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Classifications

IUIS Category

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Inheritance

1

Autosomal recessive inheritance HP:0000007

Biallelic TYK2 variants. Most reported patients are homozygous and born to consanguineous parents; heterozygous relatives are healthy. Penetrance is incomplete and is partly exposure-dependent, since a substantial share of the mycobacterial disease in this disorder follows BCG vaccination.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:26304966 SUPPORT Human Clinical

"We identified seven other TYK2-deficient patients from five families and four different ethnic groups. These patients were homozygous for one of five null mutations, different from that seen in P1. They displayed mycobacterial and/or viral infections, but no HIES."

Establishes the recessive homozygous-null genotype across five unrelated families and the phenotype that follows from it.

PMID:40949057 SUPPORT Human Clinical

"Incomplete clinical penetrance has been observed for mycobacterial and viral diseases, as 48% and 60% of patients, respectively, develop these diseases."

Quantifies the incomplete penetrance of the two defining infectious phenotypes.

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Discussions and Knowledge Gaps

3

Where does complete TYK2 deficiency end and partial TYK2 deficiency begin, given that the mechanism now held to explain mycobacterial disease is shared by both?

KNOWLEDGE GAP OPEN gap_tyk2_complete_vs_hypomorph_boundary

Attached to

genetic#TYK2 pathophysiology#Deficient Interferon-Gamma Induction in Lymphocytes

The 2022 analysis showed that impaired IL-23-dependent interferon-gamma induction is the only mechanism of mycobacterial disease common to all five forms of autosomal recessive TYK2 deficiency, from complete loss of expression through to homozygosity for the common P1104A allele. That result is what makes the boundary awkward. For the mycobacterial phenotype the two ends of the spectrum are mechanistically continuous, and the reasons for keeping them apart are that complete deficiency additionally loses type I interferon, IL-12 and IL-10 signalling and the scaffolding function, and that only complete deficiency produces viral disease. Those are real differences and the IUIS nosology encodes them as separate entities, so this entry is confined to complete deficiency. But the line is drawn on the extra pathways, not on the mechanism the two share, and no study has tested whether the mycobacterial disease seen in a complete-deficiency patient differs in kind from that seen in a P1104A homozygote once exposure is matched. Until it does, the question of whether these should be one graded entity or two is open, and this entry records that rather than settling it. Note also that the intermediate forms complicate any purely genetic rule: G1010D produces a detectable protein that is nonetheless loss-of-function across all pathways and is counted as complete deficiency, while R864C produces a hypomorph that is not.

Show evidence (2 references)

PMID:36094518 SUPPORT Human Clinical

"Impairment of the IL-23-dependent induction of IFN-γ is the only mechanism of mycobacterial disease common to patients with complete TYK2 deficiency with or without TYK2 expression, partial TYK2 deficiency across signaling pathways, or rare or common partial TYK2 deficiency specific for IL-23 signaling."

The result that makes the boundary a genuine question: one mechanism spans the whole spectrum.

PMID:36094518 SUPPORT Human Clinical

"Two types of inherited TYK2 deficiencies are known: AR complete deficiency underlying MSMD (and more rarely TB) and/or viral diseases, and homozygosity for P1104A deficiency underlying TB (and more rarely MSMD) without viral diseases."

The clinical grounds on which the same authors nonetheless keep the two apart, which is the position this entry adopts.

Does type III interferon signalling actually require TYK2 in human cells, and if it does so only in some cell types, what does that mean for the antiviral phenotype of complete TYK2 deficiency?

HUMAN MODEL MISMATCH OPEN mismatch_tyk2_type_iii_interferon

Attached to

pathophysiology#Impaired Type I Interferon Signaling

TYK2 is constitutively associated with IL-10R2, one of the two chains of the type III interferon receptor, so on the receptor architecture alone IFN-lambda signalling ought to fail in complete deficiency. The 2015 patient series found responses to IL-28/IL-29 normal, and this entry follows that in confining the antiviral lesion to type I interferon. But the cell-line evidence does not agree with itself: SV40-transformed fibroblasts from patients with complete TYK2 deficiency respond very weakly to type III interferon while their EBV-transformed B cells respond normally, and a TYK2-knockout HAP1 line responds normally to IFN-lambda1. The result is therefore cell-type-dependent, and every observation on either side comes from a transformed line rather than from a primary cell or a clinical outcome. Whether the discrepancy reflects real tissue-specific redundancy - with JAK1, or with the JAK2 phosphorylation that type III but not type I interferons trigger, taking over - or an artefact of transformation is unresolved. It matters because the epithelial surfaces where type III interferon does most of its work are exactly the surfaces on which these patients get their respiratory viral disease, and no patient-derived epithelial system has been tested.

Show evidence (4 references)

PMID:38781720 SUPPORT In Vitro

"By contrast, for complete TYK2 deficiency, SV40-transformed fibroblasts have very weak responses, whereas EBV-B cells respond normally"

The cell-type discrepancy itself, measured in two transformed lines from patients with complete deficiency.

PMID:38781720 SUPPORT In Vitro

"The response to IFN-λ1 in HAP1-TYK2KO cells is normal, suggesting that type III IFN signaling may be TYK2-independent, at least in some cell types"

An engineered knockout line supporting TYK2-independence, with the authors' own cell-type caveat attached.

PMID:38781720 SUPPORT Other

"The ligand-receptor interaction triggers the activation of JAK1 and TYK2, constitutively associated with IFNLR1 and IL10RB, respectively, leading to the heterodimerization of STAT1/STAT2, which, together with IRF9, form the ISGF3 transcription complex"

The receptor architecture that predicts a type III interferon defect, which is what makes the normal responses surprising.

+ 1 more reference

What determines whether a person homozygous for a TYK2 null allele develops mycobacterial disease, viral disease, both, or nothing at all?

KNOWLEDGE GAP OPEN gap_tyk2_penetrance_determinants

Attached to

phenotypes#Mycobacterial disease phenotypes#Severe or recurrent viral infection

Penetrance is incomplete for both defining phenotypes - roughly half of patients develop mycobacterial disease and three-fifths viral disease - and asymptomatic homozygous adults are on record, including siblings of severely affected probands. Exposure explains part of it, since several asymptomatic homozygotes were never given BCG and BCG disease is the commonest mycobacterial presentation, and the environmental link curated here records that. It does not explain the viral arm, where exposure to herpesviruses and respiratory viruses is effectively universal and yet two of five siblings in one family had hypoxaemic COVID-19 pneumonia while another was asymptomatic after infection. No modifier has been identified, and with twenty-five reported patients there is no cohort in which one could be sought.

Show evidence (2 references)

PMID:40949057 SUPPORT Human Clinical

"Incomplete clinical penetrance has been observed for mycobacterial and viral diseases, as 48% and 60% of patients, respectively, develop these diseases."

Quantifies the incomplete penetrance that the gap is about.

PMID:36094518 SUPPORT Human Clinical

"Four of these 19 patients with biallelic TYK2 variants presented only intramacrophagic infections, six had viral diseases only, seven had combinations of viral, mycobacterial, and fungal diseases, and two were asymptomatic."

The distribution of clinical outcomes across one cohort, including the asymptomatic homozygotes.

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Pathophysiology

9

Biallelic TYK2 Loss-of-Function Variants

Nonsense, frameshift and splice variants on both TYK2 alleles. Most abolish protein production outright; a smaller group produces a detectable protein that is catalytically dead across all TYK2-dependent pathways. Both are counted as complete deficiency because the cellular phenotype is the same, and both are distinct from the hypomorphic missense alleles that impair IL-23 signalling alone.

TYK2 hgnc:12440

Downstream

Loss of TYK2 Kinase Activity A null or catalytically dead allele on both chromosomes removes the kinase activity of TYK2 from every cell.

Show evidence (2 references)

PMID:26304966 SUPPORT Human Clinical

"We identified seven other TYK2-deficient patients from five families and four different ethnic groups. These patients were homozygous for one of five null mutations, different from that seen in P1. They displayed mycobacterial and/or viral infections, but no HIES."

Documents the null-allele class that defines complete deficiency.

PMID:40949057 SUPPORT Human Clinical

"Complete TYK2 deficiency was first described in 2006 in a single patient, and five forms of AR TYK2 deficiency have now been described in 25 patients: (1) complete without and (2) with residual expression, (3) partial deficiency affecting all pathways, partial deficiency affecting specifically..."

Sets out the five recognised forms and identifies which two of them are complete deficiency, the scope of this entry.

Loss of TYK2 Kinase Activity

TYK2 is a non-receptor tyrosine kinase that pairs with JAK1 or JAK2 on the receptors for type I interferons, IL-12, IL-23 and IL-10 and phosphorylates the receptor and the STATs recruited to it. In complete deficiency that catalytic activity is gone, whether because no protein is made or because the protein made cannot phosphorylate. The consequences are pathway-shared rather than pathway-specific, which is why one gene defect produces two otherwise unrelated infectious susceptibilities.

tyrosine kinase 2 catalytic activity GO:0004715 ∅ ABSENT

Downstream

Destabilised Cytokine Receptor Surface Expression Beyond phosphorylating substrates, TYK2 acts as a chaperone that holds its partner receptor chains at the cell surface; losing the protein loses that function too.

Impaired Type I Interferon Signaling TYK2 is the kinase on IFNAR1; without it the type I interferon receptor transduces poorly.

Impaired IL-12 and IL-23 Signaling TYK2 pairs with JAK2 on IL-12Rbeta1, the shared chain of the IL-12 and IL-23 receptors, so both cytokines lose signal together.

Impaired IL-10 Signaling IL-10R2 is a TYK2-associated chain, so IL-10 responses fall as well; this branch has no established clinical consequence.

Show evidence (1 reference)

PMID:17088085 SUPPORT In Vitro

"The patient's cells displayed defects in multiple cytokine signaling pathways including those for type I interferon (IFN), interleukin (IL)-6, IL-10, IL-12, and IL-23."

The original demonstration that one TYK2 genotype disables several cytokine pathways simultaneously.

Destabilised Cytokine Receptor Surface Expression

A second, non-catalytic consequence of losing the protein. TYK2 stabilises IFN-alphaR1, IL-12Rbeta1 and IL-10R2 at the plasma membrane, so complete deficiency reduces the amount of receptor available as well as the ability to signal through it. This is the part of the lesion that the common P1104A allele does not share: P1104A is catalytically dead but docks and scaffolds normally.

Downstream

Impaired Type I Interferon Signaling Less IFN-alphaR1 at the surface compounds the loss of kinase activity on the receptor that remains.

Impaired IL-12 and IL-23 Signaling IL-12Rbeta1 is the shared receptor chain for both cytokines and is destabilised by the same mechanism.

Show evidence (2 references)

PMID:36094518 SUPPORT In Vitro

"TYK2 deficiency is known to reduce the stability of the surface receptors IFN-αR1, IL-12Rβ1, and IL-10R2, by disrupting TYK2-dependent scaffolding functions."

The scaffolding function and the three receptors that depend on it.

PMID:36094518 SUPPORT In Vitro

"The P1104A variant affects the enzymatic activity of TYK2 but has no impact on its scaffolding function or capacity to be phosphorylated as a substrate."

Establishes that the scaffolding lesion is specific to complete deficiency and absent in the common hypomorphic allele.

Impaired Type I Interferon Signaling

Responses to IFN-alpha and IFN-beta are reduced across leukocyte and non-haematopoietic compartments. The defect is partial rather than absolute, which is consistent with the clinical picture: patients are not uniformly overwhelmed by every virus, but they suffer unusually severe disease with herpesviruses and respiratory viruses, and some have had adverse reactions to live attenuated vaccines. Responses to type III interferon (IFN-lambda) were normal in the cells assayed in the 2015 series, so the antiviral deficit is described as specifically a type I interferon deficit - but that generalisation does not hold across cell types, which is curated as an open question below.

type I interferon-mediated signaling pathway GO:0060337 ↓ DECREASED

Animal models

Tyk2-deficient mouse Mouse partially recapitulates The mouse reproduces the partial, dose-dependent character of the human type I interferon defect: low-dose IFN-alpha fails to signal while high concentrations still transduce fully.

Downstream

Failure of Cell-Intrinsic Antiviral Defence Type I interferon signalling is the pathway that installs the interferon-stimulated antiviral programme, so weakening it weakens cell-intrinsic viral control.

Show evidence (2 references)

PMID:36094518 SUPPORT In Vitro

"Human cells homozygous for rare loss-of-expression (LOE) TYK2 alleles have impaired, but not abolished, cellular responses to IFN-α/β (underlying viral diseases in the patients) and to IL-12 and IL-23 (underlying mycobacterial diseases)."

The measured type I interferon response defect, stated as impaired rather than abolished.

PMID:26304966 SUPPORT In Vitro

"Cellular responses to IL-21, IL-27, IFN-γ, IL-28/29 (IFN-λ), and leukemia inhibitory factor (LIF) were normal."

Shows that type III interferon and interferon-gamma responses were normal in the cells assayed, which is the basis for confining the antiviral lesion to type I interferon. See the type III interferon discussion for the cell-type-dependent exception.

Impaired IL-12 and IL-23 Signaling

IL-12 and IL-23 share the IL-12Rbeta1 chain and both use TYK2 with JAK2, so both are impaired together. The functional consequence measured in patient peripheral blood mononuclear cells is reduced interferon-gamma output on stimulation with either cytokine. IL-23-driven IL-17 induction is also weak, which accounts for the candidal disease seen in some patients, though circulating IL-17-positive T-cell proportions can be normal.

interleukin-12-mediated signaling pathway GO:0035722 ↓ DECREASED interleukin-23-mediated signaling pathway GO:0038155 ↓ DECREASED

Animal models

Tyk2-deficient mouse Mouse recapitulates IL-12-driven T-cell function is defective in the knockout, matching the IL-12 arm of the human lesion, and the macrophages fail an activation-dependent effector readout.

Downstream

Deficient Interferon-Gamma Induction in Lymphocytes IL-12 and IL-23 are the cytokines that instruct lymphocytes to make interferon-gamma; impairing both reduces that output.

Mucocutaneous candidiasis Weak IL-23-dependent IL-17 induction is the attributed cause of candidal disease. The link does not reliably produce disease: patients with normal circulating IL-17-positive T-cell proportions and no candidiasis are also reported, as the phenotype's own description records.

Show evidence (2 references)

PMID:36094518 SUPPORT In Vitro

"Furthermore, patients with complete TYK2 deficiency displayed impaired IL-12– and IL-23–mediated IFN-γ production"

The direct measurement in patients with complete deficiency, distinguishing them from the forms in which only IL-23 signalling is affected.

PMID:40949057 SUPPORT Human Clinical

"Their IL-23–dependent induction of IL-17 is also weak, accounting for their fungal diseases (Candida)."

The IL-17 arm of the same signalling defect and the fungal disease attributed to it.

Impaired IL-10 Signaling

IL-10R2 is TYK2-associated, so IL-10 responses are reduced alongside the others. No clinical consequence has been established for this branch: unlike IL-10 receptor deficiency, TYK2-deficient patients do not develop very-early-onset inflammatory bowel disease. It is curated as a node because it is a measured, reproducible part of the cellular phenotype and is used diagnostically, not because it is thought to cause disease; it therefore has no downstream edge.

interleukin-10-mediated signaling pathway GO:0140105 ↓ DECREASED

Animal models

Tyk2-deficient mouse Mouse fails to recapitulate Tyk2-deficient mice respond normally to IL-10, whereas the IL-10 response is impaired in every human patient assayed. The mouse cannot be used to study this branch.

Show evidence (2 references)

PMID:26304966 SUPPORT In Vitro

"All eight TYK2-deficient patients displayed impaired but not abolished cellular responses to (a) IL-12 and IFN-α/β, accounting for mycobacterial and viral infections, respectively; (b) IL-23, with normal proportions of circulating IL-17(+) T cells, accounting for their apparent lack of..."

Records both the IL-10 signalling defect and the absence of an attributable clinical phenotype.

PMID:40949057 SUPPORT Human Clinical

"Impaired responses to IL-10 seem to be clinically silent."

Independent restatement that this branch carries no known clinical consequence.

Deficient Interferon-Gamma Induction in Lymphocytes

Peripheral blood mononuclear cells from patients make less interferon-gamma when stimulated with IL-12 or IL-23. This is the convergence point of the mycobacterial branch: the 2022 analysis showed that impaired IL-23-dependent interferon-gamma induction is the single defect shared by every form of TYK2 deficiency that causes mycobacterial disease, whether the protein is absent, present but catalytically dead, or merely hypomorphic. In complete deficiency the IL-12-dependent arm fails as well, and the additional loss is associated with more severe mycobacterial disease.

mature alpha-beta T cell CL:0000791 natural killer cell CL:0000623 mucosal-associated invariant T cell CL:0000940 gamma-delta T cell CL:0000798

positive regulation of interferon-gamma production GO:0032729 ↓ DECREASED

Downstream

Inadequate Macrophage Control of Intramacrophagic Pathogens Interferon-gamma is the cytokine that licenses macrophages to kill intracellular mycobacteria, so less of it means less macrophage activation.

Show evidence (2 references)

PMID:36094518 SUPPORT Human Clinical

"Impairment of the IL-23-dependent induction of IFN-γ is the only mechanism of mycobacterial disease common to patients with complete TYK2 deficiency with or without TYK2 expression, partial TYK2 deficiency across signaling pathways, or rare or common partial TYK2 deficiency specific for IL-23 signaling."

Identifies this node as the shared mechanism of mycobacterial disease across every form of TYK2 deficiency.

PMID:36094518 SUPPORT In Vitro

"Single-cell IFNG expression increased in control mucosal associated invariant T, γδ T, and NK cells, but is impaired in the TYK2-deficient patient's cells"

Localises the interferon-gamma induction defect to MAIT, gamma-delta T and NK cells, which is why those cell types are bound on this node.

Inadequate Macrophage Control of Intramacrophagic Pathogens

Macrophages that are not adequately activated cannot restrict weakly virulent mycobacteria such as BCG and environmental species, nor Mycobacterium tuberculosis, nor other intramacrophagic organisms such as Salmonella. The clinical result is disseminated or refractory mycobacterial disease, most often after BCG vaccination in countries where it is routinely given.

macrophage CL:0000235

macrophage activation involved in immune response GO:0002281 ↓ DECREASED

Downstream

Mycobacterial disease Macrophages that are not licensed to kill cannot restrict mycobacteria, which is what produces disseminated or refractory mycobacterial disease.

BCG disease The live BCG vaccine strain is one of the weakly virulent mycobacteria that inadequately activated macrophages fail to contain, so vaccination turns into local or disseminated disease.

Show evidence (2 references)

PMID:40949057 SUPPORT Human Clinical

"Like patients with IL-12Rβ1 deficiency, in whom IL-12– and IL-23–mediated IFN-γ production is abolished, some TYK2-deficient patients are also susceptible to intramacrophagic pathogens (Salmonella)."

Susceptibility to intramacrophagic pathogens including Salmonella, which is the pathogen class this node names.

PMID:41465118 SUPPORT Human Clinical

"Hereditary anomalies in the TYK2 gene are the basis of a rare primary immunodeficiency, immunodeficiency-35, typified by an augmented vulnerability to mycobacterial and viral infections."

A recent case in which the failure to contain BCG and tuberculosis was the presenting problem.

Failure of Cell-Intrinsic Antiviral Defence

Without an adequate type I interferon response, cells do not install the interferon-stimulated gene programme that restricts viral replication. Reported consequences span herpesviruses, respiratory viruses and live attenuated vaccine strains, and in one patient extended to Epstein-Barr-virus-driven lymphoma and encephalitis with a neurotropic bunyavirus.

defense response to virus GO:0051607 ↓ DECREASED

Downstream

Severe or recurrent viral infection Cells that cannot mount a type I interferon response do not restrict viral replication, which is what makes herpesvirus, respiratory virus and live vaccine infections severe.

Show evidence (2 references)

PMID:40949057 SUPPORT Human Clinical

"Impaired responses to type I IFNs underlie severe viral diseases, including COVID-19 pneumonia, influenza pneumonia, herpes simplex encephalitis, and adverse reactions to live attenuated vaccines."

Enumerates the viral disease spectrum attributed to the type I interferon defect.

PMID:37695435 SUPPORT Human Clinical

"Here, we report a 4-year-old female with severe respiratory viral infections, EBV-driven Burkitt-like lymphoma, and infection with the neurotropic Jamestown Canyon virus."

The most severe reported viral phenotype in complete TYK2 deficiency.

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Pathograph

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Phenotypes

6

Blood 1

Elevated serum IgE with eczema VERY_RARE Increased circulating IgE concentration HP:0003212

Show evidence (2 references)

PMID:26304966 SUPPORT Human Clinical

"Autosomal recessive, complete TYK2 deficiency was previously described in a patient (P1) with intracellular bacterial and viral infections and features of hyper-IgE syndrome (HIES), including atopic dermatitis, high serum IgE levels, and staphylococcal abscesses."

Documents the features in the single patient in whom they occurred.

PMID:26304966 REFUTE Human Clinical

"Moreover, impaired IL-6 responses and HIES do not appear to be intrinsic features of TYK2 deficiency in humans."

Refutes hyper-IgE syndrome as a feature of the disorder, which is why this phenotype is banded very rare rather than treated as characteristic.

Immune 4

Mycobacterial disease FREQUENT Recurrent mycobacterial infections HP:0011274

Show evidence (2 references)

PMID:40949057 SUPPORT Human Clinical

"Incomplete clinical penetrance has been observed for mycobacterial and viral diseases, as 48% and 60% of patients, respectively, develop these diseases."

The 48% figure that places this phenotype in the frequent band.

PMID:26304966 SUPPORT Human Clinical

"The core clinical phenotype of TYK2 deficiency is mycobacterial and/or viral infections, caused by impaired responses to IL-12 and IFN-α/β."

Establishes mycobacterial infection as one of the two core clinical features.

BCG disease BCGosis HP:0020087

Show evidence (1 reference)

PMID:41465118 SUPPORT Human Clinical

"Clinical overlap with chronic granulomatous disease (CGD) and other granulomatous disorders complicates diagnosis, particularly in nations where universal BCG vaccination is instituted."

Records both the BCG-vaccination context and the misdiagnosis it invites.

Severe or recurrent viral infection FREQUENT Recurrent viral infections HP:0004429

Show evidence (2 references)

PMID:40949057 SUPPORT Human Clinical

"Impaired responses to type I IFNs underlie severe viral diseases, including COVID-19 pneumonia, influenza pneumonia, herpes simplex encephalitis, and adverse reactions to live attenuated vaccines."

The viral disease spectrum and its mechanistic attribution.

PMID:40949057 SUPPORT Human Clinical

"Incomplete clinical penetrance has been observed for mycobacterial and viral diseases, as 48% and 60% of patients, respectively, develop these diseases."

The 60% figure that places this phenotype in the frequent band.

Mucocutaneous candidiasis Chronic mucocutaneous candidiasis HP:0002728

Show evidence (4 references)

PMID:40949057 SUPPORT Human Clinical

"Their IL-23–dependent induction of IL-17 is also weak, accounting for their fungal diseases (Candida)."

Attributes candidal disease in these patients to the IL-17 induction defect.

