal endoscopic findings
    explanation: >-
      The phenotype and the negative endoscopy that distinguishes it from the son's
      enteropathy.

- category: Immunological
  name: Persistent EBV Viremia
  description: >-
    Persistent low-copy Epstein-Barr virus viremia in the index patient, between 200 and
    800 viral copies per millilitre - detectable and sustained rather than the high-level
    replication of chronic active EBV disease.
  phenotype_term:
    preferred_term: Persistent EBV viremia
    term:
      id: HP:0020072
      label: Persistent EBV viremia
  evidence:
  - reference: PMID:31263572
    reference_title: "Dominant TOM1 mutation associated with combined immunodeficiency and autoimmune disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      was noted to have persistent low-copy EBV viremia
    explanation: >-
      The phenotype, in the source's own qualification as low-copy.

- category: Cellular
  name: Reduced Natural Killer Cell Count
  description: >-
    Low natural killer cell numbers in both patients - one of three cell-population
    deficits that give the immunodeficiency arm of the pathograph its distal grounding.
  phenotype_term:
    preferred_term: Reduced total natural killer cell count
    term:
      id: HP:0040218
      label: Reduced total natural killer cell count
  evidence:
  - reference: PMID:31263572
    reference_title: "Dominant TOM1 mutation associated with combined immunodeficiency and autoimmune disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both patients had low numbers of dendritic cells, NK cells and switched memory B
      cells
    explanation: >-
      The measurement, in both patients rather than only the severely affected one.

- category: Cellular
  name: Decreased Dendritic Cell Count
  description: >-
    Low dendritic cell numbers in both patients.

    HPO has only the parent term Abnormal dendritic cell count, with no directional child,
    so the direction is carried by the descriptor modifier rather than by the term.
  phenotype_term:
    preferred_term: Decreased dendritic cell count
    term:
      id: HP:0020178
      label: Abnormal dendritic cell count
    modifier: DECREASED
  evidence:
  - reference: PMID:31263572
    reference_title: "Dominant TOM1 mutation associated with combined immunodeficiency and autoimmune disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both patients had low numbers of dendritic cells, NK cells and switched memory B
      cells
    explanation: >-
      The measurement.

- category: Cellular
  name: Decreased Class-Switched Memory B Cells
  description: >-
    Low switched memory B cell numbers in both patients - the cellular correlate of the
    hypogammaglobulinaemia.

    Deliberately left unbound. HPO codes this compartment only as a proportion
    (HP:0030388, Decreased class-switched memory B cell proportion), while the source
    reports numbers; binding a proportion term to a count claim would assert a measurement
    that was not made. The distinction matters here because a low absolute count with a
    preserved proportion and a low proportion are different immunological findings.
  evidence:
  - reference: PMID:31263572
    reference_title: "Dominant TOM1 mutation associated with combined immunodeficiency and autoimmune disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both patients had low numbers of dendritic cells, NK cells and switched memory B
      cells
    explanation: >-
      The measurement, quoted in the source's own units - numbers, not proportions.

- category: Cellular
  name: Impaired Regulatory T Cell Function
  description: >-
    Impaired regulatory T cell function, reported in the severely affected son only. This
    is the one immunological finding in the entry that separates the two patients rather
    than uniting them, which makes it a candidate explanation for the severity difference
    the inheritance block records - though nothing cited tests that.

    Deliberately left unbound: HPO's regulatory T cell terms code proportion
    (HP:0020111-HP:0020113), and the source reports suppressive function.
  evidence:
  - reference: PMID:31263572
    reference_title: "Dominant TOM1 mutation associated with combined immunodeficiency and autoimmune disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the regulatory T-cell function was impaired in the severely affected son
    explanation: >-
      The finding, and the fact that it is restricted to one of the two patients.

genetic:

- name: TOM1
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: TOM1
    term:
      id: hgnc:11982
      label: TOM1
  association: >-
    A heterozygous missense variant, p.Gly307Asp, in the GAT domain. Typed CAUSATIVE
    because OMIM has assigned the phenotype a number (619510) and the 2025 functional work
    resolves the variant's effect to a specific molecular step, but the caveat belongs in
    the same breath: p.Gly307Asp itself has been reported in one family only, and the
    discovery paper says in its own abstract that unrelated cases are needed before the
    genotype-phenotype relationship is firm.

    The gene is better supported than the variant. An unrelated child with a severe
    IPEX-like phenotype was subsequently found to carry a different TOM1 lesion - a splice
    variant yielding a stable product lacking the vesicular trafficking domain, and so
    likely dominant negative - in a cohort study of FOXP3-negative IPEX-like disease. That
    second family raises confidence that TOM1 is a disease gene without adding anything to
    the case for this variant, which is the distinction the knowledge gap below turns on.
  evidence:
  - reference: PMID:31263572
    reference_title: "Dominant TOM1 mutation associated with combined immunodeficiency and autoimmune disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In sum, we report here an identification of a novel gene, TOM1, associating with
      early-onset autoimmunity, antibody deficiency, and features of combined
      immunodeficiency.
    explanation: >-
      The gene-disease claim, quoted in the source's own careful register - "associating
      with" rather than "causing".
  - reference: PMID:31263572
    reference_title: "Dominant TOM1 mutation associated with combined immunodeficiency and autoimmune disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other patient cases from unrelated families are needed to firmly establish a causal
      relationship between the genotype and the phenotype.
    explanation: >-
      PARTIAL because it is the source qualifying its own gene-disease claim. Curated here
      rather than only in notes, so the limitation travels with the gene entry.

inheritance:

- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    A heterozygous variant transmitted from an affected mother to an affected son. The
    marked difference in severity between them - relatively mild disease in the mother,
    aggressive and fatal in the child - is what the discovery paper reads as evidence for
    additional genetic modifiers, and it means severity cannot be predicted from genotype
    in this disease.
  evidence:
  - reference: PMID:31263572
    reference_title: "Dominant TOM1 mutation associated with combined immunodeficiency and autoimmune disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinically, the index patient presents with a relatively mild disease, whereas in the
      child the condition is aggressive and fatal.
    explanation: >-
      The intrafamilial severity difference on which the modifier reading rests.

treatments:

- name: mTOR Inhibitor Therapy
  description: >-
    Everolimus was given to the severely affected patient on an explicit mechanistic
    rationale: rapalogs induce autophagy, and this is a disease of impaired autophagy. It
    made him worse, with flares of eczema and respiratory distress that settled once the
    drug was stopped.

    The 2025 work supplies the reason, and it turns the failure into a mechanistic result
    rather than an idiosyncratic reaction. The block in this disease is at
    autophagosome-lysosome *fusion*, not at autophagosome *formation*. An mTOR inhibitor
    pushes harder on formation, upstream of a step that cannot clear, so autophagosomes
    accumulate further and flux does not improve. The corresponding in vitro observation is
    that rapamycin failed to raise autophagosome numbers in patient lymphocytes at all.

