TNFRSF4

Inheritance Pattern: Unknown

Disease ID:MONDO:0014268

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0014268

Submitter: ClinGen

*TNFRSF4* has been reported in relation to combined immunodeficiency due to OX40 deficiency in one proband with a homozygous missense variant in 2013 (Byun et al., PMID:23897980). The one described patient from Byun et al. presented with Kaposi sarcoma along with a low proportion of peripheral effector memory CD4+ T cells and decreased cytokine response including no IFN-γ production by the patient’s PBMCs in response to recall antigens, suggestive of a deficiency in antigen-specific memory CD4+ T cells. The heterozygous parents and siblings were reportedly unaffected. The mechanism of pathogenicity appears to be loss of function. This gene-disease association is also supported by the biochemical function of OX40, where OX40 and the OX40 ligand are both expressed on T cells 24 to 48 hours following antigen presentation to a T cell. During activation, OX40 via OX40 ligand signaling influences several T cell effector mechanisms. These mechanisms include cytokine production, continued CD4+ activation, increased T cell survival, increased effector phenotypes and reduced regulatory phenotypes (PMID:26215166). Additionally, the disease relationship is supported by expression, where OX40 mRNA in lymphoid tissue greatly increases following T cell activation (PMID:8228223). The gene disease relationship is also supported by rescue, where transfection of WT-OX40 rescued OX40 ligand binding on PHA activated T cells, unlike patient variant R65C (PMID:23897980). Finally, OX40 deficient mice recapitulate several features of the disease phenotype including marked impairment of memory CD4+ T cells in response to recall antigens and decreased cytokine response to vaccinations (PMID:10975814). In summary, there is limited evidence to support this gene-disease relationship. Although more genetic evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This gene-disease pair was originally evaluated by the SCID-CID GCEP on June, 15 2023 (SOP Version 9). It was reevaluated on September 17, 2026 (SOP Version 12). As a result of this reevaluation, the classification did not change.

Inheritance Pattern: AR

Disease ID:MONDO:0014268

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0014268

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0014268

Submitter: Orphanet