PMID:36094518 SUPPORT Human Clinical

"was the only TYK2-deficient patient reported to suffer from chronic mucocutaneous candidiasis, which was attributed to impaired IL-12 and IL-23 responses and defective Th17 immunity"

Records that chronic mucocutaneous candidiasis in the strict sense has been reported in a single patient, which is why no frequency band is assigned.

PMID:36094518 SUPPORT Human Clinical

"Four of these 19 patients with biallelic TYK2 variants presented only intramacrophagic infections, six had viral diseases only, seven had combinations of viral, mycobacterial, and fungal diseases, and two were asymptomatic."

The broader fungal-disease denominator that disagrees with the strict candidiasis count.

+ 1 more reference

Other 1

Normal peripheral blood immunophenotype

Show evidence (1 reference)

PMID:40949057 SUPPORT Human Clinical

"Deep immunophenotyping revealed no peripheral blood mononuclear cells (PBMC) abnormalities in patients with the various forms of TYK2 deficiency, indicating the presence of normal numbers and percentages of the different myeloid and lymphoid cell subsets"

States the normal immunophenotype across the forms of TYK2 deficiency.

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Genetic Associations

1

TYK2 (Causal biallelic variant)

Gene: TYK2 hgnc:12440

Show evidence (2 references)

PMID:40949057 SUPPORT Human Clinical

"Complete TYK2 deficiency was first described in 2006 in a single patient, and five forms of AR TYK2 deficiency have now been described in 25 patients: (1) complete without and (2) with residual expression, (3) partial deficiency affecting all pathways, partial deficiency affecting specifically..."

Enumerates the five forms and identifies the two that constitute complete deficiency.

PMID:37695435 SUPPORT Human Clinical

"A novel, homozygous c.745C > T (p.R249*) variant was found in TYK2."

A representative nonsense allele causing complete deficiency.

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Medical Actions

3

Antimycobacterial therapy

Action: antibiotic therapy Ontology label: Antibiotic Therapy NCIT:C15620

Platform: Small molecule

Species-directed multidrug treatment for BCG disease, environmental mycobacterial disease or tuberculosis, often prolonged. It treats the infection and does not touch the signalling defect, so recurrence remains possible for as long as exposure continues.

Mechanism Target:

BYPASSES Inadequate Macrophage Control of Intramacrophagic Pathogens — Drug killing substitutes for the macrophage killing the patient cannot mount; the macrophage defect itself is unchanged.

Show evidence (1 reference)

PMID:41465118 SUPPORT Human Clinical

"Hereditary anomalies in the TYK2 gene are the basis of a rare primary immunodeficiency, immunodeficiency-35, typified by an augmented vulnerability to mycobacterial and viral infections."

Identifies the mycobacterial vulnerability that antimycobacterial treatment is given to contain; the same report describes the disease as refractory, which is why the effect is recorded as bypassing rather than correcting the mechanism.

Target Phenotypes: Recurrent mycobacterial infections HP:0011274

Show evidence (1 reference)

PMID:41465118 SUPPORT Human Clinical

"Clinical overlap with chronic granulomatous disease (CGD) and other granulomatous disorders complicates diagnosis, particularly in nations where universal BCG vaccination is instituted."

The clinical setting - refractory disseminated BCG and tuberculosis infection - in which antimycobacterial therapy is the mainstay.

Allogeneic haematopoietic stem cell transplantation

Action: hematopoietic cell transplantation Ontology label: Hematopoietic Cell Transplantation NCIT:C15431

Platform: Cell therapy

Replacing the haematopoietic compartment restores TYK2 in the cells that matter for the mycobacterial and viral branches. One patient transplanted from unrelated donors was followed for four years with reduced infection burden and restored JAK/STAT responses, at the cost of chronic graft-versus-host disease. It is not established therapy: the evidence is a single reported patient.

Mechanism Target:

RESTORES Loss of TYK2 Kinase Activity — Donor-derived cells carry wild-type TYK2, so the kinase is restored in the haematopoietic compartment; non-haematopoietic cells remain deficient.

Show evidence (1 reference)

PMID:38896258 SUPPORT Human Clinical

"We found that HSCT significantly reduced the incidence of severe infections, restored normal TKY2 levels, and reversed defects such as impaired JAK/STAT signaling in response to interferon-α or interleukin-10 treatment."

Measures restoration of TYK2 protein and of the downstream signalling defects after transplantation.

Show evidence (2 references)

PMID:38896258 SUPPORT Human Clinical

"Our findings suggest that HSCT is a feasible strategy for reconstituting the immune system in TYK2-deficient patients; however, the factors associated with GVHD and autoimmune thyroiditis development in TYK2-deficient patients undergoing HSCT warrant further investigation."

The authors' own assessment, feasible on one patient with unresolved complication risk, which is the level at which this treatment currently stands.

PMID:37695435 SUPPORT In Vitro

"The effects of the mutation could not be pharmacologically circumvented in vitro, suggesting that alternative modalities, such as hematopoietic stem cell transplantation or gene therapy, may be needed."

The negative pharmacological result that motivates transplantation as the alternative.

Mepolizumab for virus-triggered hypereosinophilia

Action: Pharmacotherapy NCIT:C15986

Agent: mepolizumab NCIT:C157376

Platform: Monoclonal antibody

Dosing: per month every 30 days

Anti-IL-5 antibody, given to one child with complete TYK2 deficiency whose dominant problem was not infection itself but the steroid-dependent hypereosinophilia and wheezing that followed each viral episode. Eosinophil counts normalised within a month and the child remained well. This is a single case and addresses a Th2-skewed complication rather than the signalling defect.

Show evidence (2 references)

PMID:40949057 SUPPORT Human Clinical

"Mepolizumab, used for the treatment of severe eosinophilic asthma, eosinophilic granulomatosis, and hypereosinophilic syndrome, was started at the age of 20 mo, at a dose of 40 mg per month delivered subcutaneously."

The indication, age and dose in the single reported patient.

PMID:40949057 SUPPORT Human Clinical

"Two weeks after the first injection, eosinophil counts had fallen strongly, to 300/mm3, reaching normal levels one month later."

The measured response.

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Environmental Factors

1

Bacille Calmette-Guerin vaccination

No ECTO exposure term is bound. ECTO was searched for a vaccination-exposure class covering administration of a live attenuated bacterial vaccine and none was found that names the exposure rather than the vaccine substance, so the entry is left with free text rather than a term chosen for the sake of having one.

Live attenuated Mycobacterium bovis BCG, given routinely in most tuberculosis-endemic countries in the first days of life. In this disorder it is not a neutral exposure: it supplies the mycobacterium that the unarmed macrophage compartment cannot contain, and BCG disease is the commonest single mycobacterial manifestation. Several reported patients have asymptomatic homozygous siblings who were simply never vaccinated, which is the clearest available demonstration that this exposure gates the phenotype rather than merely accompanying it.

Show evidence (1 reference)

PMID:40949057 SUPPORT Human Clinical

"Impaired responses to type I IFNs underlie severe viral diseases, including COVID-19 pneumonia, influenza pneumonia, herpes simplex encephalitis, and adverse reactions to live attenuated vaccines."

Records that live attenuated vaccines are a recognised hazard in this disorder; BCG is the live vaccine implicated in its mycobacterial arm.

Mechanism Target:

TRIGGERS Inadequate Macrophage Control of Intramacrophagic Pathogens — Vaccination introduces a live mycobacterium into a host whose macrophages cannot be adequately licensed to kill it.

Show evidence (1 reference)

PMID:41465118 SUPPORT Human Clinical

"Clinical overlap with chronic granulomatous disease (CGD) and other granulomatous disorders complicates diagnosis, particularly in nations where universal BCG vaccination is instituted."

Places the disease in the universal-BCG-vaccination setting in which the exposure is delivered.

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Diagnosis

2

Phospho-STAT response to IFN-alpha, IL-10, IL-12 and IL-23

Functional testing of patient cells for STAT phosphorylation and downstream responses after stimulation with each TYK2-dependent cytokine. This is the assay that separates complete deficiency, in which all four responses are impaired, from the partial forms in which only IL-23 signalling is affected - a distinction sequencing alone cannot make for a missense allele.

flow cytometry NCIT:C16585

Results: Impaired but not abolished responses to IFN-alpha/beta, IL-12, IL-23 and IL-10, with normal responses to IFN-gamma, IFN-lambda, IL-21, IL-27 and LIF.

Show evidence (2 references)

PMID:26304966 SUPPORT In Vitro

"All eight TYK2-deficient patients displayed impaired but not abolished cellular responses to (a) IL-12 and IFN-α/β, accounting for mycobacterial and viral infections, respectively; (b) IL-23, with normal proportions of circulating IL-17(+) T cells, accounting for their apparent lack of..."

The four-cytokine response pattern that constitutes the positive result.

PMID:26304966 SUPPORT In Vitro

"Cellular responses to IL-21, IL-27, IFN-γ, IL-28/29 (IFN-λ), and leukemia inhibitory factor (LIF) were normal."

The negative controls that make the pattern specific.

TYK2 sequencing

Panel, exome or genome sequencing. Because the presentation is BCG or mycobacterial disease far more often than a recognisable immunodeficiency syndrome, the gene is usually reached through an inborn-errors-of-immunity or Mendelian-susceptibility-to-mycobacterial-disease panel rather than by clinical suspicion of TYK2 itself.

genetic testing NCIT:C15709

Results: Biallelic loss-of-function TYK2 variants.

Show evidence (1 reference)

PMID:37695435 SUPPORT Human Clinical

"A novel, homozygous c.745C > T (p.R249*) variant was found in TYK2."

A worked example of the sequencing route to diagnosis.

📊

Prevalence

1

Worldwide

Cases In Literature Ultra Rare

No population estimate exists for complete TYK2 deficiency. Twenty-five patients had been reported by 2022. A separate statement puts inherited IL-12Rbeta1 and TYK2 deficiencies each at under 1 in 600,000, but that figure is offered as an order-of-magnitude comparison against a common tuberculosis-susceptibility allele rather than as a measured prevalence, so no numeric rate is recorded here.

Show evidence (2 references)

PMID:36094518 SUPPORT Human Clinical

"The 25 known patients with complete TYK2 deficiency (including 15 previously reported and 10 reported herein) have suffered from intramacrophagic infections (mostly due to mycobacteria) or viral infections (mostly due to herpesviruses) or both."

The published case count, standing in for a population prevalence estimate that has never been made.

PMID:30578352 SUPPORT Human Clinical

"Inherited IL-12Rβ1 and TYK2 deficiencies impair both IL-12- and IL-23-dependent IFN-γ immunity and are rare monogenic causes of tuberculosis, each found in less than 1/600,000 individuals."

The only order-of-magnitude frequency statement available, quoted here for the record without being converted into a rate.

🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Immunodeficiency 35:

TYK2 P1104A homozygosity

Overlapping Features The same gene, a different entity. P1104A is a common hypomorphic missense allele - homozygous in roughly one in six hundred Europeans - that is catalytically dead but docks and scaffolds normally, and that selectively disrupts IL-23 signalling while sparing IFN-alpha, IL-10 and IL-12. Its clinical expression is tuberculosis, and more rarely mycobacterial disease, without viral disease. The IUIS nosology lists it as a separate entity from Tyk2 deficiency. It is the differential that matters most here, because a literature search on TYK2 returns far more on this allele than on complete deficiency.

Distinguishing Features

Normal cellular responses to IFN-alpha, IL-10 and IL-12, with only IL-23 impaired
Normal TYK2 scaffolding of IFN-alphaR1, IL-12Rbeta1 and IL-10R2
Tuberculosis rather than viral disease as the clinical expression
Allele frequency in the general population, not a private family variant

Show evidence (2 references)

PMID:30578352 SUPPORT In Vitro

"Surprisingly, we also show that TYK2 P1104A impairs cellular responses to IL-23, but not to IFN-α, IL-10, or even IL-12, which, like IL-23, induces IFN-γ via activation of TYK2 and JAK2."

The cellular measurement that separates the two entities: three of the four TYK2-dependent responses are preserved in P1104A homozygotes.

PMID:36094518 SUPPORT Human Clinical

"Two types of inherited TYK2 deficiencies are known: AR complete deficiency underlying MSMD (and more rarely TB) and/or viral diseases, and homozygosity for P1104A deficiency underlying TB (and more rarely MSMD) without viral diseases."

The clinical statement of the same boundary, including the presence or absence of viral disease.

Interleukin-12 receptor beta-1 deficiency

Overlapping Features The commonest genetic cause of Mendelian susceptibility to mycobacterial disease and the closest phenocopy of the mycobacterial arm of this disorder. IL-12Rbeta1 is the receptor chain TYK2 sits on, so both defects impair IL-12- and IL-23-driven interferon-gamma production - but in IL-12Rbeta1 deficiency that production is abolished rather than reduced, and type I interferon signalling is intact, so there is no viral susceptibility.

Distinguishing Features

Interferon-gamma production abolished rather than impaired
Intact type I interferon responses and no severe viral disease
Biallelic IL12RB1 rather than TYK2 variants

Show evidence (2 references)

PMID:36094518 SUPPORT In Vitro

"whereas IL-12– and IL-23–mediated IFN-γ production was completely abolished in the IL-12Rβ1–deficient patient."

Contrasts the abolished production in IL-12Rbeta1 deficiency with the merely impaired production in TYK2 deficiency, measured side by side.

PMID:36094518 SUPPORT Human Clinical

"Penetrance is probably higher in patients with AR TYK2 deficiency and impaired cellular responses to both IL-12 and IL-23, and even higher in patients with IL-12Rβ1 deficiency with abolished responses to both cytokines"

Places the two disorders on the same axis, with IL-12Rbeta1 deficiency the more penetrant because its cytokine responses are abolished rather than reduced.

Chronic granulomatous disease

Overlapping Features The disorder TYK2 deficiency is most often mistaken for in practice, because both present with granulomatous disease after BCG in an infant. The discriminator is the phagocyte oxidative burst, which is normal here and absent in chronic granulomatous disease.

Distinguishing Features

Normal neutrophil oxidative burst on dihydrorhodamine or nitroblue tetrazolium testing
Viral as well as mycobacterial susceptibility

Show evidence (1 reference)

PMID:41465118 SUPPORT Human Clinical

"Clinical overlap with chronic granulomatous disease (CGD) and other granulomatous disorders complicates diagnosis, particularly in nations where universal BCG vaccination is instituted."

States the diagnostic confusion directly.

🐁

Animal Models

1

Tyk2-deficient mouse

Germline Tyk2 knockout mice, generated independently by two groups in 2000. They are viable and developmentally normal, and they reproduce the partial-signalling character of the human disorder rather than a complete block - which is the property that makes them informative and also the property that limits them. Where the mouse and the human diverge is IL-10 and IL-6: mouse responses to both are normal, whereas the human deficiency impairs IL-10 signalling, and the original human patient had an IL-6 defect as well.

Species

Mouse

Genotype

Tyk2 null (germline knockout)

Publication

PMID:11070173

Pathograph links

Impaired Type I Interferon Signaling partially recapitulates fidelity: moderate The mouse reproduces the partial, dose-dependent character of the human type I interferon defect: low-dose IFN-alpha fails to signal while high concentrations still transduce fully.

Limitations: The residual signalling is more evident in the mouse than in patients, and the antiviral phenotype is elicited by high-dose experimental challenge with vaccinia and LCMV rather than by the herpesviruses and respiratory viruses that affect patients.

Readouts

Vaccinia virus clearance and LCMV-specific T-cell response

Direction: DECREASED

Interpretation: Functional antiviral consequence of the type I interferon signalling defect in the model.

Show evidence (1 reference)

PMID:11070173 SUPPORT Model Organism

"Tyk2-/- mice are unable to clear vaccinia virus and show a reduced T cell response after LCMV challenge."

The measured antiviral failure in the knockout.

Show evidence (1 reference)

PMID:11070174 SUPPORT Model Organism

"Tyk2-deficient mice show no overt developmental abnormalities; however, they display a lack of responsiveness to a small amount of IFNalpha, although a high concentration of IFNalpha can fully transduce its signal even in the absence of tyk2."

Establishes that the model has a partial, dose-dependent type I interferon defect rather than an absolute one.

Impaired IL-12 and IL-23 Signaling recapitulates fidelity: moderate IL-12-driven T-cell function is defective in the knockout, matching the IL-12 arm of the human lesion, and the macrophages fail an activation-dependent effector readout.

Limitations: The mouse experiments predate the recognition that IL-23-dependent interferon-gamma induction is the defect shared by all human forms, and they measure IL-12-driven T-cell function and nitric oxide production rather than IL-23-driven interferon-gamma output, so the specific human convergence point is not directly modelled.

Readouts

IL-12-induced T-cell function

Direction: DECREASED

Interpretation: The IL-12 signalling arm of the human lesion is present in the mouse.

Show evidence (1 reference)

PMID:11070174 SUPPORT Model Organism

"Furthermore, IL-12-induced T cell function is defective in these mice."

Direct measurement of the IL-12 response defect.

Lipopolysaccharide-induced macrophage nitric oxide production

Direction: DECREASED

Interpretation: A macrophage effector readout that fails downstream of the same signalling lesion.

Show evidence (1 reference)

PMID:11070173 SUPPORT Model Organism

"Tyk2-/- macrophages fail to produce nitric oxide upon lipopolysaccharide induction."

The measured macrophage effector failure.

Show evidence (1 reference)

PMID:11070173 SUPPORT Model Organism

"In contrast to other Jaks, where inactivation leads to a complete loss of the respective cytokine receptor signal, Tyk2-/- mice display reduced responses to IFNalpha/beta and IL-12 and a selective deficiency in Stat3 activation in these pathways."

Establishes the partial character of the signalling defect that makes this model informative for TYK2 rather than for the other Janus kinases.

Impaired IL-10 Signaling fails to recapitulate fidelity: low Tyk2-deficient mice respond normally to IL-10, whereas the IL-10 response is impaired in every human patient assayed. The mouse cannot be used to study this branch.

Limitations: The species difference is not a matter of degree: mouse IL-10 responses are reported as normal, so there is no defect in the model to characterise. The same holds for IL-6, where the mouse is normal and the human index patient was not. The original human report drew exactly this contrast, noting that the human requirement for TYK2 across cytokine pathways differs substantially from the mouse.

Show evidence (2 references)

PMID:11070174 SUPPORT Model Organism

"In contrast, these mice respond normally to IL-6 and IL-10, both of which activate tyk2 in vitro."

The measurement showing the mouse has no IL-10 or IL-6 defect to model.

+ 1 more reference

Show evidence (1 reference)

PMID:11070174 SUPPORT Model Organism

"These observations demonstrate that tyk2 plays only a restricted role in mediating IFNalpha-dependent signaling while being required in mediating IL-12-dependent biological responses."

The summary of what this model does and does not establish about TYK2 pathway dependence.

{ }

Source YAML

click to show

name: Immunodeficiency 35
creation_date: "2026-09-01T00:00:00Z"
category: Mendelian
synonyms:
- IMD35
- immunodeficiency type 35
- tyrosine kinase 2 deficiency
- TYK2 deficiency
- complete TYK2 deficiency
- susceptibility to infection due to TYK2 deficiency
- autosomal recessive hyper-IgE syndrome due to TYK2 deficiency
- HIES with atypical Mycobacteriosis, autosomal recessive
description: >-
  Immunodeficiency 35 is an ultra-rare autosomal recessive inborn error of
  immunity caused by biallelic loss-of-function variants in TYK2, the gene
  encoding tyrosine kinase 2. TYK2 is one of the four human Janus kinases and
  sits on the receptors for type I interferons, interleukin-12, interleukin-23
  and interleukin-10. Losing it therefore removes one shared component from
  four otherwise independent cytokine circuits at once, and the clinical
  picture is the sum of the two circuits that matter for host defence: poor
  responses to IL-12 and IL-23 leave interferon-gamma induction in lymphocytes
  too weak to arm macrophages against intramacrophagic pathogens, giving
  mycobacterial disease, and poor responses to type I interferon leave cells
  unable to mount an intrinsic antiviral programme, giving severe viral
  disease. Impaired IL-10 responses appear to be clinically silent.

  This entry covers complete TYK2 deficiency only. That boundary is the main
  curation decision here, because the same gene carries a common hypomorphic
  missense allele, P1104A, which is homozygous in roughly one in six hundred
  Europeans, impairs IL-23 signalling alone, and is a common monogenic
  aetiology of tuberculosis rather than a Mendelian immunodeficiency. The
  IUIS nosology lists the two as separate entities, and the mechanistic
  literature separates them cleanly: complete deficiency compromises type I
  interferon, IL-12, IL-23 and IL-10 responses together, whereas P1104A
  homozygosity spares IFN-alpha, IL-10 and IL-12. The large pharmacological
  TYK2-inhibitor literature is likewise about deliberate partial inhibition of
  this kinase in autoimmune disease and says nothing about congenital complete
  loss.