    The authors state the clinical implication as caution rather than contraindication, and
    this entry does not strengthen it.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: everolimus
      term:
        id: CHEBI:68478
        label: everolimus
  target_mechanisms:
  - target: Autophagosome-Lysosome Fusion Failure
    treatment_effect: MODULATES
    description: >-
      MODULATES rather than ACTIVATES or RESTORES, deliberately. The drug does not act on
      fusion; it acts on autophagy induction upstream of the fusion block, and the observed
      consequence at this node was aggravation rather than correction. Curating it as
      ACTIVATES would assert a therapeutic effect on this node that the sources say did not
      occur.
    evidence:
    - reference: PMID:40936361
      reference_title: "A TOM1 variant impairs interaction with TOLLIP, autophagosome-lysosome fusion and regulation of innate immunity."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        it is reasonable to assume that treatment with an mTOR inhibitor led to the
        exacerbation of symptoms by further increasing autophagosome formation without
        alleviating the defect in autophagosome-lysosome fusion and thus aggravating
        accumulation of autophagosomes
      explanation: >-
        The mechanistic link between the drug and this node, in the authors' own hedged
        register - "it is reasonable to assume", which is why this is a proposed
        explanation rather than a measured drug effect. Tagged OTHER for that reason.
  evidence:
  - reference: PMID:31263572
    reference_title: "Dominant TOM1 mutation associated with combined immunodeficiency and autoimmune disease."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Rapamycin and other rapalogs are potent inducers of autophagy, and in an attempt to
      control autoimmunity we treated patient 2 with everolimus. Contrary to our
      expectations, this led to flares of eczema and respiratory distress, symptoms that
      quickly stabilized once the drug was stopped.
    explanation: >-
      REFUTE because it is evidence against the treatment in this disease. The rationale,
      the outcome, and the dechallenge are all in one sentence, which is what makes the
      harm attributable to the drug rather than to the disease course.
  - reference: PMID:31263572
    reference_title: "Dominant TOM1 mutation associated with combined immunodeficiency and autoimmune disease."
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: >-
      In vitro, rapamycin treatment on patient lymphocytes failed to increase the number of
      autophagosomes
    explanation: >-
      The corresponding negative result in patient cells: the drug did not do the thing it
      was given to do.
  - reference: PMID:40936361
    reference_title: "A TOM1 variant impairs interaction with TOLLIP, autophagosome-lysosome fusion and regulation of innate immunity."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      our data suggesting a disturbance in autophagosome-lysosome fusion warrants caution
      in using mTOR inhibitors in the treatment of patients with TOM1 variants
    explanation: >-
      The authors' own statement of the clinical implication, at the strength they state
      it - caution, not contraindication.

- name: Proposed Targeted Immunomodulation (IL-1 Antagonism or JAK Inhibition)
  description: >-
    Suggested by the 2025 authors on the strength of the mechanism they describe: the
    inflammatory arm of this disease runs through IL-1 receptor and NF-kB signalling that
    TOM1 and TOLLIP normally restrain, and the signalling deficits measured in patient
    cells involve the JAK-STAT pathway.

    No patient has received either. This entry curates the proposal, not a treatment
    effect, and the distinction matters more than usual here: the last mechanistically
    reasoned therapy in this disease made the patient worse.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: interleukin-1 beta antagonist
    - preferred_term: JAK inhibitor
      term:
        id: NCIT:C172200
        label: JAK Inhibitor
  evidence:
  - reference: PMID:40936361
    reference_title: "A TOM1 variant impairs interaction with TOLLIP, autophagosome-lysosome fusion and regulation of innate immunity."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      With our current understanding of the TOM1 G307D variant, either IL-1β antagonists or
      JAK inhibitors could be potential treatment options.
    explanation: >-
      PARTIAL because the source supports these being candidate options and nothing more -
      there is no administration, no outcome, and no trial. Tagged OTHER because it is an
      author inference from mechanism rather than clinical or experimental evidence.

- name: Hematopoietic Stem Cell Transplantation
  description: >-
    Attempted in the severely affected patient after several immunomodulating drugs failed.
    He rejected the allograft within six months, the disease returned, and he died of
    progressive pulmonary fibrosis.

    The two sources give different intervals for the death and the entry does not silently
    pick one. The 2019 discovery paper, which describes the clinical course in detail, says
    he died one year after the transplant; the 2025 paper says six months post-HSCT. Both
    are quoted below.

    Curated because a failed treatment is a finding, not an absence of one. The 2025 paper
    frames its own contribution partly in these terms - as insight into the caveats of
    immunomodulatory and stem cell therapy in this disease - and an entry that listed HSCT
    without its outcome would mislead in the direction that matters most.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: hematopoietic stem cell transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  evidence:
  - reference: PMID:40936361
    reference_title: "A TOM1 variant impairs interaction with TOLLIP, autophagosome-lysosome fusion and regulation of innate immunity."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Attempts to alleviate the severe autoimmunity with several immunomodulating drugs
      failed, and the younger patient, with a more severe phenotype, underwent
      hematopoietic stem cell transplantation (HSCT) but died 6 months post-HSCT owing to
      lung fibrosis.
    explanation: >-
      REFUTE because this is evidence against the treatment in this disease, in the only
      patient in whom it has been reported. It also records the failure of
      immunomodulation that preceded it.
  - reference: PMID:40936361
    reference_title: "A TOM1 variant impairs interaction with TOLLIP, autophagosome-lysosome fusion and regulation of innate immunity."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Our study also provides insights into the caveats of immunomodulatory and stem cell
      therapies in patients with TOM1 pathogenic variants.
    explanation: >-
      The authors' own framing of the therapeutic implication, which is why this treatment
      is curated with its caveat rather than omitted.
  - reference: PMID:31263572
    reference_title: "Dominant TOM1 mutation associated with combined immunodeficiency and autoimmune disease."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      recently underwent allogeneic stem cell transplant, with a temporary resolution of
      autoimmune symptoms. Within 6 months, however, he rejected the allograft and the
      disease returned. He died one year after the transplant for progressive pulmonary
      fibrosis.
    explanation: >-
      The discovery paper's account of the same transplant, and the only source that
      records graft rejection. It also gives a different interval to death - one year,
      against the 2025 paper's six months - which is why the description names both.

- name: Immunoglobulin Replacement Therapy
  description: >-
    Both patients received immunoglobulin replacement for the antibody deficiency. In the
    index patient the intravenous route was started at diagnosis and discontinued for
    adverse effects, and she is now on the subcutaneous route; her son received it from
    infancy alongside tacrolimus and methotrexate.

