Severe Combined Immunodeficiency Due To CARD11 Deficiency

Mendelian MONDO:0014081 Pathograph 16 Show in embeddings browser Severe combined immunodeficiency Combined immunodeficiency

Severe combined immunodeficiency due to CARD11 deficiency (IMD11A; OMIM #615206) is an ultra-rare autosomal recessive inborn error of immunity caused by biallelic loss-of-function variants in CARD11, the lymphocyte-restricted scaffold protein that nucleates the CARD11-BCL10-MALT1 (CBM) signalosome downstream of the antigen receptor. What distinguishes it from most SCIDs is that the cells are there and do not work. Circulating T and B lymphocytes are numerically normal; what is lost is antigen-receptor-driven activation of NF-kappaB, JNK and MALT1 paracaspase activity. The consequence is agammaglobulinemia with profoundly deficient T-cell function, a B-cell developmental block at the naive and transitional stage, and life-threatening opportunistic infection in infancy, typically presenting as Pneumocystis jirovecii pneumonia. That numerical normality has a direct clinical cost. Newborn SCID screening quantifies T-cell receptor excision circles, which detect T-cell lymphopenia, so a disease with normal T-cell numbers can pass the screen. Diagnosis depends on functional immunology and sequencing rather than on the population screening pathway built for this disease class. CARD11 sits at the centre of an allelic series whose members are different diseases rather than severity tiers, and the entry is scoped to the recessive null form only: heterozygous gain-of-function variants cause BENTA with B-cell expansion, and heterozygous dominant-interfering variants cause severe atopic disease. Those are opposite directions on the same pathway.

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1
Inheritance
4
Pathophys.
7
Phenotypes
2
Gaps
16
Pathograph
1
Genes
2
Medical Actions
3
Differentials
2
Models
1
Deep Research
🏷

Classifications

Harrison's Part
GENETICS ENVIRONMENT DISEASE
👪

Inheritance

1
Autosomal recessive HP:0000007
Biallelic loss of function, homozygous or compound heterozygous. Consanguinity recurs in the reported families because it raises the chance of homozygosity for a rare null allele.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:23374270 SUPPORT Human Clinical
"Genetic evaluation revealed a homozygous deletion of exon 21 in CARD11 as the underlying defect."
Documents homozygosity for the causal exon 21 deletion in the reported patient.
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Discussions and Knowledge Gaps

2
Are the interstitial lung disease and colitis in CARD11 deficiency driven by immune dysregulation from loss of CBM signalling, or are they infectious complications of the immunodeficiency?
KNOWLEDGE GAP card11_inflammatory_manifestations_mechanism
Attached to
phenotypes#Interstitial pneumonitis phenotypes#Colitis
The entry asserts that an inflammatory manifestation in a disease of NF-kappaB signalling is not simply another opportunistic complication, and that assertion now carries two causal edges. Neither is established. The only source reporting these features lists them in the same sentence as the viral and fungal infections, without separating cause from consequence, and no cited work reports biopsy findings, pathogen studies or regulatory T cell measurements in these patients. Both readings are live: a dysregulatory route is mechanistically plausible because CBM signalling governs regulatory T cell development, and an infectious route is plausible because the same patients had documented respiratory infection. The edges are therefore INDIRECT_UNKNOWN_INTERMEDIATES.
Proposed experiments
Pathogen and immune-cell characterisation of the inflammatory lesions
card11_inflammatory_lesion_characterisation
In CARD11-deficient patients with colitis or interstitial lung disease, characterise affected tissue for infectious organisms and for regulatory T cell content, before transplantation and after.
Readouts
Regulatory T cell frequency in affected tissue
phenotypes#Colitis
Direction: DECREASED
Interpretation: Depleted regulatory T cells with no identified pathogen would support the dysregulatory reading over the infectious one.
How often does CARD11 deficiency escape TREC-based newborn SCID screening, and is a functional or genomic second-tier screen warranted for the CBM immunodeficiencies?
KNOWLEDGE GAP card11_trec_screening_escape
Attached to
pathophysiology#Loss of Antigen-Receptor-Driven T Cell Activation
TREC screening detects T-cell lymphopenia. This disease has normal T-cell numbers, so the screening pathway built to catch SCID before the first infection is expected not to catch this one. The expectation follows directly from the biology and from the reported patients presenting with established infection rather than through screening, but no study has quantified the miss rate, and with a handful of published probands none realistically could yet. Recording it because the inference is strong, actionable, and unmeasured, which is exactly the combination that gets stated as fact.
Proposed experiments
Retrospective TREC values in genetically confirmed CBM-complex patients
card11_trec_retrospective
Collect stored newborn screening TREC values for patients later given a molecular diagnosis of CARD11, BCL10 or MALT1 deficiency, and compare against the screening cut-off in force at the time.
Readouts
Proportion of confirmed patients with a TREC value above the screening cut-off
pathophysiology#Loss of Antigen-Receptor-Driven T Cell Activation
Direction: INCREASED
Interpretation: A high proportion passing the screen would convert the expectation into a measured screening gap and support a second-tier test.
⚙

Pathophysiology

4
Biallelic CARD11 Loss of Function
Null variants abolish CARD11 protein. CARD11 is expressed only in lymphocytes, which is why a defect in a general signalling scaffold produces a purely immunological disease, and why haematopoietic stem cell transplantation is curative.
CARD11 hgnc:16393 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CARD11 (hgnc:16393). hgnc:16393 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION
Downstream
Failure of CBM Signalosome Assembly
Show evidence (1 reference)
PMID:23374270 SUPPORT Human Clinical
"This deletion abrogated protein expression and activation of the canonical nuclear factor κB (NF-κB) pathway in lymphocytes after antigen receptor or phorbol 12-myristate 13-acetate stimulation, whereas CD40 signaling in B cells was preserved."
Establishes loss of protein and, in the same sentence, that the block is antigen-receptor-specific rather than a general NF-kappaB failure. The preserved CD40 arm is the specificity control.
Failure of CBM Signalosome Assembly
CARD11 is the scaffold that nucleates the CARD11-BCL10-MALT1 complex on antigen receptor engagement. Without it the complex does not form, so three outputs fail together: canonical NF-kappaB activation, JNK signalling, and MALT1 paracaspase activity.
T cell CL:0000084 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves T cell (CL:0000084). CL:0000084 is a cell type from the Cell Ontology. B cell CL:0000236 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves B cell (CL:0000236). CL:0000236 is a cell type from the Cell Ontology.
T cell receptor signaling pathway GO:0050852 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased T cell receptor signaling pathway (GO:0050852). GO:0050852 is a biological process from the Gene Ontology. ↓ DECREASED B cell receptor signaling pathway GO:0050853 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased B cell receptor signaling pathway (GO:0050853). GO:0050853 is a biological process from the Gene Ontology. ↓ DECREASED canonical NF-kappaB signal transduction GO:0007249 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves canonical NF-kappaB signal transduction (GO:0007249), qualified as loss of function. GO:0007249 is a biological process from the Gene Ontology. ⇓ LOSS OF FUNCTION
Animal models
CARMA1-knockout mouse (thymic regulatory T cell development) Mouse partially recapitulates Loss of the same complex, in the same lineage, with a defined developmental consequence.
Downstream
Loss of Antigen-Receptor-Driven T Cell Activation
B Cell Developmental Block at the Transitional Stage
Interstitial pneumonitis Attached here rather than to the infection-susceptibility node because the entry's own reading is that this is not simply another opportunistic complication: NF-kappaB signalling downstream of the CBM complex governs immune regulation as well as antigen responsiveness. The intermediates are unknown and the infectious route is not excluded by any cited source, which is why the link is INDIRECT_UNKNOWN_INTERMEDIATES and carries an attached knowledge gap rather than a mechanism.
Colitis Same reasoning as the interstitial lung disease above. Both are reported in one sentence alongside the infections, and neither has an established mechanism in CARD11 deficiency.
Show evidence (1 reference)
PMID:33872653 SUPPORT In Vitro
"This variant prevented CBM complex formation, severely impairing the activation of nuclear factor-κB, c-Jun N-terminal kinase, and MALT1 paracaspase activity in B and T cells."
Names the three downstream arms that fail together, which is what makes this one node rather than three.
Loss of Antigen-Receptor-Driven T Cell Activation
T cells are present in normal numbers and cannot respond. The defect is in activation rather than development, which is the whole clinical problem: every quantitative measure of the T-cell compartment reads normal.
T cell CL:0000084 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves T cell (CL:0000084). CL:0000084 is a cell type from the Cell Ontology.
Animal models
CARMA1-knockout mouse (Th17 differentiation and EAE) Mouse partially recapitulates Shows that the activation defect is lineage-selective rather than global: Th17 differentiation fails while Th1 and Th2 do not.
Downstream
Abnormal T cell physiology The phenotype-side statement of this node. Both are drawn from the same source sentence: the node is the mechanism, the phenotype is the measured finding.
Pneumocystis jirovecii pneumonia
Recurrent viral infections
Recurrent fungal infections Same route as the viral susceptibility above; the two are reported in one sentence and there is no reason to treat them differently.
Show evidence (1 reference)
PMID:23561803 SUPPORT Human Clinical
"The novel entity of SCID was characterized by agammaglobulinemia and profoundly deficient T-cell function despite quantitatively normal T and B lymphocytes."
The defining dissociation of this disease, stated in one sentence: function lost, numbers preserved.
B Cell Developmental Block at the Transitional Stage
B cells are numerically normal but arrested at the naive and type 1 transitional stage, with impaired circulating T follicular helper cell development, absent germinal centre output and failed antibody responses. This is the route to the agammaglobulinemia, and it is a developmental block rather than a production failure in mature cells.
B cell CL:0000236 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves B cell (CL:0000236). CL:0000236 is a cell type from the Cell Ontology.
Downstream
Agammaglobulinemia
Show evidence (2 references)
PMID:23374270 SUPPORT Human Clinical
"B-cell differentiation, although normal in number, was distinctively blocked at the transitional stage"
Locates the block at a specific developmental stage.
PMID:33872653 SUPPORT Human Clinical
"This functional defect resulted in a developmental block in B cells at the naive and type 1 transitional B-cell stage and impaired circulating T follicular helper cell (cTFH) development, which was associated with impaired antibody responses"
Independent confirmation of the block plus the T follicular helper arm that links it to the antibody failure.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Severe Combined Immunodeficiency Due To CARD11 Deficiency Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

7
Blood 2
Agammaglobulinemia FREQUENT HP:0004432 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Agammaglobulinemia (HP:0004432). HP:0004432 is a phenotype from the Human Phenotype Ontology.
Lowered from OBLIGATE, which asserts every patient. The band had been taken from one paper's characterisation of the entity, which is a definition rather than a count. Across the published probands, agammaglobulinemia is reported in one, hypogammaglobulinemia in a second, and immunoglobulins are not reported for the two patients in the 2021 series or for the Omenn reversion case, whose syndrome is itself defined in part by elevated IgE. FREQUENT records what is attested; the developmental block that explains it is not in doubt.
Show evidence (4 references)
PMID:23561803 SUPPORT Human Clinical
"The novel entity of SCID was characterized by agammaglobulinemia and profoundly deficient T-cell function despite quantitatively normal T and B lymphocytes."
Reports agammaglobulinemia in this patient, and as the feature by which the entity was characterised. A characterisation is not a count, which is why the band is FREQUENT rather than OBLIGATE.
PMID:26277595 SUPPORT REVIEW SYNTHESIS Human Clinical
"P6 had agammaglobulinemia, but her T-cell and B-cell counts were, unexpectedly, normal."
States the agammaglobulinemia finding directly, within a single review series that also reports the paired hypogammaglobulinemia patient below, which is more directly the claim this band makes than inferring the range across two separate primary case reports.
PMID:23374270 SUPPORT Human Clinical
"Here we report a patient of consanguineous descent presenting at 13 months of age with hypogammaglobulinemia, Pneumocystis jirovecii pneumonia, and a suggestive family history."
A different reported patient, whose antibody defect is hypogammaglobulinemia rather than agammaglobulinemia.
+ 1 more reference
Abnormal T cell physiology OBLIGATE HP:0011840 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Deficient T-cell function despite normal T-cell numbers, annotated with Abnormal T cell physiology (HP:0011840). HP:0011840 is a phenotype from the Human Phenotype Ontology.
OBLIGATE rests on more than the whole-exome-sequencing case report's characterisation of the entity: the CBM complex review independently attests the functional defect by proliferation and signalling assays in both published probands, so the grade is attested rather than merely definitional.
Show evidence (3 references)
PMID:23561803 SUPPORT Human Clinical
"profoundly deficient T-cell function despite quantitatively normal T and B lymphocytes"
The functional deficit with counts explicitly preserved.
PMID:26277595 SUPPORT REVIEW SYNTHESIS Human Clinical
"Lymphocyte proliferation was strongly impaired following the stimulation of PBMCs from P6 with T-cell mitogens, such as PHA, ConA, or anti-CD3."
Attests the functional deficit directly by a proliferation assay in the agammaglobulinemia-reporting proband, independent of the characterisation sentence the OBLIGATE grade previously rested on alone.
PMID:26277595 SUPPORT REVIEW SYNTHESIS Human Clinical
"T-cell proliferation in response to CD3/CD28 stimulation was completely abolished in vitro"
A T-cell functional readout, matching the P6 proliferation item above, so OBLIGATE rests on an assay of T-cell physiology in both reported patients rather than on one paper's characterisation. The sentence sits in the P7 stretch of the paragraph and cites both primary reports, so it covers the hypogammaglobulinemia-reporting proband. The paper's IκB-α/p65 sentence for P7 is deliberately not used here: its stimuli are anti-IgM and CD40L, which makes it a B-cell receptor signalling result rather than evidence of deficient T-cell function.
Digestive 1
Colitis FREQUENT HP:0002583 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Colitis (HP:0002583), qualified as severity severe. HP:0002583 is a phenotype from the Human Phenotype Ontology.
Severity: SEVERE
Show evidence (1 reference)
PMID:33872653 SUPPORT Human Clinical
"2 unrelated patients who presented with profound CID associated with viral and fungal respiratory infections, interstitial lung disease, and severe colitis"
Documents severe colitis in both patients of that series.
Immune 3
Pneumocystis jirovecii pneumonia FREQUENT HP:0020102 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pneumocystis jirovecii pneumonia (HP:0020102). HP:0020102 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:23374270 SUPPORT Human Clinical
"Here we report a patient of consanguineous descent presenting at 13 months of age with hypogammaglobulinemia, Pneumocystis jirovecii pneumonia, and a suggestive family history."
The presenting triad in this patient.
PMID:23561803 SUPPORT Human Clinical
"an infant of consanguineous parents who presented with life-threatening Pneumocystis jirovecii pneumonia"
The same presentation in an independent proband.
Recurrent viral infections FREQUENT HP:0004429 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent viral infections (HP:0004429). HP:0004429 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33872653 SUPPORT Human Clinical
"2 unrelated patients who presented with profound CID associated with viral and fungal respiratory infections, interstitial lung disease, and severe colitis"
Documents viral and fungal respiratory infection in the reported patients. It does not characterise frequency or recurrence.
Recurrent fungal infections FREQUENT HP:0002841 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent fungal infections (HP:0002841). HP:0002841 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33872653 SUPPORT Human Clinical
"2 unrelated patients who presented with profound CID associated with viral and fungal respiratory infections, interstitial lung disease, and severe colitis"
Documents viral and fungal respiratory infection in the reported patients. It does not characterise frequency or recurrence.
Respiratory 1
Interstitial pneumonitis FREQUENT HP:0006515 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Interstitial pneumonitis (HP:0006515). HP:0006515 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33872653 SUPPORT Human Clinical
"2 unrelated patients who presented with profound CID associated with viral and fungal respiratory infections, interstitial lung disease, and severe colitis"
Documents interstitial lung disease as part of the presentation.
🧬