  The first patient, reported in 2006, was diagnosed clinically with hyper-IgE
  syndrome, and TYK2 deficiency was for several years described as a form of
  autosomal recessive hyper-IgE syndrome. A 2015 series of seven further
  patients overturned that: none had hyper-IgE syndrome, their cells responded
  normally to IL-6, and the phenotype was redefined as mycobacterial and/or
  viral infection. Twenty-five patients with complete deficiency have been
  reported. Penetrance is incomplete - mycobacterial disease occurs in about
  half and viral disease in about three-fifths - and asymptomatic homozygotes
  are on record, in some cases siblings of severely affected probands who were
  simply never given BCG.
disease_term:
  preferred_term: immunodeficiency 35
  term:
    id: MONDO:0012682
    label: immunodeficiency 35
parents:
- Mendelian susceptibility to mycobacterial disease
- Inborn error of immunity
references:
- reference: PMID:17088085
  title: Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity.
- reference: PMID:26304966
  title: "Human TYK2 deficiency: Mycobacterial and viral infections without hyper-IgE syndrome."
- reference: PMID:36094518
  title: Impaired IL-23-dependent induction of IFN-γ underlies mycobacterial disease in patients with inherited TYK2 deficiency.
- reference: PMID:40949057
  title: Mepolizumab treatment in a child with inherited TYK2 deficiency.
- reference: PMID:37695435
  title: "A Novel Homozygous Mutation Causing Complete TYK2 Deficiency, with Severe Respiratory Viral Infections, EBV-Driven Lymphoma, and Jamestown Canyon Viral Encephalitis."
- reference: PMID:38896258
  title: Successful Immune Reconstitution in a Patient with a TYK2 Deficiency after Allogeneic Stem Cell Transplantation from Unrelated Donors.
- reference: PMID:41465118
  title: "TYK2 Deficiency Presenting as Refractory Disseminated BCG/Tuberculosis Infection in a Kazakh Child: A Case Report with Genetic Confirmation."
- reference: PMID:34569645
  title: Novel mutations of TYK2 leading to divergent clinical phenotypes.
- reference: PMID:30578352
  title: Tuberculosis and impaired IL-23-dependent IFN-γ immunity in humans homozygous for a common TYK2 missense variant.
- reference: PMID:38781720
  title: "In search of a function for human type III interferons: insights from inherited and acquired deficits."
- reference: PMID:11070173
  title: Partial impairment of cytokine responses in Tyk2-deficient mice.
- reference: PMID:11070174
  title: Tyk2 plays a restricted role in IFN alpha signaling, although it is required for IL-12-mediated T cell function.
- reference: PMID:35748970
  title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
classifications:
  iuis_category:
    classification_value: innate immunity defect
    notes: >-
      IUIS 2022 classification of inborn errors of immunity, Table 6 (defects in
      intrinsic and innate immunity), where Tyk2 deficiency sits among the
      Mendelian susceptibility to mycobacterial disease entities. The same table
      lists P1104A TYK2 homozygosity as a separate row with a narrower cellular
      defect and a narrower clinical phenotype, which is the nosological basis
      for confining this entry to complete deficiency. The table rows are not
      quoted as evidence; the P1104A distinction is evidenced from the primary
      TYK2 paper instead.
    evidence:
    - reference: PMID:36094518
      reference_title: Impaired IL-23-dependent induction of IFN-γ underlies mycobacterial disease in patients with inherited TYK2 deficiency.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Cells homozygous for the common P1104A TYK2 allele have selectively impaired responses to IL-23 (underlying isolated mycobacterial disease).
      explanation: >-
        The IL-23-restricted cellular defect of P1104A homozygosity, narrower than
        the four-pathway defect of complete deficiency; the reason this entry does
        not absorb the P1104A literature.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Biallelic TYK2 variants. Most reported patients are homozygous and born to
    consanguineous parents; heterozygous relatives are healthy. Penetrance is
    incomplete and is partly exposure-dependent, since a substantial share of
    the mycobacterial disease in this disorder follows BCG vaccination.
  evidence:
  - reference: PMID:26304966
    reference_title: "Human TYK2 deficiency: Mycobacterial and viral infections without hyper-IgE syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified seven other TYK2-deficient patients from five families and four different ethnic groups. These patients were homozygous for one of five null mutations, different from that seen in P1. They displayed mycobacterial and/or viral infections, but no HIES.
    explanation: >-
      Establishes the recessive homozygous-null genotype across five unrelated
      families and the phenotype that follows from it.
  - reference: PMID:40949057
    reference_title: Mepolizumab treatment in a child with inherited TYK2 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Incomplete clinical penetrance has been observed for mycobacterial and viral diseases, as 48% and 60% of patients, respectively, develop these diseases.
    explanation: >-
      Quantifies the incomplete penetrance of the two defining infectious
      phenotypes.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    No population estimate exists for complete TYK2 deficiency. Twenty-five
    patients had been reported by 2022. A separate statement puts inherited
    IL-12Rbeta1 and TYK2 deficiencies each at under 1 in 600,000, but that
    figure is offered as an order-of-magnitude comparison against a common
    tuberculosis-susceptibility allele rather than as a measured prevalence, so
    no numeric rate is recorded here.
  evidence:
  - reference: PMID:36094518
    reference_title: Impaired IL-23-dependent induction of IFN-γ underlies mycobacterial disease in patients with inherited TYK2 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The 25 known patients with complete TYK2 deficiency (including 15 previously reported and 10 reported herein) have suffered from intramacrophagic infections (mostly due to mycobacteria) or viral infections (mostly due to herpesviruses) or both.
    explanation: >-
      The published case count, standing in for a population prevalence estimate
      that has never been made.
  - reference: PMID:30578352
    reference_title: Tuberculosis and impaired IL-23-dependent IFN-γ immunity in humans homozygous for a common TYK2 missense variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Inherited IL-12Rβ1 and TYK2 deficiencies impair both IL-12- and IL-23-dependent IFN-γ immunity and are rare monogenic causes of tuberculosis, each found in less than 1/600,000 individuals.
    explanation: >-
      The only order-of-magnitude frequency statement available, quoted here for
      the record without being converted into a rate.
pathophysiology:
- name: Biallelic TYK2 Loss-of-Function Variants
  biological_scale: MOLECULAR
  description: >-
    Nonsense, frameshift and splice variants on both TYK2 alleles. Most abolish
    protein production outright; a smaller group produces a detectable protein
    that is catalytically dead across all TYK2-dependent pathways. Both are
    counted as complete deficiency because the cellular phenotype is the same,
    and both are distinct from the hypomorphic missense alleles that impair
    IL-23 signalling alone.
  genes:
  - preferred_term: TYK2
    term:
      id: hgnc:12440
      label: TYK2
  evidence:
  - reference: PMID:26304966
    reference_title: "Human TYK2 deficiency: Mycobacterial and viral infections without hyper-IgE syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified seven other TYK2-deficient patients from five families and four different ethnic groups. These patients were homozygous for one of five null mutations, different from that seen in P1. They displayed mycobacterial and/or viral infections, but no HIES.
    explanation: >-
      Documents the null-allele class that defines complete deficiency.
  - reference: PMID:40949057
    reference_title: Mepolizumab treatment in a child with inherited TYK2 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Complete TYK2 deficiency was first described in 2006 in a single patient, and five forms of AR TYK2 deficiency have now been described in 25 patients: (1) complete without and (2) with residual expression, (3) partial deficiency affecting all pathways, partial deficiency affecting specifically IL-23 signaling due to (4) rare and (5) common variants.
    explanation: >-
      Sets out the five recognised forms and identifies which two of them are
      complete deficiency, the scope of this entry.
  downstream:
  - target: Loss of TYK2 Kinase Activity
    description: >-
      A null or catalytically dead allele on both chromosomes removes the
      kinase activity of TYK2 from every cell.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:17088085
      reference_title: Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The cytokine signals were successfully restored by transducing the intact Tyk2 gene.
      explanation: >-
        Complementation of the patient's cells with wild-type TYK2 restores the
        signalling defects, establishing that the variant genotype is what
        abolishes TYK2 function.
- name: Loss of TYK2 Kinase Activity
  biological_scale: MOLECULAR
  description: >-
    TYK2 is a non-receptor tyrosine kinase that pairs with JAK1 or JAK2 on the
    receptors for type I interferons, IL-12, IL-23 and IL-10 and phosphorylates
    the receptor and the STATs recruited to it. In complete deficiency that
    catalytic activity is gone, whether because no protein is made or because
    the protein made cannot phosphorylate. The consequences are pathway-shared
    rather than pathway-specific, which is why one gene defect produces two
    otherwise unrelated infectious susceptibilities.
  molecular_functions:
  - preferred_term: tyrosine kinase 2 catalytic activity
    modifier: ABSENT
    term:
      id: GO:0004715
      label: non-membrane spanning protein tyrosine kinase activity
  evidence:
  - reference: PMID:17088085
    reference_title: Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The patient's cells displayed defects in multiple cytokine signaling pathways including those for type I interferon (IFN), interleukin (IL)-6, IL-10, IL-12, and IL-23.
    explanation: >-
      The original demonstration that one TYK2 genotype disables several
      cytokine pathways simultaneously.
  downstream:
  - target: Destabilised Cytokine Receptor Surface Expression
    description: >-
      Beyond phosphorylating substrates, TYK2 acts as a chaperone that holds its
      partner receptor chains at the cell surface; losing the protein loses that
      function too.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36094518
      reference_title: Impaired IL-23-dependent induction of IFN-γ underlies mycobacterial disease in patients with inherited TYK2 deficiency.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        TYK2 deficiency is known to reduce the stability of the surface receptors IFN-αR1, IL-12Rβ1, and IL-10R2, by disrupting TYK2-dependent scaffolding functions.
      explanation: >-
        Names the three receptor chains destabilised by loss of the TYK2
        scaffold.
  - target: Impaired Type I Interferon Signaling
    description: >-
      TYK2 is the kinase on IFNAR1; without it the type I interferon receptor
      transduces poorly.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36094518
      reference_title: Impaired IL-23-dependent induction of IFN-γ underlies mycobacterial disease in patients with inherited TYK2 deficiency.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Human cells homozygous for rare loss-of-expression (LOE) TYK2 alleles have impaired, but not abolished, cellular responses to IFN-α/β (underlying viral diseases in the patients) and to IL-12 and IL-23 (underlying mycobacterial diseases).
      explanation: >-
        Measures the type I interferon response defect in cells carrying
        complete-deficiency alleles, and records that it is partial.
  - target: Impaired IL-12 and IL-23 Signaling
    description: >-
      TYK2 pairs with JAK2 on IL-12Rbeta1, the shared chain of the IL-12 and
      IL-23 receptors, so both cytokines lose signal together.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36094518
      reference_title: Impaired IL-23-dependent induction of IFN-γ underlies mycobacterial disease in patients with inherited TYK2 deficiency.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Human cells homozygous for rare loss-of-expression (LOE) TYK2 alleles have impaired, but not abolished, cellular responses to IFN-α/β (underlying viral diseases in the patients) and to IL-12 and IL-23 (underlying mycobacterial diseases).
      explanation: >-
        The same measurement establishes the IL-12 and IL-23 arm of the defect.
  - target: Impaired IL-10 Signaling
    description: >-
      IL-10R2 is a TYK2-associated chain, so IL-10 responses fall as well; this
      branch has no established clinical consequence.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:26304966
      reference_title: "Human TYK2 deficiency: Mycobacterial and viral infections without hyper-IgE syndrome."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        All eight TYK2-deficient patients displayed impaired but not abolished cellular responses to (a) IL-12 and IFN-α/β, accounting for mycobacterial and viral infections, respectively; (b) IL-23, with normal proportions of circulating IL-17(+) T cells, accounting for their apparent lack of mucocutaneous candidiasis; and (c) IL-10, with no overt clinical consequences, including a lack of inflammatory bowel disease.
      explanation: >-
        Records the IL-10 response defect and its clinical silence in the same
        measurement series.
- name: Destabilised Cytokine Receptor Surface Expression
  biological_scale: MOLECULAR
  description: >-
    A second, non-catalytic consequence of losing the protein. TYK2 stabilises
    IFN-alphaR1, IL-12Rbeta1 and IL-10R2 at the plasma membrane, so complete
    deficiency reduces the amount of receptor available as well as the ability
    to signal through it. This is the part of the lesion that the common P1104A
    allele does not share: P1104A is catalytically dead but docks and scaffolds
    normally.
  evidence:
  - reference: PMID:36094518
    reference_title: Impaired IL-23-dependent induction of IFN-γ underlies mycobacterial disease in patients with inherited TYK2 deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      TYK2 deficiency is known to reduce the stability of the surface receptors IFN-αR1, IL-12Rβ1, and IL-10R2, by disrupting TYK2-dependent scaffolding functions.
    explanation: >-
      The scaffolding function and the three receptors that depend on it.
  - reference: PMID:36094518
    reference_title: Impaired IL-23-dependent induction of IFN-γ underlies mycobacterial disease in patients with inherited TYK2 deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The P1104A variant affects the enzymatic activity of TYK2 but has no impact on its scaffolding function or capacity to be phosphorylated as a substrate.
    explanation: >-
      Establishes that the scaffolding lesion is specific to complete deficiency
      and absent in the common hypomorphic allele.
  downstream:
  - target: Impaired Type I Interferon Signaling
    description: >-
      Less IFN-alphaR1 at the surface compounds the loss of kinase activity on
      the receptor that remains.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36094518
      reference_title: Impaired IL-23-dependent induction of IFN-γ underlies mycobacterial disease in patients with inherited TYK2 deficiency.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        TYK2 deficiency is known to reduce the stability of the surface receptors IFN-αR1, IL-12Rβ1, and IL-10R2, by disrupting TYK2-dependent scaffolding functions.
      explanation: >-
        IFN-alphaR1 is named among the destabilised receptors.
  - target: Impaired IL-12 and IL-23 Signaling
    description: >-
      IL-12Rbeta1 is the shared receptor chain for both cytokines and is
      destabilised by the same mechanism.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36094518
      reference_title: Impaired IL-23-dependent induction of IFN-γ underlies mycobacterial disease in patients with inherited TYK2 deficiency.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        TYK2 deficiency is known to reduce the stability of the surface receptors IFN-αR1, IL-12Rβ1, and IL-10R2, by disrupting TYK2-dependent scaffolding functions.
      explanation: >-
        IL-12Rbeta1 is named among the destabilised receptors.
- name: Impaired Type I Interferon Signaling
  biological_scale: CELLULAR
  description: >-
    Responses to IFN-alpha and IFN-beta are reduced across leukocyte and
    non-haematopoietic compartments. The defect is partial rather than absolute,
    which is consistent with the clinical picture: patients are not
    uniformly overwhelmed by every virus, but they suffer unusually severe
    disease with herpesviruses and respiratory viruses, and some have had
    adverse reactions to live attenuated vaccines. Responses to type III
    interferon (IFN-lambda) were normal in the cells assayed in the 2015 series,
    so the antiviral deficit is described as specifically a type I interferon
    deficit - but that generalisation does not hold across cell types, which is
    curated as an open question below.
  biological_processes:
  - preferred_term: type I interferon-mediated signaling pathway
    modifier: DECREASED
    term:
      id: GO:0060337
      label: type I interferon-mediated signaling pathway
  evidence:
  - reference: PMID:36094518
    reference_title: Impaired IL-23-dependent induction of IFN-γ underlies mycobacterial disease in patients with inherited TYK2 deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Human cells homozygous for rare loss-of-expression (LOE) TYK2 alleles have impaired, but not abolished, cellular responses to IFN-α/β (underlying viral diseases in the patients) and to IL-12 and IL-23 (underlying mycobacterial diseases).
    explanation: >-
      The measured type I interferon response defect, stated as impaired rather
      than abolished.
  - reference: PMID:26304966
    reference_title: "Human TYK2 deficiency: Mycobacterial and viral infections without hyper-IgE syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Cellular responses to IL-21, IL-27, IFN-γ, IL-28/29 (IFN-λ), and leukemia inhibitory factor (LIF) were normal.
    explanation: >-
      Shows that type III interferon and interferon-gamma responses were normal
      in the cells assayed, which is the basis for confining the antiviral lesion
      to type I interferon. See the type III interferon discussion for the
      cell-type-dependent exception.
  downstream:
  - target: Failure of Cell-Intrinsic Antiviral Defence
    description: >-
      Type I interferon signalling is the pathway that installs the
      interferon-stimulated antiviral programme, so weakening it weakens
      cell-intrinsic viral control.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36094518
      reference_title: Impaired IL-23-dependent induction of IFN-γ underlies mycobacterial disease in patients with inherited TYK2 deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Poor responses to IFN-α/β in most if not all cell types underlie viral diseases, whereas poor IFN-γ induction in lymphocytes stimulated with IL-12 or IL-23 underlies mycobacterial diseases.
      explanation: >-
        States the causal assignment of viral disease to the type I interferon
        branch.
- name: Impaired IL-12 and IL-23 Signaling
  biological_scale: CELLULAR
  description: >-
    IL-12 and IL-23 share the IL-12Rbeta1 chain and both use TYK2 with JAK2, so
    both are impaired together. The functional consequence measured in patient
    peripheral blood mononuclear cells is reduced interferon-gamma output on
    stimulation with either cytokine. IL-23-driven IL-17 induction is also weak,
    which accounts for the candidal disease seen in some patients, though
    circulating IL-17-positive T-cell proportions can be normal.
  biological_processes:
  - preferred_term: interleukin-12-mediated signaling pathway
    modifier: DECREASED
    term:
      id: GO:0035722
      label: interleukin-12-mediated signaling pathway
  - preferred_term: interleukin-23-mediated signaling pathway
    modifier: DECREASED
    term:
      id: GO:0038155
      label: interleukin-23-mediated signaling pathway
  evidence:
  - reference: PMID:36094518
    reference_title: Impaired IL-23-dependent induction of IFN-γ underlies mycobacterial disease in patients with inherited TYK2 deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Furthermore, patients with complete TYK2 deficiency displayed impaired IL-12– and IL-23–mediated IFN-γ production
    explanation: >-
      The direct measurement in patients with complete deficiency, distinguishing
      them from the forms in which only IL-23 signalling is affected.
  - reference: PMID:40949057
    reference_title: Mepolizumab treatment in a child with inherited TYK2 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Their IL-23–dependent induction of IL-17 is also weak, accounting for their fungal diseases (Candida).
    explanation: >-
      The IL-17 arm of the same signalling defect and the fungal disease
      attributed to it.
  downstream:
  - target: Deficient Interferon-Gamma Induction in Lymphocytes
    description: >-
      IL-12 and IL-23 are the cytokines that instruct lymphocytes to make
      interferon-gamma; impairing both reduces that output.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36094518
      reference_title: Impaired IL-23-dependent induction of IFN-γ underlies mycobacterial disease in patients with inherited TYK2 deficiency.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Furthermore, patients with complete TYK2 deficiency displayed impaired IL-12– and IL-23–mediated IFN-γ production
      explanation: >-
        Links the receptor-level defect to reduced interferon-gamma production.
  - target: Mucocutaneous candidiasis
    description: >-
      Weak IL-23-dependent IL-17 induction is the attributed cause of candidal
      disease. The link does not reliably produce disease: patients with normal
      circulating IL-17-positive T-cell proportions and no candidiasis are also
      reported, as the phenotype's own description records.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:40949057
      reference_title: Mepolizumab treatment in a child with inherited TYK2 deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Their IL-23–dependent induction of IL-17 is also weak, accounting for their fungal diseases (Candida).
      explanation: >-
        Attributes candidal disease to the IL-23-dependent IL-17 induction
        defect of this node.
- name: Impaired IL-10 Signaling
  biological_scale: CELLULAR
  description: >-
    IL-10R2 is TYK2-associated, so IL-10 responses are reduced alongside the
    others. No clinical consequence has been established for this branch: unlike
    IL-10 receptor deficiency, TYK2-deficient patients do not develop
    very-early-onset inflammatory bowel disease. It is curated as a node because
    it is a measured, reproducible part of the cellular phenotype and is used
    diagnostically, not because it is thought to cause disease; it therefore has
    no downstream edge.
  biological_processes:
  - preferred_term: interleukin-10-mediated signaling pathway
    modifier: DECREASED
    term:
      id: GO:0140105
      label: interleukin-10-mediated signaling pathway
  evidence:
  - reference: PMID:26304966
    reference_title: "Human TYK2 deficiency: Mycobacterial and viral infections without hyper-IgE syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      All eight TYK2-deficient patients displayed impaired but not abolished cellular responses to (a) IL-12 and IFN-α/β, accounting for mycobacterial and viral infections, respectively; (b) IL-23, with normal proportions of circulating IL-17(+) T cells, accounting for their apparent lack of mucocutaneous candidiasis; and (c) IL-10, with no overt clinical consequences, including a lack of inflammatory bowel disease.
    explanation: >-
      Records both the IL-10 signalling defect and the absence of an attributable
      clinical phenotype.
  - reference: PMID:40949057
    reference_title: Mepolizumab treatment in a child with inherited TYK2 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Impaired responses to IL-10 seem to be clinically silent.
    explanation: >-
      Independent restatement that this branch carries no known clinical
      consequence.
- name: Deficient Interferon-Gamma Induction in Lymphocytes
  biological_scale: CELLULAR
  description: >-
    Peripheral blood mononuclear cells from patients make less interferon-gamma
    when stimulated with IL-12 or IL-23. This is the convergence point of the
    mycobacterial branch: the 2022 analysis showed that impaired
    IL-23-dependent interferon-gamma induction is the single defect shared by
    every form of TYK2 deficiency that causes mycobacterial disease, whether the
    protein is absent, present but catalytically dead, or merely hypomorphic.
    In complete deficiency the IL-12-dependent arm fails as well, and the
    additional loss is associated with more severe mycobacterial disease.
  biological_processes:
  - preferred_term: positive regulation of interferon-gamma production
    modifier: DECREASED
    term:
      id: GO:0032729
      label: positive regulation of type II interferon production
  cell_types:
  - preferred_term: mature alpha-beta T cell
    term:
      id: CL:0000791
      label: mature alpha-beta T cell
  - preferred_term: natural killer cell
    term:
      id: CL:0000623
      label: natural killer cell
  - preferred_term: mucosal-associated invariant T cell
    term:
      id: CL:0000940
      label: mucosal-associated invariant T cell
  - preferred_term: gamma-delta T cell
    term:
      id: CL:0000798
      label: gamma-delta T cell
  evidence:
  - reference: PMID:36094518
    reference_title: Impaired IL-23-dependent induction of IFN-γ underlies mycobacterial disease in patients with inherited TYK2 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Impairment of the IL-23-dependent induction of IFN-γ is the only mechanism of mycobacterial disease common to patients with complete TYK2 deficiency with or without TYK2 expression, partial TYK2 deficiency across signaling pathways, or rare or common partial TYK2 deficiency specific for IL-23 signaling.
    explanation: >-
      Identifies this node as the shared mechanism of mycobacterial disease
      across every form of TYK2 deficiency.
  - reference: PMID:36094518
    reference_title: Impaired IL-23-dependent induction of IFN-γ underlies mycobacterial disease in patients with inherited TYK2 deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Single-cell IFNG expression increased in control mucosal associated invariant T, γδ T, and NK cells, but is impaired in the TYK2-deficient patient's cells
    explanation: >-
      Localises the interferon-gamma induction defect to MAIT, gamma-delta T and
      NK cells, which is why those cell types are bound on this node.
  downstream:
  - target: Inadequate Macrophage Control of Intramacrophagic Pathogens
    description: >-
      Interferon-gamma is the cytokine that licenses macrophages to kill
      intracellular mycobacteria, so less of it means less macrophage activation.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36094518
      reference_title: Impaired IL-23-dependent induction of IFN-γ underlies mycobacterial disease in patients with inherited TYK2 deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Poor responses to IFN-α/β in most if not all cell types underlie viral diseases, whereas poor IFN-γ induction in lymphocytes stimulated with IL-12 or IL-23 underlies mycobacterial diseases.
      explanation: >-
        States that the interferon-gamma induction defect is what underlies the
        mycobacterial disease.
- name: Inadequate Macrophage Control of Intramacrophagic Pathogens
  biological_scale: CELLULAR
  description: >-
    Macrophages that are not adequately activated cannot restrict weakly
    virulent mycobacteria such as BCG and environmental species, nor
    Mycobacterium tuberculosis, nor other intramacrophagic organisms such as
    Salmonella. The clinical result is disseminated or refractory mycobacterial
    disease, most often after BCG vaccination in countries where it is
    routinely given.
  biological_processes:
  - preferred_term: macrophage activation involved in immune response
    modifier: DECREASED
    term:
      id: GO:0002281
      label: macrophage activation involved in immune response
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  evidence:
  - reference: PMID:40949057
    reference_title: Mepolizumab treatment in a child with inherited TYK2 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Like patients with IL-12Rβ1 deficiency, in whom IL-12– and IL-23–mediated IFN-γ production is abolished, some TYK2-deficient patients are also susceptible to intramacrophagic pathogens (Salmonella).
    explanation: >-
      Susceptibility to intramacrophagic pathogens including Salmonella, which is
      the pathogen class this node names.
  - reference: PMID:41465118
    reference_title: "TYK2 Deficiency Presenting as Refractory Disseminated BCG/Tuberculosis Infection in a Kazakh Child: A Case Report with Genetic Confirmation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hereditary anomalies in the TYK2 gene are the basis of a rare primary immunodeficiency, immunodeficiency-35, typified by an augmented vulnerability to mycobacterial and viral infections.
    explanation: >-
      A recent case in which the failure to contain BCG and tuberculosis was the
      presenting problem.
  downstream:
  - target: Mycobacterial disease
    description: >-
      Macrophages that are not licensed to kill cannot restrict mycobacteria,
      which is what produces disseminated or refractory mycobacterial disease.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:26304966
      reference_title: "Human TYK2 deficiency: Mycobacterial and viral infections without hyper-IgE syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The core clinical phenotype of TYK2 deficiency is mycobacterial and/or viral infections, caused by impaired responses to IL-12 and IFN-α/β.
      explanation: >-
        Attributes the mycobacterial infections to the IL-12 response defect
        that this chain runs through.
  - target: BCG disease
    description: >-
      The live BCG vaccine strain is one of the weakly virulent mycobacteria
      that inadequately activated macrophages fail to contain, so vaccination
      turns into local or disseminated disease.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36094518
      reference_title: Impaired IL-23-dependent induction of IFN-γ underlies mycobacterial disease in patients with inherited TYK2 deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Nine of these patients had mycobacterial diseases, including BCG disease (n = 6), EM disease (n = 1), and tuberculosis (TB; n = 3)
      explanation: >-
        BCG disease as the commonest mycobacterial presentation in a series of
        TYK2-deficient patients.
- name: Failure of Cell-Intrinsic Antiviral Defence
  biological_scale: CELLULAR
  description: >-
    Without an adequate type I interferon response, cells do not install the
    interferon-stimulated gene programme that restricts viral replication.
    Reported consequences span herpesviruses, respiratory viruses and live
    attenuated vaccine strains, and in one patient extended to
    Epstein-Barr-virus-driven lymphoma and encephalitis with a neurotropic
    bunyavirus.
  biological_processes:
  - preferred_term: defense response to virus
    modifier: DECREASED
    term:
      id: GO:0051607
      label: defense response to virus
  evidence:
  - reference: PMID:40949057
    reference_title: Mepolizumab treatment in a child with inherited TYK2 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Impaired responses to type I IFNs underlie severe viral diseases, including COVID-19 pneumonia, influenza pneumonia, herpes simplex encephalitis, and adverse reactions to live attenuated vaccines.
    explanation: >-
      Enumerates the viral disease spectrum attributed to the type I interferon
      defect.
  - reference: PMID:37695435
    reference_title: "A Novel Homozygous Mutation Causing Complete TYK2 Deficiency, with Severe Respiratory Viral Infections, EBV-Driven Lymphoma, and Jamestown Canyon Viral Encephalitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report a 4-year-old female with severe respiratory viral infections, EBV-driven Burkitt-like lymphoma, and infection with the neurotropic Jamestown Canyon virus.
    explanation: >-
      The most severe reported viral phenotype in complete TYK2 deficiency.
  downstream:
  - target: Severe or recurrent viral infection
    description: >-
      Cells that cannot mount a type I interferon response do not restrict viral
      replication, which is what makes herpesvirus, respiratory virus and live
      vaccine infections severe.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:40949057
      reference_title: Mepolizumab treatment in a child with inherited TYK2 deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Impaired responses to type I IFNs underlie severe viral diseases, including COVID-19 pneumonia, influenza pneumonia, herpes simplex encephalitis, and adverse reactions to live attenuated vaccines.
      explanation: >-
        States that the type I interferon defect underlies the severe viral
        diseases.
phenotypes:
- name: Mycobacterial disease
  category: Immunologic
  diagnostic: true
  frequency: FREQUENT
  description: >-
    Disseminated or refractory disease with weakly virulent mycobacteria - BCG
    vaccine strain and environmental species - and with Mycobacterium
    tuberculosis. Reported in about 48% of patients, so it is common but not
    obligate, and its occurrence depends partly on whether the patient was
    vaccinated with BCG.
  phenotype_term:
    preferred_term: Recurrent mycobacterial infections
    term:
      id: HP:0011274
      label: Recurrent mycobacterial infections
  evidence:
  - reference: PMID:40949057
    reference_title: Mepolizumab treatment in a child with inherited TYK2 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Incomplete clinical penetrance has been observed for mycobacterial and viral diseases, as 48% and 60% of patients, respectively, develop these diseases.
    explanation: >-
      The 48% figure that places this phenotype in the frequent band.
  - reference: PMID:26304966
    reference_title: "Human TYK2 deficiency: Mycobacterial and viral infections without hyper-IgE syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The core clinical phenotype of TYK2 deficiency is mycobacterial and/or viral infections, caused by impaired responses to IL-12 and IFN-α/β.
    explanation: >-
      Establishes mycobacterial infection as one of the two core clinical
      features.
- name: BCG disease
  category: Immunologic
  description: >-
    Local or disseminated disease caused by the live attenuated Mycobacterium
    bovis BCG vaccine. It is the commonest single mycobacterial presentation and
    the usual route to diagnosis in countries with universal BCG vaccination,
    where it is regularly mistaken for chronic granulomatous disease.
  phenotype_term:
    preferred_term: BCGosis
    term:
      id: HP:0020087
      label: BCGosis
  evidence:
  - reference: PMID:41465118
    reference_title: "TYK2 Deficiency Presenting as Refractory Disseminated BCG/Tuberculosis Infection in a Kazakh Child: A Case Report with Genetic Confirmation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical overlap with chronic granulomatous disease (CGD) and other granulomatous disorders complicates diagnosis, particularly in nations where universal BCG vaccination is instituted.
    explanation: >-
      Records both the BCG-vaccination context and the misdiagnosis it invites.
- name: Severe or recurrent viral infection
  category: Immunologic
  diagnostic: true
  frequency: FREQUENT
  description: >-
    Unusually severe disease with herpesviruses and respiratory viruses -
    herpes simplex including encephalitis, varicella-zoster, molluscum
    contagiosum, parainfluenza, influenza and COVID-19 pneumonia - and adverse
    reactions to live attenuated viral vaccines. Reported in about 60% of
    patients.
  phenotype_term:
    preferred_term: Recurrent viral infections
    term:
      id: HP:0004429
      label: Recurrent viral infections
  evidence:
  - reference: PMID:40949057
    reference_title: Mepolizumab treatment in a child with inherited TYK2 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Impaired responses to type I IFNs underlie severe viral diseases, including COVID-19 pneumonia, influenza pneumonia, herpes simplex encephalitis, and adverse reactions to live attenuated vaccines.
    explanation: >-
      The viral disease spectrum and its mechanistic attribution.
  - reference: PMID:40949057
    reference_title: Mepolizumab treatment in a child with inherited TYK2 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Incomplete clinical penetrance has been observed for mycobacterial and viral diseases, as 48% and 60% of patients, respectively, develop these diseases.
    explanation: >-
      The 60% figure that places this phenotype in the frequent band.
- name: Normal peripheral blood immunophenotype
  category: Immunologic
  diagnostic: true
  description: >-
    A negative finding with diagnostic weight. Deep immunophenotyping of
    TYK2-deficient patients showed normal numbers and proportions of T-cell,
    innate-like T-cell, innate lymphoid, monocyte and dendritic-cell subsets, so
    routine lymphocyte subset counts do not flag this disorder and a normal
    result must not be taken to exclude it. No HP term is bound: the claim is
    the absence of an abnormality, and binding a phenotype term would assert one.
  evidence:
  - reference: PMID:40949057
    reference_title: Mepolizumab treatment in a child with inherited TYK2 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Deep immunophenotyping revealed no peripheral blood mononuclear cells (PBMC) abnormalities in patients with the various forms of TYK2 deficiency, indicating the presence of normal numbers and percentages of the different myeloid and lymphoid cell subsets
    explanation: >-
      States the normal immunophenotype across the forms of TYK2 deficiency.
- name: Elevated serum IgE with eczema
  category: Immunologic
  frequency: VERY_RARE
  description: >-
    The feature that gave the disorder its original name and that later work
    removed from it. The 2006 index patient had atopic dermatitis, high IgE and
    staphylococcal abscesses and was diagnosed clinically with hyper-IgE
    syndrome; none of the seven patients reported in 2015 had any of this, and
    their cells responded normally to IL-6. Hyper-IgE syndrome is therefore not
    an intrinsic feature of TYK2 deficiency, and this phenotype is curated only
    to record that the historical label was wrong.
  phenotype_term:
    preferred_term: Increased circulating IgE concentration
    term:
      id: HP:0003212
      label: Increased circulating IgE concentration
  evidence:
  - reference: PMID:26304966