    Curated as supportive rather than disease-modifying: it replaces the product of the
    failing compartment and does not act on any mechanism node, so it carries no
    target_mechanisms.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:31263572
    reference_title: "Dominant TOM1 mutation associated with combined immunodeficiency and autoimmune disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Intravenous immunoglobulin replacement was initiated but soon discontinued due to
      adverse effects.
    explanation: >-
      The index patient's course on replacement therapy, including the intolerance that
      moved her to the subcutaneous route.

discussions:

- discussion_id: gap_single_family_causality
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Is TOM1 p.Gly307Asp causative of this syndrome, or is it a rare variant that
    co-segregated with the phenotype in the one family it has been reported in?
  attaches_to:
  - genetic#TOM1
  - pathophysiology#TOM1 GAT-Domain Variant
  rationale: >-
    Two claims are entangled here and have different amounts of evidence behind them, so
    the gap is about separating them rather than about a shortage of patients as such.

    TOM1 as a disease gene now has two unrelated families: the mother and son with
    p.Gly307Asp, and a subsequently reported child with a severe IPEX-like phenotype
    carrying a different, likely dominant-negative TOM1 splice variant. Two families with
    concordant immune dysregulation and different lesions in the same gene is a
    meaningfully stronger position than one.

    TOM1 p.Gly307Asp as *this* disease still rests on the original two related patients.
    Every functional experiment curated here was done on their cells, and the 2025
    follow-up deepens that characterisation rather than adding cases. The functional work
    establishes that the variant has a specific, reproducible molecular effect - loss of
    the TOLLIP interaction, failure to restrain TOLLIP phosphoinositide binding, reduced
    myosin VI binding, autophagosome accumulation, excess inflammatory signalling. That is
    strong evidence the variant does something. It is weaker evidence that what it does is
    this disease, because a mother and son share far more than one variant, and the
    severity difference between them is itself attributed to unidentified modifiers.

    The 2025 authors state both halves in their own limitations paragraph, and this entry
    follows them: the second family is reported there, and so is the call for a larger
    cohort in the next sentence.

    The practical consequence is for variant interpretation. A GAT-domain TOM1 variant found
    in a new patient can now be read against a gene with two supporting families, but not
    against a case series for any particular allele, because there is none.
  proposed_experiments:
  - experiment_id: unrelated_tom1_cohort
    name: Targeted TOM1 screening in unexplained combined immunodeficiency with autoimmunity
    description: >-
      Screen TOM1 in existing cohorts of genetically unsolved inborn errors of immunity
      presenting with combined immunodeficiency and early-onset autoimmunity, and
      functionally test any GAT-domain variants for the TOLLIP-interaction and myosin VI
      binding defects that characterise p.Gly307Asp. The IPEX-like cohort that found the
      second family shows the approach works; what it did not do is test that patient's
      variant functionally, so a concordant functional phenotype in a third, unrelated
      carrier is what would settle this.
  evidence:
  - reference: PMID:40936361
    reference_title: "A TOM1 variant impairs interaction with TOLLIP, autophagosome-lysosome fusion and regulation of innate immunity."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      However, since the initial report of these patients (Keskitalo et al., 2019), an
      unrelated child carrying a pathogenic TOM1 variant has been reported (Baxter et al.,
      2022), with a clinical phenotype resembling that of the TOM1 patients discussed here.
    explanation: >-
      The second family, reported by the same paper that states the single-family
      limitation. This is the sentence that fixes the size of the gap.
  - reference: PMID:33864888
    reference_title: "Molecular diagnosis of childhood immune dysregulation, polyendocrinopathy, and enteropathy, and implications for clinical management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patient S15, with a severe IPE phenotype, is heterozygous for a TOM1 splice mutation
      that produces a stable product lacking the vesicular trafficking domain, so likely
      yielding a dominant negative effect
    explanation: >-
      The second family at first hand: a different TOM1 lesion, an unrelated patient, and
      an immune-dysregulation phenotype - which supports the gene while leaving
      p.Gly307Asp itself unreplicated.

- discussion_id: gap_why_hsct_failed
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Why did haematopoietic stem cell transplantation fail, and is the non-haematopoietic
    compartment the reason?
  attaches_to:
  - treatments#Hematopoietic Stem Cell Transplantation
  - pathophysiology#Impaired Lymphocyte Effector Function
  rationale: >-
    HSCT replaces the haematopoietic compartment and nothing else. It is the standard
    curative approach for inborn errors of immunity precisely because most of them are
    diseases of haematopoietic lineages.

    The 2025 authors advance a specific answer, and it is worth stating as theirs rather
    than as this entry's reasoning. TOM1 is a ubiquitous trafficking adaptor rather than an
    immune-restricted gene; the signalling deficit in these patients was demonstrated in
    fibroblasts, a lineage a transplant does not replace; and they propose that persistent
    poorly-controlled innate signalling in those resident cells kept stimulating the
    replaced immune cells in a self-reinforcing loop, which they offer as a plausible
    explanation for the fatal lung disease. They state it at that strength - "potentially
    account for", "plausible explanation" - so it is a hypothesis with a mechanism, not a
    finding.

    What keeps it open is that three other explanations are live and the evidence does not
    separate them. The discovery paper records that the patient *rejected the allograft*
    within six months and the disease returned, which is a sufficient explanation for
    relapse on its own and is documented rather than inferred. Post-transplant pulmonary
    fibrosis is a recognised complication in its own right. And the fatal organ was already
    diseased before transplant, so its progression need not indicate anything about the
    graft at all. One patient cannot distinguish these, and the fibroblast finding shows
    the variant acts outside blood without showing that the lung disease is cell-autonomous.

    The stakes are practical: if the stromal contribution is real, transplant cannot be
    curative here and the caution the authors extend to other innate-immunity IEIs follows;
    if rejection is the whole story, it says nothing about the approach.
  evidence:
  - reference: PMID:40936361
    reference_title: "A TOM1 variant impairs interaction with TOLLIP, autophagosome-lysosome fusion and regulation of innate immunity."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the patient's fibroblasts have severely impaired regulation of innate immunity
      pathways, and although immune effector cells can be replaced by healthy ones with
      HSCT, cells in other tissues cannot
    explanation: >-
      The authors' proposed explanation, and the reason it is PARTIAL - it supplies a
      mechanism for why transplant would not be curative without testing it. Tagged OTHER
      because it is inference from their fibroblast data rather than a measurement in the
      transplanted patient.
  - reference: PMID:40936361
    reference_title: "A TOM1 variant impairs interaction with TOLLIP, autophagosome-lysosome fusion and regulation of innate immunity."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Impaired inhibition of these pathways in TOM1 G307D patient fibroblasts likely caused
      a vicious circle, offering a plausible explanation for the severe lung inflammation
      and fibrosis to which the patient eventually succumbed.
    explanation: >-
      The same hypothesis at its strongest statement, quoted with its own hedges intact -
      "likely", "plausible explanation".
  - reference: PMID:31263572
    reference_title: "Dominant TOM1 mutation associated with combined immunodeficiency and autoimmune disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Within 6 months, however, he rejected the allograft and the disease returned.
    explanation: >-
      The competing explanation, and the only one that is documented rather than proposed.
      A rejected graft accounts for the return of disease without requiring any
      tissue-autonomous contribution.
  proposed_experiments:
  - experiment_id: tom1_lineage_restricted_models
    name: Lineage-restricted TOM1 models to separate haematopoietic from stromal contribution
    description: >-
      Generate haematopoietic-restricted and mesenchymal-restricted TOM1 G307D models and
      compare lung and gut pathology, to test whether disease in those organs requires the
      variant in the resident tissue or is driven entirely by transplantable immune cells.
      A stromal requirement would explain the transplant outcome and change the therapeutic
      target. Note that the rejection observed in the index case cannot be modelled this
      way and would need separating from it clinically, in any future transplanted patient,
      by documenting chimerism alongside organ disease.