Genetic Associations

1
CARD11
Gene: CARD11 hgnc:16393 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CARD11 (hgnc:16393). hgnc:16393 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:33872653 SUPPORT Human Clinical
"Both patients carried identical novel pathogenic biallelic loss-of-function variants in CARD11 (c.2509C>T; p.Arg837∗) leading to undetectable protein expression."
Establishes the recurrent null allele and that it produces no detectable protein, which is what makes this a complete rather than partial deficiency.
PMID:26289640 SUPPORT Human Clinical
"A somatic second-site mutation reverting the stop codon to a missense mutation (p.Cys150Leu) was detected in tissue-infiltrating T cells of the OS patient."
Documents the reversion event, which matters twice over: it names a second null allele (p.Cys150*) and it shows that partial restoration of CARD11 converts the phenotype rather than simply softening it.
💊

Medical Actions

2
Immunoglobulin Replacement Therapy
Action: intravenous immunoglobulin therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is intravenous immunoglobulin therapy (NCIT:C121331). NCIT:C121331 is a clinical intervention from the NCI Thesaurus. Ontology label: Intravenous Immunoglobulin Therapy NCIT:C121331
Platform: Other
Immunoglobulin replacement for the agammaglobulinemia, given to P7 of the two reported CARD11-null patients in the CBM review series. It is supportive rather than corrective: it supplies the antibody the blocked B cell compartment cannot make, and does nothing for the T cell activation defect.
Target Phenotypes: Agammaglobulinemia HP:0004432 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Agammaglobulinemia (HP:0004432). HP:0004432 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26277595 SUPPORT REVIEW SYNTHESIS Human Clinical
"P7 was treated with intravenous immunoglobulin."
Records the treatment in a named CARD11-deficient patient. The same paragraph identifies P6 and P7 as the AR CARD11 deficiency cases and describes P7 presenting at 13 months with Pneumocystis jirovecii pneumonia, so this is disease-specific rather than a general SCID recommendation.
Allogeneic Hematopoietic Stem Cell Transplantation
Action: allogeneic hematopoietic stem cell transplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is allogeneic hematopoietic stem cell transplantation, annotated with Hematopoietic Cell Transplantation (NCIT:C15431). NCIT:C15431 is a clinical intervention from the NCI Thesaurus. Ontology label: Hematopoietic Cell Transplantation NCIT:C15431
Platform: Cell therapy
The only reported curative intervention. Both patients in the two-patient series were transplanted and their immune function normalised. The reason it is curative is the reason the disease is purely immunological: CARD11 expression is lymphocyte-restricted, so replacing the haematopoietic compartment replaces every cell in which the gene matters.
Mechanism Target:
Biallelic CARD11 Loss of Function — Donor haematopoiesis replaces the CARD11-null lymphocyte compartment, which corrects the lesion at its origin rather than compensating downstream of it.
Show evidence (1 reference)
PMID:33872653 SUPPORT Human Clinical
"Hematopoietic stem cell transplantation functionally restores impaired signaling pathways."
States that transplantation restores the signalling defect this node describes, which is what makes the treatment mechanism-directed rather than supportive.
Show evidence (1 reference)
PMID:33872653 SUPPORT Human Clinical
"Both patients underwent hematopoietic stem cell transplantations, which led to functional normalization."
Reports the outcome in the two probands this entry curates.
🔬

Diagnosis

2
Lymphocyte function testing with normal lymphocyte counts (PRESENT)
The diagnostic pattern, and the reason this disease is missed. Counts are normal; the abnormality is in proliferation and activation on stimulation testing. A quantitative immune workup returns reassuring numbers in a child who is dying of an opportunistic infection.
Show evidence (1 reference)
PMID:23374270 SUPPORT Human Clinical
"Profound combined immunodeficiency can present with normal numbers of T and B cells, and therefore the functional defect of the cellular and humoral immune response is often not recognized until the first severe clinical manifestation."
States the diagnostic problem directly, including that recognition typically waits for the first severe illness.
Whole-exome or targeted sequencing (PRESENT)
Both index cases reached the gene by exome sequencing rather than by a candidate panel, which reflects that CARD11 was not a recognized SCID gene at the time.
Show evidence (1 reference)
PMID:23561803 SUPPORT Human Clinical
"The search for a disease-causing mutation was performed with diagnostic whole-exome sequencing and systematic variant categorization."
Records the diagnostic route taken in this case report.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
A small number of unrelated probands, mostly from consanguineous families. No registry or population estimate exists. The recurrent p.Arg837* allele has been reported in two unrelated patients.
Show evidence (1 reference)
PMID:33872653 SUPPORT Human Clinical
"This study sought to determine the cellular, immunological, and biochemical basis of disease for 2 unrelated patients who presented with profound CID associated with viral and fungal respiratory infections, interstitial lung disease, and severe colitis."
Indicates the scale of the published experience: individual unrelated probands characterized in detail rather than a cohort.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Severe Combined Immunodeficiency Due To CARD11 Deficiency:

BCL10 and MALT1 deficiency
Overlapping Features The other two components of the CBM signalosome. Losing any of the three produces a closely similar combined immunodeficiency, so this is the core differential and it is settled by sequencing rather than by phenotype.
Show evidence (1 reference)
PMID:33872653 SUPPORT Human Clinical
"Germline pathogenic variants impairing the caspase recruitment domain family member 11 (CARD11)-B cell chronic lymphocytic leukemia/lymphoma 10 (BCL10)-MALT1 paracaspase (MALT1) (CBM) complex are associated with diverse human diseases including combined immunodeficiency (CID), atopy, and..."
Establishes the CBM complex as the shared unit and names the disease families that arise from impairing it.
CARD11-associated atopy with dominant interference (CADINS)
Overlapping Features A different CARD11 disease, not a milder version of this one. Heterozygous hypomorphic variants act dominant-negatively and cause severe atopic disease rather than SCID. The distinction is mechanistic: partial, dominantly interfering loss produces a different signalling output from complete recessive loss, and the atopic form has a metabolic feature (impaired glutamine-dependent mTORC1 signalling, partially correctable in vitro) that has no counterpart in the null form.
Show evidence (1 reference)
PMID:28628108 SUPPORT In Vitro
"Transfection of mutant CARD11 expression constructs into T cell lines demonstrated both loss-of-function and dominant-interfering activity upon antigen receptor-induced activation of nuclear factor-κB and mammalian target of rapamycin complex 1 (mTORC1)."
Establishes the dominant-interfering mechanism that separates CADINS from the recessive null disease curated here. The distinction is in how the allele acts, not in how much function is lost. Graded IN_VITRO because the mechanism was demonstrated by transfecting constructs into cell lines, not observed in the patients.
BENTA (B-cell expansion with NF-kappaB and T-cell anergy)
Overlapping Features The third member of the CARD11 allelic series and the one this entry's description names without previously curating. Heterozygous gain-of-function variants drive constitutive NF-kappaB activity and a lymphoproliferative phenotype, which is the opposite signalling direction from the biallelic null disease curated here. Getting the allele class right is what decides whether the patient needs immune reconstitution or immunosuppression.
Distinguishing Features
  • Caused by heterozygous gain-of-function CARD11 variants, not biallelic loss-of-function ones.
  • Presents with B-cell expansion and lymphoproliferation rather than agammaglobulinemia and infection.
Show evidence (1 reference)
PMID:30170123 SUPPORT Human Clinical
"Germline CARD11 mutations cause several distinct primary immune disorders in human subjects, including severe combined immune deficiency (biallelic null mutations), B-cell expansion with nuclear factor κB and T-cell anergy (heterozygous, gain-of-function mutations), and severe atopic disease"
Names the three allele classes and their diseases in one sentence, which is the argument the entry description already makes and now cites.
🐁

Animal Models

2
CARMA1-knockout mouse (thymic regulatory T cell development)
Germline Card11-null mice, used to place the CBM requirement at an early checkpoint in thymic regulatory T cell development. This is the strongest available mechanistic support for reading the human inflammatory manifestations as dysregulatory rather than purely infectious, and it is also the reason that reading remains a knowledge gap: the measurement has never been made in a CARD11-deficient patient.
Species
Mouse
Genotype
Card11 (CARMA1) knockout
Publication
PMID:19454668
Pathograph links
Failure of CBM Signalosome Assembly partially recapitulates fidelity: moderate observes: cellular Loss of the same complex, in the same lineage, with a defined developmental consequence.
Limitations: The model's readout is a regulatory T cell developmental checkpoint. The human disease is defined by preserved lymphocyte numbers with lost function and by agammaglobulinemia, and no cited human study measures regulatory T cells in a CARD11-null patient. So the mouse establishes what the complex does, not that this is what goes wrong in the patients.
Show evidence (1 reference)
PMID:19454668 SUPPORT Model Organism
"our results demonstrate that the CBM complex controls an early checkpoint in Treg development by enabling generation of thymic precursors of Tregs"
Locates the CBM requirement at a specific step of regulatory T cell development in the knockout.
Show evidence (1 reference)
PMID:26277595 SUPPORT Other
"Interestingly, human subjects with these mutations have some features in common with the corresponding knockout mice, but other features are different between human subjects and mice."
The general statement that human and mouse CBM phenotypes only partly concord. It applies to this model as much as to the Th17 one below, which is why both links are PARTIALLY_RECAPITULATES rather than RECAPITULATES.
CARMA1-knockout mouse (Th17 differentiation and EAE)
The same null background used to show that CBM signalling is required to complete Th17 differentiation, with resistance to experimental autoimmune encephalomyelitis as the in vivo consequence.
Species
Mouse
Genotype
Card11 (CARMA1) knockout
Publication
PMID:23091043
Pathograph links
Loss of Antigen-Receptor-Driven T Cell Activation partially recapitulates fidelity: moderate observes: cellular Shows that the activation defect is lineage-selective rather than global: Th17 differentiation fails while Th1 and Th2 do not.
Limitations: The in vivo readout is resistance to an induced autoimmune model, which has no counterpart in the human phenotype. The human patients present with infection and agammaglobulinemia, not with protection from autoimmunity, so this model speaks to the mechanism of the node and not to the disease as experienced.
Show evidence (1 reference)
PMID:23091043 SUPPORT Model Organism
"In proliferating cells, lack of CARMA1 selectively prevented Th17, but not Th1 or Th2 differentiation, in a cell-intrinsic manner."
Establishes the lineage-selective activation defect in the knockout.
Show evidence (1 reference)
PMID:26277595 SUPPORT Other
"Interestingly, human subjects with these mutations have some features in common with the corresponding knockout mice, but other features are different between human subjects and mice."
The explicit statement that human and mouse CBM phenotypes only partly concord, which is why both links above are PARTIALLY_RECAPITULATES rather than RECAPITULATES.
{ }

Source YAML

click to show 
name: Severe Combined Immunodeficiency Due To CARD11 Deficiency
creation_date: "2026-09-05T00:00:00Z"
category: Mendelian
synonyms:
- CARD11 deficiency
- Complete CARD11 deficiency
- CARMA1 deficiency
- Immunodeficiency 11A
- IMD11A
- Combined immunodeficiency due to CARD11 deficiency
description: >
  Severe combined immunodeficiency due to CARD11 deficiency (IMD11A; OMIM #615206)
  is an ultra-rare autosomal recessive inborn error of immunity caused by biallelic
  loss-of-function variants in CARD11, the lymphocyte-restricted scaffold protein
  that nucleates the CARD11-BCL10-MALT1 (CBM) signalosome downstream of the antigen
  receptor.

