| 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 (pqac-00000000, pqac-00000001) | 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 (pqac-00000003, pqac-00000005, pqac-00000012) | 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 (pqac-00000001, pqac-00000014) | 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 (pqac-00000008, pqac-00000009, pqac-00000010) | 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.C70Hfs*21, p.P216Rfs*14, p.E154*, p.L767*, c.2466+1G>T, c.466-1G>A, and exon 19-25 deletion (pqac-00000003, pqac-00000006, pqac-00000007) | 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 (pqac-00000005) | 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 (pqac-00000005) | 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 (pqac-00000001, pqac-00000003, pqac-00000005) | 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 (pqac-00000001) | 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 (pqac-00000008, pqac-00000010, pqac-00000012) | 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 (pqac-00000008) | 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 (pqac-00000009, pqac-00000011) | 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 (pqac-00000014, pqac-00000016) | 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 (pqac-00000005, pqac-00000010, pqac-00000012) | 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 (pqac-00000015, pqac-00000017) | 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 (pqac-00000007) | 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 (pqac-00000005, pqac-00000007) | 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 (pqac-00000014, pqac-00000015) | 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 (pqac-00000019, pqac-00000023, pqac-00000024) | 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.*