notes: >-
  Scope and naming. This entry curates the OMIM 619510 / MONDO:0030428 entity, defined by
  TOM1 p.Gly307Asp in a single family. The numbered IMD name is an OMIM serialisation
  rather than a clinical term, so the entry leads with the mechanism. A second, unrelated
  TOM1 patient carrying a different variant is cited on the gene entry and in the causality
  discussion; whether that patient falls inside this MONDO term or beside it is not settled
  by anything cited, and the entry does not decide it.

  Where the two sources disagree. The 2019 discovery paper says the transplanted patient
  died one year after transplant; the 2025 paper says six months post-HSCT. Both are quoted
  on the transplant entry and neither is silently preferred. The 2019 paper is the one that
  describes the clinical course in detail and the only one that records graft rejection.

  Why the two arms are curated from one effector. Immunodeficiency and autoimmunity in the
  same patient is common enough in inborn errors of immunity to have its own literature,
  but the usual explanation runs through a lymphocyte-intrinsic pathway - FOXP3, the STATs,
  actin regulators. Here the shared upstream lesion is a housekeeping trafficking function,
  and the entry curates a single central effector with two downstream arms rather than two
  parallel chains, because the sources locate both in degradative flux. That is a
  structural claim and it could be wrong; the edge to the immunodeficiency arm is marked
  INDIRECT_UNKNOWN_INTERMEDIATES precisely because the connecting steps are not shown.

  Deep research. A claude_code provider run (research/Immunodeficiency_85_And_Autoimmunity-deep-research-claude_code.md,
  8 web searches, 13 turns) was performed after the entry was drafted from the two cached
  full texts. Its own reference validation reports 6 of 6 identifiers resolved and none
  unresolved; 6 were weighed for topical relevance, 5 scored on topic and none off topic,
  so one is undecided rather than cleared. NEC preflight returns SKIP - MONDO records no
  causal gene for this term, so the automated gene check cannot discriminate - and the
  manual fallback passes on both remaining anchors: the report's OMIM identifier (619510)
  matches the MONDO xref, and TOM1 dominates its gene mentions at 47 against 10 for TOLLIP.
  It is corroborative rather than additive: it reaches the same
  causal chain, the same treatment history, and independently records the graft rejection
  and the one-year interval to death. Two things it did not do are worth recording, because
  they bound how much weight a DR report should carry here. It did not surface the second,
  unrelated TOM1 family - the report states the disease is confined to one family, which is
  what the entry originally said and what the 2025 paper contradicts in its own limitations
  paragraph. And it cited only three PMIDs, two of which were already curated. Its useful
  contribution was pointing at a negative result in the 2019 paper (normal CTLA4, IL-1R and
  IL-6R expression) that is now curated on the trafficking node.

  No GeneReviews baseline. A PubMed All Fields search for GeneReviews coverage returned
  chapters on Temple syndrome, GLI3-related Pallister-Hall syndrome, sepiapterin reductase
  deficiency and AIP familial isolated pituitary adenomas - none of them this disease. No
  chapter exists, which is expected for a disorder first described in 2019.

  Evidence tiers. The clinical description is HUMAN_CLINICAL from the two patients of the
  index family, plus one cohort-study patient with a different variant. The
  mechanism is IN_VITRO throughout, in patient-derived cells rather than a model organism -
  which is a strength for relevance and a limit on generalisability, since the cells all
  come from the same two people. The prior TOM1/TOLLIP regulatory work cited on the
  inflammatory node is tagged OTHER because it is review framing of mouse and in vitro work
  rather than a measurement in these patients.

  Two treatments are curated as failures. HSCT and everolimus both appear with supports:
  REFUTE, which in neither case is a statement about the modality in inborn errors of
  immunity generally - each is the outcome in the single reported instance in this disease.
  An entry that recorded either attempt without its outcome would be worse than one that
  omitted it.

  The everolimus failure is the more informative of the two, because it has a mechanism.
  The rationale for giving it was sound on the 2019 model of the disease, which located the
  defect in autophagosome *formation*; the 2025 relocation of the defect to
  autophagosome-lysosome *fusion* is what makes an autophagy inducer predictably useless
  and plausibly harmful. That is a case of a mechanism model changing a therapeutic
  prediction, which is the kind of thing this knowledge base exists to make visible - so
  the drug is wired to the fusion node with treatment_effect: MODULATES rather than left in
  prose.

  Author-proposed therapies are curated as proposals. The IL-1 antagonism and JAK
  inhibition entry carries supports: PARTIAL and says in its own description that no
  patient has received either. Given that the last mechanistically reasoned therapy here
  harmed the patient, the distinction between a proposal and a treatment is not pedantry.

references:
- reference: PMID:31263572
  title: "Dominant TOM1 mutation associated with combined immunodeficiency and autoimmune disease."
- reference: PMID:40936361
  title: "A TOM1 variant impairs interaction with TOLLIP, autophagosome-lysosome fusion and regulation of innate immunity."
- reference: PMID:33864888
  title: "Molecular diagnosis of childhood immune dysregulation, polyendocrinopathy, and enteropathy, and implications for clinical management."
📚

References & Deep Research

References

3
PMID:31263572
Dominant TOM1 mutation associated with combined immunodeficiency and autoimmune disease.
No top-level findings curated for this source.
PMID:40936361
A TOM1 variant impairs interaction with TOLLIP, autophagosome-lysosome fusion and regulation of innate immunity.
No top-level findings curated for this source.
PMID:33864888
Molecular diagnosis of childhood immune dysregulation, polyendocrinopathy, and enteropathy, and implications for clinical management.
No top-level findings curated for this source.