    reference_title: "Human TYK2 deficiency: Mycobacterial and viral infections without hyper-IgE syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Autosomal recessive, complete TYK2 deficiency was previously described in a patient (P1) with intracellular bacterial and viral infections and features of hyper-IgE syndrome (HIES), including atopic dermatitis, high serum IgE levels, and staphylococcal abscesses.
    explanation: >-
      Documents the features in the single patient in whom they occurred.
  - reference: PMID:26304966
    reference_title: "Human TYK2 deficiency: Mycobacterial and viral infections without hyper-IgE syndrome."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Moreover, impaired IL-6 responses and HIES do not appear to be intrinsic features of TYK2 deficiency in humans.
    explanation: >-
      Refutes hyper-IgE syndrome as a feature of the disorder, which is why this
      phenotype is banded very rare rather than treated as characteristic.
- name: Mucocutaneous candidiasis
  category: Immunologic
  description: >-
    Candidal disease occurs in some patients and is attributed to the weak
    IL-23-dependent induction of IL-17. No frequency band is recorded, because
    the two available denominators disagree about what is being counted: seven
    of nineteen patients in one cohort had fungal disease as part of a mixed
    infectious phenotype, which would band frequent, while chronic mucocutaneous
    candidiasis in the strict sense - the concept this HP term names - has been
    reported in exactly one patient, the 2006 index case. Assigning either band
    would misstate one of them. The 2015 series adds a third complication: it
    noted the apparent absence of mucocutaneous candidiasis alongside normal
    proportions of circulating IL-17-positive T cells, so the IL-17 deficit is
    functional rather than numerical and does not reliably produce disease.
  phenotype_term:
    preferred_term: Chronic mucocutaneous candidiasis
    term:
      id: HP:0002728
      label: Chronic mucocutaneous candidiasis
  evidence:
  - reference: PMID:40949057
    reference_title: Mepolizumab treatment in a child with inherited TYK2 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Their IL-23–dependent induction of IL-17 is also weak, accounting for their fungal diseases (Candida).
    explanation: >-
      Attributes candidal disease in these patients to the IL-17 induction
      defect.
  - reference: PMID:36094518
    reference_title: Impaired IL-23-dependent induction of IFN-γ underlies mycobacterial disease in patients with inherited TYK2 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      was the only TYK2-deficient patient reported to suffer from chronic mucocutaneous candidiasis, which was attributed to impaired IL-12 and IL-23 responses and defective Th17 immunity
    explanation: >-
      Records that chronic mucocutaneous candidiasis in the strict sense has been
      reported in a single patient, which is why no frequency band is assigned.
  - reference: PMID:36094518
    reference_title: Impaired IL-23-dependent induction of IFN-γ underlies mycobacterial disease in patients with inherited TYK2 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Four of these 19 patients with biallelic TYK2 variants presented only intramacrophagic infections, six had viral diseases only, seven had combinations of viral, mycobacterial, and fungal diseases, and two were asymptomatic.
    explanation: >-
      The broader fungal-disease denominator that disagrees with the strict
      candidiasis count.
  - reference: PMID:26304966
    reference_title: "Human TYK2 deficiency: Mycobacterial and viral infections without hyper-IgE syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      All eight TYK2-deficient patients displayed impaired but not abolished cellular responses to (a) IL-12 and IFN-α/β, accounting for mycobacterial and viral infections, respectively; (b) IL-23, with normal proportions of circulating IL-17(+) T cells, accounting for their apparent lack of mucocutaneous candidiasis; and (c) IL-10, with no overt clinical consequences, including a lack of inflammatory bowel disease.
    explanation: >-
      The counterweight: in the eight patients assayed, IL-17-positive T-cell
      proportions were normal and candidiasis was apparently absent.
genetic:
- name: TYK2
  association: Causal biallelic variant
  gene_term:
    preferred_term: TYK2
    term:
      id: hgnc:12440
      label: TYK2
  notes: >-
    Complete deficiency covers two of the five recognised forms of autosomal
    recessive TYK2 deficiency: loss-of-expression alleles that abolish protein
    production, and rare alleles such as G1010D that leave a detectable but
    catalytically dead protein. The other three forms are partial and are not
    curated here. Reported complete-deficiency alleles include the nonsense
    changes c.745C>T (p.R249*) and c.3388C>T (p.Arg1130*), splice variants, and
    frameshifts; the reported alleles are private to individual families rather
    than recurrent.
  evidence:
  - reference: PMID:40949057
    reference_title: Mepolizumab treatment in a child with inherited TYK2 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Complete TYK2 deficiency was first described in 2006 in a single patient, and five forms of AR TYK2 deficiency have now been described in 25 patients: (1) complete without and (2) with residual expression, (3) partial deficiency affecting all pathways, partial deficiency affecting specifically IL-23 signaling due to (4) rare and (5) common variants.
    explanation: >-
      Enumerates the five forms and identifies the two that constitute complete
      deficiency.
  - reference: PMID:37695435
    reference_title: "A Novel Homozygous Mutation Causing Complete TYK2 Deficiency, with Severe Respiratory Viral Infections, EBV-Driven Lymphoma, and Jamestown Canyon Viral Encephalitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A novel, homozygous c.745C > T (p.R249*) variant was found in TYK2.
    explanation: >-
      A representative nonsense allele causing complete deficiency.
environmental:
- name: Bacille Calmette-Guerin vaccination
  description: >-
    Live attenuated Mycobacterium bovis BCG, given routinely in most
    tuberculosis-endemic countries in the first days of life. In this disorder
    it is not a neutral exposure: it supplies the mycobacterium that the
    unarmed macrophage compartment cannot contain, and BCG disease is the
    commonest single mycobacterial manifestation. Several reported patients have
    asymptomatic homozygous siblings who were simply never vaccinated, which is
    the clearest available demonstration that this exposure gates the phenotype
    rather than merely accompanying it.
  effect: >-
    Triggers local or disseminated mycobacterial disease in individuals who
    cannot activate macrophages through the interferon-gamma axis.
  influences_mechanisms:
  - target: Inadequate Macrophage Control of Intramacrophagic Pathogens
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Vaccination introduces a live mycobacterium into a host whose macrophages
      cannot be adequately licensed to kill it.
    evidence:
    - reference: PMID:41465118
      reference_title: "TYK2 Deficiency Presenting as Refractory Disseminated BCG/Tuberculosis Infection in a Kazakh Child: A Case Report with Genetic Confirmation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Clinical overlap with chronic granulomatous disease (CGD) and other granulomatous disorders complicates diagnosis, particularly in nations where universal BCG vaccination is instituted.
      explanation: >-
        Places the disease in the universal-BCG-vaccination setting in which the
        exposure is delivered.
  evidence:
  - reference: PMID:40949057
    reference_title: Mepolizumab treatment in a child with inherited TYK2 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Impaired responses to type I IFNs underlie severe viral diseases, including COVID-19 pneumonia, influenza pneumonia, herpes simplex encephalitis, and adverse reactions to live attenuated vaccines.
    explanation: >-
      Records that live attenuated vaccines are a recognised hazard in this
      disorder; BCG is the live vaccine implicated in its mycobacterial arm.
  notes: >-
    No ECTO exposure term is bound. ECTO was searched for a vaccination-exposure
    class covering administration of a live attenuated bacterial vaccine and none
    was found that names the exposure rather than the vaccine substance, so the
    entry is left with free text rather than a term chosen for the sake of having
    one.
treatments:
- name: Antimycobacterial therapy
  description: >-
    Species-directed multidrug treatment for BCG disease, environmental
    mycobacterial disease or tuberculosis, often prolonged. It treats the
    infection and does not touch the signalling defect, so recurrence remains
    possible for as long as exposure continues.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: antibiotic therapy
    term:
      id: NCIT:C15620
      label: Antibiotic Therapy
  target_phenotypes:
  - preferred_term: Recurrent mycobacterial infections
    term:
      id: HP:0011274
      label: Recurrent mycobacterial infections
  target_mechanisms:
  - target: Inadequate Macrophage Control of Intramacrophagic Pathogens
    treatment_effect: BYPASSES
    description: >-
      Drug killing substitutes for the macrophage killing the patient cannot
      mount; the macrophage defect itself is unchanged.
    evidence:
    - reference: PMID:41465118
      reference_title: "TYK2 Deficiency Presenting as Refractory Disseminated BCG/Tuberculosis Infection in a Kazakh Child: A Case Report with Genetic Confirmation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Hereditary anomalies in the TYK2 gene are the basis of a rare primary immunodeficiency, immunodeficiency-35, typified by an augmented vulnerability to mycobacterial and viral infections.
      explanation: >-
        Identifies the mycobacterial vulnerability that antimycobacterial
        treatment is given to contain; the same report describes the disease as
        refractory, which is why the effect is recorded as bypassing rather than
        correcting the mechanism.
  evidence:
  - reference: PMID:41465118
    reference_title: "TYK2 Deficiency Presenting as Refractory Disseminated BCG/Tuberculosis Infection in a Kazakh Child: A Case Report with Genetic Confirmation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical overlap with chronic granulomatous disease (CGD) and other granulomatous disorders complicates diagnosis, particularly in nations where universal BCG vaccination is instituted.
    explanation: >-
      The clinical setting - refractory disseminated BCG and tuberculosis
      infection - in which antimycobacterial therapy is the mainstay.
- name: Allogeneic haematopoietic stem cell transplantation
  description: >-
    Replacing the haematopoietic compartment restores TYK2 in the cells that
    matter for the mycobacterial and viral branches. One patient transplanted
    from unrelated donors was followed for four years with reduced infection
    burden and restored JAK/STAT responses, at the cost of chronic
    graft-versus-host disease. It is not established therapy: the evidence is a
    single reported patient.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: hematopoietic cell transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  target_mechanisms:
  - target: Loss of TYK2 Kinase Activity
    treatment_effect: RESTORES
    description: >-
      Donor-derived cells carry wild-type TYK2, so the kinase is restored in the
      haematopoietic compartment; non-haematopoietic cells remain deficient.
    evidence:
    - reference: PMID:38896258
      reference_title: Successful Immune Reconstitution in a Patient with a TYK2 Deficiency after Allogeneic Stem Cell Transplantation from Unrelated Donors.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We found that HSCT significantly reduced the incidence of severe infections, restored normal TKY2 levels, and reversed defects such as impaired JAK/STAT signaling in response to interferon-α or interleukin-10 treatment.
      explanation: >-
        Measures restoration of TYK2 protein and of the downstream signalling
        defects after transplantation.
  evidence:
  - reference: PMID:38896258
    reference_title: Successful Immune Reconstitution in a Patient with a TYK2 Deficiency after Allogeneic Stem Cell Transplantation from Unrelated Donors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our findings suggest that HSCT is a feasible strategy for reconstituting the immune system in TYK2-deficient patients; however, the factors associated with GVHD and autoimmune thyroiditis development in TYK2-deficient patients undergoing HSCT warrant further investigation.
    explanation: >-
      The authors' own assessment, feasible on one patient with unresolved
      complication risk, which is the level at which this treatment currently
      stands.
  - reference: PMID:37695435
    reference_title: "A Novel Homozygous Mutation Causing Complete TYK2 Deficiency, with Severe Respiratory Viral Infections, EBV-Driven Lymphoma, and Jamestown Canyon Viral Encephalitis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The effects of the mutation could not be pharmacologically circumvented in vitro, suggesting that alternative modalities, such as hematopoietic stem cell transplantation or gene therapy, may be needed.
    explanation: >-
      The negative pharmacological result that motivates transplantation as the
      alternative.
- name: Mepolizumab for virus-triggered hypereosinophilia
  description: >-
    Anti-IL-5 antibody, given to one child with complete TYK2 deficiency whose
    dominant problem was not infection itself but the steroid-dependent
    hypereosinophilia and wheezing that followed each viral episode. Eosinophil
    counts normalised within a month and the child remained well. This is a
    single case and addresses a Th2-skewed complication rather than the
    signalling defect.
  dosing_interval: per month
  dosing_interval_days: 30
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: mepolizumab
      term:
        id: NCIT:C157376
        label: Mepolizumab
  evidence:
  - reference: PMID:40949057
    reference_title: Mepolizumab treatment in a child with inherited TYK2 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mepolizumab, used for the treatment of severe eosinophilic asthma, eosinophilic granulomatosis, and hypereosinophilic syndrome, was started at the age of 20 mo, at a dose of 40 mg per month delivered subcutaneously.
    explanation: >-
      The indication, age and dose in the single reported patient.
  - reference: PMID:40949057
    reference_title: Mepolizumab treatment in a child with inherited TYK2 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two weeks after the first injection, eosinophil counts had fallen strongly, to 300/mm3, reaching normal levels one month later.
    explanation: >-
      The measured response.
diagnosis:
- name: Phospho-STAT response to IFN-alpha, IL-10, IL-12 and IL-23
  description: >-
    Functional testing of patient cells for STAT phosphorylation and downstream
    responses after stimulation with each TYK2-dependent cytokine. This is the
    assay that separates complete deficiency, in which all four responses are
    impaired, from the partial forms in which only IL-23 signalling is affected -
    a distinction sequencing alone cannot make for a missense allele.
  results: >-
    Impaired but not abolished responses to IFN-alpha/beta, IL-12, IL-23 and
    IL-10, with normal responses to IFN-gamma, IFN-lambda, IL-21, IL-27 and LIF.
  diagnosis_term:
    preferred_term: flow cytometry
    term:
      id: NCIT:C16585
      label: Flow Cytometry
  evidence:
  - reference: PMID:26304966
    reference_title: "Human TYK2 deficiency: Mycobacterial and viral infections without hyper-IgE syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      All eight TYK2-deficient patients displayed impaired but not abolished cellular responses to (a) IL-12 and IFN-α/β, accounting for mycobacterial and viral infections, respectively; (b) IL-23, with normal proportions of circulating IL-17(+) T cells, accounting for their apparent lack of mucocutaneous candidiasis; and (c) IL-10, with no overt clinical consequences, including a lack of inflammatory bowel disease.
    explanation: >-
      The four-cytokine response pattern that constitutes the positive result.
  - reference: PMID:26304966
    reference_title: "Human TYK2 deficiency: Mycobacterial and viral infections without hyper-IgE syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Cellular responses to IL-21, IL-27, IFN-γ, IL-28/29 (IFN-λ), and leukemia inhibitory factor (LIF) were normal.
    explanation: >-
      The negative controls that make the pattern specific.
- name: TYK2 sequencing
  description: >-
    Panel, exome or genome sequencing. Because the presentation is BCG or
    mycobacterial disease far more often than a recognisable immunodeficiency
    syndrome, the gene is usually reached through an inborn-errors-of-immunity or
    Mendelian-susceptibility-to-mycobacterial-disease panel rather than by
    clinical suspicion of TYK2 itself.
  results: Biallelic loss-of-function TYK2 variants.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:37695435
    reference_title: "A Novel Homozygous Mutation Causing Complete TYK2 Deficiency, with Severe Respiratory Viral Infections, EBV-Driven Lymphoma, and Jamestown Canyon Viral Encephalitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A novel, homozygous c.745C > T (p.R249*) variant was found in TYK2.
    explanation: >-
      A worked example of the sequencing route to diagnosis.
differential_diagnoses:
- name: TYK2 P1104A homozygosity
  description: >-
    The same gene, a different entity. P1104A is a common hypomorphic missense
    allele - homozygous in roughly one in six hundred Europeans - that is
    catalytically dead but docks and scaffolds normally, and that selectively
    disrupts IL-23 signalling while sparing IFN-alpha, IL-10 and IL-12. Its
    clinical expression is tuberculosis, and more rarely mycobacterial disease,
    without viral disease. The IUIS nosology lists it as a separate entity from
    Tyk2 deficiency. It is the differential that matters most here, because a
    literature search on TYK2 returns far more on this allele than on complete
    deficiency.
  distinguishing_features:
  - Normal cellular responses to IFN-alpha, IL-10 and IL-12, with only IL-23 impaired
  - Normal TYK2 scaffolding of IFN-alphaR1, IL-12Rbeta1 and IL-10R2
  - Tuberculosis rather than viral disease as the clinical expression
  - Allele frequency in the general population, not a private family variant
  evidence:
  - reference: PMID:30578352
    reference_title: Tuberculosis and impaired IL-23-dependent IFN-γ immunity in humans homozygous for a common TYK2 missense variant.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Surprisingly, we also show that TYK2 P1104A impairs cellular responses to IL-23, but not to IFN-α, IL-10, or even IL-12, which, like IL-23, induces IFN-γ via activation of TYK2 and JAK2.
    explanation: >-
      The cellular measurement that separates the two entities: three of the four
      TYK2-dependent responses are preserved in P1104A homozygotes.
  - reference: PMID:36094518
    reference_title: Impaired IL-23-dependent induction of IFN-γ underlies mycobacterial disease in patients with inherited TYK2 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two types of inherited TYK2 deficiencies are known: AR complete deficiency underlying MSMD (and more rarely TB) and/or viral diseases, and homozygosity for P1104A deficiency underlying TB (and more rarely MSMD) without viral diseases.
    explanation: >-
      The clinical statement of the same boundary, including the presence or
      absence of viral disease.
- name: Interleukin-12 receptor beta-1 deficiency
  description: >-
    The commonest genetic cause of Mendelian susceptibility to mycobacterial
    disease and the closest phenocopy of the mycobacterial arm of this disorder.
    IL-12Rbeta1 is the receptor chain TYK2 sits on, so both defects impair
    IL-12- and IL-23-driven interferon-gamma production - but in IL-12Rbeta1
    deficiency that production is abolished rather than reduced, and type I
    interferon signalling is intact, so there is no viral susceptibility.
  distinguishing_features:
  - Interferon-gamma production abolished rather than impaired
  - Intact type I interferon responses and no severe viral disease
  - Biallelic IL12RB1 rather than TYK2 variants
  evidence:
  - reference: PMID:36094518
    reference_title: Impaired IL-23-dependent induction of IFN-γ underlies mycobacterial disease in patients with inherited TYK2 deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      whereas IL-12– and IL-23–mediated IFN-γ production was completely abolished in the IL-12Rβ1–deficient patient.
    explanation: >-
      Contrasts the abolished production in IL-12Rbeta1 deficiency with the
      merely impaired production in TYK2 deficiency, measured side by side.
  - reference: PMID:36094518
    reference_title: Impaired IL-23-dependent induction of IFN-γ underlies mycobacterial disease in patients with inherited TYK2 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Penetrance is probably higher in patients with AR TYK2 deficiency and impaired cellular responses to both IL-12 and IL-23, and even higher in patients with IL-12Rβ1 deficiency with abolished responses to both cytokines
    explanation: >-
      Places the two disorders on the same axis, with IL-12Rbeta1 deficiency the
      more penetrant because its cytokine responses are abolished rather than
      reduced.
- name: Chronic granulomatous disease
  description: >-
    The disorder TYK2 deficiency is most often mistaken for in practice, because
    both present with granulomatous disease after BCG in an infant. The
    discriminator is the phagocyte oxidative burst, which is normal here and
    absent in chronic granulomatous disease.
  distinguishing_features:
  - Normal neutrophil oxidative burst on dihydrorhodamine or nitroblue tetrazolium testing
  - Viral as well as mycobacterial susceptibility
  evidence:
  - reference: PMID:41465118
    reference_title: "TYK2 Deficiency Presenting as Refractory Disseminated BCG/Tuberculosis Infection in a Kazakh Child: A Case Report with Genetic Confirmation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical overlap with chronic granulomatous disease (CGD) and other granulomatous disorders complicates diagnosis, particularly in nations where universal BCG vaccination is instituted.
    explanation: >-
      States the diagnostic confusion directly.
animal_models:
- name: Tyk2-deficient mouse
  species: Mouse
  genotype: Tyk2 null (germline knockout)
  publication: PMID:11070173
  description: >-
    Germline Tyk2 knockout mice, generated independently by two groups in 2000.
    They are viable and developmentally normal, and they reproduce the
    partial-signalling character of the human disorder rather than a complete
    block - which is the property that makes them informative and also the
    property that limits them. Where the mouse and the human diverge is IL-10
    and IL-6: mouse responses to both are normal, whereas the human deficiency
    impairs IL-10 signalling, and the original human patient had an IL-6 defect
    as well.
  modeled_mechanisms:
  - target: Impaired Type I Interferon Signaling
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      The mouse reproduces the partial, dose-dependent character of the human
      type I interferon defect: low-dose IFN-alpha fails to signal while high
      concentrations still transduce fully.
    limitations: >-
      The residual signalling is more evident in the mouse than in patients, and
      the antiviral phenotype is elicited by high-dose experimental challenge
      with vaccinia and LCMV rather than by the herpesviruses and respiratory
      viruses that affect patients.
    readouts:
    - name: Vaccinia virus clearance and LCMV-specific T-cell response
      target: Impaired Type I Interferon Signaling
      direction: DECREASED
      interpretation: >-
        Functional antiviral consequence of the type I interferon signalling
        defect in the model.
      evidence:
      - reference: PMID:11070173
        reference_title: Partial impairment of cytokine responses in Tyk2-deficient mice.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Tyk2-/- mice are unable to clear vaccinia virus and show a reduced T cell response after LCMV challenge.
        explanation: >-
          The measured antiviral failure in the knockout.
    evidence:
    - reference: PMID:11070174
      reference_title: Tyk2 plays a restricted role in IFN alpha signaling, although it is required for IL-12-mediated T cell function.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Tyk2-deficient mice show no overt developmental abnormalities; however, they display a lack of responsiveness to a small amount of IFNalpha, although a high concentration of IFNalpha can fully transduce its signal even in the absence of tyk2.
      explanation: >-
        Establishes that the model has a partial, dose-dependent type I
        interferon defect rather than an absolute one.
  - target: Impaired IL-12 and IL-23 Signaling
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      IL-12-driven T-cell function is defective in the knockout, matching the
      IL-12 arm of the human lesion, and the macrophages fail an
      activation-dependent effector readout.
    limitations: >-
      The mouse experiments predate the recognition that IL-23-dependent
      interferon-gamma induction is the defect shared by all human forms, and
      they measure IL-12-driven T-cell function and nitric oxide production
      rather than IL-23-driven interferon-gamma output, so the specific human
      convergence point is not directly modelled.
    readouts:
    - name: IL-12-induced T-cell function
      target: Impaired IL-12 and IL-23 Signaling
      direction: DECREASED
      interpretation: >-
        The IL-12 signalling arm of the human lesion is present in the mouse.
      evidence:
      - reference: PMID:11070174
        reference_title: Tyk2 plays a restricted role in IFN alpha signaling, although it is required for IL-12-mediated T cell function.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Furthermore, IL-12-induced T cell function is defective in these mice.
        explanation: >-
          Direct measurement of the IL-12 response defect.
    - name: Lipopolysaccharide-induced macrophage nitric oxide production
      target: Impaired IL-12 and IL-23 Signaling
      direction: DECREASED
      interpretation: >-
        A macrophage effector readout that fails downstream of the same
        signalling lesion.
      evidence:
      - reference: PMID:11070173
        reference_title: Partial impairment of cytokine responses in Tyk2-deficient mice.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Tyk2-/- macrophages fail to produce nitric oxide upon lipopolysaccharide induction.
        explanation: >-
          The measured macrophage effector failure.
    evidence:
    - reference: PMID:11070173
      reference_title: Partial impairment of cytokine responses in Tyk2-deficient mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In contrast to other Jaks, where inactivation leads to a complete loss of the respective cytokine receptor signal, Tyk2-/- mice display reduced responses to IFNalpha/beta and IL-12 and a selective deficiency in Stat3 activation in these pathways.
      explanation: >-
        Establishes the partial character of the signalling defect that makes
        this model informative for TYK2 rather than for the other Janus kinases.
  - target: Impaired IL-10 Signaling
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >-
      Tyk2-deficient mice respond normally to IL-10, whereas the IL-10 response
      is impaired in every human patient assayed. The mouse cannot be used to
      study this branch.
    limitations: >-
      The species difference is not a matter of degree: mouse IL-10 responses are
      reported as normal, so there is no defect in the model to characterise. The
      same holds for IL-6, where the mouse is normal and the human index patient
      was not. The original human report drew exactly this contrast, noting that
      the human requirement for TYK2 across cytokine pathways differs
      substantially from the mouse.
    evidence:
    - reference: PMID:11070174
      reference_title: Tyk2 plays a restricted role in IFN alpha signaling, although it is required for IL-12-mediated T cell function.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In contrast, these mice respond normally to IL-6 and IL-10, both of which activate tyk2 in vitro.
      explanation: >-
        The measurement showing the mouse has no IL-10 or IL-6 defect to model.
    - reference: PMID:17088085
      reference_title: Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        This study identifies human Tyk2 deficiency and demonstrates that Tyk2 plays obligatory roles in multiple cytokine signals involved in innate and acquired immunity of humans, which differs substantially from Tyk2 function in mice.
      explanation: >-
        The authors' own statement of the species divergence in TYK2 pathway
        dependence.
  evidence:
  - reference: PMID:11070174
    reference_title: Tyk2 plays a restricted role in IFN alpha signaling, although it is required for IL-12-mediated T cell function.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These observations demonstrate that tyk2 plays only a restricted role in mediating IFNalpha-dependent signaling while being required in mediating IL-12-dependent biological responses.
    explanation: >-
      The summary of what this model does and does not establish about TYK2
      pathway dependence.
discussions:
- discussion_id: gap_tyk2_complete_vs_hypomorph_boundary
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Where does complete TYK2 deficiency end and partial TYK2 deficiency begin,
    given that the mechanism now held to explain mycobacterial disease is shared
    by both?
  attaches_to:
  - genetic#TYK2
  - pathophysiology#Deficient Interferon-Gamma Induction in Lymphocytes
  rationale: >-
    The 2022 analysis showed that impaired IL-23-dependent interferon-gamma
    induction is the only mechanism of mycobacterial disease common to all five
    forms of autosomal recessive TYK2 deficiency, from complete loss of
    expression through to homozygosity for the common P1104A allele. That result
    is what makes the boundary awkward. For the mycobacterial phenotype the two
    ends of the spectrum are mechanistically continuous, and the reasons for
    keeping them apart are that complete deficiency additionally loses type I
    interferon, IL-12 and IL-10 signalling and the scaffolding function, and that
    only complete deficiency produces viral disease. Those are real differences
    and the IUIS nosology encodes them as separate entities, so this entry is
    confined to complete deficiency. But the line is drawn on the extra
    pathways, not on the mechanism the two share, and no study has tested whether
    the mycobacterial disease seen in a complete-deficiency patient differs in
    kind from that seen in a P1104A homozygote once exposure is matched. Until
    it does, the question of whether these should be one graded entity or two is
    open, and this entry records that rather than settling it. Note also that the
    intermediate forms complicate any purely genetic rule: G1010D produces a
    detectable protein that is nonetheless loss-of-function across all pathways
    and is counted as complete deficiency, while R864C produces a hypomorph that
    is not.
  evidence:
  - reference: PMID:36094518
    reference_title: Impaired IL-23-dependent induction of IFN-γ underlies mycobacterial disease in patients with inherited TYK2 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Impairment of the IL-23-dependent induction of IFN-γ is the only mechanism of mycobacterial disease common to patients with complete TYK2 deficiency with or without TYK2 expression, partial TYK2 deficiency across signaling pathways, or rare or common partial TYK2 deficiency specific for IL-23 signaling.
    explanation: >-
      The result that makes the boundary a genuine question: one mechanism spans
      the whole spectrum.
  - reference: PMID:36094518
    reference_title: Impaired IL-23-dependent induction of IFN-γ underlies mycobacterial disease in patients with inherited TYK2 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two types of inherited TYK2 deficiencies are known: AR complete deficiency underlying MSMD (and more rarely TB) and/or viral diseases, and homozygosity for P1104A deficiency underlying TB (and more rarely MSMD) without viral diseases.
    explanation: >-
      The clinical grounds on which the same authors nonetheless keep the two
      apart, which is the position this entry adopts.
- discussion_id: mismatch_tyk2_type_iii_interferon
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Does type III interferon signalling actually require TYK2 in human cells, and
    if it does so only in some cell types, what does that mean for the antiviral
    phenotype of complete TYK2 deficiency?
  attaches_to:
  - pathophysiology#Impaired Type I Interferon Signaling
  rationale: >-
    TYK2 is constitutively associated with IL-10R2, one of the two chains of the
    type III interferon receptor, so on the receptor architecture alone
    IFN-lambda signalling ought to fail in complete deficiency. The 2015 patient
    series found responses to IL-28/IL-29 normal, and this entry follows that in
    confining the antiviral lesion to type I interferon. But the cell-line
    evidence does not agree with itself: SV40-transformed fibroblasts from
    patients with complete TYK2 deficiency respond very weakly to type III
    interferon while their EBV-transformed B cells respond normally, and a
    TYK2-knockout HAP1 line responds normally to IFN-lambda1. The result is
    therefore cell-type-dependent, and every observation on either side comes
    from a transformed line rather than from a primary cell or a clinical
    outcome. Whether the discrepancy reflects real tissue-specific redundancy -
    with JAK1, or with the JAK2 phosphorylation that type III but not type I
    interferons trigger, taking over - or an artefact of transformation is
    unresolved. It matters because the epithelial surfaces where type III
    interferon does most of its work are exactly the surfaces on which these
    patients get their respiratory viral disease, and no patient-derived
    epithelial system has been tested.
  evidence:
  - reference: PMID:38781720
    reference_title: "In search of a function for human type III interferons: insights from inherited and acquired deficits."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      By contrast, for complete TYK2 deficiency, SV40-transformed fibroblasts have very weak responses, whereas EBV-B cells respond normally
    explanation: >-
      The cell-type discrepancy itself, measured in two transformed lines from
      patients with complete deficiency.
  - reference: PMID:38781720
    reference_title: "In search of a function for human type III interferons: insights from inherited and acquired deficits."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The response to IFN-λ1 in HAP1-TYK2KO cells is normal, suggesting that type III IFN signaling may be TYK2-independent, at least in some cell types
    explanation: >-
      An engineered knockout line supporting TYK2-independence, with the authors'
      own cell-type caveat attached.
  - reference: PMID:38781720
    reference_title: "In search of a function for human type III interferons: insights from inherited and acquired deficits."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The ligand-receptor interaction triggers the activation of JAK1 and TYK2, constitutively associated with IFNLR1 and IL10RB, respectively, leading to the heterodimerization of STAT1/STAT2, which, together with IRF9, form the ISGF3 transcription complex
    explanation: >-
      The receptor architecture that predicts a type III interferon defect, which
      is what makes the normal responses surprising.
  - reference: PMID:26304966
    reference_title: "Human TYK2 deficiency: Mycobacterial and viral infections without hyper-IgE syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Cellular responses to IL-21, IL-27, IFN-γ, IL-28/29 (IFN-λ), and leukemia inhibitory factor (LIF) were normal.
    explanation: >-
      The patient-cell result this entry follows, which the cell-line data
      qualify rather than overturn.
- discussion_id: gap_tyk2_penetrance_determinants
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What determines whether a person homozygous for a TYK2 null allele develops
    mycobacterial disease, viral disease, both, or nothing at all?
  attaches_to:
  - phenotypes#Mycobacterial disease
  - phenotypes#Severe or recurrent viral infection
  rationale: >-
    Penetrance is incomplete for both defining phenotypes - roughly half of
    patients develop mycobacterial disease and three-fifths viral disease - and
    asymptomatic homozygous adults are on record, including siblings of severely
    affected probands. Exposure explains part of it, since several asymptomatic
    homozygotes were never given BCG and BCG disease is the commonest
    mycobacterial presentation, and the environmental link curated here records
    that. It does not explain the viral arm, where exposure to herpesviruses and
    respiratory viruses is effectively universal and yet two of five siblings in
    one family had hypoxaemic COVID-19 pneumonia while another was asymptomatic
    after infection. No modifier has been identified, and with twenty-five
    reported patients there is no cohort in which one could be sought.
  evidence:
  - reference: PMID:40949057
    reference_title: Mepolizumab treatment in a child with inherited TYK2 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Incomplete clinical penetrance has been observed for mycobacterial and viral diseases, as 48% and 60% of patients, respectively, develop these diseases.
    explanation: >-
      Quantifies the incomplete penetrance that the gap is about.
  - reference: PMID:36094518
    reference_title: Impaired IL-23-dependent induction of IFN-γ underlies mycobacterial disease in patients with inherited TYK2 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Four of these 19 patients with biallelic TYK2 variants presented only intramacrophagic infections, six had viral diseases only, seven had combinations of viral, mycobacterial, and fungal diseases, and two were asymptomatic.
    explanation: >-
      The distribution of clinical outcomes across one cohort, including the
      asymptomatic homozygotes.
clinical_trials: []
datasets: []
notes: >-
  Scope. This entry covers complete autosomal recessive TYK2 deficiency:
  loss-of-expression alleles, and rare alleles producing a detectable protein
  that is loss-of-function across all TYK2-dependent pathways. It deliberately
  excludes the three partial forms, above all homozygosity for the common P1104A
  allele, which is curated only as a differential diagnosis and in the boundary
  knowledge gap. Three literatures that a search on this gene returns were
  screened out rather than used: TYK2 as a GWAS susceptibility locus in
  autoimmune disease, TYK2 as a pathway member in unrelated cytokine disorders,
  and the pharmacological TYK2-inhibitor literature. None of them reports a
  patient with biallelic complete loss, and each citation used here was checked
  to be about such a patient or about a cell or mouse carrying that lesion.