  What distinguishes it from most SCIDs is that the cells are there and do not work.
  Circulating T and B lymphocytes are numerically normal; what is lost is
  antigen-receptor-driven activation of NF-kappaB, JNK and MALT1 paracaspase
  activity. The consequence is agammaglobulinemia with profoundly deficient T-cell
  function, a B-cell developmental block at the naive and transitional stage, and
  life-threatening opportunistic infection in infancy, typically presenting as
  Pneumocystis jirovecii pneumonia.

  That numerical normality has a direct clinical cost. Newborn SCID screening
  quantifies T-cell receptor excision circles, which detect T-cell lymphopenia, so a
  disease with normal T-cell numbers can pass the screen. Diagnosis depends on
  functional immunology and sequencing rather than on the population screening
  pathway built for this disease class.

  CARD11 sits at the centre of an allelic series whose members are different
  diseases rather than severity tiers, and the entry is scoped to the recessive null
  form only: heterozygous gain-of-function variants cause BENTA with B-cell
  expansion, and heterozygous dominant-interfering variants cause severe atopic
  disease. Those are opposite directions on the same pathway.
disease_term:
  preferred_term: severe combined immunodeficiency due to CARD11 deficiency
  term:
    id: MONDO:0014081
    label: severe combined immunodeficiency due to CARD11 deficiency
parents:
- Severe combined immunodeficiency
- Combined immunodeficiency
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    A small number of unrelated probands, mostly from consanguineous families. No
    registry or population estimate exists. The recurrent p.Arg837* allele has been
    reported in two unrelated patients.
  evidence:
  - reference: PMID:33872653
    reference_title: "Mechanistic understanding of the combined immunodeficiency in complete human CARD11 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study sought to determine the cellular, immunological, and biochemical basis of disease for 2 unrelated patients who presented with profound CID associated with viral and fungal respiratory infections, interstitial lung disease, and severe colitis."
    explanation: >-
      Indicates the scale of the published experience: individual unrelated
      probands characterized in detail rather than a cohort.
inheritance:
- name: Autosomal recessive
  description: >-
    Biallelic loss of function, homozygous or compound heterozygous. Consanguinity
    recurs in the reported families because it raises the chance of homozygosity for
    a rare null allele.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:23374270
    reference_title: "Deficiency of caspase recruitment domain family, member 11 (CARD11), causes profound combined immunodeficiency in human subjects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic evaluation revealed a homozygous deletion of exon 21 in CARD11 as the underlying defect."
    explanation: Documents homozygosity for the causal exon 21 deletion in the reported patient.
genetic:
- name: CARD11
  gene_term:
    preferred_term: CARD11
    term:
      id: hgnc:16393
      label: CARD11
  relationship_type: CAUSATIVE
  presence: PRESENT
  variant_origin: GERMLINE
  notes: >-
    Reported alleles include a homozygous deletion of exon 21 and the recurrent
    nonsense c.2509C>T, p.Arg837*, both of which abolish detectable protein. A
    somatic second-site reversion has been reported in one patient, partially
    restoring function and shifting the phenotype toward Omenn syndrome.
  evidence:
  - reference: PMID:33872653
    reference_title: "Mechanistic understanding of the combined immunodeficiency in complete human CARD11 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both patients carried identical novel pathogenic biallelic loss-of-function variants in CARD11 (c.2509C>T; p.Arg837∗) leading to undetectable protein expression."
    explanation: >-
      Establishes the recurrent null allele and that it produces no detectable
      protein, which is what makes this a complete rather than partial deficiency.
  - reference: PMID:26289640
    reference_title: "Omenn syndrome associated with a functional reversion due to a somatic second-site mutation in CARD11 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A somatic second-site mutation reverting the stop codon to a missense mutation (p.Cys150Leu) was detected in tissue-infiltrating T cells of the OS patient."
    explanation: >-
      Documents the reversion event, which matters twice over: it names a second
      null allele (p.Cys150*) and it shows that partial restoration of CARD11
      converts the phenotype rather than simply softening it.
pathophysiology:
- name: Biallelic CARD11 Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Null variants abolish CARD11 protein. CARD11 is expressed only in lymphocytes,
    which is why a defect in a general signalling scaffold produces a purely
    immunological disease, and why haematopoietic stem cell transplantation is
    curative.
  genes:
  - preferred_term: CARD11
    term:
      id: hgnc:16393
      label: CARD11
  genetic_context:
    functional_impact_category: LOSS_OF_FUNCTION
    zygosity: HOMOZYGOUS
    variant_origin: GERMLINE
  evidence:
  - reference: PMID:23374270
    reference_title: "Deficiency of caspase recruitment domain family, member 11 (CARD11), causes profound combined immunodeficiency in human subjects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This deletion abrogated protein expression and activation of the canonical nuclear factor κB (NF-κB) pathway in lymphocytes after antigen receptor or phorbol 12-myristate 13-acetate stimulation, whereas CD40 signaling in B cells was preserved."
    explanation: >-
      Establishes loss of protein and, in the same sentence, that the block is
      antigen-receptor-specific rather than a general NF-kappaB failure. The
      preserved CD40 arm is the specificity control.
  downstream:
  - target: Failure of CBM Signalosome Assembly
    causal_link_type: DIRECT
- name: Failure of CBM Signalosome Assembly
  biological_scale: MOLECULAR
  description: >-
    CARD11 is the scaffold that nucleates the CARD11-BCL10-MALT1 complex on antigen
    receptor engagement. Without it the complex does not form, so three outputs fail
    together: canonical NF-kappaB activation, JNK signalling, and MALT1 paracaspase
    activity.
  biological_processes:
  - preferred_term: T cell receptor signaling pathway
    term:
      id: GO:0050852
      label: T cell receptor signaling pathway
    modifier: DECREASED
  - preferred_term: B cell receptor signaling pathway
    term:
      id: GO:0050853
      label: B cell receptor signaling pathway
    modifier: DECREASED
  - preferred_term: canonical NF-kappaB signal transduction
    term:
      id: GO:0007249
      label: canonical NF-kappaB signal transduction
    modifier: LOSS_OF_FUNCTION
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  evidence:
  - reference: PMID:33872653
    reference_title: "Mechanistic understanding of the combined immunodeficiency in complete human CARD11 deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "This variant prevented CBM complex formation, severely impairing the activation of nuclear factor-κB, c-Jun N-terminal kinase, and MALT1 paracaspase activity in B and T cells."
    explanation: >-
      Names the three downstream arms that fail together, which is what makes this
      one node rather than three.
  downstream:
  - target: Loss of Antigen-Receptor-Driven T Cell Activation
    causal_link_type: DIRECT
  - target: B Cell Developmental Block at the Transitional Stage
    causal_link_type: DIRECT
  - target: Interstitial pneumonitis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Attached here rather than to the infection-susceptibility node because the
      entry's own reading is that this is not simply another opportunistic
      complication: NF-kappaB signalling downstream of the CBM complex governs
      immune regulation as well as antigen responsiveness. The intermediates are
      unknown and the infectious route is not excluded by any cited source, which
      is why the link is INDIRECT_UNKNOWN_INTERMEDIATES and carries an attached
      knowledge gap rather than a mechanism.
  - target: Colitis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Same reasoning as the interstitial lung disease above. Both are reported in
      one sentence alongside the infections, and neither has an established
      mechanism in CARD11 deficiency.
- name: Loss of Antigen-Receptor-Driven T Cell Activation
  biological_scale: CELLULAR
  description: >-
    T cells are present in normal numbers and cannot respond. The defect is in
    activation rather than development, which is the whole clinical problem: every
    quantitative measure of the T-cell compartment reads normal.
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  evidence:
  - reference: PMID:23561803
    reference_title: "Whole-exome sequencing links caspase recruitment domain 11 (CARD11) inactivation to severe combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The novel entity of SCID was characterized by agammaglobulinemia and profoundly deficient T-cell function despite quantitatively normal T and B lymphocytes."
    explanation: >-
      The defining dissociation of this disease, stated in one sentence: function
      lost, numbers preserved.
  downstream:
  - target: Abnormal T cell physiology
    causal_link_type: DIRECT
    description: >-
      The phenotype-side statement of this node. Both are drawn from the same
      source sentence: the node is the mechanism, the phenotype is the measured
      finding.
  - target: Pneumocystis jirovecii pneumonia
    causal_link_type: DIRECT
  - target: Recurrent viral infections
    causal_link_type: DIRECT
  - target: Recurrent fungal infections
    causal_link_type: DIRECT
    description: >-
      Same route as the viral susceptibility above; the two are reported in one
      sentence and there is no reason to treat them differently.
- name: B Cell Developmental Block at the Transitional Stage
  biological_scale: CELLULAR
  description: >-
    B cells are numerically normal but arrested at the naive and type 1 transitional
    stage, with impaired circulating T follicular helper cell development, absent
    germinal centre output and failed antibody responses. This is the route to the
    agammaglobulinemia, and it is a developmental block rather than a production
    failure in mature cells.
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  evidence:
  - reference: PMID:23374270
    reference_title: "Deficiency of caspase recruitment domain family, member 11 (CARD11), causes profound combined immunodeficiency in human subjects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "B-cell differentiation, although normal in number, was distinctively blocked at the transitional stage"
    explanation: Locates the block at a specific developmental stage.
  - reference: PMID:33872653
    reference_title: "Mechanistic understanding of the combined immunodeficiency in complete human CARD11 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This functional defect resulted in a developmental block in B cells at the naive and type 1 transitional B-cell stage and impaired circulating T follicular helper cell (cTFH) development, which was associated with impaired antibody responses"
    explanation: >-
      Independent confirmation of the block plus the T follicular helper arm that
      links it to the antibody failure.
  downstream:
  - target: Agammaglobulinemia
    causal_link_type: DIRECT
phenotypes:
- category: Immunologic
  name: Agammaglobulinemia
  frequency: FREQUENT
  description: >-
    Absent or profoundly reduced immunoglobulin despite numerically normal B cells,
    the laboratory counterpart of the transitional-stage developmental block. The
    whole-exome-sequencing case report describes agammaglobulinemia in its patient
    and the exon-21-deletion case report describes hypogammaglobulinemia in its
    patient, so the antibody defect is attested across a spectrum rather than
    uniformly at its severe end.
  notes: >-
    Lowered from OBLIGATE, which asserts every patient. The band had been taken from
    one paper's characterisation of the entity, which is a definition rather than a
    count. Across the published probands, agammaglobulinemia is reported in one,
    hypogammaglobulinemia in a second, and immunoglobulins are not reported for the
    two patients in the 2021 series or for the Omenn reversion case, whose syndrome
    is itself defined in part by elevated IgE. FREQUENT records what is attested;
    the developmental block that explains it is not in doubt.
  phenotype_term:
    preferred_term: Agammaglobulinemia
    term:
      id: HP:0004432
      label: Agammaglobulinemia
  evidence:
  - reference: PMID:23561803
    reference_title: "Whole-exome sequencing links caspase recruitment domain 11 (CARD11) inactivation to severe combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The novel entity of SCID was characterized by agammaglobulinemia and profoundly deficient T-cell function despite quantitatively normal T and B lymphocytes."
    explanation: >-
      Reports agammaglobulinemia in this patient, and as the feature by which the
      entity was characterised. A characterisation is not a count, which is why the
      band is FREQUENT rather than OBLIGATE.
  - reference: PMID:26277595
    reference_title: "Genetic errors of the human caspase recruitment domain-B-cell lymphoma 10-mucosa-associated lymphoid tissue lymphoma-translocation gene 1 (CBM) complex: Molecular, immunologic, and clinical heterogeneity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "P6 had agammaglobulinemia, but her T-cell and B-cell counts were, unexpectedly, normal."
    explanation: >-
      States the agammaglobulinemia finding directly, within a single review series
      that also reports the paired hypogammaglobulinemia patient below, which is
      more directly the claim this band makes than inferring the range across two
      separate primary case reports.
  - reference: PMID:23374270
    reference_title: "Deficiency of caspase recruitment domain family, member 11 (CARD11), causes profound combined immunodeficiency in human subjects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we report a patient of consanguineous descent presenting at 13 months of age with hypogammaglobulinemia, Pneumocystis jirovecii pneumonia, and a suggestive family history."
    explanation: >-
      A different reported patient, whose antibody defect is hypogammaglobulinemia
      rather than agammaglobulinemia.
  - reference: PMID:26277595
    reference_title: "Genetic errors of the human caspase recruitment domain-B-cell lymphoma 10-mucosa-associated lymphoid tissue lymphoma-translocation gene 1 (CBM) complex: Molecular, immunologic, and clinical heterogeneity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Like P6, P7 had hypogammaglobulinemia."
    explanation: >-
      States the hypogammaglobulinemia finding directly, within the same single
      review series as the agammaglobulinemia quote above, rather than requiring
      the two bands to be pieced together from separate primary reports. Read
      literally, the sentence's "Like P6" preface implies P6 was also
      hypogammaglobulinemic, two sentences after the same review states P6 had
      agammaglobulinemia - the very distinction this frequency band rests on.
      The preface is loose; the quote above carries P6's agammaglobulinemia from
      the same source, so the spectrum reading is the review's own and not an
      inference across papers.
- category: Infectious
  name: Pneumocystis jirovecii pneumonia
  frequency: FREQUENT
  description: >-
    The presenting illness in both index reports, at 13 months in one and early in
    life in the other. An opportunistic infection of this kind in an infant with
    normal lymphocyte counts is the clinical signal that should prompt functional
    testing rather than reassurance. The band is FREQUENT rather than VERY_FREQUENT
    on purpose: PJP is named in the two single-proband reports, while the
    two-patient series describes respiratory infection without naming it and the
    Omenn reversion case does not report it, so it is attested in roughly two of
    five published probands. The two quotes below establish that PJP occurred, not
    how often.
  phenotype_term:
    preferred_term: Pneumocystis jirovecii pneumonia
    term:
      id: HP:0020102
      label: Pneumocystis jirovecii pneumonia
  diagnostic: true
  evidence:
  - reference: PMID:23374270
    reference_title: "Deficiency of caspase recruitment domain family, member 11 (CARD11), causes profound combined immunodeficiency in human subjects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we report a patient of consanguineous descent presenting at 13 months of age with hypogammaglobulinemia, Pneumocystis jirovecii pneumonia, and a suggestive family history."
    explanation: The presenting triad in this patient.
  - reference: PMID:23561803
    reference_title: "Whole-exome sequencing links caspase recruitment domain 11 (CARD11) inactivation to severe combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "an infant of consanguineous parents who presented with life-threatening Pneumocystis jirovecii pneumonia"
    explanation: The same presentation in an independent proband.
- category: Immunologic
  name: Abnormal T cell physiology
  frequency: OBLIGATE
  description: >-
    Profoundly deficient T-cell function on stimulation testing, with normal T-cell
    numbers. HPO has no term for preserved-count-with-lost-function, so the binding
    is to the general physiology abnormality and the specific dissociation is
    carried in preferred_term and in the description.
  notes: >-
    OBLIGATE rests on more than the whole-exome-sequencing case report's
    characterisation of the entity: the CBM complex review independently attests
    the functional defect by proliferation and signalling assays in both published
    probands, so the grade is attested rather than merely definitional.
  phenotype_term:
    preferred_term: Deficient T-cell function despite normal T-cell numbers
    term:
      id: HP:0011840
      label: Abnormal T cell physiology
  evidence:
  - reference: PMID:23561803
    reference_title: "Whole-exome sequencing links caspase recruitment domain 11 (CARD11) inactivation to severe combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "profoundly deficient T-cell function despite quantitatively normal T and B lymphocytes"
    explanation: The functional deficit with counts explicitly preserved.
  - reference: PMID:26277595
    reference_title: "Genetic errors of the human caspase recruitment domain-B-cell lymphoma 10-mucosa-associated lymphoid tissue lymphoma-translocation gene 1 (CBM) complex: Molecular, immunologic, and clinical heterogeneity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Lymphocyte proliferation was strongly impaired following the stimulation of PBMCs from P6 with T-cell mitogens, such as PHA, ConA, or anti-CD3."
    explanation: >-
      Attests the functional deficit directly by a proliferation assay in the
      agammaglobulinemia-reporting proband, independent of the characterisation
      sentence the OBLIGATE grade previously rested on alone.
  - reference: PMID:26277595
    reference_title: "Genetic errors of the human caspase recruitment domain-B-cell lymphoma 10-mucosa-associated lymphoid tissue lymphoma-translocation gene 1 (CBM) complex: Molecular, immunologic, and clinical heterogeneity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "T-cell proliferation in response to CD3/CD28 stimulation was completely abolished in vitro"
    explanation: >-
      A T-cell functional readout, matching the P6 proliferation item above, so
      OBLIGATE rests on an assay of T-cell physiology in both reported patients
      rather than on one paper's characterisation. The sentence sits in the P7
      stretch of the paragraph and cites both primary reports, so it covers the
      hypogammaglobulinemia-reporting proband. The paper's IκB-α/p65 sentence
      for P7 is deliberately not used here: its stimuli are anti-IgM and CD40L,
      which makes it a B-cell receptor signalling result rather than evidence of
      deficient T-cell function.
- category: Respiratory
  name: Interstitial pneumonitis
  frequency: FREQUENT
  description: >-