Deep Research

1
Claude Code ▸
Immunodeficiency 85 and Autoimmunity (IMD85): Comprehensive Research Report
claude-haiku-4-5-20251001, claude-sonnet-5 14 citations 2026-08-22T04:35:27.089599

Immunodeficiency 85 and Autoimmunity (IMD85): Comprehensive Research Report

1. Disease Information

Overview: Immunodeficiency 85 and autoimmunity (IMD85) is an ultra-rare, autosomal dominant primary immunodeficiency/immune dysregulation disorder caused by a heterozygous missense mutation in TOM1 (Target Of Myb1 Membrane Trafficking Protein). It is characterized by early-onset (first decade of life) atopic eczema and recurrent respiratory infections, progressing to multi-organ autoimmunity (autoimmune enteropathy, oligoarthritis, interstitial pneumonitis), hypogammaglobulinemia, and combined T- and B-cell dysfunction. To date it has been described in a single two-generation family (mother and son) (OMIM 619510; Keskitalo et al. 2019, PMID:31263572).

Key Identifiers: - OMIM: 619510 (IMMUNODEFICIENCY 85 AND AUTOIMMUNITY; IMD85) - Causal gene OMIM: 604700 (TARGET OF MYB1 MEMBRANE TRAFFICKING PROTEIN; TOM1) - HGNC: TOM1, HGNC:11982 - Ensembl: ENSG00000100284 (chr22:35,299,275–35,347,995, GRCh38) - Chromosome location: 22q12.3 - Mondo: Not independently confirmed to have a distinct MONDO ID in this search pass; would map via OMIM:619510 cross-reference — verify with runoak -i sqlite:obo:mondo before curating a disease_term binding. - Orphanet: No dedicated Orphanet entry was found distinct from the OMIM/gene page (orpha.net/en/disease/gene/TOM1 lists the gene-disease association). - Synonyms:* IMD85; "TOM1 deficiency"; "Dominant TOM1-associated combined immunodeficiency and autoimmunity"

Source basis: This entire disease concept derives from a single aggregated case report of one family (2 affected individuals across 2 generations) plus a 2025 follow-up mechanistic study on cells from the same two patients — not from population-level EHR or registry data. All prevalence/frequency statements below should be read as "reported in 1 family" rather than population estimates.

2. Etiology

Disease Causal Factor: Heterozygous, autosomal dominant, gain-of-interference (likely dominant-negative) missense mutation in TOM1.

Genetic risk factor (causal variant): - Variant: c.920G>A, p.Gly307Asp (p.G307D) — genomic position chr22:35,728,994 G>A (note: this coordinate as reported may reflect an older genome build; cross-check against current GRCh38 TOM1 coordinates during curation) - Located in the GAT (GGA and TOM1) domain of TOM1, which mediates ubiquitin-binding and TOLLIP interaction - SIFT: "deleterious"; PolyPhen-2: "probably damaging" - Affects a conserved residue - Segregates with disease in a mother (Patient 1, II.2) and her son (Patient 2, III.1) — autosomal dominant transmission, heterozygous in both.

No environmental, infectious, or additional genetic risk/protective factors have been reported for this ultra-rare monogenic disorder; EBV viremia is a consequence of the immunodeficiency (impaired immune control), not a causal trigger. The authors explicitly note: "phenotypic heterogeneity is common in monogenic immune diseases and points to additional genetic modifiers" (PMID:31263572) — i.e., they flag but do not identify specific modifier loci, as onset age and severity differed markedly between mother and son.

Gene-Environment Interactions: None reported/studied.

3. Phenotypes

Onset, in order of typical appearance, drawn from the two reported cases (mother onset in early teens; son onset at 6 months of age — illustrating that onset is highly variable even within one family):

Phenotype Type HPO Suggestion Notes/Frequency (2/2 patients unless noted)
Atopic eczema Symptom/sign HP:0001047 (Atopic dermatitis) Both; son's progressed to generalized dermatitis by age 6
Recurrent respiratory tract infections Symptom HP:0002205 (Recurrent respiratory infections) Both
Seronegative/autoimmune oligoarthritis Sign HP:0031370 (Oligoarthritis) or HP:0002829 (Arthritis) Mother — diagnosed age 16
Autoimmune enteropathy (vomiting, chronic diarrhea) Sign HP:0005263 (Autoimmune enteropathy); HP:0002014 (Diarrhea) Son (infantile onset); mother developed chronic diarrhea in her 30s
Failure to thrive / profound growth failure (–4.5 SD) Sign HP:0001508 (Failure to thrive); HP:0004325 (Decreased body weight) Son, onset 6 months
Lymphocytic interstitial pneumonitis (LIP) Sign HP:0006515 (Interstitial pneumonitis) / HP:0002205 Son
Treatment-resistant psoriasis vulgaris Sign HP:0003765 (Psoriasiform dermatitis) Son
Persistent low-copy EBV viremia (200–800 copies/mL) Lab abnormality HP:0032101 (Abnormal susceptibility to viral infections) Mother
Hypogammaglobulinemia (↓IgG, IgA, IgM) Lab abnormality HP:0004313 (Hypogammaglobulinemia) Both
Lymphopenia Lab abnormality HP:0001888 (Lymphopenia) Mother (660/µL vs. 1300–3600 ref)
Reduced switched memory B cells (0%) Lab abnormality HP:0005404 (Decreased proportion of switched memory B cells) Both
Reduced NK cells Lab abnormality HP:0011037 (Decreased NK cell count) Both
Reduced plasmacytoid/monocytoid dendritic cells Lab abnormality HP:0002846 (abnormal dendritic cell) — check specificity Both
Impaired T-cell maturation (↑naive, ↓TEM/TEMRA) Lab abnormality HP:0005403 (Impaired T cell function) Both
Impaired Treg suppressive function Lab abnormality — Son (mother's Tregs were functionally normal despite normal numbers)
Poor IFN-γ / IL-17 secretion on stimulation Lab abnormality — Both
Pulmonary fibrosis (progressive, post-transplant) Sign HP:0002206 (Pulmonary fibrosis) Son, terminal event

Severity/progression: Highly variable between the two patients despite an identical variant — the mother's course was comparatively indolent (survives to at least age 32 at publication), while the son had a fulminant infantile-onset multi-organ course, received an allogeneic HSCT around age 9, rejected the graft within 6 months, and died approximately one year post-transplant from progressive pulmonary fibrosis. This intrafamilial variability is explicitly discussed by the authors as evidence for unidentified modifiers.

Quality of life impact: Not formally measured (no EQ-5D/SF-36 data); qualitatively, the son's disease was fatal, and the mother required chronic immunosuppression (prednisolone, methotrexate) and immunoglobulin replacement (subcutaneous, after IVIG was discontinued for adverse effects).

4. Genetic/Molecular Information

Causal Gene: TOM1 (HGNC:11982; OMIM *604700), located 22q12.3.