  Evidence-source convention. Sentences whose subject is a patient's clinical
  state, the case count, penetrance, or the genotype found on sequencing are
  graded HUMAN_CLINICAL. Sentences reporting a measurement made on cultured
  patient cells, transduced cell lines or fibroblasts - phospho-STAT responses,
  cytokine-stimulated interferon-gamma production, receptor surface expression,
  complementation with wild-type TYK2 - are graded IN_VITRO even when they appear
  in a clinical paper. Mouse data are MODEL_ORGANISM.

  Two phenotypes have no inbound causal edge, deliberately. Normal peripheral
  blood immunophenotype is the absence of an abnormality, so there is nothing
  for a mechanism to produce. Elevated serum IgE with eczema is curated to
  record that the historical hyper-IgE label was wrong, and the cited work finds
  no TYK2-dependent mechanism for it.

  Module conformance declined. `innate_antiviral_interferon_response#Type I and
  III Interferon Induction and JAK-STAT Signaling` was considered for the
  antiviral branch and not used. That module node bundles interferon *induction*
  (GO:0032606) with JAK-STAT signalling, and induction is not impaired in TYK2
  deficiency - only the response to interferon already made. Declaring
  conformance would assert a lesion the disease does not have. A narrower
  module covering JAK-STAT loss of signalling downstream of a cytokine receptor
  does not currently exist in `kb/modules/`; TYK2 deficiency would be a
  reasonable first conformer if one is created.

  Not curated. No biochemical block: the disorder has no characteristic routine
  laboratory abnormality, and the diagnostic assays are functional signalling
  tests rather than analyte measurements, which are curated under diagnosis. No
  datasets or clinical trials: none specific to complete TYK2 deficiency were
  identified. No prevalence rate, for the reason given in the prevalence record.

📚

References & Deep Research

References

13

PMID:17088085

Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity.

No top-level findings curated for this source.

PMID:26304966

Human TYK2 deficiency: Mycobacterial and viral infections without hyper-IgE syndrome.

No top-level findings curated for this source.

PMID:36094518

Impaired IL-23-dependent induction of IFN-γ underlies mycobacterial disease in patients with inherited TYK2 deficiency.

No top-level findings curated for this source.

PMID:40949057

Mepolizumab treatment in a child with inherited TYK2 deficiency.

No top-level findings curated for this source.

PMID:37695435

A Novel Homozygous Mutation Causing Complete TYK2 Deficiency, with Severe Respiratory Viral Infections, EBV-Driven Lymphoma, and Jamestown Canyon Viral Encephalitis.

No top-level findings curated for this source.

PMID:38896258

Successful Immune Reconstitution in a Patient with a TYK2 Deficiency after Allogeneic Stem Cell Transplantation from Unrelated Donors.

No top-level findings curated for this source.

PMID:41465118

TYK2 Deficiency Presenting as Refractory Disseminated BCG/Tuberculosis Infection in a Kazakh Child: A Case Report with Genetic Confirmation.

No top-level findings curated for this source.

PMID:34569645

Novel mutations of TYK2 leading to divergent clinical phenotypes.

No top-level findings curated for this source.

PMID:30578352

Tuberculosis and impaired IL-23-dependent IFN-γ immunity in humans homozygous for a common TYK2 missense variant.

No top-level findings curated for this source.

PMID:38781720

In search of a function for human type III interferons: insights from inherited and acquired deficits.

No top-level findings curated for this source.

PMID:11070173

Partial impairment of cytokine responses in Tyk2-deficient mice.

No top-level findings curated for this source.

PMID:11070174

Tyk2 plays a restricted role in IFN alpha signaling, although it is required for IL-12-mediated T cell function.

No top-level findings curated for this source.

PMID:35748970

Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee.