    Interstitial lung disease reported in both patients of the second series,
    alongside viral and fungal respiratory infection.
  phenotype_term:
    preferred_term: Interstitial pneumonitis
    term:
      id: HP:0006515
      label: Interstitial pneumonitis
  evidence:
  - reference: PMID:33872653
    reference_title: "Mechanistic understanding of the combined immunodeficiency in complete human CARD11 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "2 unrelated patients who presented with profound CID associated with viral and fungal respiratory infections, interstitial lung disease, and severe colitis"
    explanation: Documents interstitial lung disease as part of the presentation.
- category: Gastrointestinal
  name: Colitis
  frequency: FREQUENT
  description: >-
    Severe colitis, reported alongside the respiratory disease. It is worth
    distinguishing from infection: an inflammatory manifestation in a disease of
    NF-kappaB signalling is not simply another opportunistic complication.
  phenotype_term:
    preferred_term: Colitis
    term:
      id: HP:0002583
      label: Colitis
    severity: SEVERE
  evidence:
  - reference: PMID:33872653
    reference_title: "Mechanistic understanding of the combined immunodeficiency in complete human CARD11 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "2 unrelated patients who presented with profound CID associated with viral and fungal respiratory infections, interstitial lung disease, and severe colitis"
    explanation: Documents severe colitis in both patients of that series.
- category: Infectious
  name: Recurrent viral infections
  frequency: FREQUENT
  description: >-
    Viral respiratory infection in the two-patient series. The quoted sentence names
    the infection type but does not itself assert recurrence; the HPO term is the
    closest available concept, and the recurrence in its label is this entry's
    reading of a combined immunodeficiency phenotype rather than a claim the source
    makes.
  phenotype_term:
    preferred_term: Recurrent viral infections
    term:
      id: HP:0004429
      label: Recurrent viral infections
  evidence:
  - reference: PMID:33872653
    reference_title: "Mechanistic understanding of the combined immunodeficiency in complete human CARD11 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "2 unrelated patients who presented with profound CID associated with viral and fungal respiratory infections, interstitial lung disease, and severe colitis"
    explanation: >-
      Documents viral and fungal respiratory infection in the reported patients. It
      does not characterise frequency or recurrence.
- category: Infectious
  name: Recurrent fungal infections
  frequency: FREQUENT
  description: >-
    Fungal respiratory infection in the two-patient series. As with the viral entry
    above, the source names the infection type without asserting recurrence, and the
    recurrence in the HPO label is this entry's reading rather than the source's
    claim.
  phenotype_term:
    preferred_term: Recurrent fungal infections
    term:
      id: HP:0002841
      label: Recurrent fungal infections
  evidence:
  - reference: PMID:33872653
    reference_title: "Mechanistic understanding of the combined immunodeficiency in complete human CARD11 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "2 unrelated patients who presented with profound CID associated with viral and fungal respiratory infections, interstitial lung disease, and severe colitis"
    explanation: >-
      Documents viral and fungal respiratory infection in the reported patients. It
      does not characterise frequency or recurrence.
treatments:
- name: Immunoglobulin Replacement Therapy
  therapeutic_modality: OTHER
  description: >-
    Immunoglobulin replacement for the agammaglobulinemia, given to P7 of the two
    reported CARD11-null patients in the CBM review series. It is supportive rather
    than corrective: it supplies the antibody the blocked B cell compartment cannot
    make, and does nothing for the T cell activation defect.
  treatment_term:
    preferred_term: intravenous immunoglobulin therapy
    term:
      id: NCIT:C121331
      label: Intravenous Immunoglobulin Therapy
  target_phenotypes:
  - preferred_term: Agammaglobulinemia
    term:
      id: HP:0004432
      label: Agammaglobulinemia
  evidence:
  - reference: PMID:26277595
    reference_title: "Genetic errors of the human caspase recruitment domain-B-cell lymphoma 10-mucosa-associated lymphoid tissue lymphoma-translocation gene 1 (CBM) complex: Molecular, immunologic, and clinical heterogeneity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "P7 was treated with intravenous immunoglobulin."
    explanation: >-
      Records the treatment in a named CARD11-deficient patient. The same paragraph
      identifies P6 and P7 as the AR CARD11 deficiency cases and describes P7
      presenting at 13 months with Pneumocystis jirovecii pneumonia, so this is
      disease-specific rather than a general SCID recommendation.
- name: Allogeneic Hematopoietic Stem Cell Transplantation
  therapeutic_modality: CELL_THERAPY
  description: >-
    The only reported curative intervention. Both patients in the two-patient series
    were transplanted and their immune function normalised. The reason it is curative
    is the reason the disease is purely immunological: CARD11 expression is
    lymphocyte-restricted, so replacing the haematopoietic compartment replaces every
    cell in which the gene matters.
  treatment_term:
    preferred_term: allogeneic hematopoietic stem cell transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  target_mechanisms:
  - target: Biallelic CARD11 Loss of Function
    description: >-
      Donor haematopoiesis replaces the CARD11-null lymphocyte compartment, which
      corrects the lesion at its origin rather than compensating downstream of it.
    evidence:
    - reference: PMID:33872653
      reference_title: "Mechanistic understanding of the combined immunodeficiency in complete human CARD11 deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Hematopoietic stem cell transplantation functionally restores impaired signaling pathways."
      explanation: >-
        States that transplantation restores the signalling defect this node
        describes, which is what makes the treatment mechanism-directed rather than
        supportive.
  evidence:
  - reference: PMID:33872653
    reference_title: "Mechanistic understanding of the combined immunodeficiency in complete human CARD11 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both patients underwent hematopoietic stem cell transplantations, which led to functional normalization."
    explanation: >-
      Reports the outcome in the two probands this entry curates.
animal_models:
- name: CARMA1-knockout mouse (thymic regulatory T cell development)
  species: Mouse
  genotype: Card11 (CARMA1) knockout
  publication: PMID:19454668
  description: >-
    Germline Card11-null mice, used to place the CBM requirement at an early
    checkpoint in thymic regulatory T cell development. This is the strongest
    available mechanistic support for reading the human inflammatory manifestations
    as dysregulatory rather than purely infectious, and it is also the reason that
    reading remains a knowledge gap: the measurement has never been made in a
    CARD11-deficient patient.
  modeled_mechanisms:
  - target: Failure of CBM Signalosome Assembly
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Loss of the same complex, in the same lineage, with a defined developmental
      consequence.
    limitations: >-
      The model's readout is a regulatory T cell developmental checkpoint. The human
      disease is defined by preserved lymphocyte numbers with lost function and by
      agammaglobulinemia, and no cited human study measures regulatory T cells in a
      CARD11-null patient. So the mouse establishes what the complex does, not that
      this is what goes wrong in the patients.
    evidence:
    - reference: PMID:19454668
      reference_title: "CARMA1 controls an early checkpoint in the thymic development of FoxP3+ regulatory T cells."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "our results demonstrate that the CBM complex controls an early checkpoint in Treg development by enabling generation of thymic precursors of Tregs"
      explanation: >-
        Locates the CBM requirement at a specific step of regulatory T cell
        development in the knockout.
  evidence:
  - reference: PMID:26277595
    reference_title: "Genetic errors of the human caspase recruitment domain-B-cell lymphoma 10-mucosa-associated lymphoid tissue lymphoma-translocation gene 1 (CBM) complex: Molecular, immunologic, and clinical heterogeneity."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Interestingly, human subjects with these mutations have some features in common with the corresponding knockout mice, but other features are different between human subjects and mice."
    explanation: >-
      The general statement that human and mouse CBM phenotypes only partly concord.
      It applies to this model as much as to the Th17 one below, which is why both
      links are PARTIALLY_RECAPITULATES rather than RECAPITULATES.
- name: CARMA1-knockout mouse (Th17 differentiation and EAE)
  species: Mouse
  genotype: Card11 (CARMA1) knockout
  publication: PMID:23091043
  description: >-
    The same null background used to show that CBM signalling is required to
    complete Th17 differentiation, with resistance to experimental autoimmune
    encephalomyelitis as the in vivo consequence.
  modeled_mechanisms:
  - target: Loss of Antigen-Receptor-Driven T Cell Activation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Shows that the activation defect is lineage-selective rather than global:
      Th17 differentiation fails while Th1 and Th2 do not.
    limitations: >-
      The in vivo readout is resistance to an induced autoimmune model, which has no
      counterpart in the human phenotype. The human patients present with infection
      and agammaglobulinemia, not with protection from autoimmunity, so this model
      speaks to the mechanism of the node and not to the disease as experienced.
    evidence:
    - reference: PMID:23091043
      reference_title: "T cell receptor/CARMA1/NF-κB signaling controls T-helper (Th) 17 differentiation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In proliferating cells, lack of CARMA1 selectively prevented Th17, but not Th1 or Th2 differentiation, in a cell-intrinsic manner."
      explanation: >-
        Establishes the lineage-selective activation defect in the knockout.
  evidence:
  - reference: PMID:26277595
    reference_title: "Genetic errors of the human caspase recruitment domain-B-cell lymphoma 10-mucosa-associated lymphoid tissue lymphoma-translocation gene 1 (CBM) complex: Molecular, immunologic, and clinical heterogeneity."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Interestingly, human subjects with these mutations have some features in common with the corresponding knockout mice, but other features are different between human subjects and mice."
    explanation: >-
      The explicit statement that human and mouse CBM phenotypes only partly
      concord, which is why both links above are PARTIALLY_RECAPITULATES rather
      than RECAPITULATES.
diagnosis:
- name: Lymphocyte function testing with normal lymphocyte counts
  description: >-
    The diagnostic pattern, and the reason this disease is missed. Counts are normal;
    the abnormality is in proliferation and activation on stimulation testing. A
    quantitative immune workup returns reassuring numbers in a child who is dying of
    an opportunistic infection.
  presence: PRESENT
  evidence:
  - reference: PMID:23374270
    reference_title: "Deficiency of caspase recruitment domain family, member 11 (CARD11), causes profound combined immunodeficiency in human subjects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Profound combined immunodeficiency can present with normal numbers of T and B cells, and therefore the functional defect of the cellular and humoral immune response is often not recognized until the first severe clinical manifestation."
    explanation: >-
      States the diagnostic problem directly, including that recognition typically
      waits for the first severe illness.
- name: Whole-exome or targeted sequencing
  description: >-
    Both index cases reached the gene by exome sequencing rather than by a candidate
    panel, which reflects that CARD11 was not a recognized SCID gene at the time.
  presence: PRESENT
  evidence:
  - reference: PMID:23561803
    reference_title: "Whole-exome sequencing links caspase recruitment domain 11 (CARD11) inactivation to severe combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The search for a disease-causing mutation was performed with diagnostic whole-exome sequencing and systematic variant categorization."
    explanation: Records the diagnostic route taken in this case report.
differential_diagnoses:
- name: BCL10 and MALT1 deficiency
  description: >-
    The other two components of the CBM signalosome. Losing any of the three
    produces a closely similar combined immunodeficiency, so this is the core
    differential and it is settled by sequencing rather than by phenotype.
  evidence:
  - reference: PMID:33872653
    reference_title: "Mechanistic understanding of the combined immunodeficiency in complete human CARD11 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Germline pathogenic variants impairing the caspase recruitment domain family member 11 (CARD11)-B cell chronic lymphocytic leukemia/lymphoma 10 (BCL10)-MALT1 paracaspase (MALT1) (CBM) complex are associated with diverse human diseases including combined immunodeficiency (CID), atopy, and lymphoproliferation."
    explanation: >-
      Establishes the CBM complex as the shared unit and names the disease families
      that arise from impairing it.
- name: CARD11-associated atopy with dominant interference (CADINS)
  description: >-
    A different CARD11 disease, not a milder version of this one. Heterozygous
    hypomorphic variants act dominant-negatively and cause severe atopic disease
    rather than SCID. The distinction is mechanistic: partial, dominantly interfering
    loss produces a different signalling output from complete recessive loss, and
    the atopic form has a metabolic feature (impaired glutamine-dependent mTORC1
    signalling, partially correctable in vitro) that has no counterpart in the null
    form.
  evidence:
  - reference: PMID:28628108
    reference_title: "Germline hypomorphic CARD11 mutations in severe atopic disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Transfection of mutant CARD11 expression constructs into T cell lines demonstrated both loss-of-function and dominant-interfering activity upon antigen receptor-induced activation of nuclear factor-κB and mammalian target of rapamycin complex 1 (mTORC1)."
    explanation: >-
      Establishes the dominant-interfering mechanism that separates CADINS from the
      recessive null disease curated here. The distinction is in how the allele
      acts, not in how much function is lost. Graded IN_VITRO because the mechanism
      was demonstrated by transfecting constructs into cell lines, not observed in
      the patients.
- name: BENTA (B-cell expansion with NF-kappaB and T-cell anergy)
  description: >-
    The third member of the CARD11 allelic series and the one this entry's
    description names without previously curating. Heterozygous gain-of-function
    variants drive constitutive NF-kappaB activity and a lymphoproliferative
    phenotype, which is the opposite signalling direction from the biallelic null
    disease curated here. Getting the allele class right is what decides whether the
    patient needs immune reconstitution or immunosuppression.
  distinguishing_features:
  - >-
    Caused by heterozygous gain-of-function CARD11 variants, not biallelic
    loss-of-function ones.
  - >-
    Presents with B-cell expansion and lymphoproliferation rather than
    agammaglobulinemia and infection.
  evidence:
  - reference: PMID:30170123
    reference_title: "Hypomorphic caspase activation and recruitment domain 11 (CARD11) mutations associated with diverse immunologic phenotypes with or without atopic disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Germline CARD11 mutations cause several distinct primary immune disorders in human subjects, including severe combined immune deficiency (biallelic null mutations), B-cell expansion with nuclear factor κB and T-cell anergy (heterozygous, gain-of-function mutations), and severe atopic disease"
    explanation: >-
      Names the three allele classes and their diseases in one sentence, which is
      the argument the entry description already makes and now cites.
discussions:
- discussion_id: card11_inflammatory_manifestations_mechanism
  kind: KNOWLEDGE_GAP
  prompt: >-
    Are the interstitial lung disease and colitis in CARD11 deficiency driven by
    immune dysregulation from loss of CBM signalling, or are they infectious
    complications of the immunodeficiency?
  attaches_to:
  - phenotypes#Interstitial pneumonitis
  - phenotypes#Colitis
  rationale: >-
    The entry asserts that an inflammatory manifestation in a disease of NF-kappaB
    signalling is not simply another opportunistic complication, and that assertion
    now carries two causal edges. Neither is established. The only source reporting
    these features lists them in the same sentence as the viral and fungal
    infections, without separating cause from consequence, and no cited work reports
    biopsy findings, pathogen studies or regulatory T cell measurements in these
    patients. Both readings are live: a dysregulatory route is mechanistically
    plausible because CBM signalling governs regulatory T cell development, and an
    infectious route is plausible because the same patients had documented
    respiratory infection. The edges are therefore INDIRECT_UNKNOWN_INTERMEDIATES.
  proposed_experiments:
  - experiment_id: card11_inflammatory_lesion_characterisation
    name: Pathogen and immune-cell characterisation of the inflammatory lesions
    description: >-
      In CARD11-deficient patients with colitis or interstitial lung disease,
      characterise affected tissue for infectious organisms and for regulatory
      T cell content, before transplantation and after.
    readouts:
    - name: Regulatory T cell frequency in affected tissue
      target: phenotypes#Colitis
      direction: DECREASED
      interpretation: >-
        Depleted regulatory T cells with no identified pathogen would support the
        dysregulatory reading over the infectious one.
- discussion_id: card11_trec_screening_escape
  kind: KNOWLEDGE_GAP
  prompt: >-
    How often does CARD11 deficiency escape TREC-based newborn SCID screening, and
    is a functional or genomic second-tier screen warranted for the CBM
    immunodeficiencies?
  attaches_to:
  - pathophysiology#Loss of Antigen-Receptor-Driven T Cell Activation
  rationale: >-
    TREC screening detects T-cell lymphopenia. This disease has normal T-cell
    numbers, so the screening pathway built to catch SCID before the first infection
    is expected not to catch this one. The expectation follows directly from the
    biology and from the reported patients presenting with established infection
    rather than through screening, but no study has quantified the miss rate, and
    with a handful of published probands none realistically could yet. Recording it
    because the inference is strong, actionable, and unmeasured, which is exactly
    the combination that gets stated as fact.
  proposed_experiments:
  - experiment_id: card11_trec_retrospective
    name: Retrospective TREC values in genetically confirmed CBM-complex patients
    description: >-
      Collect stored newborn screening TREC values for patients later given a
      molecular diagnosis of CARD11, BCL10 or MALT1 deficiency, and compare against
      the screening cut-off in force at the time.
    readouts:
    - name: Proportion of confirmed patients with a TREC value above the screening cut-off
      target: pathophysiology#Loss of Antigen-Receptor-Driven T Cell Activation
      direction: INCREASED
      interpretation: >-
        A high proportion passing the screen would convert the expectation into a
        measured screening gap and support a second-tier test.
notes: >-
  Curation decisions worth recording.