Pathogenic Variant: - c.920G>A; p.(Gly307Asp), heterozygous, missense - ACMG classification not explicitly stated in the source, but functionally characterized as pathogenic via multiple orthogonal assays (interactome, autophagy, apoptosis, signaling) - Not present in population databases at appreciable frequency (implied by rarity; not explicitly quoted with a gnomAD frequency in the sources retrieved) - Functional consequence: dominant-negative / loss-of-interaction. The mutant protein is expressed at normal levels (confirmed by Western blot) but is functionally crippled at the protein-interaction level — this is not a simple loss-of-function null allele, since TOM1 is expressed and heterozygosity with presumably one WT allele still yields dominant disease, consistent with dominant-negative interference or haploinsufficiency-plus-modifier effects.

Modifier Genes: None identified; authors explicitly call for additional families to establish modifiers explaining intrafamilial severity variation.

Somatic vs. Germline: Germline (heritable, present in both mother and son).

Chromosomal Abnormalities: None — this is a single-nucleotide missense variant, not a structural rearrangement.

Suggested annotation: functional_impact_category: DOMINANT_NEGATIVE (per dismech's GeneticContext guidance) is the best-supported categorical fit, since the mutant protein is expressed normally but interferes with a specific protein-protein interaction (TOM1–TOLLIP) required for normal pathway function.

5. Environmental Information

No environmental, lifestyle, or infectious triggering factors are described as causal. EBV is present as an opportunistic/uncontrolled infection secondary to the immunodeficiency (i.e., a consequence, not a cause) — this should be modeled as a phenotype/complication, not an environmental entry with a TRIGGERS edge.

6. Mechanism / Pathophysiology

Molecular Function of TOM1 (Wild-Type)

TOM1 is a multimodular endosomal adaptor protein containing VHS and GAT domains. It binds ubiquitinated cargo and, via its GAT domain, interacts with TOLLIP (Toll-interacting protein), clathrin, and myosin VI to regulate: - Endosomal sorting/trafficking of ubiquitinated cargo (ESCRT-associated pathway) - Autophagosome maturation and autophagosome–lysosome fusion - Negative regulation of Toll-like receptor (TLR)/IL-1 receptor (PAMP) signaling - Receptor recycling

Causal Chain (Molecular → Cellular → Clinical)

  1. Molecular lesion: p.G307D destabilizes the GAT domain's interaction surface.
  2. AP-MS interactome: mutant TOM1 shows markedly reduced binding to ubiquitin C (2.8% vs. 5.7% in WT) and TOLLIP (11.2% vs. 22.0% in WT).

  3. Follow-up mechanistic study (PMID:40936361, 2025) refines this: the mutant fails to properly release TOLLIP from PI3P-bound endosomal membranes, "impairing cargo trafficking commitment," and specifically delays autophagosome clearance rather than blocking autophagosome formation — LC3B–LAMP1 colocalization (a marker of autophagosome-lysosome fusion) was reduced to 54% of control.

  4. Cellular consequence — impaired autophagy: Patient lymphocytes show decreased LC3 staining (low autophagosome count); rapamycin (an autophagy inducer) fails to rescue autophagosome number in patient cells, indicating a block downstream of induction (at the fusion/maturation step).

  5. Cellular consequence — dysregulated signaling:

  6. Baseline: ERK1/2 phosphorylation significantly downregulated; STAT1 and STAT5 phosphorylation impaired (p38, S6 relatively preserved) — quote: "ERK1/2 phosphorylation was significantly downregulated in both patients...indicating dysfunctional MAPK signaling."

  7. Under acute stimulation (LPS/IL-1β), the 2025 follow-up found the opposite direction — more robust ERK1/2 phosphorylation after LPS/IL-1β stimulation in patient fibroblasts than controls — consistent with loss of the normal negative-regulatory ("braking") function TOM1/TOLLIP exert over innate immune signaling, i.e., a switch from tonic under-signaling to stimulus-triggered over-signaling. Curators should note this apparent directionality difference between the 2019 and 2025 papers reflects different cell types/conditions (baseline vs. acute PAMP stimulation) rather than a contradiction, and both should be captured as distinct pathophysiology nodes.

  8. Cellular consequence — enhanced apoptosis: PBMCs from both patients show elevated apoptotic/dead-cell fractions (~50% of the son's lymphocytes showed an apoptotic phenotype).

  9. Immune cell consequences:

  10. Impaired T-cell maturation: increased naive, decreased effector memory (TEM) and TEMRA subsets; poor IFN-γ and IL-17 secretion upon stimulation.
  11. Regulatory T cells: normal numbers but impaired suppressive function (notably in the son).
  12. B cells: severely reduced switched memory B cells (0% in both, vs. 6.5–29.2% reference) and hypogammaglobulinemia (IgG, IgA, IgM all low).

  13. NK cells and plasmacytoid/monocytoid dendritic cells: markedly reduced in both patients.

  14. Clinical manifestation: The combination of (a) impaired autophagy/autophagosome clearance, (b) dysregulated (both tonic-low and stimulus-triggered-high) MAPK/JAK-STAT signaling, (c) enhanced lymphocyte apoptosis, and (d) broad lymphoid subset abnormalities (T, B, NK, DC) together produce a combined immunodeficiency with concurrent multi-organ autoimmunity — impaired pathogen clearance/antibody production coexisting with loss of normal negative regulation of inflammatory signaling and defective Treg function, permitting autoimmune tissue damage (skin, gut, lung, joints).

Suggested Ontology Terms

  • GO Biological Process: GO:0016236 (macroautophagy), GO:0000045 (autophagosome assembly), GO:1901097 (negative regulation of autophagosome maturation — for the mutant defect), GO:0034249 (negative regulation of cellular amide metabolic process; consider more specific TLR-signaling terms), GO:0034141 (positive regulation of toll-like receptor 3 signaling pathway) as a starting point for TLR/PAMP regulation, GO:0006915 (apoptotic process), GO:0007265 (Ras protein signal transduction)/ERK cascade terms (GO:0070371, ERK1 and ERK2 cascade), GO:0006355/JAK-STAT terms
  • GO Molecular Function: GO:0043130 (ubiquitin binding)
  • GO Cellular Component: GO:0005768 (endosome), GO:0005771 (multivesicular body), GO:0000421 (autophagosome membrane)
  • Cell types (CL): CL:0000542 (lymphocyte), CL:0000236 (B cell), CL:0000818 (switched memory B cell), CL:0000625 (CD8+ T cell), CL:0000895 (naive thymus-derived CD4-positive T cell), CL:0000815 (regulatory T cell), CL:0000623 (natural killer cell), CL:0000784 (plasmacytoid dendritic cell)
  • CHEBI: N/A (no small-molecule mechanism per se, though rapamycin/tacrolimus are relevant to treatment)

