Clinical Heterogeneity of TNFRSF13B Variants: A Monogenic Cause or a Genetic Modifier?

TNFRSF13B variants, mostly clustering in the cysteine-rich domain CRD2, impair the TACI receptor and its interactions with BAFF and APRIL, disrupting B cell maturation and antibody responses; incomplete penetrance and co-occurring variants make the gene behave both as a monogenic cause and as a modifier.

The authors characterised the clinical, immunological and genetic spectrum of 30 participants carrying TNFRSF13B variants (21 patients and nine relatives), split into Group 1 (n = 16) with a TACI variant only and Group 2 (n = 5) carrying an additional variant in another inborn-error-of-immunity gene. Median age was 2 years at symptom onset and 14 years at genetic diagnosis, with recurrent infections in 90%, autoimmune or inflammatory features in 62% and lymphoproliferation in 57%. Twelve distinct TNFRSF13B variants were identified, predominantly clustering in CRD2, with p.Cys104Arg the most frequent (57%). Immunophenotyping showed decreased switched-memory and marginal-zone B cells, reduced naive CD4+ T cells and increased effector memory subsets. Clinical and laboratory features overlapped between the two groups and between monoallelic and biallelic carriers, leading the authors to view TACI as both a monogenic disease gene and a genetic modifier.

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The result that matters for the laboratory is a negative one, in the best sense: the absence of difference between monoallelic and biallelic carriers, and between isolated carriers and those with a second variant, forbids calling a TNFRSF13B variant causal on genotype alone. In clinic, this argues against stopping the work-up at TACI in common variable immunodeficiency, and for caution in family counselling, since penetrance is clearly modulated by genetic background and environment. The limitation is familiar: a single-centre cohort of 21 patients, very likely consanguineous and enriched for p.Cys104Arg, so the phenotype proportions cannot be transposed as such.

Analysis by Dr Thibaut Benquey