  Review round 1, corrected in round 2. Pneumocystis prophylaxis is deliberately not
  curated as a treatment. The deep-research report names it with no citation, and no
  reference cached for this entry mentions prophylaxis, trimethoprim or
  cotrimoxazole. It belongs here once somebody brings in a general SCID-management
  reference and cites it honestly as indirect for this disease.

  Immunoglobulin replacement was declined on the same grounds in round 1 and that
  was wrong. PMID:26277595 records it in a named CARD11-deficient patient, and it is
  now curated above. The error is worth recording because of how it happened: the
  cache search that produced the claim ran before PMID:26277595 was fetched later in
  the same round for the animal models, and was never repeated. A statement about
  what the repository contains has to be re-derived immediately before it is
  written, not carried over from earlier in the same session.

  The report's transplantation recommendation is likewise cited to a MALT1
  deficiency outcome (PMID:27109639), a different disease. The treatment entry does
  not use it: PMID:33872653 reports transplantation and its outcome in the two
  CARD11-null probands curated here, which is the disease-specific evidence.

  The inflammatory manifestations are curated as INDIRECT_UNKNOWN_INTERMEDIATES
  edges off the CBM node rather than off the infection-susceptibility node, with a
  knowledge gap attached. The entry had asserted in prose that they are not simply
  opportunistic; that claim is now either an edge with its uncertainty typed, or a
  question, rather than an unbacked sentence.

  Scope. The entry is the biallelic null (recessive SCID) form only, as the MONDO
  term specifies. CARD11 gain-of-function (BENTA) and dominant-interfering
  hypomorphic (CADINS) disease are curated as differentials rather than subtypes,
  because they are opposite directions on the same pathway and produce different
  diseases. The CADINS differential deliberately says so rather than describing it
  as a milder form.

  The TREC screening point is curated as a knowledge gap rather than as a fact. It
  follows directly from the biology and the reported presentations, and no study has
  measured it, which is the combination most likely to be repeated as established.

  One binding is coarser than the finding. The defining abnormality here is
  deficient T-cell function with preserved T-cell numbers, and HPO has no term for
  that dissociation; the binding is to HP:0011840 (Abnormal T cell physiology) with
  the specific finding in preferred_term.

  Deep research. An OpenScientist report is committed with the entry. Two of its
  suggested HPO terms name different concepts and are not bound: HP:0002754, offered
  as "Recurrent respiratory infections", is Osteomyelitis, and HP:0032256, offered as
  "Pneumocystis pneumonia", is Unusual Histoplasma capsulatum infection. The entry
  binds HP:0020102 (Pneumocystis jirovecii pneumonia) instead. Neither error was
  flagged by the report's own term validation. Its CARD11 gene identifier
  (HGNC:16393) is correct, which is worth noting given that gene CURIEs in reports
  are never checked at all (#9845).
📚

References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (3)

Record notes

Curation decisions worth recording. Review round 1, corrected in round 2. Pneumocystis prophylaxis is deliberately not curated as a treatment. The deep-research report names it with no citation, and no reference cached for this entry mentions prophylaxis, trimethoprim or cotrimoxazole. It belongs here once somebody brings in a general SCID-management reference and cites it honestly as indirect for this disease. Immunoglobulin replacement was declined on the same grounds in round 1 and that was wrong. PMID:26277595 records it in a named CARD11-deficient patient, and it is now curated above. The error is worth recording because of how it happened: the cache search that produced the claim ran before PMID:26277595 was fetched later in the same round for the animal models, and was never repeated. A statement about what the repository contains has to be re-derived immediately before it is written, not carried over from earlier in the same session. The report's transplantation recommendation is likewise cited to a MALT1 deficiency outcome (PMID:27109639), a different disease. The treatment entry does not use it: PMID:33872653 reports transplantation and its outcome in the two CARD11-null probands curated here, which is the disease-specific evidence. The inflammatory manifestations are curated as INDIRECT_UNKNOWN_INTERMEDIATES edges off the CBM node rather than off the infection-susceptibility node, with a knowledge gap attached. The entry had asserted in prose that they are not simply opportunistic; that claim is now either an edge with its uncertainty typed, or a question, rather than an unbacked sentence. Scope. The entry is the biallelic null (recessive SCID) form only, as the MONDO term specifies. CARD11 gain-of-function (BENTA) and dominant-interfering hypomorphic (CADINS) disease are curated as differentials rather than subtypes, because they are opposite directions on the same pathway and produce different diseases. The CADINS differential deliberately says so rather than describing it as a milder form. The TREC screening point is curated as a knowledge gap rather than as a fact. It follows directly from the biology and the reported presentations, and no study has measured it, which is the combination most likely to be repeated as established. One binding is coarser than the finding. The defining abnormality here is deficient T-cell function with preserved T-cell numbers, and HPO has no term for that dissociation; the binding is to HP:0011840 (Abnormal T cell physiology) with the specific finding in preferred_term. Deep research. An OpenScientist report is committed with the entry. Two of its suggested HPO terms name different concepts and are not bound: HP:0002754, offered as "Recurrent respiratory infections", is Osteomyelitis, and HP:0032256, offered as "Pneumocystis pneumonia", is Unusual Histoplasma capsulatum infection. The entry binds HP:0020102 (Pneumocystis jirovecii pneumonia) instead. Neither error was flagged by the report's own term validation. Its CARD11 gene identifier (HGNC:16393) is correct, which is worth noting given that gene CURIEs in reports are never checked at all (#9845).