No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (1)

Create: Immunodeficiency 35 (complete TYK2 deficiency, MONDO:0012682) · 2026-09-02T02:00:31Z · View source

De novo curation of immunodeficiency 35 (TYK2) from the stubs/ queue, claim issue #10463. entry_type recorded as DISEASE: one conserved pathograph in which loss of a single shared Janus kinase disables four cytokine circuits, producing two coherent branches (type I interferon -> antiviral failure; IL-12/IL-23 -> deficient interferon-gamma induction -> inadequate macrophage control). Scope decision, and the main risk on this disease: the entry covers COMPLETE TYK2 deficiency only. Three literatures a TYK2 search returns were screened out rather than used - TYK2 as an autoimmune GWAS locus, TYK2 as a pathway member in unrelated entries (it already appears in Ankylosing_Spondylitis, Dermatomyositis, Down_syndrome and Interleukin-10_Receptor_Deficiency), and the deucravacitinib/TYK2-inhibitor literature. Every citation was checked to be about a patient, cell or mouse carrying biallelic complete loss. The common hypomorphic P1104A allele is cited exactly twice and only in that role: as a named differential diagnosis, and inside the boundary knowledge gap. PMID:30578352 (Boisson-Dupuis 2018) is the only P1104A paper cited and it is never used to support a claim about complete deficiency. Gene-frequency preflight passes on this disease without discriminating, as the claim issue warned, so the check was done citation by citation instead. preflight-dr PASS against MONDO:0012682 (TYK2 mentioned 97 times, OMIM 611521 matches). Boundary curated as a KNOWLEDGE_GAP rather than resolved by assertion: PMID:36094518 shows impaired IL-23-dependent interferon-gamma induction is the ONE mechanism shared by all five forms including P1104A, so for the mycobacterial phenotype the spectrum is mechanistically continuous. The entry keeps the two apart on the extra pathways lost in complete deficiency and on the IUIS nosology listing them as separate rows, and records in the gap that nobody has tested whether the mycobacterial disease differs in kind once exposure is matched. Deep research: Falcon report research/Immunodeficiency_35-deep-research-falcon.md, which had independently scoped itself to complete deficiency. Used as leads; all 73 snippets verified against cached references. Validation (all exit 0): just validate (schema, terms, 73/73 snippets), check-duplicate-keys, check-entity-refs, check-causal-targets. Two drafting errors were caught and fixed: treatment_effect CORRECTS does not exist in TreatmentEffectEnum (used RESTORES), and NCIT:C68931 resolves to Teglarinad Chloride, not Mepolizumab (used NCIT:C157376). HP:0002728 was bound with the repo cache label 'Chronic mucocutaneous candidiasis'; current OLS gives 'Recurrent mucocutaneous candidiasis', and the cache label was kept for consistency with the rest of kb/. Not curated: no prevalence rate (the only frequency statement is an order-of-magnitude comparison, so prevalence_class ULTRA_RARE with CASES_IN_LITERATURE), no biochemical block, no datasets or trials.

Falcon ▸

Disease Characteristics Research Template

Edison Scientific Literature 27 citations 2026-09-01T18:33:09.311213

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

Disease Name: immunodeficiency 35 (complete tyrosine kinase 2 / TYK2 deficiency, biallelic null variants)
MONDO ID: MONDO:0012682 (if available)
Category: Mendelian

Research Objectives

Please provide a comprehensive research report on immunodeficiency 35 (complete tyrosine kinase 2 / TYK2 deficiency, biallelic null variants) covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

What is the disease? Provide a concise overview.
What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
What are the common synonyms and alternative names?
Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
Risk Factors:

Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Genetic risk factors (causal variants, susceptibility loci, modifier genes)
Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
Protective Factors:

Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Genetic protective factors (protective variants, modifier alleles)
Environmental protective factors (diet, lifestyle, exposures that reduce risk)
Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
Pathogenic Variants:
Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
Variant type/class (missense, frameshift, nonsense, splice-site, structural)
Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
Functional consequences (loss of function, gain of function, dominant negative)
Modifier Genes: Genes that modify disease severity or expression
Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

Search first: CDC databases, WHO, PubMed, NHANES
Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Present this section as an ordered causal chain first, then the detail below. Open with a numbered sequence of mechanistic steps running from the initiating lesion (mutation, exposure, infection) to the clinical manifestation, one step per line, each naming what it causes next. State the causal verb explicitly ("leads to", "results in") and say where a step is inferred rather than demonstrated. Where the mechanism branches, show the branch. The categories below are a checklist of what to cover within those steps, not the organizing structure — a step may draw on several of them, and a category may contribute to several steps.

Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

Search first: PubMed, Gene Ontology, Reactome
Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Molecular Profiling (if available):
Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
Advanced Technologies (if applicable):
Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

Organ Level:
Primary organs directly affected
Secondary organ involvement (complications, secondary effects)
Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Tissue and Cell Level:
Specific tissue types affected (epithelial, connective, muscle, nervous)
Specific cell populations targeted (with Cell Ontology terms)

Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Subcellular Level:
Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Localization:
Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

Onset:
Typical age of onset (congenital, pediatric, adult, geriatric)
Onset pattern (acute, subacute, chronic, insidious)

Search first: OMIM, Orphanet, HPO, PubMed
Progression:
Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
Progression rate (rapid, slow, variable)
Disease course pattern (episodic, relapsing-remitting, progressive, stable)
Disease duration (self-limited, chronic lifelong)

Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Patterns:
Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

Epidemiology:
Prevalence (cases per 100,000 at given time)
Incidence (new cases per 100,000 per year)

Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
For Genetic Etiology:
Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
Population Demographics:
Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
Geographic distribution of specific variants
Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

Clinical Tests:
Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
Genetic Testing:

Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
Overview of recommended genetic testing approach
Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
FISH > Search first: ClinVar, cytogenetics databases, PubMed
Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
Omics-Based Diagnostics (if applicable):
RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
Clinical Criteria:
Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
Screening:
Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

Survival and Mortality:
Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
Morbidity and Function:
Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
Disease Course:
Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
Prediction:
Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

Pharmacotherapy:
Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
Advanced Therapeutics:
Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
Surgical and Interventional:
Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
Supportive and Rehabilitative:
Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
Experimental:
Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
Treatment Outcomes:
Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
Treatment Strategy:
Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

Prevention Levels:
Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
Immunization: Vaccine strategies (if applicable)

Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
Screening and Early Detection:
Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
Behavioral Interventions: Lifestyle modifications to reduce risk

Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Counseling: Genetic counseling (risk assessment, family planning guidance)

Search first: NSGC resources, ACMG guidelines, GeneReviews
Public Health:
Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
Prophylaxis: Preventive medications or procedures

Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

Taxonomy: Species affected (with NCBI Taxon identifiers)

Search first: NCBI Taxonomy
Breed: Specific breeds affected (with VBO identifiers if applicable)

Search first: VBO (Vertebrate Breed Ontology)
Gene: Orthologous genes in other species (with NCBI Gene IDs)

Search first: NCBI Gene
Natural Disease:
Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
Comparative Biology:
Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
Transmission (if applicable):
Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

Model Types:
Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
Genetic Models:
Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
Model Characteristics:
Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
Applications:
Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
Resources:
Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic and clinical claims
Prioritize recent reviews and landmark papers
Include direct quotes from abstracts where possible to support key statements
Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Complete TYK2 deficiency (immunodeficiency 35): research report

Scope and evidence note

This report concerns complete autosomal-recessive TYK2 deficiency caused by biallelic null/loss-of-function variants. It does not treat partial/hypomorphic TYK2 deficiency or homozygosity for the common p.Pro1104Ala allele as the same disease. Those alleles can produce narrower defects—especially isolated IL-23 signaling impairment—and materially different clinical phenotypes. The strongest disease-specific evidence remains the 2015 international series and the expanded mechanistic cohort published in September 2022; the 2023–2024 literature mainly provides broader inborn-error-of-immunity or JAK–STAT context rather than a new complete-TYK2-deficiency cohort. Because the disorder is exceptionally rare, most estimates derive from aggregated case reports rather than registries or population studies.

Domain	High-confidence finding	Evidence type	Suggested ontology/identifier
Disease identifiers	Complete autosomal recessive TYK2 deficiency corresponds to immunodeficiency 35; MONDO association is MONDO:0012682 and OMIM is 611521; causal target is TYK2, Ensembl ENSG00000105397 (OpenTargets Search: immunodeficiency 35,TYK2 deficiency-TYK2, sarrafzadeh2020anewpatient pages 1-3)	Aggregated disease database + human case series	MONDO:0012682; OMIM:611521; TYK2; ENSG00000105397
Disease definition	Mendelian inborn error of immunity caused by biallelic TYK2 loss-of-function/null alleles, distinct from partial TYK2 deficiency and the common P1104A susceptibility allele (ogishi2022impairedil23–dependentinduction pages 4-6, ogishi2022impairedil23–dependentinduction pages 2-3)	Human clinical genetics + functional immunology	Suggested label: inborn error of immunity; suggested label: Mendelian susceptibility to mycobacterial disease spectrum requiring ontology validation
Inheritance	Inheritance is autosomal recessive; unaffected heterozygous parents/carriers reported; consanguinity documented in some families (sarrafzadeh2020anewpatient pages 1-3, sarrafzadeh2020anewpatient pages 3-4)	Human pedigree/case report	Suggested label: autosomal recessive inheritance
Causal gene/protein	TYK2 encodes tyrosine kinase 2, a JAK family kinase required for signaling downstream of multiple cytokine receptors, especially IL-23, IL-12, IL-10, and type I IFN pathways in this disease context (ogishi2022impairedil23–dependentinduction pages 12-15, boissondupuis2018tuberculosisandimpaired pages 5-6, ogishi2022impairedil23–dependentinduction pages 15-17)	Human patient-cell functional studies	TYK2; suggested GO label: JAK-STAT cascade requiring ontology validation
Pathogenic variant classes	Reported complete-deficiency alleles include frameshift, nonsense, essential splice-site, and multi-exon deletion variants causing loss of expression or complete loss of function; examples include p.C70Hfs21, p.P216Rfs14, p.E154, p.L767, c.2466+1G>T, c.466-1G>A, and exon 19-25 deletion (ogishi2022impairedil23–dependentinduction pages 4-6, ogishi2022impairedil23–dependentinduction pages 7-9, ogishi2022impairedil23–dependentinduction pages 3-4)	Human molecular genetics + patient-cell assays	Suggested label: null variant; loss-of-function variant; germline variant
Hallmark phenotype: mycobacterial disease	Mycobacterial disease is a hallmark phenotype, including BCG disease/BCG-osis, environmental mycobacterial disease, and tuberculosis; in the 2022 series, 9 reported patients had mycobacterial disease, including 6 with BCG disease, 1 with environmental mycobacteria, and 3 with tuberculosis (ogishi2022impairedil23–dependentinduction pages 2-3)	Human cohort/series	Suggested HPO label: mycobacterial infection susceptibility requiring ontology validation; suggested HPO label: disseminated BCG infection requiring ontology validation
Hallmark phenotype: viral disease	Severe viral disease is also characteristic, including mucocutaneous HSV-1, HSV-1 encephalitis, VZV, molluscum contagiosum, parainfluenza pneumonia, influenza A pneumonia, COVID-19 pneumonia, and MMR vaccine disease (ogishi2022impairedil23–dependentinduction pages 2-3)	Human cohort/series	Suggested HPO label: recurrent viral infections requiring ontology validation; suggested HPO label: herpes simplex encephalitis requiring ontology validation
Additional/variable phenotype	Some patients show atopy/eczema, cellulitis, oral thrush, chronic mucocutaneous candidiasis, or parasitic infection such as Leishmania major; hyper-IgE syndrome is not universal and may be absent (sarrafzadeh2020anewpatient pages 1-3, ogishi2022impairedil23–dependentinduction pages 4-6, ogishi2022impairedil23–dependentinduction pages 2-3)	Human case reports/series	Suggested HPO labels requiring ontology validation: eczema; cellulitis; chronic mucocutaneous candidiasis; leishmaniasis susceptibility
Temporal pattern	Onset is usually pediatric/early childhood; vaccine-associated BCG complications can appear in infancy, e.g., one reported patient developed fever, lymphadenitis, and ulcers after BCG vaccination at 7 months (sarrafzadeh2020anewpatient pages 1-3)	Human case report	Suggested HPO label: infantile onset requiring ontology validation
Core molecular mechanism	Biallelic TYK2 null alleles lead to absent or nonfunctional TYK2 protein, causing impaired cellular responses to IFN-alpha/beta, IL-10, IL-12, and especially IL-23; the unifying antimycobacterial mechanism across TYK2-deficient forms is impaired IL-23-dependent induction of IFN-gamma (ogishi2022impairedil23–dependentinduction pages 12-15, ogishi2022impairedil23–dependentinduction pages 15-17, ogishi2022impairedil23–dependentinduction pages 2-3)	Human patient-cell mechanistic studies	Suggested GO labels requiring ontology validation: response to interferon-alpha; interleukin-23-mediated signaling pathway; interferon-gamma production
Immunologic cell types implicated	Defective IL-23-dependent IFN-gamma production has been demonstrated in lymphocyte subsets including MAIT cells, gamma-delta T cells, and NK cells; classic monocytes and myeloid dendritic cells also show impaired IFN-alpha responses (ogishi2022impairedil23–dependentinduction pages 12-15)	Human ex vivo cellular immunology	Suggested CL labels requiring ontology validation: mucosal associated invariant T cell; gamma-delta T cell; natural killer cell; classical monocyte; myeloid dendritic cell
Signaling readouts	Patient cells show impaired or abolished STAT1/STAT3 phosphorylation after IFN-alpha, IL-10, and IL-23 stimulation, with IL-23 signaling particularly vulnerable; receptor expression may remain intact, indicating signaling rather than receptor absence as the core defect (boissondupuis2018tuberculosisandimpaired pages 5-6, ogishi2022impairedil23–dependentinduction pages 7-9)	Human patient-cell signaling assays	Suggested GO labels requiring ontology validation: STAT1 phosphorylation; STAT3 phosphorylation
Diagnostic confirmation	Diagnosis is confirmed by molecular testing showing biallelic TYK2 variants, typically by WES followed by PCR/Sanger confirmation, plus functional immunology such as lymphocyte transformation tests and impaired IFN-gamma production after BCG + IL-12 stimulation or defective cytokine-induced STAT phosphorylation (sarrafzadeh2020anewpatient pages 3-4, sarrafzadeh2020anewpatient pages 1-3)	Human diagnostic genetics + functional assays	TYK2 sequencing; suggested NCIT label: whole exome sequencing; suggested assay labels requiring ontology validation: cytokine stimulation assay; phospho-STAT assay
Differential diagnostic context	Should be distinguished from other MSMD/type I IFN pathway defects and from partial TYK2 deficiency or TYK2 P1104A homozygosity, which can show narrower signaling defects than complete null deficiency (ogishi2022impairedil23–dependentinduction pages 2-3, ogishi2022impairedil23–dependentinduction pages 15-17)	Comparative human genetics/functional studies	Suggested labels requiring ontology validation: IL12RB1 deficiency; IFNAR pathway defects; partial TYK2 deficiency
Prevention/management	Avoidance of live BCG vaccination is strongly supported by reported vaccine complications and by families withholding BCG after an affected sibling; management is mainly infection-directed, while IFN-gamma plus antibiotics is supported at the broader MSMD level and should be considered extrapolative rather than TYK2-specific trial evidence (ogishi2022impairedil23–dependentinduction pages 3-4, bustamante2020mendeliansusceptibilityto pages 5-6)	Human case management + review/expert extrapolation	Suggested NCIT labels requiring ontology validation: Bacillus Calmette-Guerin vaccine avoidance; interferon gamma therapy; antibacterial therapy
Prognosis/outcomes	Penetrance for at least one infectious phenotype appears high among individuals with biallelic TYK2 genotypes, but precise survival, life expectancy, and long-term disability estimates are not established from current small cohorts (ogishi2022impairedil23–dependentinduction pages 3-4)	Human cohort inference	Suggested label: high infectious penetrance; data gap on survival metrics
Epidemiology/data gaps	Extremely rare disease; no robust prevalence or incidence estimates were identified; literature remains limited to small international case series/case reports, and QoL data are lacking (ogishi2022impairedil23–dependentinduction pages 2-3, ogishi2022impairedil23–dependentinduction pages 3-4)	Literature synthesis/data-gap assessment	Suggested label: ultra-rare disease
Real-world implementation	Real-world use today centers on genomic diagnosis of children with unusual mycobacterial and/or severe viral infections, especially after BCG disease or herpesvirus/COVID complications, with family-based counseling and cascade testing where relevant (sarrafzadeh2020anewpatient pages 3-4, ogishi2022impairedil23–dependentinduction pages 3-4)	Human clinical implementation	Suggested NCIT label: genetic counseling; suggested label: cascade testing requiring ontology validation
Mouse/cellular model	Tyk2-knockout mice are viable, show impaired type I IFN and IL-12/IL-23 biology, and are more susceptible to multiple viruses; they are useful mechanistic models but do not fully recapitulate the breadth of human infectious and atopic phenotypes (meyts2021viralinfectionsin pages 13-14, muromoto2022currentunderstandingof pages 2-4, muromoto2022currentunderstandingof pages 1-2)	Model organism + cellular studies	Suggested model identifiers requiring ontology validation: Tyk2 knockout mouse; Mus musculus

Table: This compact table summarizes high-confidence disease knowledge for complete autosomal recessive TYK2 deficiency only, emphasizing identifiers, hallmark phenotypes, mechanism, diagnostics, management, and key data gaps. It is structured for direct use in a knowledge base and flags ontology labels that need formal validation.

1. Disease information

Definition. Immunodeficiency 35 is a Mendelian inborn error of immunity in which biallelic TYK2 null alleles abolish or critically disrupt tyrosine kinase 2. The resulting combined cytokine-signaling defect compromises IL-12/IL-23-dependent IFN-γ immunity to intracellular pathogens and type-I-interferon-mediated antiviral immunity. Clinically, the most characteristic manifestations are BCG disease, environmental mycobacteriosis or tuberculosis, together with variably severe viral infections. Hyper-IgE/atopic manifestations occurred in the original Japanese patient but are not defining or universal. The expanded literature explicitly describes complete AR TYK2 deficiency as mycobacterial and/or viral disease with impaired IFN-α/β, IL-10, IL-12 and IL-23 responses. (nemoto2018compoundheterozygoustyk2 pages 1-2, ogishi2022impairedil23–dependentinduction pages 2-3)

Identifiers and names.

MONDO: MONDO:0012682, “immunodeficiency 35.”
OMIM phenotype: 611521, commonly rendered Immunodeficiency 35 or TYK2 deficiency.
Causal target: TYK2, Ensembl ENSG00000105397, approved name tyrosine kinase 2. Open Targets links TYK2 to MONDO:0012682 using human genetic evidence and landmark PMIDs 17088085, 26304966 and 22402565. (OpenTargets Search: immunodeficiency 35,TYK2 deficiency-TYK2)
Common synonyms: complete TYK2 deficiency, autosomal-recessive TYK2 deficiency, TYK2-associated immunodeficiency, and historically autosomal-recessive hyper-IgE syndrome due to TYK2 deficiency. The last term should be deprecated as a general synonym because most patients do not have HIES.
No disease-specific ICD-10 or ICD-11 code was established in the retrieved evidence. Operational coding generally falls under broader “other specified immunodeficiency” or inborn-error-of-immunity categories. No uniquely specific MeSH descriptor was identified.

Evidence granularity. The genetic and clinical descriptions originate from individual patients and families, later aggregated into disease-level resources such as MONDO, OMIM and Open Targets. They are not EHR-derived population estimates. Open Targets records five TYK2–immunodeficiency-35 evidence items. (OpenTargets Search: immunodeficiency 35,TYK2 deficiency-TYK2)

2. Etiology, risk and protective factors

Causal factors

The necessary initiating lesion is a germline biallelic TYK2 loss-of-function genotype inherited in an autosomal-recessive pattern. Demonstrated complete-deficiency alleles include frameshift, nonsense, essential splice-site and multi-exon deletion variants, including p.Cys70Hisfs21, p.Pro216Argfs14, p.Glu154Ter, p.Leu767Ter, c.2466+1G>T, c.466-1G>A and deletion of exons 19–25. Several were experimentally shown to cause loss of expression and loss of function. (ogishi2022impairedil23–dependentinduction pages 4-6, ogishi2022impairedil23–dependentinduction pages 7-9, ogishi2022impairedil23–dependentinduction pages 3-4)

The disease is not caused by infection itself. Rather, infections expose the inherited defect. BCG vaccination, environmental mycobacteria, M. tuberculosis, herpesviruses, respiratory viruses and other intracellular pathogens are clinical triggers.

Genetic risk factors

Two pathogenic/null alleles are the principal risk factor; heterozygous parents in reported families were healthy. (sarrafzadeh2020anewpatient pages 1-3, sarrafzadeh2020anewpatient pages 3-4)
Consanguinity increases the probability of homozygosity. One p.Pro216Argfs*14 patient was born to first-degree-consanguineous Persian-Turkish parents and had two maternal/paternal uncles who died in childhood. (sarrafzadeh2020anewpatient pages 1-3)
The common TYK2 p.Pro1104Ala allele is not complete TYK2 deficiency. Homozygosity selectively impairs IL-23 responses and predisposes principally to tuberculosis; it should be represented separately in a knowledge base. (ogishi2022impairedil23–dependentinduction pages 15-17, ogishi2022impairedil23–dependentinduction pages 2-3)
No validated modifier gene, anticipation, germline-mosaicism series, or chromosomal founder syndrome has been established.

Environmental and infectious risk

Exposure determines which phenotype becomes manifest. Live BCG is a particularly important avoidable exposure because six of nine mycobacterially affected patients summarized in the 2022 literature had BCG disease. Tuberculosis-endemic residence and contact with environmental mycobacteria plausibly increase risk, while circulating herpesviruses and respiratory viruses reveal impaired antiviral immunity. (ogishi2022impairedil23–dependentinduction pages 2-3, ogishi2022impairedil23–dependentinduction pages 3-4)

No toxin, pollution, diet, smoking, alcohol, occupational or exercise association is established. Age and sex are not causal environmental risk factors. Family history and consanguinity are useful diagnostic clues rather than independent mechanisms.

Protective factors and gene–environment interaction

No proven genetic modifier or lifestyle factor protects against complete deficiency. Avoiding live BCG and rapidly treating infections reduce exposure-related morbidity but do not correct the genotype. The clearest gene–environment interaction is:

biallelic TYK2 null genotype + BCG exposure → failure of IL-23/IL-12-dependent IFN-γ immunity → local or disseminated BCG disease.

