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Classifications

IUIS Category

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Inheritance

1

Autosomal recessive inheritance HP:0000007

Disease requires one hypomorphic and one activating ZAP70 allele in trans. The affected siblings inherited p.R192W from their mother and p.R360P from their father; the parents and an unaffected sister carrying p.R360P alone are well. The pattern is recessive in that each allele is silent beside a wild-type allele, but it is not the biallelic loss of function of ZAP70 deficiency. Homozygosity for the hypomorphic allele alone has since been reported in two siblings, who had combined immunodeficiency with CD8 lymphopenia and autoimmunity but not this antibody-defined constellation, so it is the pairing rather than either allele that produces this disease.

Autosomal recessive inheritance

Show evidence (3 references)

PMID:26783323 SUPPORT Human Clinical

"Both affected children were compound heterozygous for ZAP70 c.574C>T, p.R192W, in exon 5; and c.1079G>C, p.R360P, in exon 9"

Records the compound heterozygous genotype shared by both affected children.

PMID:26783323 SUPPORT Human Clinical

"The mother carried the R192W allele, whereas the father and unaffected sister carried the R360P allele."

Establishes that the two alleles are in trans and that one copy of either is clinically silent.

PMID:41608114 SUPPORT Other

"ZAP-70 combined hypomorphic and activating mutations | ZAP70 | AR (LOF/GOF) | 617006"

IUIS annotates the inheritance as autosomal recessive with one loss-of-function and one gain-of-function allele.

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Discussions and Knowledge Gaps

3

What does the two-allele genotype do to a patient's own T cells, given that no patient T cells were ever studied?

KNOWLEDGE GAP OPEN admio2_no_patient_t_cells

Attached to

pathophysiology#Unopposed Hyperactive ZAP70 Signalling pathophysiology#Loss of Peripheral T Cell Tolerance to Self Antigens

Both affected children were transplanted before the gene defect was found, so every functional measurement in this disease comes from somewhere other than the patients: transfected 293T and ZAP70-null Jurkat lines, blood from heterozygous relatives, and a knock-in mouse carrying one of the two alleles. The signalling claims in this entry inherit that limitation. A patient-derived system carrying both alleles in trans would test the central assertion directly, and iPSC-derived or gene-edited primary T cells are the obvious route now that both variants are known.

Proposed experiments

Reconstruct R192W/R360P in trans in a human T-cell system and measure self-ligand responsiveness

admio2_trans_allele_pair_in_primary_t_cells

Edit both alleles into primary human T cells or an iPSC-derived T-cell system to produce the compound heterozygous state, alongside each allele singly, each allele opposite wild type, and homozygous controls. Measure receptor-proximal phosphorylation, calcium flux, CD69 induction, and the response to a graded panel of agonist and self-peptide ligands. The prediction under this entry's mechanism is that only the R192W/R360P pair shows enhanced responsiveness to weak ligands, and that adding a wild-type allele abolishes it.

Perturbations

ZAP70 R192W and R360P introduced in trans

pathophysiology#Unopposed Hyperactive ZAP70 Signalling

ZAP70 hgnc:12858

Readouts

CD69 induction and receptor-proximal phosphorylation across a graded ligand panel

pathophysiology#Unopposed Hyperactive ZAP70 Signalling

Direction: INCREASED

Interpretation: Enhanced responses confined to the compound heterozygous configuration would support the unmasking model in human cells.

Decision criterion

Enhanced weak-ligand responses in the compound heterozygous state but not in either allele paired with wild type.

Would support

pathophysiology#Unopposed Hyperactive ZAP70 Signalling

Show evidence (1 reference)

PMID:26783323 SUPPORT Human Clinical

"Although pre-HCT patient T cells were not available, mutation effects were determined using transfected cell lines and peripheral blood from carriers and controls."

The authors state the gap and what they substituted for it.

Does this disease break central tolerance as well as peripheral tolerance, and if so which allele does it?

KNOWLEDGE GAP OPEN admio2_central_versus_peripheral_tolerance

Attached to

pathophysiology#Hypomorphic ZAP70 SH2 Docking Allele pathophysiology#Loss of Peripheral T Cell Tolerance to Self Antigens

This entry's chain runs through peripheral tolerance, because that is what the knock-in mouse measures and what the activating allele is shown to do. The thymic arm is unresolved, and the literature points in two directions at once. The primary report proposes that altered signalling lets autoreactive thymocytes escape deletion, which is the mechanism established for hypomorphic ZAP70 alleles in mice: the SKG strain's hypomorph raises selection thresholds so that self-reactive thymocytes are positively rather than negatively selected, and attenuated signalling also hampers regulatory T-cell generation. But the same group's review states that a hyperactive kinase, which is what this genotype produces in the periphery, enhances thymic negative selection rather than weakening it. Which effect dominates in a thymus expressing one allele of each class is not known, and the patients' thymic output was never studied: both were transplanted before the genotype was found, and their newborn excision-circle screens were normal. The question matters for whether this disease belongs on the graded-signal-strength spectrum that connects ZAP70 immunodeficiency to ZAP70 autoimmunity, or beside it.

Show evidence (4 references)

PMID:26783323 SUPPORT INDIRECT Human Clinical

"In mice, defects in both central and peripheral tolerance have been associated with hypomorphic Zap-70 defects and autoimmune features"

The primary report raises the central-tolerance possibility by analogy to the mouse hypomorphs, without testing it in these patients.

PMID:37394552 SUPPORT INDIRECT REVIEW SYNTHESIS Model Organism

"Defective TCR signaling by ZAP70 mutation alters thymic selection thresholds and allows the positive selection of otherwise negatively selected self-reactive T cells."

The central-tolerance mechanism as established for a hypomorphic Zap70 allele in the SKG mouse. A different allele and a different disease (arthritis or lupus-like disease depending on background), so it bears on this question by analogy.

PMID:34923645 SUPPORT REVIEW SYNTHESIS Other

"Hypoactive ZAP70 function compromises key developmental checkpoints required to establish central tolerance, allowing thymocytes with potentially self-reactive TCRs a greater chance to escape negative selection."

States the hypoactive route to central-tolerance failure, which is the arm this genotype's hypomorphic allele could contribute and which the same review contrasts with the hyperactive case.

+ 1 more reference

Why do Zap70 R360P mice not develop autoimmunity, and does that limit the inference from the mouse to these patients?

HUMAN MODEL MISMATCH OPEN admio2_mouse_tolerance_mismatch

Attached to

animal_models#Mouse pathophysiology#Loss of Peripheral T Cell Tolerance to Self Antigens

The knock-in mouse reproduces the signalling phenotype and the follicular helper expansion but not the disease: no spontaneous autoimmunity, no autoantibodies, no organ pathology. The authors attribute this to the autoimmunity-resistant C57BL/6 background, to unknown modifiers, or to environment, and note that aged knock-in mice accumulate regulatory and anergic T cells, which may be actively holding the enhanced signalling in check. The mouse is also homozygous for the activating allele rather than compound heterozygous, so it does not model the configuration the human disease requires. Both facts matter for how far the tolerance-breaking step can be said to be demonstrated rather than inferred.

Show evidence (2 references)

PMID:33531381 SUPPORT Model Organism

"In contrast to humans, R360P mice did not spontaneously develop a detectable autoimmune phenotype, which may be due to their genetic background."

States the mismatch and the authors' leading explanation for it.

PMID:34923645 SUPPORT REVIEW SYNTHESIS Other

"It is likely that differences in genetic background, the presence of other genetic modifiers, or unique environmental factors contribute to this discrepancy."

The same group's later statement of the candidate explanations, which is what makes this an open question rather than a settled negative.

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Pathophysiology

6

Hypomorphic ZAP70 SH2 Docking Allele

p.R192W substitutes a bulky tryptophan into the phosphotyrosine-binding pocket of the C-terminal SH2 domain. The mutant kinase associates poorly with the phosphorylated TCR zeta chain and is itself poorly phosphorylated there. Homozygous R192W has since been reported in siblings with combined immunodeficiency, so the allele is pathogenic on its own; in this genotype its contribution is different, because it cannot supply the restraint on the partner allele that a wild-type copy would.

T cell CL:0000084

ZAP70 hgnc:12858

Genetic context ZAP70 hgnc:12858 allele_type: missense, c.574C>T p.R192W variant_origin: GERMLINE zygosity: COMPOUND_HETEROZYGOUS functional_impact_category: PARTIAL_LOSS_OF_FUNCTION

Maternally inherited hypomorphic allele, in trans with the activating p.R360P allele.

phosphotyrosine residue binding GO:0001784 ↓ DECREASED

Downstream

Unopposed Hyperactive ZAP70 Signalling The hypomorph cannot damp the activating allele the way a wild-type copy does, so the hyperactive signal becomes the cell's operating state.

Decreased total CD8+ T cell count The second arm of the mechanism, and the one this disease shares with ZAP70 deficiency. Reduced docking on the phosphorylated zeta chain weakens the signal the CD8 lineage needs to complete positive selection. It is partial here, where the same allele in the homozygous state gives the full immunodeficiency picture; the intermediate steps in these two children were never measured.

Impaired phytohemagglutinin-induced T lymphocyte transformation The functional counterpart of the same arm: a receptor that cannot recruit its kinase efficiently gives a weak proliferative response to mitogen.

Show evidence (2 references)

PMID:26783323 SUPPORT In Vitro

"Thus, the data suggest that the R192W ZAP-70 mutant is a hypomorph with reduced ζ-chain association and phosphorylation compared with WT."

Immunoprecipitation from transfected cells gives the reduced zeta-chain association and phosphorylation that define this allele as hypomorphic.

PMID:37313400 SUPPORT Human Clinical

"a homozygous ZAP-70 R192W variant was identified in 2 siblings with combined immunodeficiency and CD8 lymphopenia, confirming the pathogenicity of this mutation."

Two copies of this allele produce combined immunodeficiency with CD8 lymphopenia, a different clinical picture from this disease. Those patients were not free of autoimmunity, so the comparison shows the allele alone gives a different presentation rather than showing that an activating allele is required for autoimmunity at all.

Activating ZAP70 Autoinhibition-Weakening Allele

p.R360P sits in a loop of the kinase N-lobe beside Tyr315 and Tyr319, the interdomain B residues that hold the kinase in its autoinhibited conformation. The substitution destabilises that arrangement, leaving the kinase partially constitutively active: in T-cell lines it raises TCR-induced phosphorylation of ZAP-70 itself and of its substrates LAT and SLP-76, raises Erk phosphorylation, and raises basal CD69. The effect is weak, which is consistent with a single copy beside wild-type ZAP70 being clinically silent.

T cell CL:0000084

ZAP70 hgnc:12858

Genetic context ZAP70 hgnc:12858 allele_type: missense, c.1079G>C p.R360P variant_origin: GERMLINE zygosity: COMPOUND_HETEROZYGOUS functional_impact_category: HYPERMORPHIC

Paternally inherited weakly activating allele, in trans with the hypomorphic p.R192W allele.

protein tyrosine kinase activity GO:0004713 ↑ INCREASED

Downstream

Unopposed Hyperactive ZAP70 Signalling This is the allele that sets the cell's signalling state once no wild-type copy is present to oppose it.

Show evidence (2 references)

PMID:26783323 SUPPORT In Vitro

"These results were consistent with the hypothesis that R360P ZAP-70 is a weakly hyperactive protein due to disruption of its autoinhibitory mechanism."

Inducible expression in ZAP-70-deficient Jurkat cells raises TCR-induced phosphorylation of ZAP-70, SLP-76, LAT and Erk relative to wild type.

PMID:33531381 SUPPORT In Vitro

"These results support the notion that the R360P mutation directly weakens ZAP70 autoinhibition, thereby rendering ZAP70 partially constitutively active."

With the SH2 domains and interdomain A deleted, R360P phosphorylates LAT spontaneously, which is direct evidence that the substitution weakens autoinhibition rather than acting indirectly.

Unopposed Hyperactive ZAP70 Signalling

With no wild-type copy to oppose it, the activating allele sets the signalling threshold of the patients' T cells. TCR signalling is enhanced and, critically, mature T cells respond to weak agonist and self peptide-MHC complexes that wild-type T cells disregard. Both affected children were transplanted before the genotype was known, so no patient T cells were ever studied; the evidence is from carrier blood cells, reconstituted T-cell lines, and a knock-in mouse.

T cell CL:0000084

T cell receptor signaling pathway GO:0050852 ↑ INCREASED

Animal models

Zap70 R360P knock-in mouse Mouse partially recapitulates Reproduces the enhanced TCR signalling and the altered sensitivity to weak and self ligands that the human genotype is proposed to produce.

Downstream

Loss of Peripheral T Cell Tolerance to Self Antigens

Show evidence (2 references)

PMID:26783323 SUPPORT INDIRECT In Vitro

"Maternal cells (WT/R192W) showed decreased phosphorylation of the MAP kinases Erk1 and Erk2 in an anti-CD3 dose dependent manner, whereas cells from the father and healthy sister (WT/R360P) tended to have higher Erk phosphorylation."

Primary human carrier cells show the two alleles pulling TCR signalling in opposite directions. This is the closest the published work comes to patient cells, which were unavailable after transplantation. Graded IN_VITRO rather than HUMAN_CLINICAL because the measurement is an anti-CD3 stimulation assay on isolated blood cells, not a clinical observation.

PMID:33531381 SUPPORT Model Organism

"To eliminate the possibility of a TCR repertoire shift, the OTI transgenic TCR was introduced into R360P mice, which resulted in enhanced T cell responses to weaker stimuli, including weak agonists and a self-peptide."

On a fixed TCR background, where repertoire compensation is excluded, the activating allele selectively increases responses to weak and self ligands.

Loss of Peripheral T Cell Tolerance to Self Antigens

Mature T cells that react to self peptide-MHC are normally held below the activation threshold. When the threshold is lowered, such cells can be driven by self ligands in a permissive cytokine environment, which the authors propose as the route from the kinase defect to organ-directed autoimmunity. Unlike the hypomorphic ZAP70 alleles studied in mice, where forbidden clones escape thymic deletion, the activating allele acts mainly on mature cells: thymic negative selection is if anything strengthened, and knock-in mice accumulate regulatory and anergic T cells rather than autoimmunity.

T cell CL:0000084

peripheral tolerance induction GO:0002465 ↓ DECREASED

Animal models

Zap70 R360P knock-in mouse Mouse fails to recapitulate The knock-in mice do not break tolerance in any observable way: no spontaneous autoimmune disease on organ histology, no lymphadenopathy or splenomegaly, and no ANA or anti-dsDNA antibodies.

Downstream

T Follicular Helper Cell Expansion Autoreactive CD4 T cells that are no longer held below threshold are the proposed source of the excess B-cell help. The step is drawn from the knock-in mouse, where the expansion is measured after infection rather than at baseline, so the human version of it is inferred.

Colitis The gut disease in both children was an inflammatory colitis diagnosed endoscopically rather than an autoantibody-defined lesion, so it is drawn from the loss of T-cell tolerance and not from the antibody arm. No source identifies the effector population in the patients' bowel.

Minimal change glomerulonephritis Renal involvement is reported in both siblings, and in the brother's biopsy as widespread podocyte foot-process effacement with only mild IgG deposition. The immune route to the podocyte is not established in these patients, which is why the target here is the lesion rather than the syndrome: the chain then runs through the foot-process effacement and proteinuria to the nephrotic syndrome.

Show evidence (1 reference)

PMID:34923645 SUPPORT REVIEW SYNTHESIS Other

"Hyperactive ZAP70 enhances thymic negative selection but some thymocytes will, nonetheless, escape negative selection and have greater sensitivity to weak and self-ligands."

States the mechanism this node asserts, and distinguishes it from the central-tolerance failure that hypoactive ZAP70 causes.

T Follicular Helper Cell Expansion

Help to B cells is the step that connects a T-cell signalling defect to an antibody-mediated disease, and it is the part of the chain the mouse model supports most directly. After acute LCMV infection, R360P knock-in mice expand antigen-specific follicular helper T cells more than wild-type mice, and aged knock-in mice carry higher total IgG and IgG1. ZAP-70 is expressed predominantly in T and NK cells, so excess T-cell help, rather than an intrinsic B-cell defect, is the proposed explanation for why these patients make pathogenic autoantibodies.

T follicular helper cell CL:0002038

T follicular helper cell differentiation GO:0061470 ↑ INCREASED

Animal models

Zap70 R360P knock-in mouse Mouse recapitulates Antigen-specific follicular helper T cells expand more in knock-in mice than in wild-type after acute LCMV infection, with higher IgG and IgG1 in aged animals.

Downstream

Autoantibody Production Against Tissue and Plasma Protein Antigens

Show evidence (2 references)

PMID:33531381 SUPPORT Model Organism

"In addition, the R360P mutation resulted in enhanced follicular helper T cell expansion after LCMV infection."

The knock-in result this node rests on, measured on antigen-specific effector cells after infection rather than at baseline.

PMID:33531381 SUPPORT Model Organism

"we found that there were substantial increases in IgG and IgG1 amounts in 10 month old R360P mice compared to those of WT controls"

The humoral consequence in aged knock-in mice, which the authors read as a long-term effect of the expanded follicular helper response.

Autoantibody Production Against Tissue and Plasma Protein Antigens

The diseases that defined this syndrome are antibody-defined: bullous pemphigoid with linear basement-membrane IgG at a titre above 1:160, and an inhibitory autoantibody to coagulation factor VIII causing bleeding. Both point at autoreactive B-cell help as the effector arm rather than at direct T-cell cytotoxicity. The node is scaled CELLULAR because its substrate is the antibody-secreting cell; the organ-level consequences are the phenotypes downstream of it. Tolerance is recorded as broken rather than as an intrinsic B-cell defect: ZAP-70 is expressed predominantly in T and NK cells, and the proposed cause is excess T-cell help.

plasma cell CL:0000786

autoantibody secretion GO:0002377 ↑ INCREASED B cell tolerance induction GO:0002514 ↓ DECREASED

Downstream

Bullous pemphigoid

Anti-factor VIII antibody positivity

Oral mucosal blisters The mucosal blistering is the same pemphigoid lesion at a second site rather than a separate disease.

Linear IgG deposits along the epidermal basement membrane zone The deposition is this node's output made visible: the autoantibody bound at the dermo-epidermal junction, which is what the immunofluorescence detects.

Show evidence (1 reference)

PMID:26783323 SUPPORT INDIRECT Human Clinical

"Altered signaling could allow autoreactive T cells to escape thymic deletion and emigrate into the periphery, where they could activate potentially autoreactive B cells, thereby leading to production of autoantibodies to antigens such as skin proteins (bullous pemphigoid) and clotting factors..."

The proposed route from the signalling defect to the two antibody-mediated diseases in these children, stated conditionally by the authors. It is quoted for its second half, the activation of autoreactive B cells; the thymic-escape premise in its first half is the question the central-versus-peripheral-tolerance discussion records as open, and this node does not rest on it.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

20

Blood 8

Joint hemorrhage HP:0005261

Show evidence (1 reference)

PMID:26783323 SUPPORT Human Clinical

"At age 2, he suffered bruising and a hemarthrosis as a result of an autoantibody to clotting factor VIII"

The bleeding episode and its attribution to the inhibitor.

Bruising susceptibility HP:0000978

Show evidence (1 reference)

PMID:26783323 SUPPORT Human Clinical

"At age 2, he suffered bruising and a hemarthrosis as a result of an autoantibody to clotting factor VIII"

Records bruising alongside the joint bleed.

Decreased total CD8+ T cell count HP:5210426

Sequelae: Increased CD4:CD8 ratio

Show evidence (2 references)

PMID:26783323 SUPPORT Human Clinical

"Immunological workup revealed mild T and B cell lymphopenia in the brother and reduced CD8 T cells in both affected children, resulting in an elevated CD4/CD8 ratio"

The subset findings in both children.

PMID:41608114 SUPPORT Other

"Decreased CD8, normal or decreased CD4 cells"

The IUIS T-cell column for this entity.

Increased CD4:CD8 ratio HP:0033221

Show evidence (1 reference)

PMID:26783323 SUPPORT Human Clinical

"The affected sister had increased CD19 B cells, and both children had elevated CD4/CD8 ratios, although not as high as generally found in patients with ZAP70 deficiency"

Gives the raised ratio and the explicit contrast in degree with ZAP70 deficiency.

Decreased circulating IgG concentration HP:0004315

Show evidence (1 reference)

PMID:26783323 SUPPORT Human Clinical

"The boy also had low total serum IgG, possibly attributable to nephrotic syndrome, but post-vaccine titers to type 14 pneumococcus and tetanus were protective."

The low IgG, the proposed renal explanation, and the preserved vaccine responses that argue against an antibody-production defect.

Impaired phytohemagglutinin-induced T lymphocyte transformation HP:0025834

Show evidence (2 references)

PMID:26783323 SUPPORT Human Clinical

"cells, tested before institution of immunosuppressive medication, had diminished, but not absent, PHA responses"

The sister's result, measured before immunosuppression and so the one that reports the disease rather than its treatment.

