TNFRSF13C – Common Variable Immunodeficiency

Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency, characterised by hypogammaglobulinemia and recurrent infections. TNFRSF13C encodes the B-cell activating factor receptor (BAFFR), a critical mediator of B-cell survival and maturation. A growing body of genetic and functional data supports an association between TNFRSF13C and CVID (MONDO:0015517).

Genetic studies indicate an autosomal recessive inheritance for TNFRSF13C variants in CVID. Four genes including TNFRSF13C were first implicated in CVID susceptibility, with TNFRSF13C showing recessive inheritance in linkage cohorts (PMID:17467261). Targeted amplicon NGS in 22 unrelated CVID patients identified pathogenic or likely pathogenic TNFRSF13C variants in a subset of cases (PMID:35570134).

A single‐patient case report described a heterozygous TNFRSF13C c.475C>T (p.His159Tyr) variant in one individual presenting with CVID alongside type 1 diabetes and autoimmune thrombocytopenia (PMID:36090979). This variant was associated with reduced BAFFR expression and B-cell lymphopenia.

Functional assays demonstrate that BAFFR missense variants impair receptor oligomerization, ligand binding, and downstream NF-κB signaling. Lentiviral expression of variants including Pro21Arg, Ala52Thr, Gly64Val, Pro146Ser, and His159Tyr in B-cell lines showed decreased NF-κB2 activation and altered CD79B interactions consistent with B-cell deficiency (PMID:36308663). Separately, the His159Tyr change enhanced NF-κB1/2 activity and TRAF recruitment in lymphoma cells, underlining its functional impact (PMID:21041452).

No significant conflicting evidence has refuted the role of TNFRSF13C in CVID; non‐detection in some small cohorts likely reflects allelic heterogeneity and population variation. Collectively, the identification of recessive TNFRSF13C variants in independent CVID cohorts and concordant functional data establish a Moderate level of clinical validity for TNFRSF13C in CVID.

Key take-home: TNFRSF13C should be included in diagnostic gene panels for CVID to guide patient management and genetic counseling.

References

• Current opinion in genetics & development | 2007 | Deconstructing common variable immunodeficiency by genetic analysis. PMID:17467261
• The Journal of molecular diagnostics | 2022 | A Novel Targeted Amplicon Next-Generation Sequencing Gene Panel for the Diagnosis of Common Variable Immunodeficiency Has a High Diagnostic Yield: Results from the Perth CVID Cohort Study PMID:35570134
• Frontiers in immunology | 2022 | Natural history of type 1 diabetes on an immunodysregulatory background with genetic alteration in B-cell activating factor receptor: A case report. PMID:36090979
• Journal of clinical immunology | 2023 | CVID-Associated B Cell Activating Factor Receptor Variants Change Receptor Oligomerization, Ligand Binding, and Signaling Responses. PMID:36308663
• The Journal of experimental medicine | 2010 | A BAFF-R mutation associated with non-Hodgkin lymphoma alters TRAF recruitment and reveals new insights into BAFF-R signaling. PMID:21041452

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