Two genetically affected individuals remained asymptomatic when BCG was withheld—one specifically because an affected sibling had developed BCG disease—illustrating exposure-dependent penetrance, although absence of BCG does not remove risk from wild mycobacteria or viruses. (ogishi2022impairedil23–dependentinduction pages 3-4)

3. Phenotypes

The 2022 synthesis reported 15 previously recognized patients from 13 families and expanded genetic/functional study to 19 patients from 16 families. Among the earlier clinical group, nine had mycobacterial disease: six BCG disease, one environmental mycobacterial disease and three tuberculosis; categories can overlap. Five had severe viral disease. (ogishi2022impairedil23–dependentinduction pages 2-3, ogishi2022impairedil23–dependentinduction pages 3-4)

Phenotype	Type and characteristics	Suggested HPO annotation
BCG infection/BCG-osis	Clinical infection/sign; often infancy or childhood after vaccination; potentially severe or disseminated. One child developed fever, lymphadenitis and ulcers at seven months, with M. bovis BCG recovered from biopsy and gastric secretions.	Disseminated BCG infection; recurrent mycobacterial infections; lymphadenitis; fever; skin ulceration
Tuberculosis or environmental mycobacteriosis	Infection; childhood through adulthood; episodic but potentially recurrent/severe. Three TB cases and one environmental-mycobacteria case were summarized among nine mycobacterially affected patients.	Increased susceptibility to mycobacterial infection; tuberculosis
Severe/recurrent viral infection	Infection; variable severity. Reported agents/conditions include mucocutaneous HSV-1, HSV-1 encephalitis, VZV/chickenpox, molluscum contagiosum, parainfluenza-3 pneumonia, influenza-A pneumonia, COVID-19 pneumonia and disease after live MMR vaccine.	Recurrent viral infections; recurrent herpes simplex infection; viral encephalitis; pneumonia
COVID-19	Infection/lower-respiratory manifestation. Six patients had pre-vaccination COVID-19 and four developed hypoxemic pneumonia in the expanded series.	COVID-19; hypoxemia; pneumonia
Candidiasis	Infection; uncommon/variable. Chronic mucocutaneous candidiasis was described in the original Japanese patient; oral thrush occurred in another.	Chronic mucocutaneous candidiasis; oral candidiasis
Atopy/HIES-like findings	Physical/laboratory phenotype; not universal. Eczema, skin abscesses, pneumonia and elevated IgE characterized the original case, whereas later patients often had normal IgE and no HIES phenotype.	Eczema; recurrent skin abscess; elevated serum IgE
Other infection	Cellulitis and Leishmania major infection occurred in individual patients; these are not established high-frequency hallmarks.	Cellulitis; leishmaniasis
Functional laboratory abnormality	Impaired IFN-γ production after IL-12/IL-23 stimulation; impaired IFN-α-, IL-10- and IL-23-induced STAT phosphorylation. Routine immunoglobulins, lymphocyte markers and neutrophil oxidative burst may be normal.	Abnormal cytokine secretion; abnormal interferon response; abnormality of immune-system physiology

The infection spectrum and counts are supported by the expanded human series. (ogishi2022impairedil23–dependentinduction pages 4-6, ogishi2022impairedil23–dependentinduction pages 2-3, ogishi2022impairedil23–dependentinduction pages 12-15) The p.Pro216Argfs*14 case had normal immunoglobulins, CD markers and NBT/DHR despite markedly impaired IL-12-induced IFN-γ production, demonstrating that normal routine immunology does not exclude the disorder. (sarrafzadeh2020anewpatient pages 1-3, sarrafzadeh2020anewpatient pages 3-4)

Onset/course. Onset is commonly infantile or pediatric and may be acute after vaccination, followed by episodic or recurrent infections throughout life. The Persian-Turkish patient had BCG complications at seven months, HSV at ages three and seven, aseptic meningitis at six and chickenpox at 6.5 years. (sarrafzadeh2020anewpatient pages 1-3)

Quality of life. No TYK2-specific EQ-5D, SF-36, PROMIS, school-function or caregiver-burden study was identified. Nevertheless, recurrent hospitalization, prolonged multidrug antimycobacterial therapy, neurologic viral disease and chronic infection predict substantial burden. This is a clinical inference, not a quantified TYK2-specific result.

4. Genetic and molecular information

Gene. TYK2 is the sole established causal gene for this entity. It encodes a Janus-family nonreceptor tyrosine kinase containing an N-terminal FERM receptor-binding region, SH2-like region, regulatory pseudokinase JH2 domain and catalytic JH1 kinase domain. Null alleles have been found across these regions. Open Targets identifies TYK2 as the only associated target for MONDO:0012682. (OpenTargets Search: immunodeficiency 35,TYK2 deficiency-TYK2, sarrafzadeh2020anewpatient pages 1-3)

Representative pathogenic alleles. Complete deficiency has resulted from p.Cys70Hisfs21, p.Pro216Argfs14, p.Glu154Ter, p.Leu767Ter, c.2466+1G>T, c.466-1G>A, exon-19–25 deletion and functionally null missense alleles such as p.Gly1010Asp. Their consequences include nonsense-mediated decay/loss of protein or a stable but catalytically and functionally inactive protein. (ogishi2022impairedil23–dependentinduction pages 4-6, ogishi2022impairedil23–dependentinduction pages 7-9, ogishi2022impairedil23–dependentinduction pages 3-4, ogishi2022impairedil23–dependentinduction pages 15-17)

All disease-causing variants are constitutional/germline, not somatic. Exact ACMG classifications and gnomAD frequencies must be verified per transcript and genomic build in ClinVar/gnomAD before database ingestion; the retrieved papers establish pathogenicity experimentally but do not supply a uniform modern ACMG table or frequencies for every allele. Large chromosomal abnormalities, repeat expansions, mitochondrial variants and aneuploidy are not characteristic.

Important exclusion. Compound-heterozygous p.Cys70Serfs*21/p.Arg231Trp with residual TYK2 expression and predominantly IL-23 impairment/T-cell lymphopenia is partial deficiency, not the requested complete-null disorder. (nemoto2018compoundheterozygoustyk2 pages 7-9)

Modifiers/epigenetics/omics. No validated modifier gene or disease-specific methylation, histone, metabolomic, lipidomic or spatial-transcriptomic signature is established. Patient leukocyte transcriptomics after cytokine stimulation implicated IFIT1/2/3/5, IRF7/9, ISG15/20 and MX1/2 modules under STAT1/STAT2 and IRF control; this is a stimulated signaling signature, not a validated diagnostic biomarker. (ogishi2022impairedil23–dependentinduction pages 12-15)

5. Environmental information

The relevant non-genetic factors are infectious exposures rather than toxicants or lifestyle. Confirmed agents include Mycobacterium bovis BCG, M. tuberculosis, environmental mycobacteria, HSV-1, VZV, molluscum contagiosum virus, parainfluenza virus 3, influenza A, SARS-CoV-2 and live attenuated MMR vaccine viruses. Leishmania major and candidiasis were reported in individual cases. (ogishi2022impairedil23–dependentinduction pages 4-6, ogishi2022impairedil23–dependentinduction pages 2-3)

There is no evidence that diet, exercise, smoking, alcohol, radiation, pollution or occupational chemicals initiate this Mendelian disorder. Standard sanitation, infection-control and prompt evaluation of febrile illness are sensible but have not been tested in TYK2-specific trials.

6. Mechanism/pathophysiology

Ordered causal chain

Biallelic TYK2 null variants lead to absent TYK2 protein or a completely nonfunctional kinase/scaffold.
Loss of TYK2 leads to deficient receptor-proximal JAK activation and impaired STAT phosphorylation downstream of IFN-α/β, IL-10, IL-12 and IL-23.
Defective IL-23 and IL-12 signaling leads to reduced IFN-γ induction in MAIT, γδ-T, NK and other lymphocyte populations.
Reduced IFN-γ production leads to inadequate macrophage activation and intracellular control of BCG, environmental mycobacteria and M. tuberculosis.
Defective IFN-α/β signaling leads to reduced interferon-stimulated-gene induction and impaired cell-intrinsic antiviral control across leukocyte and nonhematopoietic compartments.
These two branches result in mycobacterial disease and severe/recurrent viral disease, respectively.
Impaired IL-23/Th17-associated biology may contribute to candidiasis and some mucocutaneous phenotypes; this branch is biologically plausible and supported in selected patients but is less consistently demonstrated than the IFN-γ/mycobacterial branch.
Organ injury results secondarily from pathogen replication and host inflammation—e.g., pneumonia, lymph-node/skin disease or encephalitis—rather than a primary degenerative tissue process.

Patient cells show impaired STAT1/STAT3 phosphorylation after IFN-α, IL-10 and IL-23; IL-12 signaling affects TYK2/JAK2/STAT4, and IL-23 affects TYK2/JAK2/STAT3. Receptor abundance may remain normal, localizing the lesion to intracellular signal transduction. (ogishi2022impairedil23–dependentinduction pages 7-9, boissondupuis2018tuberculosisandimpaired pages 5-6)

The key modern mechanistic conclusion is captured in the 2022 abstract: “Impairment of IL-23–dependent induction of IFN-γ is the only mechanism of mycobacterial disease common to patients with any of the five known forms of autosomal recessive TYK2 deficiency.” [Ogishi et al., J Exp Med, published September 2022, DOI: https://doi.org/10.1084/jem.20220094]. (ogishi2022impairedil23–dependentinduction pages 2-3)

Complete deficiency impairs—but in some cell types does not abolish—IFN-α/β, IL-10, IL-12 and IL-23 responses. Responses to several other IL-10-family cytokines, including IL-26, IL-22, IL-20, IL-19 and IFN-λ, were relatively intact in the experiments retrieved. (ogishi2022impairedil23–dependentinduction pages 15-17)

Suggested GO terms/labels: JAK–STAT cascade; cytokine-mediated signaling pathway; type-I-interferon signaling pathway; cellular response to interferon-alpha; interleukin-12-mediated signaling; interleukin-23-mediated signaling; positive regulation of interferon-gamma production; defense response to bacterium; defense response to virus; STAT1/STAT3/STAT4 phosphorylation.

Suggested CL terms/labels: natural killer cell, γδ T cell, mucosal-associated invariant T cell, CD4-positive αβ T cell, classical monocyte, macrophage and conventional/myeloid dendritic cell. These labels should be reconciled against the current CL release before ingestion.

7. Anatomical structures affected

There is no fixed congenital anatomic malformation. Affected sites reflect infection:

Immune/hematopoietic system: peripheral blood leukocytes, lymphocytes, monocytes, macrophages and dendritic cells; lymph nodes are common BCG sites.
Respiratory system: lungs in TB, influenza, parainfluenza and COVID-19 pneumonia.
Skin and mucosa: BCG ulcers, HSV lesions, molluscum, eczema, abscesses, cellulitis and candidiasis.
Central nervous system: HSV encephalitis and aseptic meningitis in individual patients.
Reticuloendothelial organs: potentially involved in disseminated BCG/mycobacteriosis.

Suggested UBERON labels are blood, lymph node, lung, skin, oral mucosa and brain. Suggested cellular compartments are plasma membrane-associated cytokine-receptor complexes and cytosol (TYK2/JAK signaling), followed by nucleus (activated STAT transcription); relevant GO cellular-component labels include cytoplasm, plasma membrane and nucleus. Lateralization is not a disease feature. (sarrafzadeh2020anewpatient pages 1-3, ogishi2022impairedil23–dependentinduction pages 2-3, boissondupuis2018tuberculosisandimpaired pages 5-6)

8. Temporal development

The genetic defect is congenital and lifelong, but clinical onset depends on exposure. BCG vaccination can produce manifestations in infancy; viral and wild-type mycobacterial disease can emerge later in childhood or adulthood. The course is best characterized as chronic susceptibility with episodic infections, not a uniform progressive staging disorder. (sarrafzadeh2020anewpatient pages 1-3, ogishi2022impairedil23–dependentinduction pages 3-4)

There are no validated early/intermediate/advanced stages. Remission is generally treatment-induced clearance or suppression of an infection rather than remission of the inherited signaling defect. Critical intervention windows are before live vaccination, during early investigation of BCG complications, and before dissemination or severe pulmonary/CNS infection.

9. Inheritance and population

Inheritance is autosomal recessive. Healthy heterozygous parents and an unaffected wild-type sibling were documented in the p.Pro216Argfs*14 family. For two carrier parents, the conventional per-pregnancy risks are 25% affected, 50% carrier and 25% unaffected/noncarrier, assuming confirmed parental variants and no unusual reproductive event. (sarrafzadeh2020anewpatient pages 3-4)

The 2022 study characterized 19 patients from 16 families and described high penetrance for at least one infectious phenotype among biallelic cases, but exposure-dependent asymptomatic individuals exist. Thus, penetrance is high but not demonstrably 100%, and expressivity is markedly variable. (ogishi2022impairedil23–dependentinduction pages 3-4)

No reliable incidence, prevalence, carrier-frequency, sex-ratio or life-table estimate exists. A prior synthesis described inherited complete IL-12Rβ1 and TYK2 deficiencies individually as rarer than approximately 1 per 600,000, but that figure is not a direct prevalence estimate for complete TYK2 null deficiency and should not be entered as such. Geographic reports include Japan, Iran, Turkey, Saudi Arabia and other regions represented by international cohorts, often with consanguinity; ascertainment is too sparse to infer ethnic susceptibility. Founder effects require variant-specific confirmation.

Anticipation is not expected for a loss-of-function recessive disorder and has not been reported. Germline mosaicism has not been systematically studied.

10. Diagnostics

Recommended approach

Recognize the phenotype: unusual BCG disease, environmental mycobacteriosis/TB, severe herpesvirus or respiratory viral disease, especially with normal routine immunoglobulins and lymphocyte subsets.
Baseline testing: CBC/differential, lymphocyte subsets, immunoglobulins/IgE, vaccine antibodies, inflammatory markers, cultures/PCR and imaging directed by infection. Normal NBT/DHR helps exclude chronic granulomatous disease but does not exclude TYK2 deficiency.
Genetic testing: an inborn-error-of-immunity/MSMD panel including TYK2, or WES/WGS with copy-number calling; confirm candidate variants and segregation by Sanger sequencing. WGS is useful when exome/panel testing misses noncoding, structural or poorly captured splice variants.
Functional confirmation: TYK2 protein immunoblot/flow assay where validated; phospho-STAT testing after IFN-α, IL-10, IL-12 and IL-23; and whole-blood/PBMC assays measuring IFN-γ after BCG ± IL-12/IL-23. The reported p.Pro216Argfs*14 diagnosis used WES followed by PCR/Sanger confirmation, lymphocyte transformation testing, and BCG/IL-12 cytokine assays. (sarrafzadeh2020anewpatient pages 3-4, sarrafzadeh2020anewpatient pages 1-3)

Direct diagnostic quote: the 2018 partial-deficiency paper’s abstract summarizes the complete form as follows: “A detailed immunological investigation of these patients revealed impaired responses to type I IFN, IL-10, IL-12 and IL-23, which are associated with increased susceptibility to mycobacterial and/or viral infections.” [Nemoto et al., Scientific Reports, May 2018, DOI: https://doi.org/10.1038/s41598-018-25260-8]. (nemoto2018compoundheterozygoustyk2 pages 1-2)

Differential diagnosis

Major differentials include IL12RB1, IL12B, IL12RB2 and IL23R deficiency; IFNGR1/IFNGR2 and STAT1 loss-of-function; NEMO and CYBB-related MSMD; chronic granulomatous disease; severe combined immunodeficiency; DOCK8 or STAT3 hyper-IgE syndrome; IFNAR1/IFNAR2, STAT2, IRF9 or JAK1 defects; and acquired immunodeficiency. Combined impairment of IL-23/IL-12-driven IFN-γ plus type-I-IFN responses favors complete TYK2 deficiency over isolated IL-12/23-axis disorders. Partial TYK2 deficiency and p.Pro1104Ala homozygosity must be distinguished functionally. (ogishi2022impairedil23–dependentinduction pages 15-17, ogishi2022impairedil23–dependentinduction pages 2-3, bustamante2020mendeliansusceptibilityto pages 5-6)

CMA, karyotype, FISH, mitochondrial testing and repeat-expansion assays are not first-line unless another phenotype suggests them. RNA sequencing may resolve splice/noncoding alleles but is not a validated stand-alone diagnostic. There is no newborn biochemical screen.

11. Outcome and prognosis

No robust 5- or 10-year survival, mortality rate or life-expectancy estimate is available. Outcomes depend on pathogen, dissemination, pulmonary/CNS involvement, speed of diagnosis and access to antimicrobials. Reported complications include disseminated BCG disease, TB, severe pneumonia, hypoxemia, encephalitis and chronic mucocutaneous infection. (ogishi2022impairedil23–dependentinduction pages 4-6, ogishi2022impairedil23–dependentinduction pages 2-3)

Routine immune-cell counts may remain near normal, so absence of lymphopenia does not indicate a benign prognosis. Conversely, some genetically affected people remain asymptomatic when major exposures such as BCG are avoided. No TYK2-specific prognostic biomarker beyond genotype/function and prior infection severity has been validated. Disability and QoL have not been quantified.

12. Treatment

There is no approved TYK2-replacement drug, gene therapy or disease-specific randomized trial. Care should be coordinated by an immunologist and infectious-disease specialist.

Active mycobacterial disease: species- and susceptibility-directed multidrug antimycobacterial therapy. BCG disease may require prolonged therapy; pyrazinamide is intrinsically inactive against M. bovis and regimen design requires specialist input.
Adjunctive recombinant IFN-γ: broader MSMD expert literature supports IFN-γ with antibiotics because it bypasses impaired IL-12/IL-23-driven IFN-γ production. This is mechanistically compelling but remains extrapolated, not supported by a TYK2-specific response-rate trial. (bustamante2020mendeliansusceptibilityto pages 5-6)
Viral disease: prompt pathogen-specific therapy where available—e.g., acyclovir for HSV/VZV—and early antiviral management for influenza or COVID-19 according to contemporary guidance.
Antimicrobial prophylaxis: individualized after recurrent/disseminated infection; no standardized TYK2-specific regimen or response percentage exists.
Immunoglobulin replacement: not routinely indicated when quantitative and functional humoral immunity is normal; consider only if a clinically significant antibody defect is independently demonstrated.
HSCT: theoretically replaces hematopoietic TYK2-deficient immunity, but the retrieved disease-specific literature does not establish indications, conditioning, response rate or superiority over medical management. It should therefore be considered experimental/highly individualized rather than standard care.
Gene/RNA therapy: no established clinical implementation was identified.
Avoid TYK2 inhibitors: pharmacologic TYK2 inhibition treats autoimmune disease and would not correct this loss-of-function condition.

Suggested NCIt intervention labels include Anti-Infective Agent, Antibacterial Agent, Antiviral Agent, Interferon Gamma, Hematopoietic Stem Cell Transplantation, Genetic Counseling and Supportive Care; exact current NCIt codes should be validated before ingestion.

No disease-specific NCT study was returned by the ClinicalTrials.gov search. Accordingly, there are no evidence-based treatment-response or adverse-event rates specific to complete TYK2 deficiency.

13. Prevention

Primary prevention of genotype: impossible after conception. For known carrier couples, genetic counseling, partner testing, prenatal diagnosis and preimplantation genetic testing for the familial variants are available reproductive options.

Secondary prevention: cascade testing of siblings and relatives permits diagnosis before BCG or severe infection. There is no population newborn screen; targeted sequencing is appropriate in high-risk families.

Tertiary prevention: avoid live BCG in affected or not-yet-excluded at-risk infants. Reported families withheld BCG after disease in a sibling, and BCG complications are a recurrent hallmark. (sarrafzadeh2020anewpatient pages 3-4, ogishi2022impairedil23–dependentinduction pages 3-4) Other live vaccines require individualized specialist risk assessment because vaccine-strain MMR disease and severe viral susceptibility have been reported. Non-live vaccines should generally be maintained, although TYK2-specific immunogenicity data are sparse.

Prompt cultures/PCR, early antimicrobials, household TB risk assessment, and infection-avoidance counseling are reasonable. There is no evidence that diet or lifestyle modification changes the molecular disease.

14. Other species and natural disease

No well-established naturally occurring companion-animal, livestock or wildlife syndrome equivalent to human complete TYK2 deficiency was identified. The relevant ortholog is Tyk2 in Mus musculus (NCBI Taxonomy 10090); humans are Homo sapiens (Taxonomy 9606). Ortholog-specific NCBI Gene identifiers should be checked directly in the current NCBI Gene record before database insertion.

There is no zoonotic transmission: TYK2 deficiency is inherited, not contagious. Affected humans may acquire infections from environmental or animal reservoirs, but the immunodeficiency itself cannot cross species.

15. Model organisms

The principal model is the germline Tyk2-knockout mouse, supplemented by mouse embryonic fibroblasts, macrophages, dendritic cells, lymphocyte progenitors and engineered human cell lines.

Tyk2−/− mice are viable and lack gross developmental or hematopoietic abnormalities, but have partial type-I-IFN signaling impairment. They show defective IL-12/IL-23 biology, impaired dendritic-cell production of IL-12/IL-23 after CpG, reduced Th1/Th17 responses and increased viral susceptibility. Reported challenges include failure to clear vaccinia from spleen, increased LCMV and MCMV susceptibility, 100% mortality after intranasal VSV versus 20% after intravenous VSV, and 100% mortality after EMCV. They remain less susceptible than Ifnar1−/− mice, indicating residual antiviral signaling. (meyts2021viralinfectionsin pages 13-14, muromoto2022currentunderstandingof pages 2-4)

These mice also show reduced disease in collagen-induced arthritis, EAE, colitis and psoriasis models, illustrating why partial pharmacologic TYK2 inhibition can be anti-inflammatory. In DSS colitis, disease is delayed; in one TNBS model approximately 50% of Tyk2-deficient mice survived whereas wild-type controls were reported as lethal. (muromoto2022currentunderstandingof pages 6-7, muromoto2022currentunderstandingof pages 4-6)

Applications: dissecting receptor-specific JAK–STAT signaling, antiviral immunity, IL-12/Th1 and IL-23/Th17 biology, testing kinase-dependent versus scaffold functions, and evaluating TYK2 inhibitors.

Limitations: murine Tyk2 deficiency does not fully reproduce the breadth and variability of human BCG/TB, herpesviral, candidal and atopic phenotypes. Experimental high-dose pathogen challenge also differs from natural human exposure. Human patient cells remain essential for variant classification and pathway confirmation. (muromoto2021therapeuticadvantageof pages 2-4, muromoto2022currentunderstandingof pages 7-8, muromoto2022currentunderstandingof pages 1-2)

Evidence appraisal and recent developments

The most important recent disease-specific development is the 2022 demonstration that defective IL-23-dependent IFN-γ induction—rather than a generic failure of every TYK2-linked cytokine—is the common mechanism connecting genetically diverse TYK2 deficiencies to mycobacterial disease. The study also expanded the recognized genotype spectrum and documented COVID-19, including hypoxemic pneumonia, in affected individuals. (ogishi2022impairedil23–dependentinduction pages 4-6, ogishi2022impairedil23–dependentinduction pages 12-15, ogishi2022impairedil23–dependentinduction pages 2-3)

The 2023–2024 field increasingly uses WES/WGS, stimulated phospho-protein assays and functional genomics to diagnose inborn errors of immunity, but no 2023–2024 complete-TYK2-null cohort, validated omics diagnostic, interventional trial or gene therapy was identified in the retrieved evidence. Thus, claims about prevalence, formal clinical criteria, survival, QoL, HSCT efficacy, prophylactic regimens and treatment response must remain explicitly not available, rather than being inferred from more common immunodeficiencies.

