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

Abstract

Transmembrane activator and calcium-modulator and cyclophilin-ligand interactor (TACI), encoded by TNFRSF13B, plays a central role in B cell maturation and antibody responses through its interactions with BAFF and APRIL, with variants being linked to common variable immunodeficiency (CVID) and selective IgA deficiency. To characterise the clinical, immunological and genetic spectrum of these individuals, we recruited 30 participants (21 patients and nine family members) and classified patients into Group 1 (n = 16), carrying only TACI variants and Group 2 (n = 5), carrying both an IEI-related variant and an additional TACI variant. With a male/female ratio of 12/9, the median age was 2 years at symptom onset and 14 years at genetic diagnosis. Common clinical manifestations included recurrent infections (90%), autoimmune/inflammatory features (62%) and lymphoproliferation (57%). Twelve distinct TNFRSF13B mutations were identified, predominantly clustering in the cysteine-rich domain 2 (CRD2), with Cys104Arg being the most frequent (57%) variant. Immunophenotyping revealed decreased switched-memory and marginal zone B cells, reduced naïve CD4+ T cells and increased effector memory subsets. Notably, clinical and laboratory features overlapped between Groups 1 and 2, as well as between monoallelic and biallelic TNFRSF13B variant carriers. Patients with TNFRSF13B variants display broad phenotypic heterogeneity ranging from asymptomatic carriage to CVID and combined immunodeficiency phenotypes. Given the high polymorphism ratio and incomplete penetrance observed, TACI acts as both a genetic modifier and a monogenic disease-causing gene in this cohort, suggesting that coexisting genetic variants and exposomal factors likely determine the clinical expression and disease severity.