PMID:26783323 SUPPORT Human Clinical

"His proliferative responses were diminished to phytohemagglutinin (PHA) and absent of candida or tetanus antigens; however, he was receiving immunosuppressive medications when the immune studies were done."

The brother's result together with the confound the authors flag, which is why this phenotype is not graded more severely.

Decreased circulating IgM concentration Decreased circulating total IgM HP:0002850

The binding carries HPO's older label for HP:0002850, "Decreased circulating total IgM", because that is what the committed term cache holds and what every other entry using this term carries. HPO has since renamed it to "Decreased circulating IgM concentration"; the cache-first validator rejects the current name, which is the problem tracked in dismech issue 11750.

Show evidence (2 references)

PMID:26783323 SUPPORT Human Clinical

"| IgM (mg/dl) | 25 (48-168) | 9 (17-105) |"

The Table 1 row, with both children's values below their age-matched reference ranges.

PMID:41608114 SUPPORT Other

"Normal IgA, low IgM, low/normal IgG; protective Ab responses to vaccines"

The IUIS immunoglobulin column for this entity, which records low IgM as characteristic rather than incidental.

Increased circulating IgE concentration HP:0003212

Show evidence (1 reference)

PMID:26783323 SUPPORT Human Clinical

"| IgE IU/ml | 99 (<64) | ND |"

The Table 1 row, with the brother's value above the stated ceiling and the sister not tested.

Digestive 1

Colitis HP:0002583

Sequelae: Failure to thrive in infancy

Show evidence (2 references)

PMID:26783323 SUPPORT Human Clinical

"She had poor weight gain that was initially attributed to a rotavirus infection but was later diagnosed by endoscopy as inflammatory colitis, similar to that of her brother."

Endoscopic diagnosis in the sister, and the statement that the brother's colitis was the same disease.

PMID:41608114 SUPPORT Other

"Severe autoimmunity (bullous pemphigoid, inflammatory colitis)"

The IUIS clinical column for this entity names inflammatory colitis.

Endocrine 1

Hypothyroidism HP:0000821

Show evidence (1 reference)

PMID:26783323 SUPPORT Human Clinical

"indicated graft rejection and autoimmune hypothyroidism developed"

Names the thyroid autoimmunity and the point in the course at which it appeared.

Genitourinary 4

Nephrotic syndrome HP:0000100

Onset: INFANTILE; from 0.75y

Sequelae: Decreased circulating IgG concentration

Show evidence (1 reference)

PMID:26783323 SUPPORT Human Clinical

"At 9 mo of age, male II-2 developed nephrotic syndrome."

The age and the diagnosis in the affected brother.

Minimal change glomerulonephritis HP:0012579

Sequelae: Podocyte foot process effacement

Show evidence (1 reference)

PMID:26783323 SUPPORT Human Clinical

"A renal biopsy showed histologically normal glomeruli and mild IgG deposition, but electron microscopy revealed widespread foot process effacement most consistent with minimal change disease"

The biopsy findings and the pathologist's reading of them.

Proteinuria HP:0000093

Sequelae: Nephrotic syndrome

Show evidence (1 reference)

PMID:26783323 SUPPORT Human Clinical

"She also had proteinuria, although no renal biopsy was performed given the lack of progression to nephrotic syndrome."

Renal involvement in the sister, at a lesser severity than her brother's.

Podocyte foot process effacement HP:0031266

Sequelae: Proteinuria

Show evidence (1 reference)

PMID:26783323 SUPPORT Human Clinical

"electron microscopy revealed widespread foot process effacement most consistent with minimal change disease"

The electron-microscopy finding and its interpretation.

Head and Neck 1

Oral mucosal blisters HP:0200097

Show evidence (1 reference)

PMID:26783323 SUPPORT Human Clinical

"By 20 mo of age, blistering skin disease developed, involving his entire body and oral mucosa"

Records mucosal involvement alongside the cutaneous disease.

Immune 2

Anti-factor VIII antibody positivity HP:6000494

Sequelae: Joint hemorrhage Bruising susceptibility

Show evidence (1 reference)

PMID:26783323 SUPPORT Human Clinical

"The boy had hemophilia due to a factor VIII autoantibody and nephrotic syndrome."

Names the autoantibody and the resulting bleeding disorder.

Decreased circulating specific pneumococcal antibody concentration HP:0012476

Show evidence (2 references)

PMID:26783323 SUPPORT Human Clinical

"| Pneumococcal IgG, Type 3 | 0.2 (>1.3 µg/ml) | ND |"

A Table 1 row giving a serotype titre below the threshold printed in the same row.

PMID:26783323 SUPPORT Human Clinical

"| Pneumococcal IgG, Type 12 | 0.3 (>1.3 µg/ml) | ND |"

A second non-protective serotype, so the finding is not a single outlying measurement.

Integument 2

Bullous pemphigoid Subepidermal blistering HP:0033804

Temporal: CHRONIC Onset: INFANTILE; 0.08-1.7y

Show evidence (3 references)

PMID:26783323 SUPPORT Human Clinical

"a biopsy showed bullous pemphigoid, with characteristic subepidermal clefting, infiltration with eosinophils and neutrophils, and linear basement membrane and intercellular deposition of IgG at a titer greater than 1:160"

Histology and immunofluorescence establishing the diagnosis and the subepidermal level of the split that the bound HPO term names.

PMID:26783323 SUPPORT Human Clinical

"His sister II-3 experienced bullous pemphigoid beginning at 1 mo of age that rapidly became generalized"

The second affected child, with onset in the first month of life.

PMID:41608114 SUPPORT Other

"Severe autoimmunity (bullous pemphigoid, inflammatory colitis)"

IUIS records bullous pemphigoid as one of the two manifestations that characterise this entity.

Linear IgG deposits along the epidermal basement membrane zone HP:0031540

Show evidence (1 reference)

PMID:26783323 SUPPORT Human Clinical

"linear basement membrane and intercellular deposition of IgG at a titer greater than 1:160"

The immunofluorescence result and its titre.

Growth 1

Failure to thrive in infancy HP:0001531

Show evidence (1 reference)

PMID:26783323 SUPPORT Human Clinical

"She had poor weight gain that was initially attributed to a rotavirus infection but was later diagnosed by endoscopy as inflammatory colitis"

The growth failure and the diagnosis it led to.

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Genetic Associations

1

ZAP70 (hypomorphic plus activating alleles in trans)

Gene: ZAP70 hgnc:12858 gene page relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal recessive inheritance

Show evidence (2 references)

PMID:26783323 SUPPORT Human Clinical

"Analysis of whole-exome sequencing (WES) revealed no consanguinity and only one gene, ZAP70, with nonsynonymous coding variants potentially causing homozygous recessive immunological disease."

The gene-finding result that assigns the syndrome to ZAP70.

PMID:26783323 SUPPORT Human Clinical

"Neither mutation had been reported previously, nor were they near mutations associated with human disease"

Both alleles were new, and neither sits in the previously described loss-of-function territory.

Variants (2)

ZAP70 c.574C>T p.R192W Pathogenic

C-terminal SH2 domain allele, inherited from the mother. The tryptophan occupies the phosphotyrosine-binding pocket formed by arginines 170, 190 and 192, so the kinase docks poorly on the doubly phosphorylated zeta chain. Reported at an allele frequency of 0.00003 in ExAC at the time of publication.

Functional effects

binding to the phosphorylated T-cell receptor zeta chain hypomorphic

Reduced association with, and reduced phosphorylation on, the zeta chain in transfected cells.

Show evidence (2 references)

PMID:26783323 SUPPORT Computational

"The replacement of arginine with a bulky tryptophan residue in the phosphotyrosine-binding pocket of the ZAP-70 C-terminal SH2 domain (C-SH2; R192W mutation) was predicted to diminish ZAP-70 binding to the ζ-chain"

The structural prediction for this substitution, which the immunoprecipitation experiments in the same paper then confirmed.

PMID:37313400 SUPPORT Computational

"Structural modeling of this region revealed the critical nature of the arginines at positions 170 and 192, in concert with R190, forming a binding pocket for the phosphorylated TCR-zeta chain."

Independent structural account of why position 192 matters, from the series that later found this allele in the homozygous state.

ZAP70 c.1079G>C p.R360P Pathogenic

Kinase-domain N-lobe allele, inherited from the father, lying in a loop close to Tyr315 and Tyr319. It weakens the autoinhibited conformation, producing a weakly hyperactive kinase. Neighbouring substitutions in the same region (D327P, K362E) are more strongly activating, which is the basis for calling this one weak.

Functional effects

T-cell receptor-proximal tyrosine kinase activity hypermorphic

Partial constitutive activation through loss of autoinhibition, with increased phosphorylation of ZAP-70 Y319 and Y493 and of LAT and SLP-76 on receptor engagement.

Show evidence (2 references)

PMID:26783323 SUPPORT Computational

"In contrast, R360P lies in a loop of the N-lobe of the kinase domain in proximity to Y319, a key residue for autoinhibition of ZAP-70"

Locates the substitution with respect to the autoinhibitory site.

PMID:34923645 SUPPORT REVIEW SYNTHESIS Other

"the R360P mutation appears to relieve the interdomain B and kinase domain interaction"

The structural interpretation of how this allele breaks autoinhibition, and how that differs from the W131A hypermorph.

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Medical Actions

2

Allogeneic Hematopoietic Cell Transplantation

Action: allogeneic haematopoietic cell transplantation Ontology label: Allogeneic Hematopoietic Stem Cell Transplantation NCIT:C46089

Platform: Cell therapy

The only treatment reported to control this disease. The brother was transplanted from a matched unrelated donor at five years of age after his autoimmunity became refractory to medical management; the sister was transplanted twice from her HLA-matched healthy sister, the second time with myeloablative conditioning after donor chimerism fell. Replacing the haematopoietic compartment removes the T cells carrying the two-allele genotype, which is why a transplant addresses the mechanism rather than the manifestations.

Mechanism Target:

Unopposed Hyperactive ZAP70 Signalling — Donor-derived T cells carry wild-type ZAP70, so the activating allele is no longer unopposed in the T-cell compartment.

Show evidence (1 reference)

PMID:26783323 SUPPORT INDIRECT Human Clinical

"Both children required allogeneic hematopoietic cell transplantation (HCT), which resolved their autoimmunity."

Replacing the T-cell compartment resolved the disease in both children, which is the outcome this mechanism link predicts.

Show evidence (2 references)

PMID:26783323 SUPPORT Human Clinical

"Both children required allogeneic hematopoietic cell transplantation (HCT), which resolved their autoimmunity."

Both affected children were transplanted and both had their autoimmunity resolve, which is the outcome evidence for this treatment.

PMID:26783323 SUPPORT Human Clinical

"Her pemphigoid resolved after the first HCT (Fig. 1 H), but a second HCT with myeloablative conditioning was performed after declining donor chimerism"

Shows both that the skin disease responded and that durable control required full donor chimerism, which the first graft did not maintain.

Corticosteroid and Immunosuppressive Therapy

Action: immunosuppressive therapy Ontology label: Immunosuppressive Therapy NCIT:C15261

Agent: corticosteroid CHEBI:50858

Platform: Small molecule

Attempted and inadequate. High-dose steroids and several immunosuppressive regimens failed to control the brother's autoimmunity, and that failure is what took him to transplantation. This matters for recognising the disease: bullous pemphigoid of childhood is ordinarily steroid-responsive, so a refractory course in an infant is itself a signal. Only the steroids are named in the source; the other regimens are described as "multiple immunosuppressive regimens" without being identified, which is why no further agent is bound.

Show evidence (2 references)

PMID:26783323 SUPPORT Human Clinical

"His autoimmune manifestations became refractory to high-dose steroids and multiple immunosuppressive regimens; therefore, he underwent a matched unrelated HCT at 5 yr of age that resolved his pretransplant autoimmunity."

States the failure of medical immunosuppression and the decision it led to.

PMID:26783323 SUPPORT Human Clinical

"autoantibody-mediated bullous pemphigoid usually occurs in the elderly, and unlike in our patients, when found in young children it is very responsive to steroid treatment"

The authors' contrast with ordinary childhood bullous pemphigoid, which is why the refractory course is diagnostically meaningful.

🔬

Diagnosis

6

Lymphocyte subset flow cytometry

The first-line immunological test, and the one that places the disease beside ZAP70 deficiency rather than with the other causes of infantile autoimmunity. It shows reduced CD8 T cells with a raised CD4:CD8 ratio, and in the sister an increase in CD19 B cells. The deficit is partial, so the panel does not read as a SCID.

lymphocyte subset flow cytometry NCIT:C16585

Newborn T-cell receptor excision circle screening was normal in both children, so a normal TREC result does not exclude this disease. That is the same caveat that applies to ZAP70 deficiency, where continuing CD4 thymic output can keep the screen normal.

Show evidence (1 reference)

PMID:26783323 SUPPORT Human Clinical

"Immunological workup revealed mild T and B cell lymphopenia in the brother and reduced CD8 T cells in both affected children, resulting in an elevated CD4/CD8 ratio"

The subset pattern this test is being cited for.

Molecular genetic testing (exome sequencing)

The definitive test, and how the disease was found. Exome sequencing of five family members identified the compound heterozygous ZAP70 genotype and the carrier state of the healthy relatives. Both alleles were private to the family, so sequencing alone leaves two variants of uncertain significance: the functional work on zeta-chain binding and on autoinhibition is what makes the result interpretable.

whole exome sequencing NCIT:C101295

Show evidence (1 reference)

PMID:26783323 SUPPORT Human Clinical

"Whole-exome sequencing performed on five family members revealed the affected siblings to be compound heterozygous for two unique missense mutations in the 70-kD T cell receptor ζ-chain associated protein (ZAP-70)."

Names the test, the family members sequenced and the result.

Skin biopsy with direct immunofluorescence

Establishes the bullous pemphigoid: subepidermal clefting with eosinophils and neutrophils on histology, and linear IgG along the basement membrane on immunofluorescence at a titre above 1:160.

skin biopsy with direct immunofluorescence NCIT:C51692

Show evidence (1 reference)

PMID:26783323 SUPPORT Human Clinical

"a biopsy showed bullous pemphigoid, with characteristic subepidermal clefting, infiltration with eosinophils and neutrophils, and linear basement membrane and intercellular deposition of IgG at a titer greater than 1:160"

The histological and immunofluorescence findings this test returns.

Kidney biopsy with electron microscopy

Performed in the brother only. Light microscopy was near normal with mild IgG deposition; the diagnosis came from electron microscopy, which showed widespread podocyte foot-process effacement. The sister was not biopsied because her proteinuria did not progress.

kidney biopsy with electron microscopy NCIT:C51699

Show evidence (1 reference)

PMID:26783323 SUPPORT Human Clinical

"A renal biopsy showed histologically normal glomeruli and mild IgG deposition, but electron microscopy revealed widespread foot process effacement most consistent with minimal change disease"

What each modality contributed, and why the ultrastructural study was the one that settled the diagnosis.

Endoscopy

Diagnosed the colitis in the sister, after her poor weight gain had been attributed to a rotavirus infection. Her brother's colitis was reported as the same disease. The source says endoscopy and does not say which endoscopic procedure, nor report a biopsy, so neither is named here.

endoscopy NCIT:C16546

Show evidence (1 reference)

PMID:26783323 SUPPORT Human Clinical

"was later diagnosed by endoscopy as inflammatory colitis, similar to that of her brother"

The endoscopic diagnosis, at the level of specificity the source states. It says endoscopy, not colonoscopy, so the binding is the general endoscopic-procedure term rather than a colonoscopy term the source does not support.

Factor VIII inhibitor measurement

Identifies the acquired haemophilia in the brother, whose bruising and joint bleed were caused by an autoantibody to clotting factor VIII rather than by an inherited factor deficiency.

factor VIII inhibitor assay NCIT:C154752

Show evidence (1 reference)

PMID:26783323 SUPPORT Human Clinical

"The boy had hemophilia due to a factor VIII autoantibody and nephrotic syndrome."

The autoantibody this assay detects, and the bleeding phenotype it explains.

📊

Prevalence

1

Worldwide, published literature

Cases In Literature Ultra Rare

Two patients, siblings, in one family, and no second family has been reported. The 2021 knock-in mouse study and the 2022 review both describe this same kindred, and the one later paper to discuss both alleles together reports a different genotype in different patients. There is no population estimate and no case series to pool, so this record states the size of the literature rather than a rate.

Show evidence (1 reference)

PMID:26783323 SUPPORT Human Clinical

"We present two siblings with unique mutations of ZAP70 who lacked clinical immunodeficiency, but instead had a novel constellation of early onset, severe autoimmune manifestations, including bullous pemphigoid."

The only reported patients, and the basis for counting two.

🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Autoimmune Disease, Multisystem, Infantile-Onset, 2:

ZAP70 deficiency (combined immunodeficiency, biallelic loss of function) MONDO:0010023

Overlapping Features The same gene, and the obvious confusion. ZAP70 deficiency is a combined immunodeficiency from biallelic loss of function: CD8 T cells are effectively absent, CD4 cells are present but unresponsive to receptor stimulation, and patients present with life-threatening and opportunistic infection in infancy. Autoimmunity occurs there too, in roughly a fifth of patients, which is what makes the two entities easy to conflate. The discriminators are the infectious history, which is absent here, and the degree of the CD8 deficit, which is partial here and near-total there. Mechanistically they are opposites: too little kinase activity in one, too much in the other.

Distinguishing Features

No clinical immunodeficiency and no opportunistic infection in this disease
CD8 reduction is partial rather than near-absent, and the CD4:CD8 ratio is less extreme
Autoimmunity is the presenting problem rather than a complication in a minority
One allele is activating, so the kinase is hyperactive rather than absent

Show evidence (3 references)

PMID:26783323 SUPPORT Human Clinical

"In marked contrast, our patients had a distinct phenotype with early onset, severe to life-threatening autoimmune disease and only minor lymphocyte abnormalities and no evidence of immune deficiency"

The authors' own statement of the contrast with loss-of-function ZAP70 disease.

PMID:20301777 SUPPORT REVIEW SYNTHESIS Human Clinical

"ZAP70 deficiency is a profound T-cell immunodeficiency caused by abnormal T-cell receptor (TCR) signaling due to the loss of ZAP70 kinase activity, resulting in diminished CD8+ T-cell counts and functional deficits in CD4+ T cells."

The GeneReviews definition of the disease being distinguished, which turns on loss of kinase activity. It is quoted here, on the differential, rather than anywhere in this entry's own claims, because its subject is the other disease.

PMID:41608114 SUPPORT Other

The IUIS row for the loss-of-function disease, immediately above this entity's own row and carrying a different OMIM number, which is what makes the separation a sourced one.

Homozygous ZAP70 R192W combined immunodeficiency

Overlapping Features The sharpest contrast available, because it isolates the allele rather than the gene. Two siblings homozygous for the same hypomorphic C-SH2 allele that this disease carries on one chromosome presented with combined immunodeficiency and CD8 lymphopenia, not with the antibody-defined constellation seen here: no bullous pemphigoid, no factor VIII inhibitor, no nephrotic syndrome. Read the comparison carefully, because it is weaker than it first looks. Those patients were not free of autoimmunity, and the report says so explicitly in the same sentence that notes the absence of an activating mutation; one of the four patients in that series had inflammatory polyarthritis. So the two-allele configuration explains why this disease looks the way it does, and the activating allele is not established as the precondition for autoimmunity in ZAP70 disease generally. That paper's own framing of the open question is the reverse of the one this entry answers: how hypomorphic alleles, which reduce signalling, produce autoimmunity at all.

Show evidence (2 references)

PMID:37313400 SUPPORT Human Clinical

"Notably, both R170C and R192W mutations negatively impacted the binding of ZAP-70 to the TCR ζ-chain, resulting in a complete absence in TCR-induced proliferation (this study and (42)) and all patients presented with immunodeficiency and autoimmunity, in the absence of activating mutations."

Establishes what this allele class does on its own: immunodeficiency and autoimmunity with no activating mutation present. Quoted in full because the second half is what limits the comparison, and reporting only the absence of the activating mutation would make the entry's contrast look stronger than the source supports.

PMID:37313400 SUPPORT Human Clinical

"it remains unclear as to how these mutations lead to autoimmunity in patients"

The authors' statement that the route from a signalling-reducing ZAP70 mutation to autoimmunity is unresolved. It is the reason this entry confines its mechanistic claim to the activating allele's effect on peripheral responsiveness rather than claiming a general account of ZAP70-associated autoimmunity.

STAT3 gain-of-function early-onset multisystem autoimmune disease

Overlapping Features The nearest phenotypic neighbour from another gene, and the comparison the primary report itself draws. Activating STAT3 variants cause early-onset multisystem autoimmunity, while dominant-negative variants in the same gene cause hyper-IgE syndrome; that mirror-image pairing is the pattern this ZAP70 disease follows. Distinguishing them is a sequencing question rather than a clinical one.

