A novel linker region truncating variant in BCL10 underlies a leaky immunodeficiency phenotype

BCL10 is a core CBM (CARD-BCL10-MALT1) complex component required for antigen receptor-mediated NF-κB activation. BCL10 deficiency is an exceptionally rare autosomal recessive combined immunodeficiency, with only six patients reported to date. We aimed to characterize the clinical, immunologic, and molecular features of a novel homozygous BCL10 variant and explore mechanisms associated with its leaky phenotype.

Clinical/immunologic phenotyping, whole-exome and Sanger sequencing, transcript and protein studies, signaling, cytokine, and T cell proliferation assays, and scRNA-seq were performed.

A novel homozygous BCL10 c.345_346dup (p.Gly116GlufsTer3) variant was identified in a patient with combined immunodeficiency and immune dysregulation, with relatively mild infections, terminal effector-skewed lymphocytes, and partial Treg preservation. In PBMCs, the variant reduced full-length BCL10 transcripts and BCL10 protein while increasing N-terminal transcripts; HEK293T overexpression showed that the mutant construct could produce a low-abundance truncated protein in vitro. NF-κB signaling was stimulus dependent, with near-absent p-p65 induction in T cells after PMA/ionomycin but relative preservation or enhancement after TNF-α or LPS. T cell proliferation was partially preserved with anti-CD3/CD28 but nearly absent with anti-CD3 alone. ScRNA-seq revealed aberrant Treg-associated gene expression, increased activation/apoptosis/senescence programs in T and NK cells, enhanced inflammatory signaling in B cells and monocytes, and enrichment of AP-1/MAPK, inflammatory NF-κB, and IFN-response pathways.

This novel linker-region truncating BCL10 variant was associated with leaky combined immunodeficiency with immune dysregulation. Defective CBM-dependent NF-κB activation coexisted with secondary activation of CBM-independent inflammatory and AP-1/MAPK-related programs, suggesting that inflammatory remodeling may contribute to the nonclassical phenotype.