Bi-allelic mutation of CARD11 resulting in fatal immune dysregulation with dramatic B cell expansion
Bibliographic record
Abstract
Abstract Caspase recruitment domain family member 11 (CARD11) functions as a scaffold to bridge antigen receptors with downstream immune signaling pathways that enable antigen-dependent lymphocyte activation. Given its pleiotropic role in regulating adaptive immunity, different genetic variants in CARD11 can result in diverse phenotypic consequences in humans. Here we describe a patient harboring a novel bi-allelic CARD11 mutation that results in potentially fatal immune dysregulation with massive B cell expansion. He presented with splenomegaly, amenia, leukocytosis and thrombocytopenia within the first year of life. A sibling showed similar symptoms before passing away in infancy. Due to parental consanguinity, an autosomal recessive inborn error of immunity was suspected; whole exome sequencing revealed a homozygous missense mutation in the coiled-coil (CC) domain of CARD11 (p.Arg331Pro, R331P). Functional testing revealed the R331P mutation caused a mild gain-of-function effect relative to wild-type CARD11 in driving constitutive NF-kB activation, suggesting that R331P may disrupt interactions needed to maintain CARD11 autoinhibition in resting lymphocytes. Dramatic B cell lymphocytosis noted in the patient was not present in his heterozygous parents, indicating that 2 mutant alleles are required for this phenotype. In contrast, the patient’s T cells responded poorly to TCR stimulation with severely reduced proliferation. Collectively, these results indicate that the novel R331P CARD11 mutation manifests as the first known recessive form of B cell Expansion with NF-kB and T cell Anergy (BENTA disease), and illustrate how rare monogenic inborn errors of immunity provide a unique discovery platform for basic immunology.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.002 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".