Review round 1: treatments, pathograph connectivity, frequency band · 2026-09-06T03:44:03Z · View source

Addressed the ai4c-reviewer CHANGES_REQUESTED review on PR 11177 in a single push. Blocking items. (1) No treatments section existed, while a pathophysiology description asserted in prose that transplantation is curative. Added allogeneic HSCT (NCIT:C15431, CELL_THERAPY) with target_mechanisms joining the pathograph at Biallelic CARD11 Loss of Function, quoting the two disease-specific sentences already sitting unused in the cached PMID:33872653. (2) Four phenotypes had no incoming causal edge. Abnormal T cell physiology and Recurrent fungal infections now hang off Loss of Antigen-Receptor-Driven T Cell Activation, both DIRECT. Interstitial pneumonitis and Colitis hang off Failure of CBM Signalosome Assembly as INDIRECT_UNKNOWN_INTERMEDIATES, with a new KNOWLEDGE_GAP asking whether they are dysregulatory or infectious. Verified by recomputing in-edges from the file: all seven phenotypes now connected, no unresolved targets. (3) Pneumocystis pneumonia was VERY_FREQUENT (80-99%) on evidence attesting occurrence in roughly two of five published probands. Lowered to FREQUENT with the denominator stated in the description. Also from item 3: the five-word fragment 'viral and fungal respiratory infections' backed two phenotypes and asserts neither recurrence nor frequency. Replaced with the fuller sentence already quoted elsewhere in the file, and both phenotypes now say the recurrence in the HPO label is this entry's reading rather than the source's claim. Suggestions taken. (4) BENTA added as a third differential with distinguishing_features, citing the newly fetched PMID:30170123 sentence naming all three allele classes. (5) Two animal models added: the CARMA1-knockout Treg checkpoint (PMID:19454668) and the Th17/EAE model (PMID:23091043), both PARTIALLY_RECAPITULATES with model_scale CELLULAR and explicit limitations, plus a model-level caveat quoting PMID:26277595 on partial human-mouse concordance. Suggestions declined, with reasons recorded in notes. Immunoglobulin replacement and Pneumocystis prophylaxis were requested on the strength of deep-research section 12. That section names them with no citation at all, and none of the entry's cached references mentions either, so adding them would mean an evidence-free treatment or a manufactured quote. The report's own HSCT recommendation is cited to a MALT1-deficiency outcome, a different disease, and was not used; the CARD11-specific PMID:33872653 evidence was used instead. The top-level references block was left absent. Validation: schema pass, term validation pass, 27/27 snippets verified against the local cache (was 21/21), entity refs, causal targets, duplicate keys, enum values, qualifier terms all clean, whole-KB gates report nothing for this entry. No cache change; every term was already cached.

Create: SCID due to CARD11 deficiency (IMD11A) · 2026-09-05T20:07:20Z · View source

De-novo curation of SCID due to CARD11 deficiency (MONDO:0014081, IMD11A), claimed at #11156. entry_type resolved to DISEASE and the stub deleted. Preflight. CARD11 appears in kb/ on main only as an incidental gene-list string inside snippets on lymphoma entries and on Immunodeficiency_60.yaml, whose causal gene is BACH2. There was no existing coverage to extend. Scope. The entry is the biallelic null (recessive SCID) form only. CARD11 gain-of-function (BENTA) and dominant-interfering hypomorphic disease (CADINS) are curated as differentials rather than subtypes, because they act in opposite directions on the same pathway. The CADINS differential says so explicitly rather than describing it as a milder form, and cites the transfection result showing dominant interference. Deep research: one OpenScientist run, committed with the entry. It contributed the TREC-screening gap, the CBM-complex differential group and the allelic series framing. Its CARD11 gene identifier (HGNC:16393) is correct, which is worth recording given that report gene CURIEs are never checked at all (#9845). Two of its HPO terms name different concepts and are not bound. HP:0002754, offered as "Recurrent respiratory infections", is Osteomyelitis. HP:0032256, offered as "Pneumocystis pneumonia", is Unusual Histoplasma capsulatum infection; the entry binds HP:0020102 (Pneumocystis jirovecii pneumonia) instead. Neither was flagged by the report's own term validation. That pattern is reported on #10459. preflight-dr returns WARN on MALT1 at 29% of CARD11 mentions. That is expected rather than entity confusion: MALT1 and BCL10 are the other two components of the CBM signalosome and a correct mechanistic report has to discuss them. No MALT1-deficiency clinical content was taken; MALT1 appears in this entry only in the signalosome mechanism and in the differential. The TREC newborn-screening gap is curated as a KNOWLEDGE_GAP rather than as a fact. It follows directly from the biology, since TREC screening detects T-cell lymphopenia and this disease has normal T-cell counts, and the reported patients presented with established infection rather than through screening. But no study has measured the miss rate, and with a handful of published probands none realistically could yet. A retrospective TREC study is proposed. One binding is coarser than the finding. The defining abnormality is deficient T-cell function with preserved T-cell numbers, and HPO has no term for that dissociation; the binding is HP:0011840 (Abnormal T cell physiology) with the specific finding in preferred_term. Validation: just validate-disorders passes schema, terms and 21/21 snippets. check-entity-refs, check-causal-targets, check-duplicate-keys and check-enum-values are clean. No GeneReviews chapter exists (PubMed search for "CARD11 GeneReviews" returns zero). Seventeen references fetched during research but not cited were pruned from references_cache rather than staged.

OpenScientist ▸
Severe Combined Immunodeficiency Due To CARD11 Deficiency — Comprehensive Disease Report
openscientist-autonomous 19 citations 2026-09-05T19:43:14.658909

Severe Combined Immunodeficiency Due To CARD11 Deficiency — Comprehensive Disease Report

MONDO ID: MONDO:0014081 · Category: Genetic (autosomal-recessive inborn error of immunity) Gene: CARD11 (HGNC:16393; 7p22.2) · OMIM phenotype: #615206 (Immunodeficiency 11A, IMD11A)

Summary

Severe combined immunodeficiency (SCID) due to CARD11 deficiency is an ultra-rare, autosomal-recessive inborn error of immunity caused by biallelic loss-of-function (LOF) variants in CARD11, the lymphocyte-restricted scaffold protein that nucleates the CARD11–BCL10–MALT1 (CBM) signalosome downstream of the T- and B-cell antigen receptors. Complete absence of functional CARD11 abolishes assembly of the CBM complex and cripples antigen-receptor–driven activation of NF-κB, c-Jun N-terminal kinase (JNK), and MALT1 paracaspase, together with a metabolic arm that couples the antigen receptor to glutamine uptake and mTORC1. The immunological hallmark is agammaglobulinemia with profoundly deficient T-cell function despite numerically normal circulating T and B lymphocytes — a functional SCID phenotype (PMID: 23561803; PMID: 33872653).

Affected infants present early in life with life-threatening opportunistic infections (e.g., Pneumocystis jirovecii pneumonia, cytomegalovirus, recurrent viral and fungal respiratory infections), interstitial lung disease, and severe colitis. Because standard SCID newborn screening relies on quantifying T-cell receptor excision circles (TRECs), which detect T-cell lymphopenia, CARD11 deficiency — with numerically normal T cells — can escape TREC-based screening, making functional immunology and genetic sequencing essential for diagnosis (PMID: 42466165). The definitive therapy is allogeneic hematopoietic stem cell transplantation (HSCT), which is curative because CARD11 is lineage-restricted to hematopoietic tissue and the defect is intrinsic to lymphocytes (PMID: 40625738; PMID: 27109639).

CARD11 sits at the center of a striking allelic series: biallelic null variants cause SCID/combined immunodeficiency; heterozygous gain-of-function (GOF) variants cause BENTA (B-cell Expansion with NF-κB and T-cell Anergy); and heterozygous dominant-interfering LOF variants cause severe atopic disease/CID. CARD11 deficiency is furthermore one of three interchangeable CBM-complex combined immunodeficiencies (with BCL10 and MALT1 deficiency) that phenocopy one another, defining the core differential-diagnosis group. This report synthesizes 10 confirmed findings from 42 reviewed papers across all requested disease-characteristic dimensions.

1. Disease Information

Overview. CARD11-deficiency SCID is a monogenic combined immunodeficiency in which complete loss of the CARD11 scaffold prevents antigen-receptor signaling in T and B lymphocytes. It was first defined as a novel SCID entity by whole-exome sequencing in 2013 (PMID: 23561803). Clinically it behaves as a SCID/profound combined immunodeficiency (CID) but is biochemically distinct from lymphopenic SCIDs because lymphocyte numbers are preserved while lymphocyte function is lost.

Key identifiers.

Resource Identifier
MONDO MONDO:0014081
OMIM (phenotype) #615206 — Immunodeficiency 11A (IMD11A)
Gene CARD11, HGNC:16393, NCBI Gene 84433, UniProt Q9BXL7
Cytoband 7p22.2
Orphanet Combined immunodeficiency due to CARD11 deficiency (rare inborn error of immunity)
ICD-11 4A00.1 (combined immunodeficiencies)
MeSH Severe Combined Immunodeficiency (D016511); CARD Signaling Adaptor Proteins

Synonyms / alternative names. Immunodeficiency 11A; CARD11 deficiency; complete CARD11 deficiency; combined immunodeficiency due to CARD11 deficiency; CARMA1 deficiency (CARD11 = CARMA1 = "CARD-containing MAGUK protein 1").

Source of information. Predominantly aggregated disease-level and individual-patient case reports — the literature comprises a small number of unrelated families/probands described in detail, plus mechanistic and structural studies. There is no large registry or EHR-derived cohort given the rarity.

2. Etiology

Disease causal factors. The disease is purely genetic and monogenic: biallelic (homozygous or compound-heterozygous) LOF variants in CARD11 are necessary and sufficient. There is no environmental, infectious, or lifestyle cause — infections are consequences, not causes. Consanguinity is a recurrent contributing circumstance because it raises the chance of homozygosity for a rare recessive null allele (the index case was an infant of consanguineous parents; PMID: 23561803).

Genetic risk factors. The causal variants themselves are the risk factor. Reported pathogenic alleles include the nonsense variant c.2509C>T; p.Arg837* (recurrent, producing undetectable protein) and p.Cys150* (PMID: 33872653; PMID: 26289640). No common susceptibility loci or modifier genes have been established for the recessive SCID form.

Environmental / protective factors. None established. The only "protective" genetic event documented is a somatic second-site reversion in a patient that partially restored CARD11 function and converted the phenotype toward Omenn syndrome (PMID: 26289640). In hypomorphic (not null) CARD11 disease, glutamine supplementation partially rescued downstream mTORC1/IFN-γ defects — a metabolic modifier relevant to residual-function alleles but not to complete deficiency (PMID: 28628108).

Gene–environment interactions. Not applicable in the classical GxE sense; the phenotype is fully genetically determined, though clinical severity is shaped by the pathogen exposures the immunodeficient host encounters.

3. Phenotypes

CARD11-deficiency SCID phenotypes fall into infection, immune-dysregulation/inflammatory, and laboratory categories. Onset is neonatal to early-infancy; severity is severe; course is progressive/life-threatening without treatment.

Phenotype Type Onset / severity Suggested HPO term
Recurrent/opportunistic infections (Pneumocystis jirovecii pneumonia, CMV, sepsis) Clinical sign Neonatal–infancy; severe HP:0002718 (Recurrent bacterial infections); HP:0002754 (Recurrent respiratory infections); HP:0032256 (Pneumocystis pneumonia)
Interstitial lung disease Clinical/imaging sign Infancy; severe HP:0006530 (Interstitial pulmonary abnormality)
Severe colitis / chronic diarrhea Clinical sign Infancy; severe HP:0002583 (Colitis); HP:0002014 (Diarrhea)
Agammaglobulinemia / hypogammaglobulinemia Laboratory abnormality Congenital; severe HP:0004432 (Decreased circulating total IgG); HP:0002090
Profoundly deficient T-cell function (poor proliferation to mitogens/antigens) Laboratory abnormality Congenital; severe HP:0002843 (Abnormal T cell proliferation); HP:0005435 (Impaired T cell function)
Numerically normal T and B lymphocyte counts (distinguishing feature) Laboratory finding Congenital (normal count — diagnostic caveat)
Omenn features on reversion (erythroderma, lymphoproliferation, elevated IgE, oligoclonal T cells) Physical/laboratory Infancy; severe HP:0001019 (Erythroderma); HP:0003212 (Increased circulating IgE); HP:0100827 (Lymphocytosis)
Failure to thrive Physical manifestation Infancy HP:0001508 (Failure to thrive)

"presented with profound CID associated with viral and fungal respiratory infections, interstitial lung disease, and severe colitis" — PMID: 33872653.

"The novel entity of SCID was characterized by agammaglobulinemia and profoundly deficient T-cell function despite quantitatively normal T and B lymphocytes." — PMID: 23561803.

Frequency. With only a handful of reported patients, frequencies are qualitative: opportunistic infection, agammaglobulinemia, and defective T-cell function are essentially universal; interstitial lung disease and colitis are frequently reported; Omenn-syndrome presentation is exceptional (reversion-dependent).

Quality-of-life impact. Untreated disease is incompatible with normal life — recurrent life-threatening infection, chronic colitis with malabsorption, and respiratory compromise impose profound morbidity. Successful HSCT can restore near-normal immune function and quality of life.

4. Genetic / Molecular Information

Causal gene. CARD11 (CARMA1), 7p22.2, encoding a 1154-aa multidomain membrane-associated guanylate kinase (MAGUK) scaffold with an N-terminal CARD, a LATCH, a coiled-coil, an autoinhibitory inhibitory domain (ID), and C-terminal PDZ–SH3–GUK modules.

Pathogenic variants (recessive SCID form).

Variant (cDNA / protein) Type Consequence Reference
c.2509C>T; p.Arg837* Nonsense Undetectable protein (complete deficiency); prevents CBM assembly PMID: 33872653
Homozygous nonsense (truncating) Nonsense Truncated CARD11 defective in antigen-receptor signaling and NF-κB activation PMID: 23561803
p.Cys150* Nonsense Impaired NF-κB signaling and IL-2 production PMID: 26289640

Variant classification. Truncating null alleles are pathogenic (ACMG: PVS1 loss-of-function + segregation + functional data). Functional reconstitution assays confirmed patient-derived truncated CARD11 is signaling-defective (PMID: 23561803).

Variant type/class. Predominantly nonsense/truncating LOF. Allele frequency: these specific pathogenic nulls are extremely rare/private in gnomAD, consistent with a severe recessive disease. Origin: germline (the disease-causing alleles); note the exception of a somatic second-site reversion that mitigated one patient's phenotype (PMID: 26289640). Somatic CARD11 GOF mutations are separately associated with B-cell lymphomas (not this disease).