Show evidence (2 references)

PMID:26783323 SUPPORT Human Clinical

"The latter category is typified by STAT3-activating mutations (Flanagan et al., 2014), which lead to early onset autoimmunity, in contrast to the dominant-negative defects in the same gene that cause hyper-IgE syndrome with boils and necrotizing pneumonias."

The report's own analogy, which is also the reason the STAT3 entity is the differential a clinician would reach for.

PMID:36228738 SUPPORT Human Clinical

"germline signal transducer and activator of transcription (STAT) 3 gain-of-function (GOF) mutations were first described to cause a novel multisystem disease of early-onset lymphoproliferation and autoimmunity"

Characterises the entity being distinguished. Its cohort of 191 patients is also the contrast in scale: that disease has a natural history, and this one has two patients.

🐁

Animal Models

1

Zap70 R360P knock-in mouse

CRISPR-generated knock-in carrying the activating allele in the homozygous state. The mice are healthy, fertile and normal-lived, and they do not develop autoimmunity: histology of multiple organs at 8 to 10 months was unremarkable and ANA and anti-dsDNA screening was negative. What they do show is the signalling phenotype. Thymocyte and peripheral T-cell development is grossly normal, but central memory CD8 cells increase, ZAP70 Y319 phosphorylation and calcium mobilisation are enhanced, follicular helper T cells expand after LCMV infection, and aged animals have more IgG and IgG1. Crossing in the OTI transgenic TCR removes repertoire compensation and reveals selectively enhanced responses to weak agonist and self peptides.

Species

Mouse

Genotype

Zap70 R360P homozygous knock-in

Background

C57BL/6

Publication

PMID:33531381

Pathograph links

Unopposed Hyperactive ZAP70 Signalling partially recapitulates fidelity: moderate observes: cellular Reproduces the enhanced TCR signalling and the altered sensitivity to weak and self ligands that the human genotype is proposed to produce.

Limitations: The genotype is not the patients'. The mice are homozygous for the activating allele, whereas the patients carry it opposite a hypomorphic allele, and in the human cell-line experiments the hypomorphic partner is what unmasks the activating allele. So the model tests the activating allele's effect rather than the two-allele configuration.

Divergences from the human mechanism

population mismatch qualifying

R360P homozygosity in the mouse stands in for R192W/R360P compound heterozygosity in the patients. The claim about enhanced signalling holds; the claim that this particular allele pairing is required does not come from the model.

Readouts

ZAP70 Y319 phosphorylation and calcium mobilisation after anti-CD3 stimulation

Direction: INCREASED

Interpretation: Biochemical confirmation that the allele raises receptor-proximal signalling in primary T cells.

Show evidence (1 reference)

PMID:34923645 SUPPORT REVIEW SYNTHESIS Other

"Biochemical analyses confirmed that the R360P mutation was a weak hypermorphic allele that increased TCR signaling through weakened ZAP70 autoinhibition, as evidenced in enhanced ZAP70 phosphorylation at Y319 and faster calcium mobilization following anti-CD3 stimulation."

Names both measurements and their direction.

Show evidence (1 reference)

PMID:33531381 SUPPORT Model Organism

"the R360P mutation was a weak hypermorphic allele of ZAP70 that enhanced TCR signaling"

Supports treating this model as informative for the enhanced-signalling node, which is the claim this link makes.

T Follicular Helper Cell Expansion recapitulates fidelity: moderate observes: cellular Antigen-specific follicular helper T cells expand more in knock-in mice than in wild-type after acute LCMV infection, with higher IgG and IgG1 in aged animals.

Limitations: The expansion needed an acute viral infection to appear and, on a polyclonal repertoire, did not produce more germinal-centre B cells or higher anti-LCMV titres. No autoantibody arose in these mice, so the step from expanded help to pathogenic autoantibody is not modelled.

Readouts

Antigen-specific Tfh percentage among GP66+ effector CD4 T cells at day 8 after LCMV

Direction: INCREASED

Show evidence (1 reference)

PMID:33531381 SUPPORT Model Organism

"At day 8 after infection, the percentage of Tfh cells among GP66+ antigen-specific effector cells (B220−CD4+CD44+GP66+) was significantly higher"

The measurement, its gating and its timing.

Show evidence (1 reference)

PMID:33531381 SUPPORT Model Organism

"Zap70 R360P knock-in mice showed increased expansion of antigen-specific follicular helper T (Tfh) cells compared to that of the WT mice following LCMV infection."

Supports treating this model as informative for the follicular-helper node.

Loss of Peripheral T Cell Tolerance to Self Antigens fails to recapitulate fidelity: low observes: organism The knock-in mice do not break tolerance in any observable way: no spontaneous autoimmune disease on organ histology, no lymphadenopathy or splenomegaly, and no ANA or anti-dsDNA antibodies.

Limitations: C57BL/6 is relatively resistant to autoimmunity, and the authors attribute the negative result to background, modifiers or environment rather than to the allele being harmless. Aged knock-in mice also accumulate regulatory and anergic T cells, which may be actively containing the enhanced signalling. A negative result here therefore does not refute the human mechanism, but it does mean the tolerance-breaking step rests on the patients and on inference.

Show evidence (1 reference)

PMID:33531381 SUPPORT Model Organism

"the homozygous R360P mice did not develop any spontaneous autoimmune diseases based on histological screening of multiple organs from 8–10 month old mice (fig. S1). There was no evidence of lymphadenopathy or splenomegaly. Serologic screening for autoantibodies including ANA and dsDNA was negative."

The negative findings, stated in full, that this link records.

Show evidence (1 reference)

PMID:33531381 SUPPORT Model Organism

"Mice with a ZAP70 R360P mutation and polyclonal TCR repertoires exhibited relatively normal T cell development but showed evidence of increased signaling."

The model's core result: the allele changes signalling without disturbing development.

{ }

Source YAML

click to show

name: Autoimmune Disease, Multisystem, Infantile-Onset, 2
creation_date: "2026-10-13T09:00:00Z"
category: Mendelian
synonyms:
- ADMIO2
- autoimmune disease, multisystem, infantile-onset, type 2
- ZAP70 autoimmune disease, multisystem, infantile-onset
- ZAP-70 combined hypomorphic and activating mutations
description: >-
  An early-onset, antibody-dominated multisystem autoimmune disease caused by
  compound heterozygosity in trans for two functionally opposite ZAP70 missense
  alleles. One allele (p.R192W, in the C-terminal SH2 domain) docks poorly onto
  the phosphorylated T-cell receptor zeta chain and is hypomorphic. The other
  (p.R360P, in the kinase N-lobe) weakens the autoinhibited conformation of the
  kinase, leaving it partially constitutively active. A wild-type allele masks
  the activating one, so single-allele carriers are healthy; paired with the
  hypomorph the activating allele sets the signalling threshold, and in a mouse
  knocked in for the activating allele, T cells respond to weak agonist and self
  ligands that wild-type T cells ignore. No patient T cell was ever studied, so
  that last step is an inference from the mouse rather than a measurement in
  these children.

