CARD11 – B cell Expansion with NF-κB and T cell Anergy Disease

CARD11 (HGNC:16393) is implicated in B cell Expansion with NF-κB and T cell Anergy (BENTA) disease (MONDO:0014645), an autosomal dominant primary immunodeficiency marked by early-onset polyclonal B cell lymphocytosis and splenomegaly. Gain-of-function germline variants in CARD11 disrupt scaffold autoinhibition, leading to constitutive NF-κB activation and B cell expansion.

Genetic evidence for this association includes at least 7 unrelated probands harboring heterozygous CARD11 variants across 5 families, with 3 de novo events and familial segregation supporting pathogenicity ([PMID:23129749], [PMID:25352053], [PMID:31897776], [PMID:34557185], [PMID:36203613]). Key variants span the coiled-coil and linker regions, exemplified by c.368G>A (p.Gly123Asp) in a de novo patient with severe congenital B cell lymphocytosis ([PMID:25352053]).

Inheritance is autosomal dominant, with pedigrees demonstrating co-segregation of CARD11 gain-of-function alleles and BENTA phenotypes, including lymphocytosis (HP:0100827) and splenomegaly (HP:0001744). Functional assays in patient lymphocytes and transfected cell lines reveal enhanced baseline NF-κB reporter activity, exaggerated B cell receptor–driven proliferation, and survival advantages concordant with clinical severity.

Mechanistic studies show that mutant CARD11 disrupts intramolecular autoinhibition, promoting aberrant assembly of the CARMA1–BCL10–MALT1 signalosome and sustained IκB kinase activation. In vitro transfection of CARD11 variants (e.g., p.Gly123Asp, p.Lys215del) increases NF-κB-driven transcription in unstimulated lymphocytes, recapitulating the B cell expansion seen in patients.

No conflicting reports of benign or loss-of-function variants causing BENTA have been described. The convergence of multiple independent case reports, consistent segregation, and robust functional data yields a Strong ClinGen-level gene–disease association.

Key take-home: CARD11 gain-of-function variants should be screened in early-onset polyclonal B cell lymphocytosis with splenomegaly to confirm BENTA disease and guide management.

References

• The Journal of experimental medicine • 2012 • Congenital B cell lymphocytosis explained by novel germline CARD11 mutations PMID:23129749
• Journal of clinical immunology • 2015 • Germline CARD11 Mutation in a Patient with Severe Congenital B Cell Lymphocytosis PMID:25352053
• Journal of clinical immunology • 2020 • A Novel, Heterozygous Three Base-Pair Deletion in CARD11 Results in B Cell Expansion with NF-κB and T Cell Anergy Disease PMID:31897776
• Frontiers in immunology • 2021 • Identification and Characterization of a Germline Mutation in CARD11 From a Chinese Case of B Cell Expansion With NF-κB and T Cell Anergy PMID:34557185
• Frontiers in immunology • 2022 • A novel CARD11 germline mutation in a Chinese patient of B cell expansion with NF-κB and T cell anergy (BENTA) and literature review PMID:36203613

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