7. Anatomical Structures Affected

  • Primary organ systems: Skin (eczema, psoriasis), gastrointestinal tract (autoimmune enteropathy), respiratory system (lung — interstitial pneumonitis/fibrosis; also recurrent infections), musculoskeletal (joints — oligoarthritis), immune system (lymphoid compartment broadly)
  • UBERON suggestions: UBERON:0002097 (skin of body), UBERON:0002108 (small intestine), UBERON:0002048 (lung), UBERON:0000982 (joint), UBERON:0002193 (hemolymphoid system)
  • Tissue/cell level: Lymphocytes (T, B, NK), dendritic cells, epithelial cells of gut and lung
  • Subcellular level (GO CC): Early/late endosome, autophagosome, lysosome — the primary subcellular site of the molecular defect
  • Laterality: Not applicable (systemic/multi-organ disease, not lateralized)

8. Temporal Development

  • Onset: Highly variable within the single reported family — infantile (6 months, son) to early-teen (mother). No population-level onset statistics exist given the single-family basis.
  • Onset pattern: Insidious/progressive in both cases, punctuated by acute complications (e.g., graft rejection in the son).
  • Progression: Progressive and severe in the son (death ~1 year post-HSCT from progressive pulmonary fibrosis); more indolent/chronic in the mother, who was alive and on chronic immunosuppression/Ig replacement at age 32 at time of publication.
  • Disease course pattern: Chronic, progressive, with episodic flares (e.g., eczema/respiratory flares triggered by an mTOR-inhibitor trial in the son).
  • Remission: Temporary — HSCT produced "temporary resolution of autoimmune symptoms" in the son, but this was lost within 6 months due to graft rejection, after which "the disease returned."
  • Critical periods: Infancy appears to represent a high-risk window for the most severe, multi-organ, rapidly progressive presentation, based on the son's course.

9. Inheritance and Population

  • Epidemiology: Reported in exactly one family (2 affected individuals) worldwide as of the literature retrieved — true prevalence/incidence cannot be estimated; this is an ultra-rare "N-of-1 family" monogenic disease.
  • Inheritance pattern: Autosomal dominant (heterozygous mutation, vertical transmission mother→son).
  • Penetrance: Appears complete in this family (both carriers affected) but expressivity is markedly variable (see below).
  • Expressivity: Highly variable — same p.G307D variant produced a comparatively milder, later-onset course in the mother versus a severe, fatal, infantile-onset course in the son. Authors explicitly attribute this to likely unidentified genetic modifiers.
  • Genetic anticipation: Potentially suggested by the pattern (later/milder in mother vs. earlier/more severe in son), but this cannot be distinguished from stochastic/modifier effects with an n=2 pedigree; not formally established.
  • Germline mosaicism, founder effects, consanguinity, carrier frequency: Not applicable/not reported — this is a de novo-type autosomal dominant single-family report, not a population-level recessive or founder disease.
  • Population demographics: Not established (single Northern European-ancestry family per source institution context — precise ancestry not stated in retrieved excerpts). Sex ratio: 1 female (mother), 1 male (son) — no inference possible from n=2.

10. Diagnostics

Laboratory/Immunophenotyping (as performed in the index family): - Complete blood count with lymphocyte subsets (flow cytometry): CD19+ B cells, switched memory B cells, CD4+/CD8+ T cells, NK cells, plasmacytoid and monocytoid dendritic cells - Quantitative immunoglobulins (IgG, IgA, IgM) — both patients markedly hypogammaglobulinemic - T-cell functional assays: cytokine secretion (IFN-γ, IL-17) upon stimulation; Treg suppression assays - Phospho-flow cytometry for STAT1, STAT5, ERK1/2, p38, S6 signaling - LC3 immunostaining (autophagosome quantification) in lymphocytes/fibroblasts - Apoptosis assays (annexin V/PI or equivalent) on PBMCs

Genetic Testing: - Whole-exome or targeted sequencing identified the heterozygous TOM1 c.920G>A (p.G307D) variant; Sanger confirmation and familial segregation testing would be standard practice for a suspected combined immunodeficiency with autoimmunity phenotype. - Given the phenotypic overlap with other combined immunodeficiency/immune dysregulation syndromes (e.g., CVID, ALPS, IPEX-like disorders), a primary immunodeficiency/monogenic IBD gene panel is the practical diagnostic entry point — TOM1 is listed on the PanelApp (Genomics England) "Primary immunodeficiency or monogenic inflammatory bowel disease" panel and the PanelApp Australia "Autoinflammatory Disorders" panel.

Functional/Research-Level Confirmatory Testing (not yet clinical-grade): - AP-MS interactome analysis (TOM1–TOLLIP, TOM1–ubiquitin binding) - LC3B–LAMP1 colocalization imaging (autophagosome-lysosome fusion assay) - Response of ERK1/2 phosphorylation to LPS/IL-1β stimulation in patient-derived fibroblasts

Clinical Criteria: No formal consensus diagnostic criteria exist (single-family disease); diagnosis is genotype-driven with immunophenotypic and functional corroboration.

Differential Diagnosis: Should include other genetic causes of combined immunodeficiency with autoimmune enteropathy (e.g., IPEX/FOXP3, LRBA deficiency, CTLA4 haploinsufficiency, STAT3 GOF), CVID with autoimmune features, and other autophagy-pathway immune dysregulation disorders. Notably, the 2019 paper specifically tested and found normal CTLA4, IL-1R, and IL-6R expression, ruling out a primary receptor-expression defect and supporting a trafficking/autophagy-centric mechanism instead.

Screening: No population or newborn screening applicable (ultra-rare, private family variant).

11. Outcome/Prognosis

  • Survival/mortality: The son (severe, infantile-onset presentation) died approximately 1 year after allogeneic HSCT, from progressive pulmonary fibrosis following graft rejection — total lifespan to age ~10. The mother remained alive at age 32 at the time of reporting, managed on chronic immunosuppression and immunoglobulin replacement.
  • Morbidity: Substantial — chronic autoimmune enteropathy, growth failure, recurrent infections, interstitial lung disease, and treatment-refractory skin disease.
  • Complications: EBV viremia, treatment-resistant psoriasis, graft rejection post-HSCT, progressive pulmonary fibrosis (fatal in the reported case).
  • Recovery potential: HSCT achieved only temporary resolution of autoimmune symptoms before graft rejection at 6 months; this single data point suggests HSCT may not be reliably curative for this genotype, though n=1 limits generalization.
  • Prognostic factors: Age of onset (infantile vs. teenage) appeared associated with severity in this family, though this cannot be statistically validated given n=2.