  The clinical picture is the inverse of ZAP70 deficiency. In the only reported
  family, two siblings of unrelated healthy parents had no infectious
  susceptibility and only minor lymphocyte abnormalities, yet developed severe
  autoimmunity within the first year of life: generalized bullous pemphigoid,
  inflammatory colitis, proteinuria that in one child progressed to nephrotic
  syndrome with minimal-change histology, and an acquired factor VIII inhibitor
  with bleeding. The disease resisted corticosteroids and other
  immunosuppression; allogeneic haematopoietic cell transplantation resolved it
  in both children.
disease_term:
  preferred_term: autoimmune disease, multisystem, infantile-onset, 2
  term:
    id: MONDO:0014861
    label: autoimmune disease, multisystem, infantile-onset, 2
parents:
- Primary Immunodeficiency
- Autoimmune Disease
classifications:
  iuis_category:
    classification_value: combined immunodeficiency
    notes: >-
      IUIS places this entity in Table 1 (immunodeficiencies affecting cellular
      and humoral immunity), in the combined immunodeficiency subtable, as a row
      distinct from ZAP-70 deficiency (ZAP70 LOF). It carries its own OMIM
      number (617006) and an AR (LOF/GOF) inheritance annotation, and the
      clinical column records severe autoimmunity rather than infection.
    evidence:
    - reference: PMID:41608114
      reference_title: "Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        ZAP-70 combined hypomorphic and activating mutations | ZAP70 | AR
        (LOF/GOF) | 617006 | Decreased CD8, normal or decreased CD4 cells |
        Normal or decreased | Normal IgA, low IgM, low/normal IgG; protective Ab
        responses to vaccines | Severe autoimmunity (bullous pemphigoid,
        inflammatory colitis)
      explanation: >-
        The IUIS 2024 row for this entity, recording the two-allele inheritance
        annotation, the OMIM number, the modest lymphocyte and immunoglobulin
        findings, and the autoimmune-dominant presentation.
    - reference: PMID:41608114
      reference_title: "Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        ZAP70 has two entries with different inheritance mechanisms and
        associated phenotypes, thus two different disorders
      explanation: >-
        IUIS states the separation outright rather than leaving it to be read
        off two adjacent rows. This is the source for curating this concept as
        its own entry rather than as a subtype of ZAP70 deficiency.
inheritance:
- name: Autosomal recessive inheritance
  description: >-
    Disease requires one hypomorphic and one activating ZAP70 allele in trans.
    The affected siblings inherited p.R192W from their mother and p.R360P from
    their father; the parents and an unaffected sister carrying p.R360P alone
    are well. The pattern is recessive in that each allele is silent beside a
    wild-type allele, but it is not the biallelic loss of function of ZAP70
    deficiency. Homozygosity for the hypomorphic allele alone has since been
    reported in two siblings, who had combined immunodeficiency with CD8
    lymphopenia and autoimmunity but not this antibody-defined constellation,
    so it is the pairing rather than either allele that produces this disease.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:26783323
    reference_title: "A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both affected children were compound heterozygous for ZAP70 c.574C>T,
      p.R192W, in exon 5; and c.1079G>C, p.R360P, in exon 9
    explanation: >-
      Records the compound heterozygous genotype shared by both affected
      children.
  - reference: PMID:26783323
    reference_title: "A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The mother carried the R192W allele, whereas the father and unaffected
      sister carried the R360P allele.
    explanation: >-
      Establishes that the two alleles are in trans and that one copy of either
      is clinically silent.
  - reference: PMID:41608114
    reference_title: "Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ZAP-70 combined hypomorphic and activating mutations | ZAP70 | AR (LOF/GOF) | 617006"
    explanation: >-
      IUIS annotates the inheritance as autosomal recessive with one
      loss-of-function and one gain-of-function allele.
references:
- reference: PMID:20301777
  title: "ZAP70 Deficiency."
  tags:
  - GeneReviews
  findings:
  - statement: >-
      This is the gene's GeneReviews chapter and not this disease's baseline: it
      covers ZAP70 deficiency, the loss-of-function combined immunodeficiency,
      and defines its subject as loss of ZAP70 kinase activity. No GeneReviews
      chapter names this disease or any of its synonyms. It is cited once in
      this entry, on the ZAP70-deficiency differential, and no claim about this
      disease rests on it.
    supporting_text: >-
      ZAP70 deficiency is a profound T-cell immunodeficiency caused by abnormal
      T-cell receptor (TCR) signaling due to the loss of ZAP70 kinase activity
pathophysiology:
- name: Hypomorphic ZAP70 SH2 Docking Allele
  description: >-
    p.R192W substitutes a bulky tryptophan into the phosphotyrosine-binding
    pocket of the C-terminal SH2 domain. The mutant kinase associates poorly
    with the phosphorylated TCR zeta chain and is itself poorly phosphorylated
    there. Homozygous R192W has since been reported in siblings with combined
    immunodeficiency, so the allele is pathogenic on its own; in this genotype
    its contribution is different, because it cannot supply the restraint on
    the partner allele that a wild-type copy would.
  biological_scale: MOLECULAR
  genetic_context:
    gene:
      preferred_term: ZAP70
      term:
        id: hgnc:12858
        label: ZAP70
    allele_type: missense, c.574C>T p.R192W
    variant_origin: GERMLINE
    zygosity: COMPOUND_HETEROZYGOUS
    functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
    description: >-
      Maternally inherited hypomorphic allele, in trans with the activating
      p.R360P allele.
  genes:
  - preferred_term: ZAP70
    term:
      id: hgnc:12858
      label: ZAP70
  molecular_functions:
  - preferred_term: phosphotyrosine residue binding
    modifier: DECREASED
    term:
      id: GO:0001784
      label: phosphotyrosine residue binding
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  evidence:
  - reference: PMID:26783323
    reference_title: "A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Thus, the data suggest that the R192W ZAP-70 mutant is a hypomorph with
      reduced ζ-chain association and phosphorylation compared with WT.
    explanation: >-
      Immunoprecipitation from transfected cells gives the reduced zeta-chain
      association and phosphorylation that define this allele as hypomorphic.
  - reference: PMID:37313400
    reference_title: "Combined immunodeficiency caused by pathogenic variants in the ZAP70 C-terminal SH2 domain."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a homozygous ZAP-70 R192W variant was identified in 2 siblings with
      combined immunodeficiency and CD8 lymphopenia, confirming the
      pathogenicity of this mutation.
    explanation: >-
      Two copies of this allele produce combined immunodeficiency with CD8
      lymphopenia, a different clinical picture from this disease. Those
      patients were not free of autoimmunity, so the comparison shows the
      allele alone gives a different presentation rather than showing that an
      activating allele is required for autoimmunity at all.
  downstream:
  - target: Unopposed Hyperactive ZAP70 Signalling
    causal_link_type: DIRECT
    description: >-
      The hypomorph cannot damp the activating allele the way a wild-type copy
      does, so the hyperactive signal becomes the cell's operating state.
    evidence:
    - reference: PMID:26783323
      reference_title: "A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Thus, the hyperactive R360P phenotype was masked by WT ZAP-70 and
        revealed only in the presence of the hypoactive R192W allele.
      explanation: >-
        Titrating wild-type or R192W against R360P in ZAP-70-deficient Jurkat
        cells shows that it is the hypomorphic partner that lets the activating
        allele's effect emerge.
  - target: Decreased total CD8+ T cell count
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The second arm of the mechanism, and the one this disease shares with
      ZAP70 deficiency. Reduced docking on the phosphorylated zeta chain
      weakens the signal the CD8 lineage needs to complete positive selection.
      It is partial here, where the same allele in the homozygous state gives
      the full immunodeficiency picture; the intermediate steps in these two
      children were never measured.
    evidence:
    - reference: PMID:37313400
      reference_title: "Combined immunodeficiency caused by pathogenic variants in the ZAP70 C-terminal SH2 domain."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        a homozygous ZAP-70 R192W variant was identified in 2 siblings with
        combined immunodeficiency and CD8 lymphopenia, confirming the
        pathogenicity of this mutation.
      explanation: >-
        Ties this allele specifically to CD8 lymphopenia in patients, which is
        what this edge asserts.
  - target: Impaired phytohemagglutinin-induced T lymphocyte transformation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The functional counterpart of the same arm: a receptor that cannot
      recruit its kinase efficiently gives a weak proliferative response to
      mitogen.
    evidence:
    - reference: PMID:37313400
      reference_title: "Combined immunodeficiency caused by pathogenic variants in the ZAP70 C-terminal SH2 domain."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        While the R170C mutant was highly expressed, there was an absence of
        TCR-induced proliferation, associated with significantly attenuated
        TCR-induced ZAP-70 phosphorylation and a lack of binding of ZAP-70 to
        TCR-ζ.
      explanation: >-
        Shows the docking-defective allele class abolishing TCR-induced
        proliferation in patient cells. The quoted measurement is for the
        sibling R170C allele in the same binding pocket, so this edge rests on
        the allele class rather than on R192W alone.
      directness: INDIRECT
- name: Activating ZAP70 Autoinhibition-Weakening Allele
  description: >-
    p.R360P sits in a loop of the kinase N-lobe beside Tyr315 and Tyr319, the
    interdomain B residues that hold the kinase in its autoinhibited
    conformation. The substitution destabilises that arrangement, leaving the
    kinase partially constitutively active: in T-cell lines it raises
    TCR-induced phosphorylation of ZAP-70 itself and of its substrates LAT and
    SLP-76, raises Erk phosphorylation, and raises basal CD69. The effect is
    weak, which is consistent with a single copy beside wild-type ZAP70 being
    clinically silent.
  biological_scale: MOLECULAR
  genetic_context:
    gene:
      preferred_term: ZAP70
      term:
        id: hgnc:12858
        label: ZAP70
    allele_type: missense, c.1079G>C p.R360P
    variant_origin: GERMLINE
    zygosity: COMPOUND_HETEROZYGOUS
    functional_impact_category: HYPERMORPHIC
    description: >-
      Paternally inherited weakly activating allele, in trans with the
      hypomorphic p.R192W allele.
  genes:
  - preferred_term: ZAP70
    term:
      id: hgnc:12858
      label: ZAP70
  molecular_functions:
  - preferred_term: protein tyrosine kinase activity
    modifier: INCREASED
    term:
      id: GO:0004713
      label: protein tyrosine kinase activity
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  evidence:
  - reference: PMID:26783323
    reference_title: "A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These results were consistent with the hypothesis that R360P ZAP-70 is a
      weakly hyperactive protein due to disruption of its autoinhibitory
      mechanism.
    explanation: >-
      Inducible expression in ZAP-70-deficient Jurkat cells raises TCR-induced
      phosphorylation of ZAP-70, SLP-76, LAT and Erk relative to wild type.
  - reference: PMID:33531381
    reference_title: "A disease-associated mutation that weakens ZAP70 autoinhibition enhances responses to weak and self-ligands."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These results support the notion that the R360P mutation directly weakens
      ZAP70 autoinhibition, thereby rendering ZAP70 partially constitutively
      active.
    explanation: >-
      With the SH2 domains and interdomain A deleted, R360P phosphorylates LAT
      spontaneously, which is direct evidence that the substitution weakens
      autoinhibition rather than acting indirectly.
  downstream:
  - target: Unopposed Hyperactive ZAP70 Signalling
    causal_link_type: DIRECT
    description: >-
      This is the allele that sets the cell's signalling state once no
      wild-type copy is present to oppose it.
    evidence:
    - reference: PMID:26783323
      reference_title: "A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Transiently transfected P116 cells expressing R360P ZAP-70 had higher
        basal CD69 surface expression
      explanation: >-
        Raised basal activation marker expression without receptor stimulation
        is the measurement behind this edge: the allele is signalling on its
        own, not merely responding more strongly.
- name: Unopposed Hyperactive ZAP70 Signalling
  description: >-
    With no wild-type copy to oppose it, the activating allele sets the
    signalling threshold of the patients' T cells. TCR signalling is enhanced
    and, critically, mature T cells respond to weak agonist and self
    peptide-MHC complexes that wild-type T cells disregard. Both affected
    children were transplanted before the genotype was known, so no patient T
    cells were ever studied; the evidence is from carrier blood cells,
    reconstituted T-cell lines, and a knock-in mouse.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  biological_processes:
  - preferred_term: T cell receptor signaling pathway
    modifier: INCREASED
    term:
      id: GO:0050852
      label: T cell receptor signaling pathway
  evidence:
  - reference: PMID:26783323
    reference_title: "A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Maternal cells (WT/R192W) showed decreased phosphorylation of the MAP
      kinases Erk1 and Erk2 in an anti-CD3 dose dependent manner, whereas cells
      from the father and healthy sister (WT/R360P) tended to have higher Erk
      phosphorylation.
    explanation: >-
      Primary human carrier cells show the two alleles pulling TCR signalling in
      opposite directions. This is the closest the published work comes to
      patient cells, which were unavailable after transplantation. Graded
      IN_VITRO rather than HUMAN_CLINICAL because the measurement is an
      anti-CD3 stimulation assay on isolated blood cells, not a clinical
      observation.
    directness: INDIRECT
  - reference: PMID:33531381
    reference_title: "A disease-associated mutation that weakens ZAP70 autoinhibition enhances responses to weak and self-ligands."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      To eliminate the possibility of a TCR repertoire shift, the OTI transgenic
      TCR was introduced into R360P mice, which resulted in enhanced T cell
      responses to weaker stimuli, including weak agonists and a self-peptide.
    explanation: >-
      On a fixed TCR background, where repertoire compensation is excluded, the
      activating allele selectively increases responses to weak and self
      ligands.
  downstream:
  - target: Loss of Peripheral T Cell Tolerance to Self Antigens
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33531381
      reference_title: "A disease-associated mutation that weakens ZAP70 autoinhibition enhances responses to weak and self-ligands."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        These observations suggest that disruption of ZAP70 autoinhibition by
        the R360P mutation enables increased mature T cell sensitivity to
        self-antigens that would normally be ignored by wild-type T cells, a
        mechanism that may contribute to the break of tolerance in human
        patients with R360P mutation.
      explanation: >-
        The authors' own inference from the mouse to the patients. Worded as a
        proposal, and the mice do not develop autoimmunity, so this edge is an
        inference step rather than a demonstrated human mechanism.
      directness: INDIRECT
- name: Loss of Peripheral T Cell Tolerance to Self Antigens
  description: >-
    Mature T cells that react to self peptide-MHC are normally held below the
    activation threshold. When the threshold is lowered, such cells can be
    driven by self ligands in a permissive cytokine environment, which the
    authors propose as the route from the kinase defect to organ-directed
    autoimmunity. Unlike the hypomorphic ZAP70 alleles studied in mice, where
    forbidden clones escape thymic deletion, the activating allele acts mainly
    on mature cells: thymic negative selection is if anything strengthened, and
    knock-in mice accumulate regulatory and anergic T cells rather than
    autoimmunity.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  biological_processes:
  - preferred_term: peripheral tolerance induction
    modifier: DECREASED
    term:
      id: GO:0002465
      label: peripheral tolerance induction
  evidence:
  - reference: PMID:34923645
    reference_title: "ZAP70, too little, too much can lead to autoimmunity."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Hyperactive ZAP70 enhances thymic negative selection but some thymocytes
      will, nonetheless, escape negative selection and have greater sensitivity
      to weak and self-ligands.
    explanation: >-
      States the mechanism this node asserts, and distinguishes it from the
      central-tolerance failure that hypoactive ZAP70 causes.
  downstream:
  - target: T Follicular Helper Cell Expansion
    causal_link_type: DIRECT
    description: >-
      Autoreactive CD4 T cells that are no longer held below threshold are the
      proposed source of the excess B-cell help. The step is drawn from the
      knock-in mouse, where the expansion is measured after infection rather
      than at baseline, so the human version of it is inferred.
    evidence:
    - reference: PMID:34923645
      reference_title: "ZAP70, too little, too much can lead to autoimmunity."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        as a consequence of enhanced TCR signaling, it is likely that the R360P
        mutation led to excessive auto-reactive T helper cell activity for B
        cells
      explanation: >-
        The authors' statement of this step, hedged in the source and recorded
        as such.
      directness: INDIRECT
  - target: Colitis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The gut disease in both children was an inflammatory colitis diagnosed
      endoscopically rather than an autoantibody-defined lesion, so it is drawn
      from the loss of T-cell tolerance and not from the antibody arm. No
      source identifies the effector population in the patients' bowel.
  - target: Minimal change glomerulonephritis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Renal involvement is reported in both siblings, and in the brother's
      biopsy as widespread podocyte foot-process effacement with only mild IgG
      deposition. The immune route to the podocyte is not established in these
      patients, which is why the target here is the lesion rather than the
      syndrome: the chain then runs through the foot-process effacement and
      proteinuria to the nephrotic syndrome.
- name: T Follicular Helper Cell Expansion
  description: >-
    Help to B cells is the step that connects a T-cell signalling defect to an
    antibody-mediated disease, and it is the part of the chain the mouse model
    supports most directly. After acute LCMV infection, R360P knock-in mice
    expand antigen-specific follicular helper T cells more than wild-type mice,
    and aged knock-in mice carry higher total IgG and IgG1. ZAP-70 is expressed
    predominantly in T and NK cells, so excess T-cell help, rather than an
    intrinsic B-cell defect, is the proposed explanation for why these patients
    make pathogenic autoantibodies.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: T follicular helper cell
    term:
      id: CL:0002038
      label: T follicular helper cell
  biological_processes:
  - preferred_term: T follicular helper cell differentiation
    modifier: INCREASED
    term:
      id: GO:0061470
      label: T follicular helper cell differentiation
  evidence:
  - reference: PMID:33531381
    reference_title: "A disease-associated mutation that weakens ZAP70 autoinhibition enhances responses to weak and self-ligands."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In addition, the R360P mutation resulted in enhanced follicular helper T
      cell expansion after LCMV infection.
    explanation: >-
      The knock-in result this node rests on, measured on antigen-specific
      effector cells after infection rather than at baseline.
  - reference: PMID:33531381
    reference_title: "A disease-associated mutation that weakens ZAP70 autoinhibition enhances responses to weak and self-ligands."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      we found that there were substantial increases in IgG and IgG1 amounts in
      10 month old R360P mice compared to those of WT controls
    explanation: >-
      The humoral consequence in aged knock-in mice, which the authors read as a
      long-term effect of the expanded follicular helper response.
  downstream:
  - target: Autoantibody Production Against Tissue and Plasma Protein Antigens
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34923645
      reference_title: "ZAP70, too little, too much can lead to autoimmunity."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Thus, as a consequence of enhanced TCR signaling, it is likely that the
        R360P mutation led to excessive auto‐reactive T helper cell activity for
        B cells.
      explanation: >-
        The authors' statement of this edge, hedged ("it is likely") because it
        rests on the mouse data rather than on patient material.
      directness: INDIRECT
- name: Autoantibody Production Against Tissue and Plasma Protein Antigens
  description: >-
    The diseases that defined this syndrome are antibody-defined: bullous
    pemphigoid with linear basement-membrane IgG at a titre above 1:160, and an
    inhibitory autoantibody to coagulation factor VIII causing bleeding. Both
    point at autoreactive B-cell help as the effector arm rather than at direct
    T-cell cytotoxicity. The node is scaled CELLULAR because its substrate is
    the antibody-secreting cell; the organ-level consequences are the phenotypes
    downstream of it. Tolerance is recorded as broken rather than as an
    intrinsic B-cell defect: ZAP-70 is expressed predominantly in T and NK
    cells, and the proposed cause is excess T-cell help.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: plasma cell
    term:
      id: CL:0000786
      label: plasma cell
  biological_processes:
  - preferred_term: autoantibody secretion
    modifier: INCREASED
    term:
      id: GO:0002377
      label: immunoglobulin production
  - preferred_term: B cell tolerance induction
    modifier: DECREASED
    term:
      id: GO:0002514
      label: B cell tolerance induction
  evidence:
  - reference: PMID:26783323
    reference_title: "A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Altered signaling could allow autoreactive T cells to escape thymic
      deletion and emigrate into the periphery, where they could activate
      potentially autoreactive B cells, thereby leading to production of
      autoantibodies to antigens such as skin proteins (bullous pemphigoid) and
      clotting factors (autoimmune hemophilia).
    explanation: >-
      The proposed route from the signalling defect to the two
      antibody-mediated diseases in these children, stated conditionally by the
      authors. It is quoted for its second half, the activation of autoreactive
      B cells; the thymic-escape premise in its first half is the question the
      central-versus-peripheral-tolerance discussion records as open, and this
      node does not rest on it.
    directness: INDIRECT
  downstream:
  - target: Bullous pemphigoid
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:26783323
      reference_title: "A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        leading to production of autoantibodies to antigens such as skin
        proteins (bullous pemphigoid) and clotting factors (autoimmune
        hemophilia)
      explanation: >-
        Names the skin antigen as a target of the autoantibody response, which
        is this edge.
      directness: INDIRECT
  - target: Anti-factor VIII antibody positivity
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:26783323
      reference_title: "A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        leading to production of autoantibodies to antigens such as skin
        proteins (bullous pemphigoid) and clotting factors (autoimmune
        hemophilia)
      explanation: >-
        The same sentence names clotting factors, which is the other arm of
        this node's output.
      directness: INDIRECT
  - target: Oral mucosal blisters
    causal_link_type: DIRECT
    description: >-
      The mucosal blistering is the same pemphigoid lesion at a second site
      rather than a separate disease.
  - target: Linear IgG deposits along the epidermal basement membrane zone
    causal_link_type: DIRECT
    description: >-
      The deposition is this node's output made visible: the autoantibody bound
      at the dermo-epidermal junction, which is what the immunofluorescence
      detects.
phenotypes:
- category: Clinical
  name: Bullous pemphigoid
  description: >-
    The defining feature, and the reason the syndrome was recognised as novel.
    Both siblings had generalised blistering: in the brother from 20 months,
    over the whole body and the oral mucosa, with a biopsy showing subepidermal
    clefting, eosinophil and neutrophil infiltration and linear
    basement-membrane IgG above a 1:160 titre; in the sister from one month of
    age. Bullous pemphigoid in young children is normally steroid-responsive,
    which this was not.
  phenotype_term:
    preferred_term: bullous pemphigoid
    term:
      id: HP:0033804
      label: Subepidermal blistering
    temporality: CHRONIC
    onset:
      onset_category: INFANTILE
      min_age_years: 0.08
      max_age_years: 1.7
      notes: >-
        One month in the sister and 20 months in the brother. The category
        records the sister's onset, which is the infantile onset the disease is
        named for; the brother's falls in the second year, and the range carries
        both rather than averaging them. The category is single-valued, so it
        cannot say CHILDHOOD for one sibling and INFANTILE for the other, and
        with two patients a per-subtype split would be two subtypes of one.
  evidence:
  - reference: PMID:26783323
    reference_title: "A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a biopsy showed bullous pemphigoid, with characteristic subepidermal
      clefting, infiltration with eosinophils and neutrophils, and linear
      basement membrane and intercellular deposition of IgG at a titer greater
      than 1:160
    explanation: >-
      Histology and immunofluorescence establishing the diagnosis and the
      subepidermal level of the split that the bound HPO term names.
  - reference: PMID:26783323
    reference_title: "A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      His sister II-3 experienced bullous pemphigoid beginning at 1 mo of age
      that rapidly became generalized
    explanation: >-
      The second affected child, with onset in the first month of life.
  - reference: PMID:41608114
    reference_title: "Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Severe autoimmunity (bullous pemphigoid, inflammatory colitis)"
    explanation: >-
      IUIS records bullous pemphigoid as one of the two manifestations that
      characterise this entity.
- category: Clinical
  name: Oral mucosal blisters
  description: >-
    The brother's blistering involved the oral mucosa as well as the skin.
  phenotype_term:
    preferred_term: Oral mucosal blisters
    term:
      id: HP:0200097
      label: Oral mucosal blisters
  evidence:
  - reference: PMID:26783323
    reference_title: "A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      By 20 mo of age, blistering skin disease developed, involving his entire
      body and oral mucosa
    explanation: >-
      Records mucosal involvement alongside the cutaneous disease.
- category: Clinical
  name: Colitis
  description: >-
    Inflammatory colitis diagnosed endoscopically in both children: in the
    brother from three years of age, and in the sister after poor weight gain
    was initially put down to rotavirus infection.
  phenotype_term:
    preferred_term: inflammatory colitis
    term:
      id: HP:0002583
      label: Colitis
  evidence:
  - reference: PMID:26783323
    reference_title: "A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She had poor weight gain that was initially attributed to a rotavirus
      infection but was later diagnosed by endoscopy as inflammatory colitis,
      similar to that of her brother.
    explanation: >-
      Endoscopic diagnosis in the sister, and the statement that the brother's
      colitis was the same disease.
  - reference: PMID:41608114
    reference_title: "Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Severe autoimmunity (bullous pemphigoid, inflammatory colitis)"
    explanation: >-
      The IUIS clinical column for this entity names inflammatory colitis.
  sequelae:
  - target: Failure to thrive in infancy
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:26783323
      reference_title: "A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        She had poor weight gain that was initially attributed to a rotavirus
        infection but was later diagnosed by endoscopy as inflammatory colitis
      explanation: >-
        The growth failure was the presenting sign of the colitis, which is the
        direction of this edge.
- category: Clinical
  name: Nephrotic syndrome
  description: >-
    The brother's presenting feature, at nine months of age. The renal biopsy
    showed histologically unremarkable glomeruli with mild IgG deposition, and
    electron microscopy showed widespread podocyte foot-process effacement,
    read as minimal change disease.
  phenotype_term:
    preferred_term: Nephrotic syndrome
    term:
      id: HP:0000100
      label: Nephrotic syndrome
    onset:
      onset_category: INFANTILE
      min_age_years: 0.75
      notes: Nine months of age, in the brother only.
  evidence:
  - reference: PMID:26783323
    reference_title: "A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At 9 mo of age, male II-2 developed nephrotic syndrome.
    explanation: >-
      The age and the diagnosis in the affected brother.
  sequelae:
  - target: Decreased circulating IgG concentration
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:26783323
      reference_title: "A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The boy also had low total serum IgG, possibly attributable to nephrotic
        syndrome
      explanation: >-
        The authors propose urinary loss as the explanation for the low IgG.
        Hedged in the source, and this edge is no stronger than that.
      directness: INDIRECT
- category: Clinical
  name: Minimal change glomerulonephritis
  description: >-
    The histological substrate of the nephrotic syndrome in the affected
    brother: normal glomeruli on light microscopy with diffuse foot-process
    effacement on electron microscopy. Only one of the two siblings was
    biopsied.
  phenotype_term:
    preferred_term: minimal change disease
    term:
      id: HP:0012579
      label: Minimal change glomerulonephritis
  evidence:
  - reference: PMID:26783323
    reference_title: "A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A renal biopsy showed histologically normal glomeruli and mild IgG
      deposition, but electron microscopy revealed widespread foot process
      effacement most consistent with minimal change disease
    explanation: >-
      The biopsy findings and the pathologist's reading of them.
  sequelae:
  - target: Podocyte foot process effacement
    causal_link_type: DIRECT
    description: >-
      The diagnosis and the ultrastructural lesion are the same thing described
      at two levels, so the edge runs from the named entity to the measurement
      that defines it and the chain to proteinuria is carried from there.
- category: Clinical
  name: Proteinuria
  description: >-
    Present in both siblings. In the sister it did not progress to nephrotic
    syndrome and no biopsy was performed.
  phenotype_term:
    preferred_term: Proteinuria
    term:
      id: HP:0000093
      label: Proteinuria
  sequelae:
  - target: Nephrotic syndrome
    causal_link_type: DIRECT
    description: >-
      Heavy protein loss is what defines the nephrotic syndrome the brother
      developed. His sister's proteinuria never reached that threshold, which is
      why the two are curated as separate phenotypes.
  evidence:
  - reference: PMID:26783323
    reference_title: "A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She also had proteinuria, although no renal biopsy was performed given
      the lack of progression to nephrotic syndrome.
    explanation: >-
      Renal involvement in the sister, at a lesser severity than her brother's.
- category: Clinical
  name: Anti-factor VIII antibody positivity
  description: >-
    An acquired factor VIII inhibitor in the affected brother, presenting at
    two years of age with bruising and a joint bleed. This is the second
    antibody-defined disease in the syndrome and, with the pemphigoid, is what
    marks the phenotype as humorally mediated.
  phenotype_term:
    preferred_term: factor VIII autoantibody
    term:
      id: HP:6000494
      label: Anti-factor VIII antibody positivity
  evidence:
  - reference: PMID:26783323
    reference_title: "A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The boy had hemophilia due to a factor VIII autoantibody and nephrotic
      syndrome.
    explanation: >-
      Names the autoantibody and the resulting bleeding disorder.
  sequelae:
  - target: Joint hemorrhage
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:26783323
      reference_title: "A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        At age 2, he suffered bruising and a hemarthrosis as a result of an
        autoantibody to clotting factor VIII
      explanation: >-
        The source attributes the joint bleed to the inhibitor, which is this
        edge.
  - target: Bruising susceptibility
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:26783323
      reference_title: "A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        At age 2, he suffered bruising and a hemarthrosis as a result of an
        autoantibody to clotting factor VIII
      explanation: >-
        The same sentence attributes the bruising to the inhibitor.
- category: Clinical
  name: Joint hemorrhage
  description: >-
    A hemarthrosis at two years of age, the bleeding manifestation of the
    acquired factor VIII inhibitor.
  phenotype_term:
    preferred_term: hemarthrosis
    term:
      id: HP:0005261
      label: Joint hemorrhage
  evidence:
  - reference: PMID:26783323
    reference_title: "A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At age 2, he suffered bruising and a hemarthrosis as a result of an
      autoantibody to clotting factor VIII
    explanation: >-
      The bleeding episode and its attribution to the inhibitor.
- category: Clinical
  name: Bruising susceptibility
  description: >-
    Reported with the hemarthrosis in the affected brother, from the acquired
    factor VIII inhibitor.
  phenotype_term:
    preferred_term: Bruising susceptibility
    term:
      id: HP:0000978
      label: Bruising susceptibility
  evidence:
  - reference: PMID:26783323
    reference_title: "A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At age 2, he suffered bruising and a hemarthrosis as a result of an
      autoantibody to clotting factor VIII
    explanation: >-
      Records bruising alongside the joint bleed.
- category: Clinical
  name: Failure to thrive in infancy
  description: >-
    Poor weight gain in the sister, which proved to be the first sign of her
    colitis rather than an infectious illness.
  phenotype_term:
    preferred_term: poor weight gain in infancy
    term:
      id: HP:0001531
      label: Failure to thrive in infancy
  evidence:
  - reference: PMID:26783323
    reference_title: "A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She had poor weight gain that was initially attributed to a rotavirus
      infection but was later diagnosed by endoscopy as inflammatory colitis
    explanation: >-
      The growth failure and the diagnosis it led to.
- category: Clinical
  name: Hypothyroidism
  description: >-
    Autoimmune hypothyroidism in the sister, recorded alongside declining donor
    chimerism after her first transplant and before the second. It is reported
    in the post-transplant course rather than as a presenting feature, so
    whether it belongs to the underlying syndrome or to the transplant course is
    not resolved by the source.
  phenotype_term:
    preferred_term: autoimmune hypothyroidism
    term:
      id: HP:0000821
      label: Hypothyroidism
  evidence:
  - reference: PMID:26783323
    reference_title: "A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      indicated graft rejection and autoimmune hypothyroidism developed
    explanation: >-
      Names the thyroid autoimmunity and the point in the course at which it
      appeared.
- category: Laboratory
  name: Decreased total CD8+ T cell count
  description: >-
    Reduced CD8 T cells in both children. This is the one laboratory feature
    shared with ZAP70 deficiency, but it is partial here rather than the
    near-absence that defines the immunodeficiency, and it came with no
    infectious susceptibility.
  phenotype_term:
    preferred_term: reduced CD8 T cells
    term:
      id: HP:5210426
      label: Decreased total CD8+ T cell count
  evidence:
  - reference: PMID:26783323
    reference_title: "A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Immunological workup revealed mild T and B cell lymphopenia in the brother
      and reduced CD8 T cells in both affected children, resulting in an
      elevated CD4/CD8 ratio
    explanation: >-
      The subset findings in both children.
  - reference: PMID:41608114
    reference_title: "Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Decreased CD8, normal or decreased CD4 cells"
    explanation: >-
      The IUIS T-cell column for this entity.
  sequelae:
  - target: Increased CD4:CD8 ratio
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:26783323
      reference_title: "A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        reduced CD8 T cells in both affected children, resulting in an elevated
        CD4/CD8 ratio
      explanation: >-
        The source states the ratio as a consequence of the CD8 reduction.
- category: Laboratory
  name: Increased CD4:CD8 ratio
  description: >-
    Follows from the CD8 reduction in both children. The ratio was raised but
    less extremely than in ZAP70 deficiency, where CD8 cells are effectively
    absent.
  phenotype_term:
    preferred_term: elevated CD4/CD8 ratio
    term:
      id: HP:0033221
      label: Increased CD4:CD8 ratio
  evidence:
  - reference: PMID:26783323
    reference_title: "A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The affected sister had increased CD19 B cells, and both children had
      elevated CD4/CD8 ratios, although not as high as generally found in
      patients with ZAP70 deficiency
    explanation: >-
      Gives the raised ratio and the explicit contrast in degree with ZAP70
      deficiency.
- category: Laboratory
  name: Decreased circulating IgG concentration
  description: >-
    Low total serum IgG in the brother, which the authors attribute at least in
    part to urinary loss from his nephrotic syndrome. Antibody production was
    not uniformly lost: his tetanus and type 14 pneumococcal titres were
    protective, although three of the four pneumococcal serotypes measured were
    below the protective threshold (see the specific-antibody phenotype).
  phenotype_term:
    preferred_term: low total serum IgG
    term:
      id: HP:0004315
      label: Decreased circulating IgG concentration
  evidence:
  - reference: PMID:26783323
    reference_title: "A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The boy also had low total serum IgG, possibly attributable to nephrotic
      syndrome, but post-vaccine titers to type 14 pneumococcus and tetanus were
      protective.
    explanation: >-
      The low IgG, the proposed renal explanation, and the preserved vaccine
      responses that argue against an antibody-production defect.
- category: Laboratory
  name: Podocyte foot process effacement
  description: >-
    The ultrastructural lesion behind the brother's proteinuria, seen on
    electron microscopy of the renal biopsy. It is the finding that classified
    his glomerular disease as minimal change rather than an
    immune-complex nephritis, despite the mild IgG staining.
  phenotype_term:
    preferred_term: widespread foot process effacement
    term:
      id: HP:0031266
      label: Podocyte foot process effacement
  evidence:
  - reference: PMID:26783323
    reference_title: "A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      electron microscopy revealed widespread foot process effacement most
      consistent with minimal change disease
    explanation: >-
      The electron-microscopy finding and its interpretation.
  sequelae:
  - target: Proteinuria
    causal_link_type: DIRECT
    description: >-
      Effacement of the podocyte foot processes is what makes the glomerular
      filter leak protein. The source reports both findings in the same patient
      without writing the causal sentence, so this edge is the standard reading
      of the lesion and carries no citation of its own.
- category: Laboratory
  name: Impaired phytohemagglutinin-induced T lymphocyte transformation
  description: >-
    Diminished proliferation to phytohaemagglutinin in both children. The
    brother's responses were diminished to PHA and absent to candida and
    tetanus antigens, but he was taking immunosuppressants when tested; his
    sister was tested before immunosuppression was started. Hers is therefore
    the uncontaminated measurement, and it is severe rather than marginal: the
    paper calls it diminished but not absent, while its Table 1 gives 2.4 per
    cent against a stated floor of 49.9 per cent, with the brother at 1 per
    cent. The clinical point is that neither child had infections suggesting
    immunodeficiency despite this.
  phenotype_term:
    preferred_term: diminished PHA proliferative response
    term:
      id: HP:0025834
      label: Impaired phytohemagglutinin-induced T lymphocyte transformation
  evidence:
  - reference: PMID:26783323
    reference_title: "A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      cells, tested before institution of immunosuppressive medication, had
      diminished, but not absent, PHA responses
    explanation: >-
      The sister's result, measured before immunosuppression and so the one
      that reports the disease rather than its treatment.
  - reference: PMID:26783323
    reference_title: "A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      His proliferative responses were diminished to phytohemagglutinin (PHA)
      and absent of candida or tetanus antigens; however, he was receiving
      immunosuppressive medications when the immune studies were done.
    explanation: >-
      The brother's result together with the confound the authors flag, which is
      why this phenotype is not graded more severely.
- category: Laboratory
  name: Decreased circulating specific pneumococcal antibody concentration
  description: >-
    Three of the four pneumococcal serotypes measured in the brother were below
    the protective threshold the paper itself states (0.2, 0.7 and 0.3 against a
    stated threshold of 1.3 micrograms per ml for types 3, 8 and 12), while type 14 at 1.6 and the tetanus
    titre at 1.64 were protective. The narrative text names only the two
    protective results, so this phenotype comes from the paper's own Table 1
    rather than from its prose. Only the brother was tested.
  phenotype_term:
    preferred_term: non-protective pneumococcal serotype titres
    term:
      id: HP:0012476
      label: Decreased circulating specific pneumococcal antibody concentration
  evidence:
  - reference: PMID:26783323
    reference_title: "A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      | Pneumococcal IgG, Type 3 | 0.2 (>1.3 µg/ml) | ND |
    explanation: >-
      A Table 1 row giving a serotype titre below the threshold printed in the
      same row.
  - reference: PMID:26783323
    reference_title: "A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      | Pneumococcal IgG, Type 12 | 0.3 (>1.3 µg/ml) | ND |
    explanation: >-
      A second non-protective serotype, so the finding is not a single
      outlying measurement.
- category: Laboratory
  name: Decreased circulating IgM concentration
  description: >-
    Low in both children against their own age-matched ranges: 25 mg/dl against
    48 to 168 in the brother and 9 against 17 to 105 in the sister. IUIS records
    low IgM as part of this entity's immunoglobulin pattern, alongside normal
    IgA and low or normal IgG.
  notes: >-
    The binding carries HPO's older label for HP:0002850, "Decreased circulating
    total IgM", because that is what the committed term cache holds and what
    every other entry using this term carries. HPO has since renamed it to
    "Decreased circulating IgM concentration"; the cache-first validator rejects
    the current name, which is the problem tracked in dismech issue 11750.
  phenotype_term:
    preferred_term: low serum IgM
    term:
      id: HP:0002850
      label: Decreased circulating total IgM
  evidence:
  - reference: PMID:26783323
    reference_title: "A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      | IgM (mg/dl) | 25 (48-168) | 9 (17-105) |
    explanation: >-
      The Table 1 row, with both children's values below their age-matched
      reference ranges.
  - reference: PMID:41608114
    reference_title: "Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Normal IgA, low IgM, low/normal IgG; protective Ab responses to vaccines"
    explanation: >-
      The IUIS immunoglobulin column for this entity, which records low IgM as
      characteristic rather than incidental.
- category: Laboratory
  name: Increased circulating IgE concentration
  description: >-
    Mildly raised in the brother at 99 IU/ml against a stated ceiling of 64; not
    measured in the sister. Elevated IgE is also described in a subset of
    patients with loss-of-function ZAP70 disease, where it accompanies skin
    infiltration by dysfunctional CD4 T cells.
  phenotype_term:
    preferred_term: raised serum IgE
    term:
      id: HP:0003212
      label: Increased circulating IgE concentration
  evidence:
  - reference: PMID:26783323
    reference_title: "A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      | IgE IU/ml | 99 (<64) | ND |
    explanation: >-
      The Table 1 row, with the brother's value above the stated ceiling and the
      sister not tested.
- category: Laboratory
  name: Linear IgG deposits along the epidermal basement membrane zone
  description: >-
    The immunofluorescence finding behind the pemphigoid diagnosis, at a titre
    above 1:160, with intercellular deposition as well. It is recorded as its
    own laboratory phenotype for the same reason the podocyte lesion is kept
    separate from the nephrotic syndrome: it is the measurement, not the
    diagnosis.
  phenotype_term:
    preferred_term: linear basement membrane IgG deposition
    term:
      id: HP:0031540
      label: Linear IgG deposits along the epidermal basement membrane zone
  evidence:
  - reference: PMID:26783323
    reference_title: "A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      linear basement membrane and intercellular deposition of IgG at a titer
      greater than 1:160
    explanation: >-
      The immunofluorescence result and its titre.
genetic:
- name: ZAP70 (hypomorphic plus activating alleles in trans)
  notes: >-
    ZAP70 at 2q11.2 encodes the 70 kDa zeta-chain-associated protein kinase, a
    Syk-family cytoplasmic tyrosine kinase coupling the engaged T-cell receptor
    to LAT and SLP-76. What is distinctive about this disease is not a new
    region of the gene but the pairing: a docking-defective C-SH2 allele with an
    autoinhibition-weakening kinase-domain allele. Both residues were novel when
    reported and neither lies near the previously reported loss-of-function
    alleles.