Functional consequence. Complete loss of function — abolition of the scaffold prevents any BCL10 nucleation. This contrasts with (a) dominant-negative heterozygous LOF alleles that poison wild-type CARD11 (atopy/CID) and (b) gain-of-function alleles that bypass autoinhibition (BENTA / lymphoma).

The CARD11 allelic series (a defining feature): "Germline CARD11 mutations cause several distinct primary immune disorders in human subjects, including severe combined immune deficiency (biallelic null mutations), B-cell expansion with nuclear factor κB and T-cell anergy (heterozygous, gain-of-function mutations), and severe atopic disease (loss-of-function, heterozygous, dominant interfering mutations)" — PMID: 30170123.

Modifier genes / epigenetics / chromosomal abnormalities. No established modifier genes for the recessive SCID form. No disease-specific epigenetic signature or chromosomal abnormality — this is a single-gene coding disorder.

5. Environmental Information

Not applicable as a cause. CARD11-deficiency SCID has no environmental, lifestyle, or toxicological etiology. Infectious agents (Pneumocystis jirovecii, cytomegalovirus, and other viral/fungal/bacterial pathogens) are downstream consequences of the immunodeficiency rather than triggers. Practical environmental relevance is limited to infection-avoidance / protective isolation and avoidance of live vaccines in the immunodeficient host prior to definitive therapy.

6. Mechanism / Pathophysiology

Ordered causal chain

  1. Biallelic null CARD11 variant (e.g., p.Arg837*) → absent/non-functional CARD11 scaffold protein in lymphocytes (demonstrated: undetectable protein) — PMID: 33872653.
  2. Absent CARD11 → failure of receptor-triggered closed→open conformational activation of the scaffold (CARD11 normally relieved from autoinhibition by PKCθ/β phosphorylation) — PMID: 20799731.
  3. No open CARD11 → no nucleation of BCL10 filaments and failure of CARD11–BCL10–MALT1 (CBM) complex assembly — PMID: 31296852; PMID: 33872653.
  4. No CBM signalosome → severely impaired activation of NF-κB, JNK, and MALT1 paracaspase in both B and T cells (demonstrated) — PMID: 33872653.
  5. Branch A (metabolic): CBM loss → impaired TCR-stimulated glutamine uptake and mTORC1 activation, independent of IKK — PMID: 24792914.
  6. Branch B (cytokine): CBM loss → impaired IL-2 production — PMID: 26289640.
  7. Impaired NF-κB/JNK/MALT1 signaling → developmental block in B cells at the naive/type-1 transitional stage and impaired circulating T follicular helper cells / defective T-cell effector function — PMID: 33872653.
  8. Defective lymphocyte activation and differentiation → agammaglobulinemia + profoundly deficient T-cell function despite normal lymphocyte counts — PMID: 23561803.
  9. Loss of protective adaptive immunity → early-life opportunistic infections, interstitial lung disease, colitis → life-threatening combined immunodeficiency — PMID: 33872653.

(Inferred branch: an Omenn-syndrome phenotype can arise when a somatic second-site reversion partially restores CARD11, generating oligoclonal autoreactive T cells — PMID: 26289640.)

Detail by category

  • Molecular pathways. Antigen-receptor (TCR/BCR) → PKCθ/β → CARD11 → BCL10/MALT1 → IKK → canonical NF-κB; parallel arms to JNK/AP-1 and MALT1 protease; and a metabolic arm to glutamine/ASCT2 → mTORC1 (PMID: 24792914; PMID: 26260210). Suggested pathway refs: KEGG NF-κB signaling; Reactome "CARD11-BCL10-MALT1 assembly."
  • Cellular processes. Lymphocyte activation, proliferation, survival, and effector-lineage differentiation (Th17 differentiation requires CARMA1; PMID: 23091043); thymic Treg commitment (see model organisms).
  • Protein dysfunction. Complete loss of scaffold function (null); by contrast, GOF variants disrupt the autoinhibitory ID interface causing spontaneous BCL10 filament formation — PMID: 31296852; PMID: 26884335.
  • Metabolic changes. Loss of CARD11-dependent glutamine import → reduced mTORC1 activity → reduced IFN-γ (documented in hypomorphic disease, partially glutamine-rescuable) — PMID: 28628108.
  • Immune-system involvement. Combined (T + B) immunodeficiency; the immune failure is the disease.
  • Molecular profiling. Reconstitution and reporter assays establish the NF-κB defect; patient B-cell developmental staging documents the transitional block (PMID: 33872653).

Upstream vs downstream: the mutation and absent scaffold are upstream; NF-κB/JNK/MALT1/mTORC1 failure is intermediate; lymphocyte developmental/functional defects and clinical infection are downstream.

Suggested GO / CL terms. GO:0007249 (I-κB kinase/NF-κB signaling); GO:0050852 (T-cell receptor signaling pathway); GO:0050853 (B-cell receptor signaling pathway); GO:0002250 (adaptive immune response). Cell types: CL:0000084 (T cell), CL:0000236 (B cell), CL:0002679 (regulatory T cell), CL:0000788 (naive B cell).

7. Anatomical Structures Affected

  • Organ / system level. Immune (lymphoid) system primarily: thymus, bone marrow, spleen, lymph nodes, mucosa-associated lymphoid tissue. Secondary organ involvement from immune failure: lungs (interstitial lung disease; UBERON:0002048) and gastrointestinal tract / colon (colitis; UBERON:0001155). Systems involved: immune/hematopoietic; secondarily respiratory and digestive.
  • Tissue / cell level. Lymphocytes — T cells (CL:0000084), B cells (CL:0000236), T follicular helper cells (CL:0002038), regulatory T cells (CL:0002679), naive/transitional B cells (CL:0000788). Hematopoietic tissue is the site of the intrinsic defect.
  • Subcellular level. CARD11 acts at the plasma membrane / cytoplasmic signalosome; GO cellular components: GO:0032449 (CBM complex), GO:0005886 (plasma membrane), GO:0005829 (cytosol).
  • Localization / lateralization. Systemic and bilateral/diffuse — a whole-body lymphoid disorder, not a focal lesion. The immune-restricted anatomy is explained by lineage-restricted CARD11 expression: "CARD11 is primarily expressed in hematopoietic tissues and lymphocytes and plays a crucial role in the proper activation of B and T cells in response to antigen recognition" — PMID: 40625738.

8. Temporal Development

  • Onset. Congenital defect; clinical onset in the neonatal period/early infancy with opportunistic infection — "in patients with severe combined immunodeficiency (SCID), infections caused by opportunistic pathogens are typically life-threatening early in life" — PMID: 23561803. Onset pattern is acute-on-chronic (an underlying congenital immune defect punctuated by acute infections).
  • Progression. Progressive and life-threatening without intervention; no spontaneous remission (except the rare partial, somatic-reversion event that alters rather than cures the phenotype). Disease duration is lifelong unless corrected by HSCT.
  • Critical period / window of opportunity. Early diagnosis before overwhelming infection is critical; HSCT before infectious/organ damage accrues offers the best outcomes, as for other SCIDs.

9. Inheritance and Population

  • Inheritance. Autosomal recessive (biallelic null). Consanguinity increases risk via homozygosity (PMID: 23561803). By contrast, dominant-negative LOF and GOF CARD11 disorders are autosomal dominant — the same gene yields different inheritance depending on allele class (PMID: 30170123; PMID: 25645939).
  • Penetrance / expressivity. Biallelic null penetrance is presumed complete for the immunodeficiency; expressivity can vary (e.g., Omenn presentation via somatic reversion).
  • Epidemiology. Ultra-rare — described in a small number of unrelated families worldwide; no reliable prevalence/incidence estimate exists. It is a small fraction of overall SCID incidence (SCID overall ~1 in 50,000–100,000 births).
  • Founder effects / carrier frequency. No established founder allele; carrier frequency is expected to be very low, elevated within consanguineous kindreds.
  • Demographics. No sex predilection (autosomal). Reported across different populations; consanguineous families are over-represented among cases.

10. Diagnostics

Laboratory / immunological. Serum immunoglobulins (agammaglobulinemia/hypogammaglobulinemia), lymphocyte subset enumeration (T and B counts normal — a key discriminator), and functional T-cell proliferation to mitogens (PHA) and antigens (profoundly reduced) (PMID: 23561803). Suggested LOINC-type panels: immunoglobulin quantitation, lymphocyte subset panel, lymphocyte mitogen stimulation.

Functional confirmation. NF-κB activation and CBM assembly assays / reconstitution assays demonstrating that patient-derived CARD11 is signaling-defective (PMID: 23561803; PMID: 33872653).

Genetic testing. WES/WGS or targeted PID gene panels including CARD11 are the definitive diagnostic modality; single-gene sequencing confirms biallelic variants and segregation. Chromosomal microarray/karyotype/FISH are not indicated (point mutations, not structural).

Newborn-screening caveat (critical). SCID NBS quantifies TRECs, which reflect T-cell lymphopenia; CARD11-deficient patients have numerically normal T cells and may therefore screen normal (false-negative). "Newborn screening (NBS) based on quantifying T cell receptor excision circles (TRECs) is highly sensitive for detecting severe combined immunodeficiency (SCID)" — PMID: 42466165 — but this sensitivity depends on lymphopenia the patient does not exhibit. Second-tier genetic screening can improve accuracy for such non-lymphopenic T-cell defects.

Differential diagnosis. Other CBM-complex combined immunodeficiencies — BCL10 and MALT1 deficiency — phenocopy CARD11 deficiency and constitute the primary differential group: "a broad range of clinical manifestations, including those characteristic of T- and B-lymphocyte defects, are associated with CARD11, MALT1, and BCL10 deficiencies" — PMID: 26277595. CARD9 deficiency is distinguished because it causes isolated invasive fungal infection (innate CBM), not combined immunodeficiency (PMID: 26277595). Also consider other SCID/CID genes, hyper-IgE syndromes, and (for the reversion phenotype) Omenn syndrome.

11. Outcome / Prognosis

  • Natural history (untreated). Poor — early-life opportunistic infection, interstitial lung disease, and colitis carry high mortality, consistent with SCID.
  • With treatment. Allogeneic HSCT is potentially curative. By analogy within the CBM group, MALT1 deficiency has been successfully treated and immunologically normalized by HSCT (PMID: 27109639), and CARD11's lineage-restricted (hematopoietic) expression means donor immune reconstitution corrects the intrinsic defect (PMID: 40625738).
  • Morbidity / complications. Chronic lung disease, colitis with malabsorption/failure to thrive, disseminated infection; transplant-related complications (GVHD, conditioning toxicity, viral reactivation).
  • Prognostic factors. Age at diagnosis and transplant, organ/infectious damage at HSCT, donor match, and conditioning regimen. Early, pre-damage transplant favors better outcomes.

12. Treatment

Definitive therapy. - Allogeneic hematopoietic stem cell transplantation (HSCT) — the curative standard for CBM-complex combined immunodeficiencies, ideally with reduced-intensity conditioning; supported by successful normalization in MALT1 deficiency (PMID: 27109639). NCIT: C15431 (Hematopoietic Stem Cell Transplantation).

Supportive / bridging pharmacotherapy. - Immunoglobulin replacement therapy (IVIG/SCIG) for agammaglobulinemia. NCIT: C29294 (Intravenous Immunoglobulin Therapy). - Anti-infective prophylaxis — Pneumocystis jirovecii prophylaxis (trimethoprim-sulfamethoxazole), antifungal and antiviral prophylaxis; treatment of intercurrent infections. - Avoid live vaccines; use irradiated/CMV-safe blood products.

Experimental / metabolic. In hypomorphic (residual-function) CARD11 disease, glutamine supplementation partially rescued mTORC1 and IFN-γ defects — a proof-of-concept metabolic intervention that requires residual CARD11 for glutamine import and is therefore not expected to help complete null deficiency (PMID: 28628108). Gene therapy/gene correction is conceptually attractive (hematopoietic-restricted, single-gene) but not clinically established for this disease.

Personalized-medicine note. Treatment is genotype-specific across the allelic series: null SCID → immune reconstitution (HSCT); GOF BENTA → immunosuppression (e.g., sirolimus/mTOR inhibition; PMID: 39998705). Correctly classifying the allele is essential to avoid opposite treatment errors.

13. Prevention

  • Primary prevention. Not preventable at the individual level (germline recessive). Population-level: genetic counseling and carrier testing in consanguineous families or families with a prior affected child; preimplantation/prenatal genetic diagnosis and cascade testing of relatives once the familial variant is known.
  • Secondary prevention. Early detection — although TREC NBS may miss CARD11 deficiency (normal T-cell counts), second-tier genetic screening and a high index of suspicion in infants with hypogammaglobulinemia + poor T-cell function improve early diagnosis (PMID: 42466165).
  • Tertiary prevention. Infection prophylaxis, protective isolation, irradiated blood products, avoidance of live vaccines, and timely HSCT to prevent irreversible organ damage.

14. Other Species / Natural Disease

  • Taxonomy / orthologs. Human CARD11 has a conserved mouse ortholog Card11 (a.k.a. Carma1; NCBI Gene 108723; Mus musculus, NCBI:txid10090). Orthologs exist across mammals; the CBM signaling module is evolutionarily conserved.
  • Natural disease in other species. No well-characterized naturally occurring companion-animal or wildlife disease is established for CARD11 in OMIA; disease knowledge derives from engineered mouse models rather than spontaneous animal disease.
  • Comparative biology. Mouse Card11 loss recapitulates key lymphocyte-activation and Treg defects (below), but concordance with humans is partial: "human subjects with these mutations have some features in common with the corresponding knockout mice, but other features are different between human subjects and mice" — PMID: 26277595.
  • Zoonotic potential. Not applicable (non-infectious genetic disease).

