TNFRSF9

Inheritance Pattern: AR

Disease ID:MONDO:0859526

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0859526

Submitter: ClinGen

TNFRSF9 (also commonly referred to as CD137 and 4-1BB) was first reported in relation to an autosomal recessive lymphoproliferative disease designated “immunodeficiency 109 with lymphoproliferation” in 2019 (Alosaimi et al., PMID: 30872117). In addition to lymphoproliferation, the core features of TNFRSF9 deficiency include persistent or recurrent EBV viremia, hepatosplenomegaly, sinopulmonary infections, and increased risk of progression to lymphoma. Additional frequently reported manifestations include recurrent fevers, autoimmune cytopenias and impaired vaccine antibody responses. In laboratory testing, most patients have reduced memory B-cell, plasmablast, and T effector memory cell populations, though total CD4+ T cell, CD8+ T cell, B cell, and NK cells numbers are typically normal. Immunoglobulin abnormalities are common, including both elevations or reductions in IgG, IgM, or IgA. 8 variants affecting 7 probands (PMIDs: 30872117, 31501153, 37144041) are included in this curation. These probands include homozygous or compound heterozygous missense, frameshift, deletional, and splice variants. Significant functional evidence is available for these probands including impaired T cell activation and proliferation, which could be rescued upon exogenous expression of TNFRSF9 (PMID: 31501153). Primary CD8 T-cells from patients were also defective in virus-specific cytotoxicity. Evidence for additional probands is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be loss-of-function. All variants curated resulted in loss of TNFRSF9 expression on the cell surface of activated T-cells, preventing T-cell costimulation via the ligand TNFSF9 (also known as CD137L and 4-1BBL). This gene-disease relationship is further supported by in vitro functional assays that demonstrate that direct ligation of TNFRSF9 on human T cells results in CD8+ T-cell proliferation, IFNg production, and antigen specific cytotoxicity (PMID: 12356681). Among other mechanisms, TNFRSF9 signaling is known to occur via TRAF2 and NF-kB (PMID 9464265) and a similar phenotype of EBV susceptibility and lymphoproliferation is seen in NFKB1 haploinsufficiency (PMID 27338827). In addition, a mouse model of TNFRSF9 deficiency exhibits corresponding impairment in virus specific T-cell cytotoxicity (PMID: 12023342). Though unscored, further evidence supporting the gene-phenotype relationship for TNFRSF9 comes from mice lacking the TNFRSF9 ligand, TNFSF9, which is not known to bind any additional receptors. These mice develop spontaneous B-cell lymphoma (PMID: 19608748), recapitulating the increased risk of lymphoma seen in patients with TNFRSF9 variants. Similarly, the EBV protein LMP1 induces upregulation of TNFSF9 in B-cells, which in turn promotes expansion of cytotoxic, Eomes+ CD8+ T-cells, suggesting an EBV-specific host defense mechanism that is disrupted in individuals with pathogenic TNFRSF9 variants (PMID 29311309). In summary, there is definitive evidence supporting the relationship between TNFRSF9 and autosomal recessive immunodeficiency 109 with lymphoproliferation. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. In addition, based on the consistent phenotype among curated probands, the PIRD GCEP endorses renaming “autosomal recessive immunodeficiency 109 with lymphoproliferation” to “autosomal recessive TNFRSF9 lymphoproliferative disorder with immune deficiency” at the next evaluation of naming conventions for this disease.

Inheritance Pattern: AR

Disease ID:MONDO:0859526

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0859526

Submitter: PanelApp Australia