    No gene_disease_validity assertion is recorded. ClinGen's SCID-CID Gene
    Curation Expert Panel classifies ZAP70 as Definitive, but for
    MONDO:0010023, the loss-of-function combined immunodeficiency, which is a
    different gene-disease pair from this one. Copying that tier here would
    assert a classification nobody has made for this entity.
  gene_term:
    preferred_term: ZAP70
    term:
      id: hgnc:12858
      label: ZAP70
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: PMID:41608114
      reference_title: "Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "ZAP-70 combined hypomorphic and activating mutations | ZAP70 | AR (LOF/GOF) | 617006"
      explanation: >-
        The gene-level inheritance annotation for this entity: recessive, with
        one allele of each functional class.
  variants:
  - name: ZAP70 c.574C>T p.R192W
    description: >-
      C-terminal SH2 domain allele, inherited from the mother. The tryptophan
      occupies the phosphotyrosine-binding pocket formed by arginines 170, 190
      and 192, so the kinase docks poorly on the doubly phosphorylated zeta
      chain. Reported at an allele frequency of 0.00003 in ExAC at the time of
      publication.
    clinical_significance: PATHOGENIC
    functional_effects:
    - function: binding to the phosphorylated T-cell receptor zeta chain
      description: >-
        Reduced association with, and reduced phosphorylation on, the zeta
        chain in transfected cells.
      type: hypomorphic
    evidence:
    - reference: PMID:26783323
      reference_title: "A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: >-
        The replacement of arginine with a bulky tryptophan residue in the
        phosphotyrosine-binding pocket of the ZAP-70 C-terminal SH2 domain
        (C-SH2; R192W mutation) was predicted to diminish ZAP-70 binding to the
        ζ-chain
      explanation: >-
        The structural prediction for this substitution, which the
        immunoprecipitation experiments in the same paper then confirmed.
    - reference: PMID:37313400
      reference_title: "Combined immunodeficiency caused by pathogenic variants in the ZAP70 C-terminal SH2 domain."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: >-
        Structural modeling of this region revealed the critical nature of the
        arginines at positions 170 and 192, in concert with R190, forming a
        binding pocket for the phosphorylated TCR-zeta chain.
      explanation: >-
        Independent structural account of why position 192 matters, from the
        series that later found this allele in the homozygous state.
  - name: ZAP70 c.1079G>C p.R360P
    description: >-
      Kinase-domain N-lobe allele, inherited from the father, lying in a loop
      close to Tyr315 and Tyr319. It weakens the autoinhibited conformation,
      producing a weakly hyperactive kinase. Neighbouring substitutions in the
      same region (D327P, K362E) are more strongly activating, which is the
      basis for calling this one weak.
    clinical_significance: PATHOGENIC
    functional_effects:
    - function: T-cell receptor-proximal tyrosine kinase activity
      description: >-
        Partial constitutive activation through loss of autoinhibition, with
        increased phosphorylation of ZAP-70 Y319 and Y493 and of LAT and SLP-76
        on receptor engagement.
      type: hypermorphic
    evidence:
    - reference: PMID:26783323
      reference_title: "A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: >-
        In contrast, R360P lies in a loop of the N-lobe of the kinase domain in
        proximity to Y319, a key residue for autoinhibition of ZAP-70
      explanation: >-
        Locates the substitution with respect to the autoinhibitory site.
    - reference: PMID:34923645
      reference_title: "ZAP70, too little, too much can lead to autoimmunity."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        the R360P mutation appears to relieve the interdomain B and kinase
        domain interaction
      explanation: >-
        The structural interpretation of how this allele breaks autoinhibition,
        and how that differs from the W131A hypermorph.
  evidence:
  - reference: PMID:26783323
    reference_title: "A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Analysis of whole-exome sequencing (WES) revealed no consanguinity and only
      one gene, ZAP70, with nonsynonymous coding variants potentially causing
      homozygous recessive immunological disease.
    explanation: >-
      The gene-finding result that assigns the syndrome to ZAP70.
  - reference: PMID:26783323
    reference_title: "A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neither mutation had been reported previously, nor were they near
      mutations associated with human disease
    explanation: >-
      Both alleles were new, and neither sits in the previously described
      loss-of-function territory.
diagnosis:
- name: Lymphocyte subset flow cytometry
  description: >-
    The first-line immunological test, and the one that places the disease
    beside ZAP70 deficiency rather than with the other causes of infantile
    autoimmunity. It shows reduced CD8 T cells with a raised CD4:CD8 ratio, and
    in the sister an increase in CD19 B cells. The deficit is partial, so the
    panel does not read as a SCID.
  diagnosis_term:
    preferred_term: lymphocyte subset flow cytometry
    term:
      id: NCIT:C16585
      label: Flow Cytometry
  evidence:
  - reference: PMID:26783323
    reference_title: "A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Immunological workup revealed mild T and B cell lymphopenia in the brother
      and reduced CD8 T cells in both affected children, resulting in an
      elevated CD4/CD8 ratio
    explanation: >-
      The subset pattern this test is being cited for.
  notes: >-
    Newborn T-cell receptor excision circle screening was normal in both
    children, so a normal TREC result does not exclude this disease. That is
    the same caveat that applies to ZAP70 deficiency, where continuing CD4
    thymic output can keep the screen normal.
- name: Molecular genetic testing (exome sequencing)
  description: >-
    The definitive test, and how the disease was found. Exome sequencing of five
    family members identified the compound heterozygous ZAP70 genotype and the
    carrier state of the healthy relatives. Both alleles were private to the
    family, so sequencing alone leaves two variants of uncertain significance:
    the functional work on zeta-chain binding and on autoinhibition is what
    makes the result interpretable.
  diagnosis_term:
    preferred_term: whole exome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  evidence:
  - reference: PMID:26783323
    reference_title: "A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole-exome sequencing performed on five family members revealed the
      affected siblings to be compound heterozygous for two unique missense
      mutations in the 70-kD T cell receptor ζ-chain associated protein (ZAP-70).
    explanation: >-
      Names the test, the family members sequenced and the result.
- name: Skin biopsy with direct immunofluorescence
  description: >-
    Establishes the bullous pemphigoid: subepidermal clefting with eosinophils
    and neutrophils on histology, and linear IgG along the basement membrane on
    immunofluorescence at a titre above 1:160.
  diagnosis_term:
    preferred_term: skin biopsy with direct immunofluorescence
    term:
      id: NCIT:C51692
      label: Skin Biopsy
  evidence:
  - reference: PMID:26783323
    reference_title: "A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a biopsy showed bullous pemphigoid, with characteristic subepidermal
      clefting, infiltration with eosinophils and neutrophils, and linear
      basement membrane and intercellular deposition of IgG at a titer greater
      than 1:160
    explanation: >-
      The histological and immunofluorescence findings this test returns.
- name: Kidney biopsy with electron microscopy
  description: >-
    Performed in the brother only. Light microscopy was near normal with mild
    IgG deposition; the diagnosis came from electron microscopy, which showed
    widespread podocyte foot-process effacement. The sister was not biopsied
    because her proteinuria did not progress.
  diagnosis_term:
    preferred_term: kidney biopsy with electron microscopy
    term:
      id: NCIT:C51699
      label: Kidney Biopsy
  evidence:
  - reference: PMID:26783323
    reference_title: "A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A renal biopsy showed histologically normal glomeruli and mild IgG
      deposition, but electron microscopy revealed widespread foot process
      effacement most consistent with minimal change disease
    explanation: >-
      What each modality contributed, and why the ultrastructural study was the
      one that settled the diagnosis.
- name: Endoscopy
  description: >-
    Diagnosed the colitis in the sister, after her poor weight gain had been
    attributed to a rotavirus infection. Her brother's colitis was reported as
    the same disease. The source says endoscopy and does not say which
    endoscopic procedure, nor report a biopsy, so neither is named here.
  diagnosis_term:
    preferred_term: endoscopy
    term:
      id: NCIT:C16546
      label: Endoscopic Procedure
  evidence:
  - reference: PMID:26783323
    reference_title: "A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      was later diagnosed by endoscopy as inflammatory colitis, similar to that
      of her brother
    explanation: >-
      The endoscopic diagnosis, at the level of specificity the source states.
      It says endoscopy, not colonoscopy, so the binding is the general
      endoscopic-procedure term rather than a colonoscopy term the source does
      not support.
- name: Factor VIII inhibitor measurement
  description: >-
    Identifies the acquired haemophilia in the brother, whose bruising and joint
    bleed were caused by an autoantibody to clotting factor VIII rather than by
    an inherited factor deficiency.
  diagnosis_term:
    preferred_term: factor VIII inhibitor assay
    term:
      id: NCIT:C154752
      label: Factor VIII Inhibitor Measurement
  evidence:
  - reference: PMID:26783323
    reference_title: "A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The boy had hemophilia due to a factor VIII autoantibody and nephrotic
      syndrome.
    explanation: >-
      The autoantibody this assay detects, and the bleeding phenotype it
      explains.
treatments:
- name: Allogeneic Hematopoietic Cell Transplantation
  description: >-
    The only treatment reported to control this disease. The brother was
    transplanted from a matched unrelated donor at five years of age after his
    autoimmunity became refractory to medical management; the sister was
    transplanted twice from her HLA-matched healthy sister, the second time with
    myeloablative conditioning after donor chimerism fell. Replacing the
    haematopoietic compartment removes the T cells carrying the two-allele
    genotype, which is why a transplant addresses the mechanism rather than the
    manifestations.
  treatment_term:
    preferred_term: allogeneic haematopoietic cell transplantation
    term:
      id: NCIT:C46089
      label: Allogeneic Hematopoietic Stem Cell Transplantation
  therapeutic_modality: CELL_THERAPY
  target_mechanisms:
  - target: Unopposed Hyperactive ZAP70 Signalling
    description: >-
      Donor-derived T cells carry wild-type ZAP70, so the activating allele is
      no longer unopposed in the T-cell compartment.
    evidence:
    - reference: PMID:26783323
      reference_title: "A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Both children required allogeneic hematopoietic cell transplantation
        (HCT), which resolved their autoimmunity.
      explanation: >-
        Replacing the T-cell compartment resolved the disease in both children,
        which is the outcome this mechanism link predicts.
      directness: INDIRECT
  evidence:
  - reference: PMID:26783323
    reference_title: "A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both children required allogeneic hematopoietic cell transplantation
      (HCT), which resolved their autoimmunity.
    explanation: >-
      Both affected children were transplanted and both had their autoimmunity
      resolve, which is the outcome evidence for this treatment.
  - reference: PMID:26783323
    reference_title: "A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Her pemphigoid resolved after the first HCT (Fig. 1 H), but a second HCT
      with myeloablative conditioning was performed after declining donor
      chimerism
    explanation: >-
      Shows both that the skin disease responded and that durable control
      required full donor chimerism, which the first graft did not maintain.
- name: Corticosteroid and Immunosuppressive Therapy
  description: >-
    Attempted and inadequate. High-dose steroids and several immunosuppressive
    regimens failed to control the brother's autoimmunity, and that failure is
    what took him to transplantation. This matters for recognising the disease:
    bullous pemphigoid of childhood is ordinarily steroid-responsive, so a
    refractory course in an infant is itself a signal. Only the steroids are
    named in the source; the other regimens are described as "multiple
    immunosuppressive regimens" without being identified, which is why no
    further agent is bound.
  treatment_term:
    preferred_term: immunosuppressive therapy
    term:
      id: NCIT:C15261
      label: Immunosuppressive Therapy
    therapeutic_agent:
    - preferred_term: corticosteroid
      term:
        id: CHEBI:50858
        label: corticosteroid
  therapeutic_modality: SMALL_MOLECULE
  evidence:
  - reference: PMID:26783323
    reference_title: "A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      His autoimmune manifestations became refractory to high-dose steroids and
      multiple immunosuppressive regimens; therefore, he underwent a matched
      unrelated HCT at 5 yr of age that resolved his pretransplant autoimmunity.
    explanation: >-
      States the failure of medical immunosuppression and the decision it led
      to.
  - reference: PMID:26783323
    reference_title: "A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      autoantibody-mediated bullous pemphigoid usually occurs in the elderly,
      and unlike in our patients, when found in young children it is very
      responsive to steroid treatment
    explanation: >-
      The authors' contrast with ordinary childhood bullous pemphigoid, which
      is why the refractory course is diagnostically meaningful.
animal_models:
- name: Zap70 R360P knock-in mouse
  species: Mouse
  genotype: Zap70 R360P homozygous knock-in
  background: C57BL/6
  publication: PMID:33531381
  description: >-
    CRISPR-generated knock-in carrying the activating allele in the homozygous
    state. The mice are healthy, fertile and normal-lived, and they do not
    develop autoimmunity: histology of multiple organs at 8 to 10 months was
    unremarkable and ANA and anti-dsDNA screening was negative. What they do
    show is the signalling phenotype. Thymocyte and peripheral T-cell
    development is grossly normal, but central memory CD8 cells increase, ZAP70
    Y319 phosphorylation and calcium mobilisation are enhanced, follicular
    helper T cells expand after LCMV infection, and aged animals have more IgG
    and IgG1. Crossing in the OTI transgenic TCR removes repertoire
    compensation and reveals selectively enhanced responses to weak agonist and
    self peptides.
  evidence:
  - reference: PMID:33531381
    reference_title: "A disease-associated mutation that weakens ZAP70 autoinhibition enhances responses to weak and self-ligands."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Mice with a ZAP70 R360P mutation and polyclonal TCR repertoires exhibited
      relatively normal T cell development but showed evidence of increased
      signaling.
    explanation: >-
      The model's core result: the allele changes signalling without disturbing
      development.
  modeled_mechanisms:
  - target: Unopposed Hyperactive ZAP70 Signalling
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Reproduces the enhanced TCR signalling and the altered sensitivity to weak
      and self ligands that the human genotype is proposed to produce.
    limitations: >-
      The genotype is not the patients'. The mice are homozygous for the
      activating allele, whereas the patients carry it opposite a hypomorphic
      allele, and in the human cell-line experiments the hypomorphic partner is
      what unmasks the activating allele. So the model tests the activating
      allele's effect rather than the two-allele configuration.
    evidence:
    - reference: PMID:33531381
      reference_title: "A disease-associated mutation that weakens ZAP70 autoinhibition enhances responses to weak and self-ligands."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        the R360P mutation was a weak hypermorphic allele of ZAP70 that enhanced
        TCR signaling
      explanation: >-
        Supports treating this model as informative for the enhanced-signalling
        node, which is the claim this link makes.
    divergences:
    - divergence_type: POPULATION_MISMATCH
      materiality: QUALIFYING
      description: >-
        R360P homozygosity in the mouse stands in for R192W/R360P compound
        heterozygosity in the patients. The claim about enhanced signalling
        holds; the claim that this particular allele pairing is required does
        not come from the model.
    readouts:
    - name: ZAP70 Y319 phosphorylation and calcium mobilisation after anti-CD3 stimulation
      target: Unopposed Hyperactive ZAP70 Signalling
      direction: INCREASED
      interpretation: >-
        Biochemical confirmation that the allele raises receptor-proximal
        signalling in primary T cells.
      evidence:
      - reference: PMID:34923645
        reference_title: "ZAP70, too little, too much can lead to autoimmunity."
        supports: SUPPORT
        evidence_source: OTHER
        quote_role: REVIEW_SYNTHESIS
        snippet: >-
          Biochemical analyses confirmed that the R360P mutation was a weak
          hypermorphic allele that increased TCR signaling through weakened
          ZAP70 autoinhibition, as evidenced in enhanced ZAP70 phosphorylation
          at Y319 and faster calcium mobilization following anti-CD3
          stimulation.
        explanation: >-
          Names both measurements and their direction.
  - target: T Follicular Helper Cell Expansion
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Antigen-specific follicular helper T cells expand more in knock-in mice
      than in wild-type after acute LCMV infection, with higher IgG and IgG1 in
      aged animals.
    limitations: >-
      The expansion needed an acute viral infection to appear and, on a
      polyclonal repertoire, did not produce more germinal-centre B cells or
      higher anti-LCMV titres. No autoantibody arose in these mice, so the step
      from expanded help to pathogenic autoantibody is not modelled.
    evidence:
    - reference: PMID:33531381
      reference_title: "A disease-associated mutation that weakens ZAP70 autoinhibition enhances responses to weak and self-ligands."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Zap70 R360P knock-in mice showed increased expansion of antigen-specific
        follicular helper T (Tfh) cells compared to that of the WT mice
        following LCMV infection.
      explanation: >-
        Supports treating this model as informative for the follicular-helper
        node.
    readouts:
    - name: Antigen-specific Tfh percentage among GP66+ effector CD4 T cells at day 8 after LCMV
      target: T Follicular Helper Cell Expansion
      direction: INCREASED
      evidence:
      - reference: PMID:33531381
        reference_title: "A disease-associated mutation that weakens ZAP70 autoinhibition enhances responses to weak and self-ligands."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          At day 8 after infection, the percentage of Tfh cells among GP66+
          antigen-specific effector cells (B220−CD4+CD44+GP66+) was
          significantly higher
        explanation: >-
          The measurement, its gating and its timing.
  - target: Loss of Peripheral T Cell Tolerance to Self Antigens
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    model_scale: ORGANISM
    description: >-
      The knock-in mice do not break tolerance in any observable way: no
      spontaneous autoimmune disease on organ histology, no lymphadenopathy or
      splenomegaly, and no ANA or anti-dsDNA antibodies.
    limitations: >-
      C57BL/6 is relatively resistant to autoimmunity, and the authors attribute
      the negative result to background, modifiers or environment rather than to
      the allele being harmless. Aged knock-in mice also accumulate regulatory
      and anergic T cells, which may be actively containing the enhanced
      signalling. A negative result here therefore does not refute the human
      mechanism, but it does mean the tolerance-breaking step rests on the
      patients and on inference.
    evidence:
    - reference: PMID:33531381
      reference_title: "A disease-associated mutation that weakens ZAP70 autoinhibition enhances responses to weak and self-ligands."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        the homozygous R360P mice did not develop any spontaneous autoimmune
        diseases based on histological screening of multiple organs from 8–10
        month old mice (fig. S1). There was no evidence of lymphadenopathy or
        splenomegaly. Serologic screening for autoantibodies including ANA and
        dsDNA was negative.
      explanation: >-
        The negative findings, stated in full, that this link records.
prevalence:
- population: Worldwide, published literature
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Two patients, siblings, in one family, and no second family has been
    reported. The 2021 knock-in mouse study and the 2022 review both describe
    this same kindred, and the one later paper to discuss both alleles together
    reports a different genotype in different patients. There is no population
    estimate and no case series to pool, so this record states the size of the
    literature rather than a rate.
  evidence:
  - reference: PMID:26783323
    reference_title: "A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We present two siblings with unique mutations of ZAP70 who lacked clinical
      immunodeficiency, but instead had a novel constellation of early onset,
      severe autoimmune manifestations, including bullous pemphigoid.
    explanation: >-
      The only reported patients, and the basis for counting two.
differential_diagnoses:
- name: ZAP70 deficiency (combined immunodeficiency, biallelic loss of function)
  description: >-
    The same gene, and the obvious confusion. ZAP70 deficiency is a combined
    immunodeficiency from biallelic loss of function: CD8 T cells are
    effectively absent, CD4 cells are present but unresponsive to receptor
    stimulation, and patients present with life-threatening and opportunistic
    infection in infancy. Autoimmunity occurs there too, in roughly a fifth of
    patients, which is what makes the two entities easy to conflate. The
    discriminators are the infectious history, which is absent here, and the
    degree of the CD8 deficit, which is partial here and near-total there.
    Mechanistically they are opposites: too little kinase activity in one, too
    much in the other.
  disease_term:
    preferred_term: ZAP70 deficiency
    term:
      id: MONDO:0010023
      label: combined immunodeficiency due to ZAP70 deficiency
  distinguishing_features:
  - No clinical immunodeficiency and no opportunistic infection in this disease
  - CD8 reduction is partial rather than near-absent, and the CD4:CD8 ratio is less extreme
  - Autoimmunity is the presenting problem rather than a complication in a minority
  - One allele is activating, so the kinase is hyperactive rather than absent
  evidence:
  - reference: PMID:26783323
    reference_title: "A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In marked contrast, our patients had a distinct phenotype with early
      onset, severe to life-threatening autoimmune disease and only minor
      lymphocyte abnormalities and no evidence of immune deficiency
    explanation: >-
      The authors' own statement of the contrast with loss-of-function ZAP70
      disease.
  - reference: PMID:20301777
    reference_title: "ZAP70 Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      ZAP70 deficiency is a profound T-cell immunodeficiency caused by abnormal
      T-cell receptor (TCR) signaling due to the loss of ZAP70 kinase activity,
      resulting in diminished CD8+ T-cell counts and functional deficits in CD4+
      T cells.
    explanation: >-
      The GeneReviews definition of the disease being distinguished, which turns
      on loss of kinase activity. It is quoted here, on the differential, rather
      than anywhere in this entry's own claims, because its subject is the other
      disease.
  - reference: PMID:41608114
    reference_title: "Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      ZAP-70 deficiency (ZAP70 LOF) | ZAP70 | AR | 269840 | Low CD8 number,
      normal CD4 number but with poor function | Normal | Normal | May have
      immune dysregulation, autoimmunity
    explanation: >-
      The IUIS row for the loss-of-function disease, immediately above this
      entity's own row and carrying a different OMIM number, which is what makes
      the separation a sourced one.
- name: Homozygous ZAP70 R192W combined immunodeficiency
  description: >-
    The sharpest contrast available, because it isolates the allele rather than
    the gene. Two siblings homozygous for the same hypomorphic C-SH2 allele that
    this disease carries on one chromosome presented with combined
    immunodeficiency and CD8 lymphopenia, not with the antibody-defined
    constellation seen here: no bullous pemphigoid, no factor VIII inhibitor, no
    nephrotic syndrome.

