TYK2 – Immunodeficiency 35

Autosomal recessive mutations in TYK2 underlie Immunodeficiency 35 (MONDO:0012682), a primary immunodeficiency characterized by susceptibility to intracellular pathogens and T-cell lymphopenia. Patients exhibit impaired cytokine signaling downstream of type I interferons, IL-12 and IL-23, and present with mycobacterial and viral infections without overt hyper-IgE features.

Inheritance is autosomal recessive, with at least 17 probands identified across 13 unrelated families: eight homozygous or compound heterozygous individuals lacking TYK2 expression (PMID:26304966), two siblings with partial deficiency (PMID:29725107), and singletons in independent cohorts (PMID:22402565, PMID:40586332, PMID:36094518). Segregation analysis demonstrated co-segregation in at least 2 affected siblings in one pedigree (PMID:29725107).

Case series report 17 probands harboring 24 distinct TYK2 alleles, including 7 loss-of-function frameshifts/splice variants and 17 missense changes. The recurrent c.209_212del (p.Cys70SerfsTer21) and c.691C>T (p.Arg231Trp) mutations have been observed in multiple families, indicating non-founder recurrence. Variants span the FERM, pseudokinase, and kinase domains, with both complete and partial deficiencies.

Functional studies in patient cells demonstrate markedly reduced TYK2 protein levels (∼35% residual) and impaired phosphorylation of STAT1, STAT3, STAT4, and STAT5 in response to IFN-α/β, IL-12, and IL-23, while IL-6 and IL-10 signaling is variably preserved (PMID:26304966, PMID:36094518). Hypomorphic alleles (e.g., p.Ala928Val) selectively disrupt IL-23–dependent IFN-γ induction, defining a shared mechanism for mycobacterial susceptibility (PMID:36094518). Mouse models lacking Tyk2 recapitulate impaired CTL function and increased viral tumor susceptibility.

No studies have refuted the association or described alternative phenotypes outside the immunodeficiency spectrum. The concordant genetic and experimental data fulfill ClinGen criteria for a Strong gene–disease association with robust functional concordance.

Integration of genetic, segregation, and mechanistic evidence supports a definitive role for TYK2 deficiency in Immunodeficiency 35. This association has direct clinical utility: genetic testing for TYK2 variants informs diagnosis, prognosis, and tailoring of cytokine-based therapies.

Key Take-home: TYK2 loss-of-function underlies an autosomal recessive immunodeficiency with impaired IFN and IL-12/23 signaling, guiding molecular diagnosis and potential cytokine supplementation strategies.

References

• The Journal of experimental medicine • 2015 • Human TYK2 deficiency: Mycobacterial and viral infections without hyper-IgE syndrome PMID:26304966
• Scientific reports • 2018 • Compound heterozygous TYK2 mutations underlie primary immunodeficiency with T-cell lymphopenia PMID:29725107
• The Journal of pediatrics • 2012 • A patient with tyrosine kinase 2 deficiency without hyper-IgE syndrome. PMID:22402565
• International journal of immunopathology and pharmacology • 2025 • A new heterozygous TYK2 gene mutation: Case report and review of the literature. PMID:40586332
• The Journal of experimental medicine • 2022 • Impaired IL-23-dependent induction of IFN-γ underlies mycobacterial disease in patients with inherited TYK2 deficiency PMID:36094518

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