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Clinical Heterogeneity of TNFRSF13B Variants: A Monogenic Cause or a Genetic Modifier?
Begum Cicek1,2,3, Deniz Ilgun Gurel2,4, Ismail Yaz1,2,3
1Division of Immunology, Department of Pediatric Basic Sciences, Institute of Child Health, Hacettepe University, Ankara, Turkey.
Immunology
|August 14, 2026
Summary
Genetic variants in Transmembrane activator and calcium-modulator and cyclophilin-ligand interactor (TACI) cause a spectrum of immunodeficiencies. TACI variants present with varied clinical features, influenced by other genetic and environmental factors.
Area of Science:
- Immunology
- Genetics
- Molecular Biology
Background:
- Transmembrane activator and calcium-modulator and cyclophilin-ligand interactor (TACI), encoded by TNFRSF13B, is crucial for B cell maturation and antibody production.
- TACI variants are associated with primary immunodeficiencies like common variable immunodeficiency (CVID) and selective IgA deficiency.
Purpose of the Study:
- To characterize the clinical, immunological, and genetic spectrum of individuals with TACI variants.
- To investigate the role of TACI in different immunodeficiency phenotypes.
Main Methods:
- Recruited 30 participants (21 patients, 9 family members) and classified them into groups based on TACI variants and other immune dysregulation-related variants.
- Performed genetic analysis to identify TNFRSF13B mutations.
- Conducted immunophenotyping of B and T cell subsets.
Main Results:
- Identified 12 distinct TNFRSF13B mutations, with Cys104Arg being the most common.
- Observed clinical manifestations including recurrent infections (90%), autoimmune features (62%), and lymphoproliferation (57%).
- Immunophenotyping showed decreased switched-memory B cells, reduced naïve CD4+ T cells, and increased effector memory T cells.
Conclusions:
- TNFRSF13B variants exhibit broad phenotypic heterogeneity, ranging from asymptomatic carriage to CVID and combined immunodeficiency.
- TACI functions as both a genetic modifier and a monogenic disease-causing gene.
- Clinical presentation is likely influenced by coexisting genetic variants and exposomal factors, leading to incomplete penetrance and variable severity.
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