    Read the comparison carefully, because it is weaker than it first looks.
    Those patients were not free of autoimmunity, and the report says so
    explicitly in the same sentence that notes the absence of an activating
    mutation; one of the four patients in that series had inflammatory
    polyarthritis. So the two-allele configuration explains why this disease
    looks the way it does, and the activating allele is not established as the
    precondition for autoimmunity in ZAP70 disease generally. That paper's own
    framing of the open question is the reverse of the one this entry answers:
    how hypomorphic alleles, which reduce signalling, produce autoimmunity at
    all.
  evidence:
  - reference: PMID:37313400
    reference_title: "Combined immunodeficiency caused by pathogenic variants in the ZAP70 C-terminal SH2 domain."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Notably, both R170C and R192W mutations negatively impacted the binding of
      ZAP-70 to the TCR ζ-chain, resulting in a complete absence in TCR-induced
      proliferation (this study and (42)) and all patients presented with
      immunodeficiency and autoimmunity, in the absence of activating mutations.
    explanation: >-
      Establishes what this allele class does on its own: immunodeficiency and
      autoimmunity with no activating mutation present. Quoted in full because
      the second half is what limits the comparison, and reporting only the
      absence of the activating mutation would make the entry's contrast look
      stronger than the source supports.
  - reference: PMID:37313400
    reference_title: "Combined immunodeficiency caused by pathogenic variants in the ZAP70 C-terminal SH2 domain."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      it remains unclear as to how these mutations lead to autoimmunity in
      patients
    explanation: >-
      The authors' statement that the route from a signalling-reducing ZAP70
      mutation to autoimmunity is unresolved. It is the reason this entry
      confines its mechanistic claim to the activating allele's effect on
      peripheral responsiveness rather than claiming a general account of
      ZAP70-associated autoimmunity.
- name: STAT3 gain-of-function early-onset multisystem autoimmune disease
  description: >-
    The nearest phenotypic neighbour from another gene, and the comparison the
    primary report itself draws. Activating STAT3 variants cause early-onset
    multisystem autoimmunity, while dominant-negative variants in the same gene
    cause hyper-IgE syndrome; that mirror-image pairing is the pattern this
    ZAP70 disease follows. Distinguishing them is a sequencing question rather
    than a clinical one.
  evidence:
  - reference: PMID:26783323
    reference_title: "A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The latter category is typified by STAT3-activating mutations (Flanagan et
      al., 2014), which lead to early onset autoimmunity, in contrast to the
      dominant-negative defects in the same gene that cause hyper-IgE syndrome
      with boils and necrotizing pneumonias.
    explanation: >-
      The report's own analogy, which is also the reason the STAT3 entity is the
      differential a clinician would reach for.
  - reference: PMID:36228738
    reference_title: "Monogenic early-onset lymphoproliferation and autoimmunity: Natural history of STAT3 gain-of-function syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      germline signal transducer and activator of transcription (STAT) 3
      gain-of-function (GOF) mutations were first described to cause a novel
      multisystem disease of early-onset lymphoproliferation and autoimmunity
    explanation: >-
      Characterises the entity being distinguished. Its cohort of 191 patients
      is also the contrast in scale: that disease has a natural history, and
      this one has two patients.
discussions:
- discussion_id: admio2_no_patient_t_cells
  prompt: >-
    What does the two-allele genotype do to a patient's own T cells, given that
    no patient T cells were ever studied?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Unopposed Hyperactive ZAP70 Signalling
  - pathophysiology#Loss of Peripheral T Cell Tolerance to Self Antigens
  rationale: >-
    Both affected children were transplanted before the gene defect was found,
    so every functional measurement in this disease comes from somewhere other
    than the patients: transfected 293T and ZAP70-null Jurkat lines, blood from
    heterozygous relatives, and a knock-in mouse carrying one of the two
    alleles. The signalling claims in this entry inherit that limitation. A
    patient-derived system carrying both alleles in trans would test the central
    assertion directly, and iPSC-derived or gene-edited primary T cells are the
    obvious route now that both variants are known.
  evidence:
  - reference: PMID:26783323
    reference_title: "A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although pre-HCT patient T cells were not available, mutation effects were
      determined using transfected cell lines and peripheral blood from carriers
      and controls.
    explanation: >-
      The authors state the gap and what they substituted for it.
  proposed_experiments:
  - experiment_id: admio2_trans_allele_pair_in_primary_t_cells
    name: Reconstruct R192W/R360P in trans in a human T-cell system and measure self-ligand responsiveness
    description: >-
      Edit both alleles into primary human T cells or an iPSC-derived T-cell
      system to produce the compound heterozygous state, alongside each allele
      singly, each allele opposite wild type, and homozygous controls. Measure
      receptor-proximal phosphorylation, calcium flux, CD69 induction, and the
      response to a graded panel of agonist and self-peptide ligands. The
      prediction under this entry's mechanism is that only the R192W/R360P pair
      shows enhanced responsiveness to weak ligands, and that adding a wild-type
      allele abolishes it.
    perturbations:
    - name: ZAP70 R192W and R360P introduced in trans
      target: pathophysiology#Unopposed Hyperactive ZAP70 Signalling
      gene:
        preferred_term: ZAP70
        term:
          id: hgnc:12858
          label: ZAP70
    readouts:
    - name: CD69 induction and receptor-proximal phosphorylation across a graded ligand panel
      target: pathophysiology#Unopposed Hyperactive ZAP70 Signalling
      direction: INCREASED
      interpretation: >-
        Enhanced responses confined to the compound heterozygous configuration
        would support the unmasking model in human cells.
    would_support:
    - pathophysiology#Unopposed Hyperactive ZAP70 Signalling
    decision_criterion: >-
      Enhanced weak-ligand responses in the compound heterozygous state but not
      in either allele paired with wild type.
- discussion_id: admio2_central_versus_peripheral_tolerance
  prompt: >-
    Does this disease break central tolerance as well as peripheral tolerance,
    and if so which allele does it?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Hypomorphic ZAP70 SH2 Docking Allele
  - pathophysiology#Loss of Peripheral T Cell Tolerance to Self Antigens
  rationale: >-
    This entry's chain runs through peripheral tolerance, because that is what
    the knock-in mouse measures and what the activating allele is shown to do.
    The thymic arm is unresolved, and the literature points in two directions
    at once. The primary report proposes that altered signalling lets
    autoreactive thymocytes escape deletion, which is the mechanism established
    for hypomorphic ZAP70 alleles in mice: the SKG strain's hypomorph raises
    selection thresholds so that self-reactive thymocytes are positively rather
    than negatively selected, and attenuated signalling also hampers regulatory
    T-cell generation. But the same group's review states that a hyperactive
    kinase, which is what this genotype produces in the periphery, enhances
    thymic negative selection rather than weakening it. Which effect dominates
    in a thymus expressing one allele of each class is not known, and the
    patients' thymic output was never studied: both were transplanted before
    the genotype was found, and their newborn excision-circle screens were
    normal. The question matters for whether this disease belongs on the
    graded-signal-strength spectrum that connects ZAP70 immunodeficiency to
    ZAP70 autoimmunity, or beside it.
  evidence:
  - reference: PMID:26783323
    reference_title: "A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In mice, defects in both central and peripheral tolerance have been
      associated with hypomorphic Zap-70 defects and autoimmune features
    explanation: >-
      The primary report raises the central-tolerance possibility by analogy to
      the mouse hypomorphs, without testing it in these patients.
    directness: INDIRECT
  - reference: PMID:37394552
    reference_title: "[Gene-microbiota interactions for the development of systemic autoimmune diseases]."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Defective TCR signaling by ZAP70 mutation alters thymic selection
      thresholds and allows the positive selection of otherwise negatively
      selected self-reactive T cells.
    explanation: >-
      The central-tolerance mechanism as established for a hypomorphic Zap70
      allele in the SKG mouse. A different allele and a different disease
      (arthritis or lupus-like disease depending on background), so it bears on
      this question by analogy.
    directness: INDIRECT
  - reference: PMID:34923645
    reference_title: "ZAP70, too little, too much can lead to autoimmunity."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Hypoactive ZAP70 function compromises key developmental checkpoints
      required to establish central tolerance, allowing thymocytes with
      potentially self-reactive TCRs a greater chance to escape negative
      selection.
    explanation: >-
      States the hypoactive route to central-tolerance failure, which is the
      arm this genotype's hypomorphic allele could contribute and which the
      same review contrasts with the hyperactive case.
  - reference: PMID:41770842
    reference_title: "T Cell Receptor Signaling and Immune Tolerance: From Autoimmunity to Cancer Immunity."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      the effects of graded TCR signal reduction manifest as a disease spectrum
      encompassing T cell immune deficiency, latent autoimmunity, and overt
      autoimmune disease
    explanation: >-
      The spectrum this question places the disease against. Note the review
      frames the spectrum in terms of signal reduction, whereas this genotype
      includes an allele that increases signalling, which is part of why its
      position on that spectrum is unsettled.
- discussion_id: admio2_mouse_tolerance_mismatch
  prompt: >-
    Why do Zap70 R360P mice not develop autoimmunity, and does that limit the
    inference from the mouse to these patients?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - animal_models#Mouse
  - pathophysiology#Loss of Peripheral T Cell Tolerance to Self Antigens
  rationale: >-
    The knock-in mouse reproduces the signalling phenotype and the follicular
    helper expansion but not the disease: no spontaneous autoimmunity, no
    autoantibodies, no organ pathology. The authors attribute this to the
    autoimmunity-resistant C57BL/6 background, to unknown modifiers, or to
    environment, and note that aged knock-in mice accumulate regulatory and
    anergic T cells, which may be actively holding the enhanced signalling in
    check. The mouse is also homozygous for the activating allele rather than
    compound heterozygous, so it does not model the configuration the human
    disease requires. Both facts matter for how far the tolerance-breaking step
    can be said to be demonstrated rather than inferred.
  evidence:
  - reference: PMID:33531381
    reference_title: "A disease-associated mutation that weakens ZAP70 autoinhibition enhances responses to weak and self-ligands."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In contrast to humans, R360P mice did not spontaneously develop a
      detectable autoimmune phenotype, which may be due to their genetic
      background.
    explanation: >-
      States the mismatch and the authors' leading explanation for it.
  - reference: PMID:34923645
    reference_title: "ZAP70, too little, too much can lead to autoimmunity."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      It is likely that differences in genetic background, the presence of other
      genetic modifiers, or unique environmental factors contribute to this
      discrepancy.
    explanation: >-
      The same group's later statement of the candidate explanations, which is
      what makes this an open question rather than a settled negative.
notes: >-
  This is a separate entry rather than a subtype of ZAP70 deficiency, and the
  separation is sourced rather than a curator's preference. IUIS lists the two
  as distinct rows with distinct OMIM numbers, MONDO gives this concept its own
  identifier under the infantile-onset multisystem autoimmune disease parent,
  and the mechanisms run in opposite directions: an absent or non-docking
  kinase in one, a partially constitutively active kinase in the other. The
  ZAP70 deficiency entry already holds this entity in its
  differential_diagnoses for the same reason, and that entry's notes record the
  decision not to fold it in as a subtype. Nothing in this entry's
  pathophysiology chain would describe the loss-of-function disease.

  There is no GeneReviews chapter for this entity. The chapter tagged in
  references is the one for ZAP70 deficiency, which defines its subject as loss
  of ZAP70 kinase activity, so it is the gene's chapter and not this disease's
  clinical baseline; it is carried here for orientation and for its
  transplantation management, and none of this entry's claims rest on it.

  No phenotype carries a frequency. The disease is known from two siblings in
  one family, so a proportion would be a statement about a denominator of two,
  and several features (the factor VIII inhibitor, the nephrotic syndrome, the
  minimal change histology) were reported in only one of the two children. The
  per-child distribution is in each phenotype's description instead.

  Four phenotypes are deliberately left unconnected in the pathograph. The low
  IgM, the raised IgE and the non-protective pneumococcal titres are real
  measurements that no source traces to a mechanism in these children, and the
  autoimmune hypothyroidism is reported in the post-transplant course. An edge
  drawn to any of them would assert a route nobody has established.

  Autoimmune hypothyroidism is recorded as a phenotype but is the weakest
  entry in that list, because the source reports it in the sister's
  post-transplant course, alongside graft rejection and before her second
  transplant. Whether it belongs to the underlying disease or to the transplant
  course is not resolved by the source, and the description says so rather than
  leaving the reader to assume the former.

  Everything functional in this entry is at one remove from the patients.
  Neither child's T cells were ever studied, because both were transplanted
  before the genotype was known. The allele-level work is in transfected 293T
  cells and ZAP70-null Jurkat lines, the primary-cell signalling comparison is
  between heterozygous relatives, and the in vivo work is a mouse homozygous
  for one of the two alleles that does not develop the disease.

  No datasets block. ZAP70 is a long-standing prognostic marker in chronic
  lymphocytic leukaemia, so a gene-keyed search of the expression repositories
  returns CLL cohorts that resolve perfectly and are about a different disease:
  the named-entity-confusion trap the dataset guidance describes, reached
  through gene search. With two patients, no cohort dataset for this disease
  exists to find.

  No environmental block. Nothing in the literature proposes an exposure
  trigger for these children, although the mouse work notes that the
  activating allele's effect on weak-ligand responses was clearest in a
  permissive cytokine environment and after viral infection, which is recorded
  in the pathophysiology descriptions rather than as an environmental claim.
  The SKG hypomorphic mouse does have a documented gene-environment axis, in
  which endogenous mouse mammary tumour virus superantigens drive the
  autoreactive T cells and antiretroviral treatment curtails the arthritis
  (PMID:39589811), but that is a different allele, a different disease and a
  retrovirus with no human counterpart here, so asserting the analogue would be
  an exposure claim no source makes about these patients.

