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. 2025 Nov 3;1(4):e20250016.
doi: 10.70962/jhi.20250016. Epub 2025 Aug 19.

Re-evaluation of the contribution of TNFRSF13B variants to antibody deficiency

Hassan Abolhassani  1   2 , Andres Caballero-Oteyza  3   4   5 , Mingyu Yang  1 , Michele Proietti  3   4   5 , Samaneh Delavari  2 , Patrick Maffucci  6 , Alejandro A Schäffer  7 , Bertrand Boisson  8   9   10 , Jean-Laurent Casanova  8   9   10   11   12 , Nima Rezaei  2 , Qiang Pan-Hammarström  1 , Charlotte Cunningham-Rundles  6 , Lennart Hammarström  1 , Bodo Grimbacher  3   5   13   14   15
Affiliations

Re-evaluation of the contribution of TNFRSF13B variants to antibody deficiency

Hassan Abolhassani et al. J Hum Immun. .

Abstract

Predominantly antibody deficiency (PAD) is the most prevalent form of human inborn errors of immunity (IEI). PAD is characterized by recurrent bacterial infections, immune dysregulation, and impaired immunoglobulin production. A monogenic cause of PAD can be identified in about 20% of cases. Approximately 10% of patients carry heterozygous mutations in the tumor necrosis factor receptor superfamily member 13B gene (TNFRSF13B), encoding the B cell surface protein TACI. Heterozygous variants in TNFRSF13B are not sufficient to cause PAD, as approximately 1% of the healthy population carries one of these variants. To identify additional genetic contributors to the immune defect in these individuals, we examined the exomes of 161 PAD patients with rare-damaging variants in TNFRSF13B. We identified (i) biallelic mutations in TNFRSF13B, (ii) the HLA-class II marker (DPA1*03), and (iii) multiple single nucleotide polymorphisms in known B-cell related genes, as additional genetic risk factors. Moreover, pathogenic mutations in other known IEI genes were presented in 16% of patients with heterozygous TNFRSF13B variants.

Keywords: Inborn errors of immunity; TACI; TNFRSF13B; antibody deficiency; common variable immunodeficiency; immunoglobulin A deficiency; modifier genes; phenotypic expression; primary immunodeficiency.

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Conflict of interest statement

Conflict of interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Spectrum of 38 unique TNFRSF13B variants identified in 161 PAD patients, showing the exonic locations, affected protein domains, AlphaMissense pathogenicity heatmap, population allele frequency, and CADD predicted damaging score compared with MSC and other variants observed in normal populations based on Genome Aggregation Database (gnomAD).
Figure S1.
Figure S1.
Frequencies of most common TNFRSF13B variants and significantly associated HLA alleles in PAD patients from three different cohorts.
Figure 2.
Figure 2.
GWAS analysis of modifier gene polymorphisms between 161 TACI patients and 1,241 unsolved PAD patients. Enrichment analysis of significant modifier gene polymorphism using gene set enrichment analysis (GSEA), based on KEGG (yellow color) and HPO (blue color) ontology for significant SNPs identified in PAD patients with heterozygous TNFRSF13B variants.
Figure 3.
Figure 3.
Overview of the findings of the WES of patients with monoallelic and biallelic variants in TNFRSF13B. The proportion of each etiology has been depicted with (left pie chart) or without (right pie chart) the inclusion of other known IEI pathogenic mutations with complete Mendelian inheritance.
See this image and copyright information in PMC

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