15. Model Organisms

  • Model type. Mammalian (mouse) genetic models predominate — Card11/CARMA1 knockout and point-mutant mice — plus in vitro cellular systems (Jurkat T cells, HEK293T reconstitution/reporter assays) used for functional validation.
  • Phenotype recapitulation. Card11/CARMA1-KO mice show that the CBM complex is required cell-intrinsically for thymic development of Foxp3+ regulatory T cells and gate an early Treg-commitment checkpoint: "The CARMA1/Bcl10/Malt1 (CBM) complex... is required for development of regulatory T cells (Tregs) but not conventional T cells" — PMID: 19454668. CARMA1 is also required for Th17 differentiation, and KO mice are resistant to experimental autoimmune encephalomyelitis (PMID: 23091043).
  • Model limitations. Human–mouse concordance is partial (PMID: 26277595); mouse models capture the lymphocyte-activation/Treg biology but not every clinical feature (e.g., the human interstitial lung disease/colitis spectrum).
  • Applications. Dissecting CBM signaling, Treg/Th17 development, NF-κB thresholds, and glutamine/mTORC1 coupling (PMID: 24792914; PMID: 39368135).
  • Resources. MGI (Card11), IMPC/KOMP for knockout alleles; Cellosaurus for Jurkat/HEK293T lines.

Key Findings (with evidence)

F001 — Biallelic loss-of-function CARD11 variants cause autosomal-recessive SCID

Multiple unrelated patients with homozygous null CARD11 variants (e.g., p.Arg837* / c.2509C>T; other nonsense mutations; p.Cys150*) present with profound combined immunodeficiency, and reconstitution assays confirm patient-derived truncated CARD11 is defective in antigen-receptor signaling and NF-κB activation. Consanguinity recurs (index case born to consanguineous parents). "Genetic analysis revealed a single pathogenic homozygous nonsense mutation of the caspase recruitment domain 11 (CARD11) gene. In reconstitution assays we demonstrated that the patient-derived truncated CARD11 protein is defective in antigen receptor signaling and nuclear factor κB activation." — PMID: 23561803. "Both patients carried identical novel pathogenic biallelic loss-of-function variants in CARD11 (c.2509C>T; p.Arg837∗) leading to undetectable protein expression." — PMID: 33872653.

F002 — Mechanism: CARD11 loss abrogates CBM-driven NF-κB, JNK and MALT1 activation

In patient B and T cells, biallelic null variants prevent CBM-complex formation and severely impair NF-κB, JNK, and MALT1 paracaspase activity, producing a B-cell developmental block at the naive/type-1 transitional stage and impaired IL-2 production. "This variant prevented CBM complex formation, severely impairing the activation of nuclear factor-κB, c-Jun N-terminal kinase, and MALT1 paracaspase activity in B and T cells. This functional defect resulted in a developmental block in B cells at the naive and type 1 transitional B-cell stage" — PMID: 33872653. "Both carried homozygous germline mutations in CARD11 (p.Cys150*), impairing NF-κB signaling and IL-2 production." — PMID: 26289640.

F003 — Clinical spectrum and curative HSCT

Patients present early in life with life-threatening infections, interstitial lung disease, and severe colitis; the laboratory hallmark is agammaglobulinemia with deficient T-cell function despite normal counts; an Omenn phenotype can arise via somatic reversion; and HSCT is definitive therapy for CBM-complex CID. "presented with profound CID associated with viral and fungal respiratory infections, interstitial lung disease, and severe colitis" — PMID: 33872653. "The clinical and immunological phenotype of MALT1 deficiency can be successfully treated with hematopoietic stem cell transplantation following reduced intensity conditioning." — PMID: 27109639.

F004 — CARD11 allelic series (null SCID vs dominant-negative atopy vs GOF BENTA)

Distinct germline CARD11 variant classes cause distinct diseases. "Germline CARD11 mutations cause several distinct primary immune disorders in human subjects, including severe combined immune deficiency (biallelic null mutations), B-cell expansion with nuclear factor κB and T-cell anergy (heterozygous, gain-of-function mutations), and severe atopic disease (loss-of-function, heterozygous, dominant interfering mutations)" — PMID: 30170123.

F005 — Mouse models recapitulate lymphocyte-activation and thymic Treg defects

"The CARMA1/Bcl10/Malt1 (CBM) complex... is required for development of regulatory T cells (Tregs) but not conventional T cells" — PMID: 19454668, with partial human concordance — PMID: 26277595.

F006 — CARD11 couples the antigen receptor to glutamine/mTORC1

"TCR-stimulated glutamine uptake and mTORC1 activation also required a TCR signaling complex composed of the scaffold protein CARMA1, the adaptor molecule BCL10, and the paracaspase MALT1. This function was independent of IKK kinase" — PMID: 24792914. "The mTORC1 and IFN-γ production defects were partially rescued by supplementation with glutamine, which requires CARD11 for import into T cells." — PMID: 28628108.

F007 — TREC newborn screening can miss CARD11 deficiency

Because T-cell numbers are normal, TREC-based NBS may be falsely normal. "The novel entity of SCID was characterized by agammaglobulinemia and profoundly deficient T-cell function despite quantitatively normal T and B lymphocytes." — PMID: 23561803. "Newborn screening (NBS) based on quantifying T cell receptor excision circles (TRECs) is highly sensitive for detecting severe combined immunodeficiency (SCID)" — PMID: 42466165.

F008 — One of three phenocopying CBM-complex immunodeficiencies

"a broad range of clinical manifestations, including those characteristic of T- and B-lymphocyte defects, are associated with CARD11, MALT1, and BCL10 deficiencies" and "Isolated invasive fungal infections of unclear cellular basis are associated with CARD9 deficiency" — PMID: 26277595.

F009 — Structural basis: autoinhibited scaffold that templates BCL10 filaments

"disruption of this interface leads to hyperactivation in cells and to the formation of Bcl10-templating filaments in vitro, illuminating the mechanism of action of numerous oncogenic mutations of CARD11" — PMID: 31296852. "the multidomain scaffold protein CARD11 undergoes a transition from a closed, inactive state to an open, active conformation that recruits several signaling proteins into a complex, leading to IKK kinase activation" — PMID: 20799731.

F010 — Lineage-restricted expression explains the immune-restricted phenotype

"CARD11 is primarily expressed in hematopoietic tissues and lymphocytes and plays a crucial role in the proper activation of B and T cells in response to antigen recognition" — PMID: 40625738.

Mechanistic Model / Interpretation

 Biallelic null CARD11 (e.g., p.Arg837*)   [germline, autosomal recessive]
 |  absent/nonfunctional scaffold
 v
 No PKCtheta/beta-triggered closed->open CARD11 activation   [PMID:20799731]
 |
 v
 No BCL10 filament nucleation -> no CBM signalosome   [PMID:31296852, 33872653]
 |
     +-----------+---------------+-------------------+
     v           v               v                   v
   NF-kB v     JNK/AP-1 v     MALT1 protease v    Glutamine->mTORC1 v (IKK-independent)
     |           |               |                   |            [PMID:24792914]
     +-----+-----+-------+-------+                   +-- IFN-gamma v, IL-2 v [PMID:26289640]
   v             v
  B-cell block at        Defective T-cell effector /
  naive/transitional     Tfh function                 [PMID:33872653]
   |             |
   +------+------+
  v
  Agammaglobulinemia + poor T-cell function
  DESPITE NORMAL T & B CELL COUNTS         [PMID:23561803]  -> TREC NBS may miss it [PMID:42466165]
  |
  v
  Early-life opportunistic infection, interstitial lung disease, colitis
  |                              (Omenn variant via somatic reversion [PMID:26289640])
  v
  Curative: allogeneic HSCT (lineage-restricted, hematopoietic-intrinsic) [PMID:40625738, 27109639]

The unifying insight is that CARD11 is a lymphocyte-restricted molecular switch: an autoinhibited scaffold whose receptor-triggered opening nucleates the CBM signalosome. The direction and dose of the perturbation dictate the disease — complete loss disables adaptive immunity (SCID), dominant-interfering loss partially poisons it (atopy/CID), and constitutive gain hyperactivates it (BENTA/lymphoma). Because expression is confined to hematopoietic cells, the phenotype is immune-restricted and, crucially, fully correctable by replacing the hematopoietic compartment via HSCT.

Evidence Base

PMID Contribution Type
23561803 Defines CARD11 inactivation as SCID; normal counts, defective function; reconstitution assay Human clinical + in vitro
33872653 Complete CARD11 deficiency (p.Arg837*); CBM/NF-κB/JNK/MALT1 defect; B-cell block; ILD/colitis Human clinical + mechanistic
26289640 p.Cys150*; impaired NF-κB/IL-2; Omenn via somatic reversion Human clinical
30170123 CARD11 allelic series (null SCID / GOF BENTA / DN atopy) Human clinical review
26277595 CBM-complex heterogeneity; CARD11/BCL10/MALT1 phenocopy; CARD9 distinct; human–mouse concordance Review
27109639 HSCT normalizes CBM (MALT1) deficiency — supports curative therapy Human clinical
24792914 CARD11/BCL10/MALT1 required for glutamine uptake & mTORC1, IKK-independent In vitro / mechanistic
28628108 Glutamine partially rescues mTORC1/IFN-γ in hypomorphic CARD11 disease Human clinical + mechanistic
19454668 Card11/CARMA1 KO: thymic Treg checkpoint Mouse model
23091043 CARMA1 required for Th17; EAE resistance Mouse model
31296852 Structural: autoinhibition + BCL10-templating filaments Structural / in vitro
20799731 Closed→open conformational activation of CARD11 Mechanistic
42466165 TREC NBS sensitivity relies on lymphopenia; second-tier genetics Diagnostic methodology
40625738 CARD11 lineage-restricted expression in hematopoietic/lymphoid tissue Review

Evidence spans human clinical case series, in vitro reconstitution/reporter assays, structural biology, and mouse genetic models, giving convergent, multi-modal support for the core mechanism and clinical picture.

Limitations and Knowledge Gaps

  • Extreme rarity / small N. Only a handful of unrelated biallelic-null probands are described; there are no registry-scale prevalence, penetrance, survival, or QoL data specific to CARD11-deficiency SCID. Many prognosis statements are extrapolated from the broader CBM/SCID literature.
  • HSCT outcome data are indirect. Curability is inferred from MALT1 deficiency and general CBM-CID practice (PMID: 27109639); large CARD11-specific transplant series are lacking.
  • Genotype–phenotype granularity. The full spectrum of null alleles, modifier effects, and the frequency of Omenn-via-reversion are not quantified.
  • No disease-specific omics/epigenetic signature is established for the null SCID form; molecular profiling comes largely from single-patient studies and model systems.
  • Metabolic rescue is allele-dependent. Glutamine/mTORC1 rescue applies to hypomorphic alleles and is not expected to benefit complete deficiency — this should not be over-generalized.
  • Model concordance is partial (PMID: 26277595); mouse phenotypes do not fully reproduce human ILD/colitis.

Proposed Follow-up Experiments / Actions

  1. Establish an international CARD11-deficiency registry to capture genotype, presentation, TREC-NBS results, transplant outcomes, and survival — directly filling the epidemiology/prognosis gaps.
  2. Systematically evaluate second-tier genetic newborn screening (or KREC + functional add-ons) to catch non-lymphopenic T-cell defects like CARD11 deficiency that TREC screening misses (PMID: 42466165).
  3. Report standardized HSCT outcomes (conditioning, chimerism, immune reconstitution, GVHD, survival) for biallelic-null CARD11 patients to formalize the curative claim.
  4. Deep immunophenotyping / single-cell RNA-seq of patient lymphocytes to map the B-cell transitional block and Tfh/Treg defects at cell-type resolution and benchmark against BCL10/MALT1 deficiency.
  5. Preclinical HSC gene-correction/gene-therapy studies — attractive given hematopoietic-restricted, single-gene, LOF biology — as an alternative to allogeneic HSCT for patients lacking matched donors.
  6. Curate the ontology mappings (MONDO:0014081, OMIM #615206, HGNC:16393, HPO/GO/CL/UBERON/NCIT terms listed above) into the knowledge base with the verified PMID-anchored evidence quotes.

Report compiled from 10 confirmed findings and 42 reviewed papers over a 5-iteration autonomous investigation. All quoted snippets are verbatim from the cited PubMed abstracts.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 19
Resolved 19
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 19
On topic 11
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 30
Resolved 28
Unresolved (possible confabulation) 0
Obsolete 1
Unverifiable 1
Terms whose name was checked 14
Terms named correctly 10
Terms named as a different term 2
Terms whose name is worth a second look 2

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • MONDO:0014081 (3 mentions) - the report calls it "MONDO"; MONDO calls it severe combined immunodeficiency due to CARD11 deficiency
  • CL:0002679 (2 mentions) - the report calls it "regulatory T cell"; CL calls it natural helper lymphocyte

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

  • HP:0005435 (obsolete Impaired T cell function) (1 mention) - replaced by HP:0011840

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • HP:0006530 (1 mention) - the report calls it "Interstitial pulmonary abnormality"; HP calls it Abnormal pulmonary interstitial morphology, and lists "Interstitial pulmonary disease" among its other names
  • GO:0007249 (1 mention) - the report calls it "I-κB kinase/NF-κB signaling"; GO calls it canonical NF-kappaB signal transduction, and lists "I-kappaB kinase/NF-kappaB signaling" among its other names