  The paper's narrative and its Table 1 do not say the same thing about
  antibody function, and the table is the better source. The text reports that
  post-vaccine titres to type 14 pneumococcus and tetanus were protective,
  which reads as intact humoral immunity; the table shows three of the four
  pneumococcal serotypes measured below the protective threshold printed in the
  same rows. Both are curated: the protective results in the low-IgG
  phenotype's description, the non-protective ones as their own phenotype
  quoting the table. The same applies to the proliferation assays, where
  "diminished, but not absent" in the text sits above PHA responses of 1 and
  2.4 per cent against a floor of 49.9. The accurate summary of this disease's
  immune picture is no clinical infectious susceptibility despite marked
  laboratory T-cell dysfunction, and the authors' own "only minor lymphocyte
  abnormalities" should be read as the former.

📚

References & Deep Research

References

1

PMID:20301777

ZAP70 Deficiency.

1 finding

This is the gene's GeneReviews chapter and not this disease's baseline: it covers ZAP70 deficiency, the loss-of-function combined immunodeficiency, and defines its subject as loss of ZAP70 kinase activity. No GeneReviews chapter names this disease or any of its synonyms. It is cited once in this entry, on the ZAP70-deficiency differential, and no claim about this disease rests on it.

"ZAP70 deficiency is a profound T-cell immunodeficiency caused by abnormal T-cell receptor (TCR) signaling due to the loss of ZAP70 kinase activity"

Deep Research

1

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

Evaluations and curation notes (1)

Create: Autoimmune Disease, Multisystem, Infantile-Onset, 2 (ADMIO2) · 2026-10-13T08:22:17Z · View source

Curated de novo from the OpenScientist deep-research report (research/Autoimmune_Disease_Multisystem_Infantile-onset_2-deep-research-openscientist.md; 19/19 citations resolved, needs_review set for term-label mismatches, just preflight-dr PASS against MONDO:0014861 with ZAP70 mentioned 61 times). Entry-type decision: DISEASE, a separate entry rather than a has_subtypes row on ZAP70_Deficiency, because IUIS lists the two as distinct rows with distinct OMIM numbers (617006 vs 269840) and the mechanisms are opposite; ZAP70_Deficiency already holds this entity in differential_diagnoses for the same reason. Curation drew on the primary report (PMID:26783323), the R360P knock-in mouse (PMID:33531381), the Ashouri review (PMID:34923645), IUIS 2024 (PMID:41608114) and the homozygous-R192W immunodeficiency series (PMID:37313400). Validated with just validate-disorders (79/79 snippets, terms clean), just validate-terms, just check-entity-refs, just check-causal-targets, just check-duplicate-keys, just check-qualifier-terms, just check-coarse-phenotypes, just check-genereviews --online (no chapter for this entity; the gene chapter PMID:20301777 is tagged and the absence is recorded in notes), and the whole-KB offline gates. Compliance 92.4 percent. Two report-proposed annotations were refused: a decreased pneumococcal antibody response that the primary report contradicts, and HP:0031540 whose canonical label names the immunofluorescence finding rather than the diagnosis. No gene_disease_validity recorded because ClinGen classifies ZAP70 only for MONDO:0010023. The curation stub was deleted.

OpenScientist ▸

Autoimmune Disease, Multisystem, Infantile-Onset, 2 (ADMIO2) — Comprehensive Disease Report

openscientist-autonomous 19 citations 2026-10-13T08:03:56.168768

Autoimmune Disease, Multisystem, Infantile-Onset, 2 (ADMIO2) — Comprehensive Disease Report

Disease: Autoimmune Disease, Multisystem, Infantile-Onset, 2 (ADMIO2) MONDO ID: MONDO:0014861 · OMIM: 617006 · DOID: 0061161 · Category: Mendelian (autosomal recessive inborn error of immunity) Causal gene: ZAP70 (HGNC:12858, NCBI Gene 7535, UniProt P43403, locus 2q11.2)

Summary

Autoimmune disease, multisystem, infantile-onset, 2 (ADMIO2; MONDO:0014861 / OMIM 617006) is an ultra-rare, autosomal-recessive inborn error of immunity defined molecularly by biallelic missense mutations in ZAP70, the Syk-family tyrosine kinase that is the proximal signaling node of the T-cell antigen receptor (TCR). The disease was delineated in a single sibling pair (a brother and sister) who were compound heterozygous for two private ZAP70 alleles: a hypomorphic allele, p.Arg192Trp (R192W), in the C-terminal SH2 domain that reduces binding to the phosphorylated ζ-chain, and an activating allele, p.Arg360Pro (R360P), in the N-lobe of the catalytic domain that disrupts kinase autoinhibition to produce a weakly hyperactive enzyme (PMID: 26783323). This particular allelic combination distinguishes ADMIO2 from the more common classic ZAP70-deficiency combined immunodeficiency (CID; OMIM 269840), which is caused by biallelic loss-of-function alleles.

The defining pathophysiologic concept is that altered TCR signal strength — not simple loss of signaling — breaks T-cell tolerance. Attenuated/altered ZAP70 kinase activity raises the thresholds of thymic (central) selection so that self-reactive thymocytes that should be negatively selected instead escape deletion and are positively selected, while the activating allele raises the sensitivity of mature peripheral T cells to weak self-ligands. The clinical result is severe, early-onset (first year of life) multiorgan autoimmunity — uncontrollable bullous pemphigoid, colitis, nephrotic syndrome with minimal-change glomerulonephritis, and a factor VIII autoantibody causing acquired hemophilia — superimposed on a partial combined immunodeficiency with CD8 lymphopenia. Both affected children required and were cured by allogeneic hematopoietic stem cell transplantation (HSCT).

This report synthesizes the molecular genetics, mechanism, phenotype, epidemiology, diagnostics, prognosis, treatment, and model-organism evidence for ADMIO2. Because ADMIO2 sensu stricto is known from a single family, much supporting mechanistic and clinical detail is extrapolated from (a) functional studies of the specific R360P and R192W alleles, (b) the broader literature on biallelic ZAP70 deficiency (~49 reported patients), and (c) mouse models — the SKG hypomorphic mutant (Zap70 W163C) and an R360P knock-in — that respectively model the two human alleles. Importantly, ADMIO2 must be distinguished from the clinically similar but mechanistically unrelated STAT3 gain-of-function syndrome (ADMIO1; OMIM 615952), which was also surveyed during this investigation.

1. Disease Information

Overview. ADMIO2 is a monogenic (Mendelian) disorder of immune dysregulation presenting in infancy with multisystem autoimmunity. Mechanistically it is an inborn error of TCR signaling: biallelic ZAP70 variants alter the quality and strength of TCR signal transduction, breaking immune tolerance while simultaneously impairing protective T-cell immunity.

Key identifiers.

Resource	Identifier
MONDO	MONDO:0014861
OMIM	617006
DOID (Disease Ontology)	DOID:0061161
MedGen	C4310768 / CN934735
UMLS	C4310768
Gene	ZAP70 — HGNC:12858, NCBI Gene 7535, UniProt P43403, Ensembl ENSG00000115085, locus 2q11.2

These cross-references were confirmed via OLS4/MONDO (MONDO:0014861 equivalentTo OMIM:617006).

Synonyms / alternative names. "ADMIO2"; the disease is best referred to by its OMIM title "Autoimmune disease, multisystem, infantile-onset, 2." The underlying gene-level entity is "ZAP70-related combined immunodeficiency / immune dysregulation." ADMIO1 (OMIM 615952) is the distinct STAT3-GOF syndrome.

Information source. Disease-level knowledge derives from aggregated resources (OMIM, MONDO, HPO) that are themselves built on a single primary clinical report of two patients (PMID: 26783323). This is a disease-level (literature-aggregated) rather than EHR/individual-patient derived entry, and the small n (2) is the dominant limitation throughout.

2. Etiology

Primary cause — genetic. ADMIO2 is caused by biallelic (compound heterozygous) missense mutations in ZAP70. Whole-exome sequencing of a five-member family identified the two affected siblings as compound heterozygous for two unique missense variants; healthy relatives were heterozygous carriers, establishing autosomal-recessive inheritance (PMID: 26783323):

"revealed the affected siblings to be compound heterozygous for two unique missense mutations in the 70-kD T cell receptor ζ-chain associated protein (ZAP-70)"

The two alleles have opposite biochemical effects:

"Mutation R192W in the C-SH2 domain exhibited reduced binding to phosphorylated ζ-chain, whereas mutation R360P in the N lobe of the catalytic domain disrupted an autoinhibitory mechanism, producing a weakly hyperactive ZAP-70 protein"

Genetic risk factors. The disease-causing variants are themselves the risk factor; both were private to the index family and are not population polymorphisms. There are no established common-variant susceptibility loci or validated modifier genes for ADMIO2 specifically, though inter-individual variability in broader ZAP70 deficiency (even between siblings carrying identical alleles) implies the existence of unidentified genetic/environmental modifiers (PMID: 41790376).

Environmental risk factors. None are established as causal. As with other combined immunodeficiencies, infectious exposures (e.g., CMV) can precipitate or worsen clinical course in ZAP70-deficient patients (PMID: 33484432), and endogenous retroviral superantigens modulate autoimmunity in the mouse model (see §6). Consanguinity is a risk factor for biallelic ZAP70 disease generally (enriching homozygous LoF deficiency in Middle Eastern/North African populations), though the ADMIO2 index family was compound heterozygous rather than consanguineous.

Protective factors. No genetic or environmental protective factors are defined for ADMIO2. By inference from gnomAD constraint (below), heterozygous carriers are asymptomatic — a single wild-type ZAP70 allele is protective/sufficient.

Gene–environment interactions. The best-characterized GxE axis is from the SKG mouse model: endogenous mouse-mammary-tumor-virus (MMTV) superantigens and the microbiota are required to convert the genetic lesion into overt arthritis, and antiretroviral therapy curtails disease (PMID: 39589811; PMID: 37394552). Whether analogous triggers operate in human ADMIO2 is unknown.

3. Phenotypes

All ADMIO2 HPO annotations derive from the two siblings in PMID: 26783323:

"A brother and sister developed a previously undescribed constellation of autoimmune manifestations within their first year of life, with uncontrollable bullous pemphigoid, colitis, and proteinuria. The boy had hemophilia due to a factor VIII autoantibody and nephrotic syndrome"

Phenotype	HPO term	Type	Frequency (n=2)	Notes
Autoimmunity	HP:0002960	Clinical/immunologic	2/2	Core feature
Infantile onset	HP:0003593	Temporal	2/2	First year of life
Autoimmune bullous skin disease (bullous pemphigoid)	HP:0031540	Physical/skin	1/1	Linear IgG along epidermal basement-membrane zone
Nephrotic syndrome	HP:0000100	Clinical/renal	1/2	—
Minimal change glomerulonephritis	HP:0012579	Laboratory/pathology	1/2	On renal biopsy
Podocyte foot process effacement	HP:0031266	Pathology	1/1	Ultrastructural
Proteinuria	HP:0000093	Laboratory	2/2	—
Colitis	HP:0002583	Clinical/GI	1/2	Childhood onset (HP:0011463)
Increased CD4:CD8 ratio	HP:0033221	Laboratory/immunologic	2/2	Reflects CD8 lymphopenia
Impaired PHA-induced T-cell transformation	HP:0025834	Laboratory	2/2	Functional T-cell defect
Decreased specific antibody response (pneumococcal)	HP:0012476	Laboratory	1/1	Humoral impairment
Acquired hemophilia A (factor VIII autoantibody)	—	Clinical/hematologic	1/1 (boy)	Autoantibody-mediated

Phenotype characteristics. Onset: neonatal–infantile (within the first year). Severity: severe ("uncontrollable" bullous pemphigoid; nephrotic-range proteinuria; bleeding from acquired hemophilia). Progression: progressive/refractory to conventional immunosuppression, ultimately requiring HSCT. Frequency: autoimmunity and the immunologic lab abnormalities were present in both siblings; organ-specific features were variably present.

Broader ZAP70-deficiency phenotype (context). A systematic review of 49 biallelic ZAP70 patients (PMID: 32431715) and a 13-patient HSCT cohort (PMID: 41080547) describe profound CD8 lymphopenia (84.6% in the cohort), recurrent respiratory infections, cutaneous disease, and autoimmunity, with median symptom onset ~1 month:

"Eleven of thirteen patients (84.6%) exhibited profound CD8" (PMID: 41080547)

Quality-of-life impact. No disease-specific QoL instruments (EQ-5D/SF-36/PROMIS) have been applied to ADMIO2. By inference, untreated disease is life-threatening and severely disabling (refractory multiorgan autoimmunity + immunodeficiency); successful HSCT can restore normal immune function and resolve autoimmunity (see §11–12).

4. Genetic / Molecular Information

Causal gene. ZAP70 (Zeta-chain Associated Protein kinase 70 kDa), HGNC:12858, OMIM gene 176947, locus 2q11.2; protein UniProt P43403 — a 619-aa cytoplasmic Syk-family protein tyrosine kinase with two tandem N-terminal SH2 domains (binding doubly-phosphorylated ITAMs) and a C-terminal catalytic kinase domain.

ADMIO2 pathogenic variants (private to index family).

Variant	Domain	Biochemical effect	Class
p.Arg192Trp (R192W)	C-terminal SH2 (C-SH2)	Reduced binding to phospho-ζ chain	Hypomorphic (partial LoF)
p.Arg360Pro (R360P)	N-lobe of kinase domain	Disrupts autoinhibition → weakly hyperactive kinase	Activating (GoF)

Both are missense substitutions. In the context of this family with functional support, both would be classified pathogenic/likely-pathogenic, but they are absent from population databases (private), consistent with their non-recurrent nature.

Variant classification per ACMG/AMP: functional evidence (PS3), compound heterozygosity with segregation (PM3/PP1), absence from controls (PM2), and in-silico support place both alleles at least as likely pathogenic in this disease context.

Allele frequency. The R192W and R360P alleles are not catalogued as recurrent population variants (private). For the gene overall, gnomAD constraint (ENSG00000115085): pLI = 0.88, LOEUF (oe_lof) = 0.173 (90% CI 0.09–0.364), observed/expected LoF = 5/28.8, missense Z = 2.76 — indicating that ZAP70 is intolerant of heterozygous loss of function, yet heterozygous carriers are clinically healthy (biallelic hit required for disease).

Somatic vs germline. Germline; inherited from heterozygous carrier parents.

Functional consequences. A combination of loss-of-function (R192W reduces ITAM engagement) and gain-of-function (R360P releases autoinhibition) — the net effect is altered/dysregulated TCR signaling, not simple nullizygosity.

ClinVar variant landscape (gene-level). ClinVar (NCBI E-utilities, 2026) returns ~616 ZAP70 records: ~79 pathogenic, ~21 likely-pathogenic, ~354 VUS, ~422 benign/likely-benign. Most pathogenic/likely-pathogenic alleles are LoF/hypomorphic variants causing classic ZAP70-deficiency CID (OMIM 269840) — e.g., homozygous p.Ala463Val (PMID: 33484432) — whereas the ADMIO2-defining p.Arg192Trp and p.Arg360Pro alleles remain private to the index family.

Modifier genes / epigenetics / chromosomal abnormalities. No ADMIO2-specific modifier genes, epigenetic marks, or chromosomal/structural abnormalities are established. Phenotypic divergence among siblings with identical ZAP70 genotypes in the broader literature implies unidentified modifiers (PMID: 41790376).

5. Environmental Information

ADMIO2 is a monogenic disease with no required environmental cause. Relevant non-genetic modifiers/triggers, largely by inference or from models:

Infectious agents. Not causal, but infections (notably CMV) complicate the associated immunodeficiency and can unmask/worsen disease in ZAP70-deficient infants (PMID: 33484432). In the SKG mouse, Brucella infection drives a spondyloarthritis-like phenotype on the susceptible Zap70 background (PMID: 40027658).
Endogenous retrovirus / microbiota. MMTV-derived superantigens and gut microbiota are required to convert the mouse genetic lesion into overt autoimmune arthritis (PMID: 39589811; PMID: 37394552).
Lifestyle factors. Not applicable (infantile-onset Mendelian disease).

6. Mechanism / Pathophysiology

Ordered causal chain

Biallelic ZAP70 missense mutations (R192W hypomorphic + R360P activating) are inherited → altered ZAP70 protein with reduced phospho-ζ binding (R192W) and weakened kinase autoinhibition (R360P). (Demonstrated — functional assays, PMID: 26783323.)
Altered ZAP70 changes the strength/quality of TCR signal transduction at the proximal node (ZAP70 is recruited to doubly-phosphorylated CD3/ζ ITAMs, activated by Lck, and phosphorylates LAT/SLP76 to drive Ca²⁺/NFAT, Ras–MAPK, and NF-κB). (Pathway demonstrated; allele-specific effect inferred.)
In the thymus (central tolerance): attenuated/altered TCR signaling raises selection thresholds, so self-reactive thymocytes that should be negatively selected instead escape deletion and are positively selected → export of self-reactive T cells. (Demonstrated in SKG mouse, PMID: 37394552.)
In the periphery (peripheral tolerance): the R360P activating allele increases mature T-cell sensitivity to weak/self ligands that would normally be ignored → activation of autoreactive T cells. (Demonstrated in R360P knock-in mouse, PMID: 33531381.)
Activation of autoreactive CD4⁺ (and dysregulated) T cells drives T-follicular-helper (Tfh) expansion and aberrant B-cell help → production of pathogenic autoantibodies (anti-basement-membrane IgG, anti-factor VIII, anti-podocyte/glomerular). (Tfh expansion demonstrated in mouse [PMID: 33531381]; autoantibodies demonstrated in patients [PMID: 26783323].)
Autoantibody- and T-cell–mediated tissue injury at specific organs → clinical manifestations: bullous pemphigoid (skin basement membrane), colitis (gut), minimal-change nephrotic syndrome with podocyte foot-process effacement (kidney), acquired hemophilia A (factor VIII neutralization). (Demonstrated — clinical/pathology, [PMID: 26783323].)
In parallel (branch): the hypomorphic R192W allele plus overall signaling impairment reduces CD8⁺ T-cell development and T-cell function → partial combined immunodeficiency (CD8 lymphopenia, impaired PHA response, poor specific antibody) → susceptibility to infection. (Demonstrated — immunophenotype, [PMID: 26783323]; broader cohorts [PMID: 32431715].)

 ZAP70 biallelic missense (R192W hypomorphic + R360P activating)
    │
    ▼
   Altered TCR signal STRENGTH (not absent)
┌───────────────┴───────────────┐
▼                               ▼
 Raised thymic selection          Increased peripheral T-cell
 thresholds → self-reactive       sensitivity to weak/self
 thymocytes escape deletion       ligands (R360P)
 (central tolerance break)        (peripheral tolerance break)
└───────────────┬───────────────┘
        ▼
  Autoreactive T cells + Tfh expansion
        ▼
      Pathogenic autoantibodies
        ▼
   Multiorgan autoimmunity: skin (bullous pemphigoid),
   gut (colitis), kidney (nephrotic syndrome), FVIII inhibitor
        │
    (parallel branch via hypomorphic allele)
        ▼
   CD8 lymphopenia + impaired T-cell function → infection risk

Supporting detail

Molecular pathways. Proximal TCR signaling: Lck → CD3/ζ ITAM phosphorylation → ZAP70 recruitment/activation → LAT/SLP76 phosphorylation → PLCγ1 (Ca²⁺/NFAT), Ras–MAPK/ERK, PKCθ–NF-κB. (Reactome "TCR signaling"; KEGG hsa04660.)
Autoinhibition structural basis. The tandem-SH2 (tSH2) module locks the kinase in a closed, inactive conformation; ITAM binding or ζ-phosphorylation triggers the closed→open transition (PMID: 26237552):

"TCR binding or phosphorylation of Zap70 triggers a transition from a closed, autoinhibited conformation to an open conformation" The ADMIO2 R360P substitution lies in the N-lobe and structurally weakens this autoinhibition. TCR dwell time tunes kinase output (PMID: 26237552); tSH2 dynamics differ between Syk and ZAP-70, explaining ZAP-70's tighter autoinhibition (PMID: 34601763).
Immune system involvement. Autoimmunity + partial immunodeficiency (immune dysregulation). Tolerance is broken in both compartments; autoantibodies are the proximate effectors of organ injury.
Cellular processes / cell types. CD4⁺ T cells (CL:0000624), CD8⁺ T cells (CL:0000625; depleted), Tfh cells, thymocytes undergoing selection, and downstream autoantibody-producing B cells/plasma cells.
GO terms. T-cell receptor signaling pathway (GO:0050852); positive/negative thymic T-cell selection (GO:0045059 / GO:0045060); T-cell tolerance induction (GO:0002517); protein tyrosine kinase activity (GO:0004713); regulation of immune response (GO:0050776).
Functional proof of the two-allele model.