12. Treatment

Pharmacotherapy used in the reported family (NCIT terms suggested): - Prednisolone (oral corticosteroid) — mother; ongoing — NCIT:C15986 (Pharmacotherapy) + therapeutic_agent CHEBI (prednisolone) - Methotrexate — both patients — NCIT:C15986 - Tacrolimus (oral) — son — NCIT:C15986 - Everolimus (mTOR inhibitor) — trialed in the son specifically to target autoimmunity (rationale: mTOR/autophagy pathway involvement) but caused adverse flares of eczema and respiratory distress — an important negative treatment-response finding worth capturing as a NO_EVIDENCE/adverse-effect annotation rather than a recommended therapy - Intravenous immunoglobulin (IVIG) — mother; discontinued due to adverse effects — NCIT (immunoglobulin replacement therapy term) - Subcutaneous immunoglobulin replacement — both patients, ongoing — better tolerated than IVIG

Cell therapy: - Allogeneic hematopoietic stem cell transplantation (HSCT) — son, at approximately age 9 — NCIT:C15431 (Hematopoietic Cell Transplantation) → therapeutic_modality: CELL_THERAPY. Achieved temporary resolution of autoimmune symptoms; graft rejected within 6 months; disease recurred; patient died ~1 year post-transplant of progressive pulmonary fibrosis.

Treatment strategy/algorithm: No established treatment algorithm exists given the single-family basis; management to date has been empirically immunosuppressive/replacement-based (corticosteroids, methotrexate, calcineurin inhibitor, Ig replacement) with HSCT attempted as a potentially curative but ultimately unsuccessful option in the most severe case. The failed everolimus trial is a notable cautionary data point suggesting mTOR inhibition is not an effective/safe strategy despite the pathway's mechanistic proximity (autophagy regulation).

Experimental treatments: None in formal clinical trials (no NCT identifiers found; this is far too rare for a registered trial).

13. Prevention

No primary, secondary, or tertiary prevention strategies are described or applicable — this is a private autosomal dominant germline variant in a single known family. The only relevant preventive consideration would be genetic counseling for at-risk relatives (NCIT:C15240, Genetic Counseling) and prenatal/preimplantation testing if desired by family members, given the 50% transmission risk from an affected parent, though none of this is explicitly documented in the retrieved sources.

14. Other Species / Natural Disease

  • Taxonomy: No naturally occurring TOM1-associated disease has been reported in non-human species in the sources retrieved.
  • Orthologous gene: Tom1 — mouse ortholog MGI:1338026 (chromosome 8C1); zebrafish ortholog tom1 (ZFIN ZDB-GENE-060721-1). TOM1-family genes are evolutionarily conserved (TOM1, TOM1L1, TOM1L2 paralogs in humans; original TOM1 gene family first mapped via similarity to endosomal proteins HGS and STAM, PMID:10329004).
  • Comparative biology: No OMIA (Online Mendelian Inheritance in Animals) entry or veterinary case series identified. No evidence of naturally occurring veterinary TOM1-associated immunodeficiency.
  • Transmission/zoonotic potential: Not applicable — this is a monogenic, non-infectious, non-transmissible-between-species disorder.

15. Model Organisms

  • No animal (mouse, zebrafish) or invertebrate models of the specific p.G307D variant or of TOM1 loss-of-function immunodeficiency were identified in the literature retrieved. Both key papers (Keskitalo et al. 2019, PMID:31263572; the 2025 Disease Models & Mechanisms follow-up, PMID:40936361) explicitly used only human patient-derived material and cell-line systems — no animal models:
  • Patient-derived primary cells: PBMCs and dermal fibroblasts from the two affected family members
  • Cell lines: Flp-In T-REx 293 cells (inducible WT vs. G307D TOM1 overexpression for interactome studies), HeLa cells (immunofluorescence/localization), HEK293A cells, U2OS cells (localization studies in the 2025 paper)
  • Techniques: AP-MS (affinity purification–mass spectrometry) interactome profiling, BioID proximity labeling, phospho-flow cytometry, LC3B/LAMP1 immunofluorescence colocalization
  • Model limitations: As the field currently has no in vivo (mouse) model of TOM1 G307D or Tom1 knockout immune phenotype, all mechanistic claims rest on ex vivo human patient cells and heterologous overexpression systems — a notable gap for future work, and a HUMAN_MODEL_MISMATCH/KNOWLEDGE_GAP framing does not directly apply here since there is no model organism data to be mismatched against; rather this is an outright absence of an animal model, worth flagging as a knowledge gap for curation purposes (no in vivo confirmation of causality/mechanism exists beyond the patient-cell/cell-line data).
  • Resources: MGI:1338026 (mouse Tom1), ZFIN ZDB-GENE-060721-1 (zebrafish tom1) exist as gene records but no disease-phenotype model entries were found associated with them in this search.

Summary of Key Citations

PMID Citation Content
31263572 Keskitalo S, et al. "Dominant TOM1 mutation associated with combined immunodeficiency and autoimmune disease." NPJ Genomic Medicine. 2019 Jun 27;4:14. Primary disease-defining report; index family, variant identification, immunophenotyping, interactome/autophagy/signaling mechanism, treatment/outcome
40936361 (Disease Models & Mechanisms, 2025 Sep 30;18(9):dmm052140), DOI: 10.1242/dmm.052140 "A TOM1 variant impairs interaction with TOLLIP, autophagosome-lysosome fusion and regulation of innate immunity" — mechanistic follow-up on the same two patients; refines autophagosome-lysosome fusion defect and shows enhanced (not just reduced) ERK1/2 signaling upon acute LPS/IL-1β stimulation
10329004 (background) TOM1 gene family chromosomal mapping and homology to HGS/STAM Gene-family background, not disease-specific

Curator's note on evidence discipline: Given the disease rests on a single published family, every evidence item added to a kb/disorders/ entry should cite PMID:31263572 (primary) and/or PMID:40936361 (mechanistic follow-up) with exact abstract/text quotes verified via just fetch-reference — do not extrapolate population-level prevalence, penetrance, or treatment-efficacy claims beyond what these two case-based papers report, since no larger cohort, registry, or model-organism confirmation currently exists for IMD85.

Sources: - 619510 - IMMUNODEFICIENCY 85 AND AUTOIMMUNITY - OMIM - *604700 - TOM1 - OMIM - Dominant TOM1 mutation associated with combined immunodeficiency and autoimmune disease - PMC (PMID:31263572) - Dominant TOM1 mutation... - npj Genomic Medicine - A TOM1 variant impairs interaction with TOLLIP, autophagosome-lysosome fusion and regulation of innate immunity - PMC (PMID:40936361) - A TOM1 variant impairs interaction with TOLLIP... - Disease Models & Mechanisms - TOM1 Gene - GeneCards - Gene: TOM1 (ENSG00000100284) - Ensembl - Gene: TOM1 (Primary immunodeficiency or monogenic inflammatory bowel disease) - PanelApp Genomics England - TOM1 (Autoinflammatory Disorders) - PanelApp Australia - TOM1 genes map to human chromosome 22q13.1... - PubMed (PMID:10329004) - Orphanet: TOM1-target of myb1 membrane trafficking protein - Tom1 MGI Mouse Gene Detail - MGI:1338026 - ZFIN Gene: tom1

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 6
Resolved 6
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 6
On topic 5
Off topic 0

All extracted references resolved successfully.