Principal primary sources

Minegishi et al. Initial human TYK2-deficiency report, PMID 17088085 (2006).
Kreins et al. Human TYK2 deficiency: mycobacterial and viral infections without hyper-IgE syndrome, J Exp Med (2015), PMID 26304966, DOI: https://doi.org/10.1084/jem.20140280.
Sarrafzadeh et al. A New Patient with Inherited TYK2 Deficiency, J Clin Immunol (online November 2019; volume publication 2020), DOI: https://doi.org/10.1007/s10875-019-00713-5. (sarrafzadeh2020anewpatient pages 1-3, sarrafzadeh2020anewpatient pages 3-4)
Ogishi et al. Impaired IL-23–dependent induction of IFN-γ underlies mycobacterial disease in patients with inherited TYK2 deficiency, J Exp Med, September 2022, DOI: https://doi.org/10.1084/jem.20220094. (ogishi2022impairedil23–dependentinduction pages 4-6, ogishi2022impairedil23–dependentinduction pages 12-15, ogishi2022impairedil23–dependentinduction pages 2-3)
Nemoto et al. Compound heterozygous TYK2 mutations underlie primary immunodeficiency with T-cell lymphopenia, Scientific Reports, May 2018, DOI: https://doi.org/10.1038/s41598-018-25260-8; relevant chiefly for distinguishing partial from complete deficiency. (nemoto2018compoundheterozygoustyk2 pages 7-9)

Knowledge-base recommendation: represent complete biallelic-null TYK2 deficiency as a distinct disease node, while linking but not merging it with partial TYK2 deficiency and TYK2 p.Pro1104Ala-associated tuberculosis susceptibility. This separation is required because cytokine defects, penetrance and clinical management differ substantially across these molecular forms. (ogishi2022impairedil23–dependentinduction pages 15-17, ogishi2022impairedil23–dependentinduction pages 7-9, ogishi2022impairedil23–dependentinduction pages 2-3)

References

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(sarrafzadeh2020anewpatient pages 1-3): Shokouh Azam Sarrafzadeh, Maryam Mahloojirad, Jean-Laurent Casanova, Mohsen Badalzadeh, Jacinta Bustamante, Stephanie Boisson-Dupuis, Zahra Pourpak, Maryam Nourizadeh, and Mostafa Moin. A new patient with inherited tyk2 deficiency. Journal of Clinical Immunology, 40:232-235, Nov 2020. URL: https://doi.org/10.1007/s10875-019-00713-5, doi:10.1007/s10875-019-00713-5. This article has 39 citations and is from a domain leading peer-reviewed journal.
(ogishi2022impairedil23–dependentinduction pages 4-6): Masato Ogishi, Andrés Augusto Arias, Rui Yang, Ji Eun Han, Peng Zhang, Darawan Rinchai, Joshua Halpern, Jeanette Mulwa, Narelle Keating, Maya Chrabieh, Candice Lainé, Yoann Seeleuthner, Noé Ramírez-Alejo, Nioosha Nekooie-Marnany, Andrea Guennoun, Ingrid Muller-Fleckenstein, Bernhard Fleckenstein, Sara S. Kilic, Yoshiyuki Minegishi, Stephan Ehl, Petra Kaiser-Labusch, Yasemin Kendir-Demirkol, Flore Rozenberg, Abderrahmane Errami, Shen-Ying Zhang, Qian Zhang, Jonathan Bohlen, Quentin Philippot, Anne Puel, Emmanuelle Jouanguy, Zahra Pourmoghaddas, Shahrzad Bakhtiar, Andre M. Willasch, Gerd Horneff, Genevieve Llanora, Lynette P. Shek, Louis Y.A. Chai, Sen Hee Tay, Hamid H. Rahimi, Seyed Alireza Mahdaviani, Serdar Nepesov, Aziz A. Bousfiha, Emine Hafize Erdeniz, Adem Karbuz, Nico Marr, Carmen Navarrete, Mehdi Adeli, Lennart Hammarstrom, Hassan Abolhassani, Nima Parvaneh, Saleh Al Muhsen, Mohammed F. Alosaimi, Fahad Alsohime, Maryam Nourizadeh, Mostafa Moin, Rand Arnaout, Saad Alshareef, Jamila El-Baghdadi, Ferah Genel, Roya Sherkat, Ayça Kiykim, Esra Yücel, Sevgi Keles, Jacinta Bustamante, Laurent Abel, Jean-Laurent Casanova, and Stéphanie Boisson-Dupuis. Impaired il-23–dependent induction of ifn-γ underlies mycobacterial disease in patients with inherited tyk2 deficiency. The Journal of Experimental Medicine, Sep 2022. URL: https://doi.org/10.1084/jem.20220094, doi:10.1084/jem.20220094. This article has 83 citations.
(ogishi2022impairedil23–dependentinduction pages 2-3): Masato Ogishi, Andrés Augusto Arias, Rui Yang, Ji Eun Han, Peng Zhang, Darawan Rinchai, Joshua Halpern, Jeanette Mulwa, Narelle Keating, Maya Chrabieh, Candice Lainé, Yoann Seeleuthner, Noé Ramírez-Alejo, Nioosha Nekooie-Marnany, Andrea Guennoun, Ingrid Muller-Fleckenstein, Bernhard Fleckenstein, Sara S. Kilic, Yoshiyuki Minegishi, Stephan Ehl, Petra Kaiser-Labusch, Yasemin Kendir-Demirkol, Flore Rozenberg, Abderrahmane Errami, Shen-Ying Zhang, Qian Zhang, Jonathan Bohlen, Quentin Philippot, Anne Puel, Emmanuelle Jouanguy, Zahra Pourmoghaddas, Shahrzad Bakhtiar, Andre M. Willasch, Gerd Horneff, Genevieve Llanora, Lynette P. Shek, Louis Y.A. Chai, Sen Hee Tay, Hamid H. Rahimi, Seyed Alireza Mahdaviani, Serdar Nepesov, Aziz A. Bousfiha, Emine Hafize Erdeniz, Adem Karbuz, Nico Marr, Carmen Navarrete, Mehdi Adeli, Lennart Hammarstrom, Hassan Abolhassani, Nima Parvaneh, Saleh Al Muhsen, Mohammed F. Alosaimi, Fahad Alsohime, Maryam Nourizadeh, Mostafa Moin, Rand Arnaout, Saad Alshareef, Jamila El-Baghdadi, Ferah Genel, Roya Sherkat, Ayça Kiykim, Esra Yücel, Sevgi Keles, Jacinta Bustamante, Laurent Abel, Jean-Laurent Casanova, and Stéphanie Boisson-Dupuis. Impaired il-23–dependent induction of ifn-γ underlies mycobacterial disease in patients with inherited tyk2 deficiency. The Journal of Experimental Medicine, Sep 2022. URL: https://doi.org/10.1084/jem.20220094, doi:10.1084/jem.20220094. This article has 83 citations.
(sarrafzadeh2020anewpatient pages 3-4): Shokouh Azam Sarrafzadeh, Maryam Mahloojirad, Jean-Laurent Casanova, Mohsen Badalzadeh, Jacinta Bustamante, Stephanie Boisson-Dupuis, Zahra Pourpak, Maryam Nourizadeh, and Mostafa Moin. A new patient with inherited tyk2 deficiency. Journal of Clinical Immunology, 40:232-235, Nov 2020. URL: https://doi.org/10.1007/s10875-019-00713-5, doi:10.1007/s10875-019-00713-5. This article has 39 citations and is from a domain leading peer-reviewed journal.
(ogishi2022impairedil23–dependentinduction pages 12-15): Masato Ogishi, Andrés Augusto Arias, Rui Yang, Ji Eun Han, Peng Zhang, Darawan Rinchai, Joshua Halpern, Jeanette Mulwa, Narelle Keating, Maya Chrabieh, Candice Lainé, Yoann Seeleuthner, Noé Ramírez-Alejo, Nioosha Nekooie-Marnany, Andrea Guennoun, Ingrid Muller-Fleckenstein, Bernhard Fleckenstein, Sara S. Kilic, Yoshiyuki Minegishi, Stephan Ehl, Petra Kaiser-Labusch, Yasemin Kendir-Demirkol, Flore Rozenberg, Abderrahmane Errami, Shen-Ying Zhang, Qian Zhang, Jonathan Bohlen, Quentin Philippot, Anne Puel, Emmanuelle Jouanguy, Zahra Pourmoghaddas, Shahrzad Bakhtiar, Andre M. Willasch, Gerd Horneff, Genevieve Llanora, Lynette P. Shek, Louis Y.A. Chai, Sen Hee Tay, Hamid H. Rahimi, Seyed Alireza Mahdaviani, Serdar Nepesov, Aziz A. Bousfiha, Emine Hafize Erdeniz, Adem Karbuz, Nico Marr, Carmen Navarrete, Mehdi Adeli, Lennart Hammarstrom, Hassan Abolhassani, Nima Parvaneh, Saleh Al Muhsen, Mohammed F. Alosaimi, Fahad Alsohime, Maryam Nourizadeh, Mostafa Moin, Rand Arnaout, Saad Alshareef, Jamila El-Baghdadi, Ferah Genel, Roya Sherkat, Ayça Kiykim, Esra Yücel, Sevgi Keles, Jacinta Bustamante, Laurent Abel, Jean-Laurent Casanova, and Stéphanie Boisson-Dupuis. Impaired il-23–dependent induction of ifn-γ underlies mycobacterial disease in patients with inherited tyk2 deficiency. The Journal of Experimental Medicine, Sep 2022. URL: https://doi.org/10.1084/jem.20220094, doi:10.1084/jem.20220094. This article has 83 citations.
(boissondupuis2018tuberculosisandimpaired pages 5-6): Stéphanie Boisson-Dupuis, Noe Ramirez-Alejo, Zhi Li, Etienne Patin, Geetha Rao, Gaspard Kerner, Che Kang Lim, Dimitry N. Krementsov, Nicholas Hernandez, Cindy S. Ma, Qian Zhang, Janet Markle, Ruben Martinez-Barricarte, Kathryn Payne, Robert Fisch, Caroline Deswarte, Joshua Halpern, Matthieu Bouaziz, Jeanette Mulwa, Durga Sivanesan, Tomi Lazarov, Rodrigo Naves, Patricia Garcia, Yuval Itan, Bertrand Boisson, Alix Checchi, Fabienne Jabot-Hanin, Aurélie Cobat, Andrea Guennoun, Carolyn C. Jackson, Sevgi Pekcan, Zafer Caliskaner, Jaime Inostroza, Beatriz Tavares Costa-Carvalho, Jose Antonio Tavares de Albuquerque, Humberto Garcia-Ortiz, Lorena Orozco, Tayfun Ozcelik, Ahmed Abid, Ismail Abderahmani Rhorfi, Hicham Souhi, Hicham Naji Amrani, Adil Zegmout, Frédéric Geissmann, Stephen W. Michnick, Ingrid Muller-Fleckenstein, Bernhard Fleckenstein, Anne Puel, Michael J. Ciancanelli, Nico Marr, Hassan Abolhassani, María Elvira Balcells, Antonio Condino-Neto, Alexis Strickler, Katia Abarca, Cory Teuscher, Hans D. Ochs, Ismail Reisli, Esra H. Sayar, Jamila El-Baghdadi, Jacinta Bustamante, Lennart Hammarström, Stuart G. Tangye, Sandra Pellegrini, Lluis Quintana-Murci, Laurent Abel, and Jean-Laurent Casanova. Tuberculosis and impaired il-23–dependent ifn-γ immunity in humans homozygous for a common tyk2 missense variant. Science Immunology, Dec 2018. URL: https://doi.org/10.1126/sciimmunol.aau8714, doi:10.1126/sciimmunol.aau8714. This article has 246 citations and is from a highest quality peer-reviewed journal.
(ogishi2022impairedil23–dependentinduction pages 15-17): Masato Ogishi, Andrés Augusto Arias, Rui Yang, Ji Eun Han, Peng Zhang, Darawan Rinchai, Joshua Halpern, Jeanette Mulwa, Narelle Keating, Maya Chrabieh, Candice Lainé, Yoann Seeleuthner, Noé Ramírez-Alejo, Nioosha Nekooie-Marnany, Andrea Guennoun, Ingrid Muller-Fleckenstein, Bernhard Fleckenstein, Sara S. Kilic, Yoshiyuki Minegishi, Stephan Ehl, Petra Kaiser-Labusch, Yasemin Kendir-Demirkol, Flore Rozenberg, Abderrahmane Errami, Shen-Ying Zhang, Qian Zhang, Jonathan Bohlen, Quentin Philippot, Anne Puel, Emmanuelle Jouanguy, Zahra Pourmoghaddas, Shahrzad Bakhtiar, Andre M. Willasch, Gerd Horneff, Genevieve Llanora, Lynette P. Shek, Louis Y.A. Chai, Sen Hee Tay, Hamid H. Rahimi, Seyed Alireza Mahdaviani, Serdar Nepesov, Aziz A. Bousfiha, Emine Hafize Erdeniz, Adem Karbuz, Nico Marr, Carmen Navarrete, Mehdi Adeli, Lennart Hammarstrom, Hassan Abolhassani, Nima Parvaneh, Saleh Al Muhsen, Mohammed F. Alosaimi, Fahad Alsohime, Maryam Nourizadeh, Mostafa Moin, Rand Arnaout, Saad Alshareef, Jamila El-Baghdadi, Ferah Genel, Roya Sherkat, Ayça Kiykim, Esra Yücel, Sevgi Keles, Jacinta Bustamante, Laurent Abel, Jean-Laurent Casanova, and Stéphanie Boisson-Dupuis. Impaired il-23–dependent induction of ifn-γ underlies mycobacterial disease in patients with inherited tyk2 deficiency. The Journal of Experimental Medicine, Sep 2022. URL: https://doi.org/10.1084/jem.20220094, doi:10.1084/jem.20220094. This article has 83 citations.
(ogishi2022impairedil23–dependentinduction pages 7-9): Masato Ogishi, Andrés Augusto Arias, Rui Yang, Ji Eun Han, Peng Zhang, Darawan Rinchai, Joshua Halpern, Jeanette Mulwa, Narelle Keating, Maya Chrabieh, Candice Lainé, Yoann Seeleuthner, Noé Ramírez-Alejo, Nioosha Nekooie-Marnany, Andrea Guennoun, Ingrid Muller-Fleckenstein, Bernhard Fleckenstein, Sara S. Kilic, Yoshiyuki Minegishi, Stephan Ehl, Petra Kaiser-Labusch, Yasemin Kendir-Demirkol, Flore Rozenberg, Abderrahmane Errami, Shen-Ying Zhang, Qian Zhang, Jonathan Bohlen, Quentin Philippot, Anne Puel, Emmanuelle Jouanguy, Zahra Pourmoghaddas, Shahrzad Bakhtiar, Andre M. Willasch, Gerd Horneff, Genevieve Llanora, Lynette P. Shek, Louis Y.A. Chai, Sen Hee Tay, Hamid H. Rahimi, Seyed Alireza Mahdaviani, Serdar Nepesov, Aziz A. Bousfiha, Emine Hafize Erdeniz, Adem Karbuz, Nico Marr, Carmen Navarrete, Mehdi Adeli, Lennart Hammarstrom, Hassan Abolhassani, Nima Parvaneh, Saleh Al Muhsen, Mohammed F. Alosaimi, Fahad Alsohime, Maryam Nourizadeh, Mostafa Moin, Rand Arnaout, Saad Alshareef, Jamila El-Baghdadi, Ferah Genel, Roya Sherkat, Ayça Kiykim, Esra Yücel, Sevgi Keles, Jacinta Bustamante, Laurent Abel, Jean-Laurent Casanova, and Stéphanie Boisson-Dupuis. Impaired il-23–dependent induction of ifn-γ underlies mycobacterial disease in patients with inherited tyk2 deficiency. The Journal of Experimental Medicine, Sep 2022. URL: https://doi.org/10.1084/jem.20220094, doi:10.1084/jem.20220094. This article has 83 citations.
(ogishi2022impairedil23–dependentinduction pages 3-4): Masato Ogishi, Andrés Augusto Arias, Rui Yang, Ji Eun Han, Peng Zhang, Darawan Rinchai, Joshua Halpern, Jeanette Mulwa, Narelle Keating, Maya Chrabieh, Candice Lainé, Yoann Seeleuthner, Noé Ramírez-Alejo, Nioosha Nekooie-Marnany, Andrea Guennoun, Ingrid Muller-Fleckenstein, Bernhard Fleckenstein, Sara S. Kilic, Yoshiyuki Minegishi, Stephan Ehl, Petra Kaiser-Labusch, Yasemin Kendir-Demirkol, Flore Rozenberg, Abderrahmane Errami, Shen-Ying Zhang, Qian Zhang, Jonathan Bohlen, Quentin Philippot, Anne Puel, Emmanuelle Jouanguy, Zahra Pourmoghaddas, Shahrzad Bakhtiar, Andre M. Willasch, Gerd Horneff, Genevieve Llanora, Lynette P. Shek, Louis Y.A. Chai, Sen Hee Tay, Hamid H. Rahimi, Seyed Alireza Mahdaviani, Serdar Nepesov, Aziz A. Bousfiha, Emine Hafize Erdeniz, Adem Karbuz, Nico Marr, Carmen Navarrete, Mehdi Adeli, Lennart Hammarstrom, Hassan Abolhassani, Nima Parvaneh, Saleh Al Muhsen, Mohammed F. Alosaimi, Fahad Alsohime, Maryam Nourizadeh, Mostafa Moin, Rand Arnaout, Saad Alshareef, Jamila El-Baghdadi, Ferah Genel, Roya Sherkat, Ayça Kiykim, Esra Yücel, Sevgi Keles, Jacinta Bustamante, Laurent Abel, Jean-Laurent Casanova, and Stéphanie Boisson-Dupuis. Impaired il-23–dependent induction of ifn-γ underlies mycobacterial disease in patients with inherited tyk2 deficiency. The Journal of Experimental Medicine, Sep 2022. URL: https://doi.org/10.1084/jem.20220094, doi:10.1084/jem.20220094. This article has 83 citations.
(bustamante2020mendeliansusceptibilityto pages 5-6): Jacinta Bustamante. Mendelian susceptibility to mycobacterial disease: recent discoveries. Human Genetics, 139:993-1000, Feb 2020. URL: https://doi.org/10.1007/s00439-020-02120-y, doi:10.1007/s00439-020-02120-y. This article has 232 citations and is from a peer-reviewed journal.
(meyts2021viralinfectionsin pages 13-14): Isabelle Meyts and Jean‐Laurent Casanova. Viral infections in humans and mice with genetic deficiencies of the type i ifn response pathway. Apr 2021. URL: https://doi.org/10.1002/eji.202048793, doi:10.1002/eji.202048793. This article has 128 citations and is from a peer-reviewed journal.
(muromoto2022currentunderstandingof pages 2-4): Ryuta Muromoto, Kenji Oritani, and Tadashi Matsuda. Current understanding of the role of tyrosine kinase 2 signaling in immune responses. World Journal of Biological Chemistry, 13:1-14, Jan 2022. URL: https://doi.org/10.4331/wjbc.v13.i1.1, doi:10.4331/wjbc.v13.i1.1. This article has 88 citations.
(muromoto2022currentunderstandingof pages 1-2): Ryuta Muromoto, Kenji Oritani, and Tadashi Matsuda. Current understanding of the role of tyrosine kinase 2 signaling in immune responses. World Journal of Biological Chemistry, 13:1-14, Jan 2022. URL: https://doi.org/10.4331/wjbc.v13.i1.1, doi:10.4331/wjbc.v13.i1.1. This article has 88 citations.
(nemoto2018compoundheterozygoustyk2 pages 1-2): Michiko Nemoto, Hiroyoshi Hattori, Naoko Maeda, Nobuhiro Akita, Hideki Muramatsu, Suzuko Moritani, Tomonori Kawasaki, Masami Maejima, Hirotaka Ode, Atsuko Hachiya, Wataru Sugiura, Yoshiyuki Yokomaku, Keizo Horibe, and Yasumasa Iwatani. Compound heterozygous tyk2 mutations underlie primary immunodeficiency with t-cell lymphopenia. Scientific Reports, May 2018. URL: https://doi.org/10.1038/s41598-018-25260-8, doi:10.1038/s41598-018-25260-8. This article has 47 citations and is from a peer-reviewed journal.
(nemoto2018compoundheterozygoustyk2 pages 7-9): Michiko Nemoto, Hiroyoshi Hattori, Naoko Maeda, Nobuhiro Akita, Hideki Muramatsu, Suzuko Moritani, Tomonori Kawasaki, Masami Maejima, Hirotaka Ode, Atsuko Hachiya, Wataru Sugiura, Yoshiyuki Yokomaku, Keizo Horibe, and Yasumasa Iwatani. Compound heterozygous tyk2 mutations underlie primary immunodeficiency with t-cell lymphopenia. Scientific Reports, May 2018. URL: https://doi.org/10.1038/s41598-018-25260-8, doi:10.1038/s41598-018-25260-8. This article has 47 citations and is from a peer-reviewed journal.
(muromoto2022currentunderstandingof pages 6-7): Ryuta Muromoto, Kenji Oritani, and Tadashi Matsuda. Current understanding of the role of tyrosine kinase 2 signaling in immune responses. World Journal of Biological Chemistry, 13:1-14, Jan 2022. URL: https://doi.org/10.4331/wjbc.v13.i1.1, doi:10.4331/wjbc.v13.i1.1. This article has 88 citations.
(muromoto2022currentunderstandingof pages 4-6): Ryuta Muromoto, Kenji Oritani, and Tadashi Matsuda. Current understanding of the role of tyrosine kinase 2 signaling in immune responses. World Journal of Biological Chemistry, 13:1-14, Jan 2022. URL: https://doi.org/10.4331/wjbc.v13.i1.1, doi:10.4331/wjbc.v13.i1.1. This article has 88 citations.
(muromoto2021therapeuticadvantageof pages 2-4): Ryuta Muromoto, Kazuya Shimoda, Kenji Oritani, and Tadashi Matsuda. Therapeutic advantage of tyk2 inhibition for treating autoimmune and chronic inflammatory diseases. Biological & pharmaceutical bulletin, 44 11:1585-1592, Nov 2021. URL: https://doi.org/10.1248/bpb.b21-00609, doi:10.1248/bpb.b21-00609. This article has 30 citations and is from a peer-reviewed journal.
(muromoto2022currentunderstandingof pages 7-8): Ryuta Muromoto, Kenji Oritani, and Tadashi Matsuda. Current understanding of the role of tyrosine kinase 2 signaling in immune responses. World Journal of Biological Chemistry, 13:1-14, Jan 2022. URL: https://doi.org/10.4331/wjbc.v13.i1.1, doi:10.4331/wjbc.v13.i1.1. This article has 88 citations.

Artifacts

Edison artifact artifact-00

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	9
Resolved	9
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	9
On topic	3
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	2
Resolved	1
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	1
Terms whose name was checked	1
Terms named correctly	0
Terms named as a different term	1

Terms the report names something else

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

MONDO:0012682 (6 mentions) - the report calls it "if available"; MONDO calls it immunodeficiency 35

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.

Ask OpenScientist

OpenScientist Report

Classifications

Inheritance

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Environmental Factors

Diagnosis

Prevalence

Differential Diagnoses

Animal Models

Source YAML

References & Deep Research

References

Deep Research

Disease Characteristics Research Template

Target Disease

Research Objectives

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

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

Citation Requirements

Output Format

Complete TYK2 deficiency (immunodeficiency 35): research report

Scope and evidence note

1. Disease information

2. Etiology, risk and protective factors

Causal factors

Genetic risk factors

Environmental and infectious risk

Protective factors and gene–environment interaction

3. Phenotypes

4. Genetic and molecular information

5. Environmental information

6. Mechanism/pathophysiology

Ordered causal chain

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

Recommended approach

Differential diagnosis

11. Outcome and prognosis

12. Treatment

13. Prevention

14. Other species and natural disease

15. Model organisms

Evidence appraisal and recent developments

Principal primary sources

Artifacts

Reference Validation

Term Validation

Terms the report names something else

Prefixes with no resolver