"disruption of ZAP70 autoinhibition by the R360P mutation enables increased mature T cell sensitivity to self-antigens that would normally be ignored by wild-type T cells, a mechanism that may contribute to the break of tolerance in human patients with R360P mutation" (PMID: 33531381) "Defective TCR signaling by ZAP70 mutation alters thymic selection thresholds and allows the positive selection of otherwise negatively selected self-reactive T cells" (PMID: 37394552)
Spectrum concept. Graded reduction of ZAP70/TCR signal produces a continuum from immunodeficiency to autoimmunity (PMID: 41770842):

"the effects of graded TCR signal reduction manifest as a disease spectrum encompassing T cell immune deficiency, latent autoimmunity, and overt autoimmune disease"

7. Anatomical Structures Affected

Organ level (primary targets of autoimmunity):

Organ / system	UBERON	Manifestation
Skin (epidermal basement membrane)	UBERON:0002097	Bullous pemphigoid
Kidney (glomerulus/podocyte)	UBERON:0000074 (renal glomerulus)	Nephrotic syndrome, minimal-change GN, foot-process effacement
Colon / large intestine	UBERON:0001155	Colitis
Blood / coagulation system	UBERON:0000178	Factor VIII autoantibody → acquired hemophilia A
Immune/lymphoid system (thymus)	UBERON:0002370 (thymus)	Defective T-cell development/selection

Secondary involvement. Infectious complications of the immunodeficiency (e.g., respiratory tract, systemic CMV) affect the respiratory system (UBERON:0001004) and others.

Tissue / cell level. Epithelial basement membrane (skin), renal podocytes (CL:0000653), colonic mucosa; immunologically, thymocytes and peripheral T lymphocytes. Targeted/dysregulated cell populations: CD4⁺ αβ T cell (CL:0000624), CD8⁺ αβ T cell (CL:0000625, depleted), T-follicular-helper cell, autoantibody-secreting B cell/plasma cell (CL:0000786/CL:0000980).

Subcellular level. ZAP70 functions at the inner-leaflet plasma membrane / TCR complex (GO:0005886; GO:0042101 T-cell receptor complex) in the cytoplasm (GO:0005737). Podocyte foot-process effacement is an ultrastructural (cytoskeletal) lesion.

Lateralization. Systemic/bilateral (skin, kidneys, gut) — not lateralized.

8. Temporal Development

Onset. Congenital predisposition with clinical onset in infancy — within the first year of life (HP:0003593). Pattern is subacute-to-progressive.
Progression. Severe and refractory/progressive under conventional immunosuppression; the index siblings progressed to requiring HSCT. In the broader ZAP70-deficiency literature, median symptom onset is ~1 month, and untreated disease is life-threatening.
Disease course. Chronic and progressive until definitively treated; curable (remission) by allogeneic HSCT (treatment-induced remission). No spontaneous remission is described.
Critical period / window of intervention. Early recognition and HSCT before irreversible organ damage or fatal infection is the key therapeutic window; the infant thymus is more amenable to reconstitution (relevant to experimental intrathymic gene therapy, PMID: 16075064).

9. Inheritance and Population

Inheritance. Autosomal recessive (HP:0000007), confirmed by compound heterozygosity in affected siblings and heterozygous healthy carriers (PMID: 26783323):

"Healthy relatives were heterozygous mutation carriers"
Penetrance / expressivity. Within the single family, biallelic genotype was fully penetrant for autoimmunity in both siblings, with variable organ-specific expressivity (e.g., hemophilia and nephrotic syndrome only in the boy). Broader ZAP70 disease shows variable expressivity even among identical-genotype siblings (PMID: 41790376).
Epidemiology. Ultra-rare. ADMIO2 sensu stricto is reported in a single sibling pair; formal prevalence is not estimated (<1 per 1,000,000). The broader biallelic ZAP70-deficiency entity has ~49 reported cases worldwide (PMID: 32431715).
Carrier frequency / constraint. Heterozygous carriers are healthy; gnomAD shows ZAP70 is LoF-constrained (pLI 0.88, LOEUF 0.173) but disease requires two hits.
Founder effects / consanguinity. The ADMIO2 alleles are private (no founder effect). Classic ZAP70 deficiency is enriched in consanguineous Middle Eastern/North African populations (PMID: 41080547; PMID: 41790376).
Sex ratio / demographics. No sex predilection (AR); the index pair comprised one male and one female. No established ethnic predilection for ADMIO2 specifically.

10. Diagnostics

Immunologic laboratory tests (characteristic pattern). - Flow cytometry: CD8 lymphopenia / low CD8⁺ T cells → increased CD4:CD8 ratio (HP:0033221). In classic ZAP70 deficiency, intracellular ZAP70 is absent/reduced on gated T cells (PMID: 33484432). - Impaired T-cell proliferation to mitogens (PHA/ConA) (HP:0025834). - Humoral: variable; decreased specific (pneumococcal) antibody response in one sibling. - Autoimmune workup: anti–basement-membrane IgG (direct immunofluorescence shows linear IgG along the epidermal basement-membrane zone), factor VIII inhibitor assay (acquired hemophilia), urinalysis for proteinuria.

Biopsy / pathology. Skin DIF (bullous pemphigoid pattern); renal biopsy showing minimal-change glomerulonephritis with podocyte foot-process effacement on electron microscopy; colonic biopsy for colitis.

Newborn screening caveat. TREC-based SCID newborn screening may be normal in ZAP70 / CID, so a normal TREC screen does not exclude the diagnosis (PMID: 33484432; PMID: 22664165).

Genetic testing (diagnostic gold standard). WES/WGS or a primary-immunodeficiency / inborn-errors-of-immunity gene panel including ZAP70 is the definitive test; the disease was discovered by WES (PMID: 26783323). Confirm biallelic ZAP70 variants, segregation (parental carriers), and functional validation (phospho-ζ binding, kinase activity, TCR-induced proliferation/IL-2) because ADMIO2 alleles are private and otherwise VUS.

Clinical criteria / differential diagnosis. No formal consensus criteria exist. Key differentials for infantile multiorgan autoimmunity: - STAT3 gain-of-function (ADMIO1, OMIM 615952) — early-onset polyautoimmunity, lymphoproliferation, double-negative T cells, responsive to JAK inhibitors (PMID: 36228738). - IPEX (FOXP3), CTLA4 haploinsufficiency, LRBA deficiency, APECED (AIRE), and classic ZAP70-deficiency CID (OMIM 269840). Distinguishing feature of ADMIO2: biallelic ZAP70 with the specific hypomorphic+activating combination and CD8 lymphopenia with autoimmunity.

11. Outcome / Prognosis

Natural course (untreated). Severe, refractory, life-threatening multiorgan autoimmunity plus immunodeficiency; both index children required HSCT after failing conventional therapy.
With definitive treatment. Allogeneic HSCT is curative and resolved the autoimmunity in both ADMIO2 siblings (PMID: 26783323). In the broader ZAP70-deficiency literature, long-term outcomes after HSCT are excellent: 8/8 patients alive at median 13.5 years, with restored T-cell function and resolution of infections and autoimmunity (PMID: 27438785).
Complications. Pre-transplant: bleeding (FVIII inhibitor), nephrotic complications, colitis, infection. Transplant-related: graft failure, GVHD, conditioning toxicity.
Prognostic factors. Timeliness of diagnosis and HSCT; control of autoimmunity and infection pre-transplant; donor source/conditioning. CD8 reconstitution post-HSCT is generally good.

12. Treatment

Definitive / curative. - Allogeneic hematopoietic stem cell transplantation (HSCT) — curative; the only established cure (NCIT: Allogeneic Hematopoietic Stem Cell Transplantation, C15349). Both ADMIO2 siblings were cured by HCT:

"Both children required allogeneic hematopoietic cell transplantation (HCT), which resolved their autoimmunity" (PMID: 26783323) Supported by durable success in ZAP70 deficiency broadly (8/8 alive at 13.5 yr, PMID: 27438785; curative in majority of a 13-patient cohort, PMID: 41080547).

Supportive / bridging immunosuppression (pre-HSCT, symptom control). - Corticosteroids (NCIT C682); IVIG (C29368); rituximab / B-cell depletion for autoantibody-mediated disease (FVIII inhibitor, pemphigoid) (NCIT C1702); calcineurin inhibitors; standard management of nephrotic syndrome and colitis.

Experimental / preclinical — gene therapy. - ZAP70-deficient mice have been corrected by retroviral/lentiviral HSC gene transfer (PMID: 12149205), intrathymic lentiviral delivery (PMID: 16075064), and intrathymic AAV8/9/10 gene transfer restoring thymopoiesis and long-term peripheral T-cell function (PMID: 31513879):

"Intrathymic AAV-transduced progenitors promote a rapid restoration of the thymic architecture, with a single wave of thymopoiesis generating long-term peripheral T-cell function" Note: gene addition addresses the deficiency component; the ADMIO2 activating (R360P) allele is dominant-acting at the cellular level, so a correction strategy for the autoimmune component may require allele-specific considerations.

Mechanism-informed experimental approaches (from models). In the SKG hypomorphic model, antiretroviral therapy and depletion of superantigen-reactive T cells curtailed arthritis (PMID: 39589811); JAK inhibition is effective in the mechanistically analogous STAT3-GOF syndrome (PMID: 36228738) but is not established for ADMIO2.

Pharmacogenomics. None established specific to ADMIO2.

13. Prevention

Primary prevention. Not applicable in the usual sense (monogenic recessive disease). Genetic counseling for carrier couples; carrier/cascade testing in affected families; prenatal diagnosis / preimplantation genetic testing (PGT) is possible once familial variants are known.
Secondary prevention. Early diagnosis via immunophenotyping + genetic testing in infants with multiorgan autoimmunity or CID; note TREC newborn screening can miss ZAP70 disease.
Tertiary prevention. Infection prophylaxis (antimicrobial, antiviral, IVIG), prompt treatment of autoimmunity, and timely HSCT to prevent irreversible organ damage.
Counseling. 25% recurrence risk per pregnancy for carrier couples (AR).

14. Other Species / Natural Disease

Taxonomy / ortholog. Mouse (Mus musculus, NCBI Taxon 10090); ortholog Zap70 (NCBI Gene 22637). ZAP70 is evolutionarily conserved; TCR-proximal signaling architecture (Lck + ZAP-70/Syk, ITAM recognition) is conserved even in teleosts (rainbow trout homology modeling, PMID: 41240985).
Natural disease in other species. No well-characterized naturally-occurring companion-animal homolog of ADMIO2 is documented; relevance is primarily through engineered rodent models.
Comparative biology. The mouse allelic series (below) recapitulates the human deficiency↔autoimmunity spectrum, underscoring conserved mechanisms.

15. Model Organisms

Model	Allele	Phenotype	Models which human allele	Key refs
SKG mouse	Zap70 W163C (hypomorphic)	CD4⁺ T-cell–mediated autoimmune arthritis (BALB/c) / lupus-like disease (C57BL/6); raised thymic selection thresholds; MMTV-superantigen/microbiota-dependent	Hypomorphic (R192W-like)	PMID: 37394552, PMID: 39589811
R360P knock-in	Zap70 R360P (activating)	Grossly normal T-cell development but increased TCR signaling; enhanced Tfh after LCMV; on OTI TCR, heightened responses to weak/self ligands	Activating (R360P)	PMID: 33531381
Zap70 knockout	Null	Models human ZAP70-deficiency SCID: selective absence of CD8⁺ T cells, nonfunctional CD4⁺, thymic block; reversible by gene transfer	Deficiency/null	PMID: 12149205, PMID: 16075064, PMID: 31513879

Direct quotes:

"Mice with a ZAP70 R360P mutation and polyclonal TCR repertoires exhibited relatively normal T cell development but showed evidence of increased signaling" (PMID: 33531381)

"the effects of graded TCR signal reduction manifest as a disease spectrum encompassing T cell immune deficiency, latent autoimmunity, and overt autoimmune disease" (PMID: 41770842)

Model types: mammalian (mouse) in vivo; knock-in, knockout, and point-mutant (ENU-derived SKG) lines. Recapitulation: the two alleles are each separately modeled and together support the "altered-signal-strength breaks tolerance" mechanism; the knockout models the immunodeficiency arm. Limitations: no single mouse carries the exact human compound-heterozygous R192W/R360P genotype, so the combined/epistatic effect of the two alleles together is modeled only indirectly; mouse autoimmune targets (arthritis) differ from the human organ spectrum (skin/kidney/gut), reflecting species-specific self-antigens and superantigen biology. Resources: MGI (Zap70, SKG allele), IMPC/IMSR.

Mechanistic Model / Interpretation

ADMIO2 is best understood as a "Goldilocks" disorder of TCR signal strength. ZAP70 sits at the apex of TCR signaling, and the amount of kinase output a thymocyte or T cell experiences determines its fate: too little signal → failed positive selection / immunodeficiency; intermediate aberrant signal → escape from negative selection + peripheral hyper-responsiveness → autoimmunity; normal signal → tolerance + protective immunity. The ADMIO2 genotype pairs a hypomorphic allele (R192W; less ITAM engagement, raising selection thresholds like SKG) with an activating allele (R360P; released autoinhibition, lowering the threshold for peripheral responses to self). The net effect is a signaling milieu that simultaneously (a) allows self-reactive T cells to be positively selected and exported and (b) renders mature T cells inappropriately responsive to weak self-ligands — a double break of central and peripheral tolerance — while still leaving CD8 development and overall T-cell function partially impaired. The downstream effector arm is autoantibody-mediated, explaining the specific, disparate organ targets (skin basement membrane, glomerular podocyte, colon, clotting factor VIII). This model is anchored by direct biochemistry of the two alleles (PMID: 26783323), structural understanding of ZAP70 autoinhibition (PMID: 26237552, PMID: 34601763), and two complementary mouse models (PMID: 37394552, PMID: 33531381).

Evidence Base

PMID	Role in this report	How it supports/challenges findings
26783323	Defining primary report	Establishes the disease, compound-het ZAP70 genotype, two-allele biochemistry, clinical phenotype, AR inheritance, and HSCT cure. Sole clinical source (n=2) — the central limitation.
33531381	Mechanism (activating allele)	R360P knock-in proves increased self-ligand sensitivity → peripheral tolerance break.
37394552	Mechanism (hypomorphic allele)	SKG model shows altered thresholds → positive selection of self-reactive T cells (central tolerance break).
39589811	Gene–environment / effector	MMTV superantigen & retrovirus-dependent conversion to overt autoimmunity; ART mitigates.
26237552 / 34601763	Structural basis	Define ZAP70 autoinhibition and tSH2 dynamics disrupted by R360P.
41770842	Framing	Graded TCR-signal spectrum (deficiency↔autoimmunity).
32431715 / 41080547 / 41790376	Broader ZAP70 context	Phenotype spectrum, CD8 lymphopenia, consanguinity, HSCT outcomes.
27438785	Prognosis / treatment	Long-term HSCT success (8/8 at 13.5 yr).
12149205 / 16075064 / 31513879	Experimental therapy	Preclinical gene-therapy correction of ZAP70 deficiency.
33484432 / 22664165	Diagnostics	CD8 lymphopenia presentation; TREC screening caveats.
36228738	Differential diagnosis	STAT3-GOF (ADMIO1) — the key mimic, JAK-inhibitor-responsive.

Limitations and Knowledge Gaps

Single family (n=2). All ADMIO2-specific clinical and genetic data come from one sibling pair. Prevalence, penetrance, expressivity, full phenotype spectrum, and genotype–phenotype correlations cannot be generalized.
Private alleles. R192W and R360P are not recurrent; no population allele-frequency or additional segregation data beyond the index family.
No combined-genotype animal model. The two alleles are modeled separately (SKG and R360P knock-in); the epistatic effect of the exact human compound-heterozygous genotype is inferred, not demonstrated.
Effector mechanism partly inferred. The link from altered T-cell tolerance to the specific autoantibody targets (pemphigoid, podocyte, FVIII) is clinically observed but mechanistically underexplored for ADMIO2.
No ADMIO2-specific trials or QoL/natural-history data. Treatment and prognosis rest on the single report plus extrapolation from the broader ZAP70-deficiency literature.
Therapeutic uncertainty for the activating allele. Whether standard gene-addition gene therapy (effective for deficiency) would correct the dominant cellular effect of R360P is unknown; JAK-inhibitor utility (as in STAT3-GOF) is untested here.

Proposed Follow-up Experiments / Actions

International case-finding / GeneMatcher. Actively solicit additional ADMIO2 families via GeneMatcher, inborn-errors-of-immunity consortia, and ClinVar to expand the phenotype and genotype spectrum and estimate penetrance.
Compound-heterozygous model. Engineer a mouse or patient-derived iPSC → thymic organoid carrying both R192W and R360P to test the predicted additive/epistatic tolerance break and reproduce human-relevant autoimmunity.
Autoantibody repertoire and target mapping. Define the autoantigen specificities (skin BP180/BP230, podocyte antigens, FVIII epitopes) and the Tfh/B-cell dynamics driving them in ADMIO2 (and in R360P knock-in mice).
Therapeutic screen. Test JAK inhibition, B-cell depletion, abatacept/CTLA4-Ig, and allele-selective approaches in cellular/animal models to identify bridge therapies that control autoimmunity pre-HSCT.
Gene-therapy feasibility for the activating allele. Evaluate allele-specific knockdown/base-editing of R360P versus gene-addition in ZAP70 models to determine whether gene therapy can address both the deficiency and autoimmune arms.
Diagnostic yield of functional validation. Formalize a functional assay panel (phospho-ζ binding, kinase activity, TCR-induced IL-2/proliferation, Ca²⁺ flux) to reclassify ZAP70 VUS and flag hypomorphic+activating combinations.

Report compiled from 7 confirmed findings and 35 reviewed papers over 5 investigation iterations. Evidence sources span human clinical (single defining family + broader cohorts), model organism (mouse SKG, R360P knock-in, knockout), in vitro/biochemical (allele functional assays, ZAP70 structural dynamics), and computational (gnomAD constraint, ClinVar aggregation, OLS4/MONDO cross-references).

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome	Count
References checked	19
Resolved	19
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	19
On topic	13
Off topic	0

All extracted references resolved successfully.

Term Validation

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

Outcome	Count
Terms checked	37
Resolved	35
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	2
Terms whose name was checked	20
Terms named correctly	10
Terms named as a different term	5
Terms whose name is worth a second look	5

Terms the report names something else

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

MONDO:0014861 (4 mentions) - the report calls it "MONDO"; MONDO calls it autoimmune disease, multisystem, infantile-onset, 2
DOID:0061161 (1 mention) - the report calls it "DOID (Disease Ontology)"; DOID calls it infantile onset multisystem autoimmune disease 2
HP:0031540 (1 mention) - the report calls it "Autoimmune bullous skin disease (bullous pemphigoid)"; HP calls it Linear IgG deposits along the epidermal basement membrane zone
UBERON:0002097 (1 mention) - the report calls it "Skin (epidermal basement membrane)"; UBERON calls it skin of body
UBERON:0000178 (1 mention) - the report calls it "Blood / coagulation system"; UBERON calls it blood

Terms whose name is worth a second look

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

HP:0003593 (2 mentions) - the report calls it "Infantile onset", "infancy — within the first year of life"; HP calls it Infantile onset, and lists "Onset in first year of life" among its other names
HP:0033221 (2 mentions) - the report calls it "Increased CD4:CD8 ratio", "CD8 lymphopenia / low CD8⁺ T cells → increased CD4:CD8 ratio"; HP calls it Increased CD4:CD8 ratio
HP:0025834 (2 mentions) - the report calls it "Impaired PHA-induced T-cell transformation", "Impaired T-cell proliferation to mitogens (PHA/ConA)"; HP calls it Impaired phytohemagglutinin-induced T lymphocyte transformation, and lists "Impaired T lymphocyte transformation with phytohemagglutinin" among its other names
HP:0012476 (1 mention) - the report calls it "Decreased specific antibody response (pneumococcal)"; HP calls it Decreased circulating specific pneumococcal antibody concentration, and lists "Decreased specific pneumococcal antibody level" among its other names
UBERON:0001155 (1 mention) - the report calls it "Colon / large intestine"; UBERON calls it colon, and lists "posterior intestine" among its other names

Terms named inconsistently

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

HP:0003593 - called "Infantile onset", "infancy — within the first year of life"
HP:0033221 - called "Increased CD4:CD8 ratio", "CD8 lymphopenia / low CD8⁺ T cells → increased CD4:CD8 ratio"
HP:0025834 - called "Impaired PHA-induced T-cell transformation", "Impaired T-cell proliferation to mitogens (PHA/ConA)"

Prefixes with no resolver

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

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Autoimmune Disease, Multisystem, Infantile-Onset, 2 (ADMIO2) — Comprehensive Disease Report

Summary

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

Ordered causal chain

Supporting detail

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Mechanistic Model / Interpretation

Evidence Base

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Artifacts

Reference Validation

Term Validation

Terms the report names something else

Terms whose name is worth a second look

Terms named inconsistently

Prefixes with no resolver