Immunodeficiency 89 and Autoimmunity

Immunodeficiency 89 and autoimmunity is an autosomal recessive inborn error of immunity attributed to biallelic CARD10 variants. CARD10, also called CARMA3, is a membrane-associated guanylate kinase family scaffold that assembles the CBM complex with BCL10 and MALT1 and couples G-protein-coupled receptor and epidermal growth factor receptor signalling to NF-kappaB activation. Its paralogues CARD9, CARD11 and CARD14 already account for recognised immunodeficiency and inflammatory syndromes, so a CARD10 defect sits inside an established mechanistic family rather than standing alone. The presentation is the combination that marks immune dysregulation rather than pure immunodeficiency: recurrent infection alongside autoimmune and allergic disease. The reported siblings had recurrent infections with bronchiectasis, lung abscess and pulmonary bulla, asthma, autoimmune anaemia and Crohn disease. Onset was late - both presented in their fifth decade - which places this among the mild primary immunodeficiencies that surface as adult autoimmunity or allergy rather than as childhood infection. Two observations sharpen the mechanism. The siblings had asthma with low rather than raised blood eosinophils, which matches the Card10-deficient mouse asthma model in which airway eosinophils fall while airway hyperresponsiveness does not. And intermediate and non-classical monocyte and monocyte-derived dendritic cell populations were reduced while inflammatory chemokines were raised - a combination of effector-cell depletion with inflammatory drive rather than global immune failure. The evidence base is narrow and the entry says so rather than reading as though the gene-disease relationship were settled. The entity rests on a single consanguineous family with two affected siblings homozygous for one missense variant in the CARD10 coiled-coil domain, and the authors describe that variant as the possible rather than the established cause. The two siblings differed substantially in severity despite an identical genotype, which the report attributes to environmental modifiers - so even within the one reported family the genotype does not predict the phenotype.

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1
Inheritance
6
Pathophys.
7
Phenotypes
2
Gaps
16
Pathograph
1
Genes
1
Variants
1
Models
1
References
1
Deep Research
👪

Inheritance

1
Autosomal recessive HP:0000007
Reported in two siblings of a consanguineous family homozygous for CARD10 p.Arg420Cys.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:32238915 SUPPORT Human Clinical
"we identified aCARD10mutation as the possible cause of a novel form of autosomal recessive genetic disease characterized by primary immunodeficiency accompanied by autoimmune disease"
States both the inheritance pattern and, in the authors' own words, that causation is proposed rather than established.
?

Discussions and Knowledge Gaps

2
Is CARD10 established as the cause of immunodeficiency 89 and autoimmunity, or is it still a single-family candidate?
KNOWLEDGE GAP card10_imd89_evidence_strength
Attached to
The entity rests on one consanguineous family with two affected siblings homozygous for a single missense variant, reported as a short communication whose authors call the variant the possible cause. No independent family has been reported. The gene is biologically plausible - its paralogues CARD9, CARD11 and CARD14 all cause recognised immune disease, and CARD10 is highly expressed in gastrointestinal epithelium - but plausibility is not replication. Independent families, or a ClinGen gene-disease validity assertion, would settle it. The genetic relationship_type is recorded as DISPUTED for this reason.
Show evidence (1 reference)
PMID:32238915 SUPPORT Human Clinical
"we identified aCARD10mutation as the possible cause of a novel form of autosomal recessive genetic disease"
The authors' own hedged causal claim, which is the reason this entry does not assert an established gene-disease relationship.
Why did two siblings with the same homozygous CARD10 genotype differ so much in severity and age at presentation?
OPEN QUESTION card10_intrafamilial_variability
Attached to
The elder brother, who had an unhealthy lifestyle and occupational metal dust exposure, developed immunodeficiency and autoimmune disease substantially earlier than his sister, who had a milder course. The reporting authors attribute the difference to environmental factors. With only two affected individuals described, this is a hypothesis about modifiers rather than a demonstrated gene-environment interaction, but it is the only account currently offered for the variability and it bears directly on how a future carrier should be counselled.
Show evidence (1 reference)
PMID:32238915 SUPPORT Human Clinical
"The elder brother, who lived an unhealthy lifestyle and was exposed to metal dust, suffered immunodeficiency and autoimmune disease much earlier than his sister."
Documents the intrafamilial variability and the environmental exposure the authors propose as its explanation.
⚙

Pathophysiology

6
CARD10 Loss of Function
A homozygous missense variant in the highly conserved coiled-coil domain of CARD10 reduces CARD10 mRNA and protein. The lesion is a destabilising missense rather than a null, which fits the late-onset, slowly progressive course.
Genetic context CARD10 hgnc:16422 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns CARD10 (hgnc:16422). hgnc:16422 is a gene from the HUGO Gene Nomenclature Committee. zygosity: HOMOZYGOUS functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
Show evidence (2 references)
PMID:32238915 SUPPORT Human Clinical
"This variant (R420C) is located in the coiled-coil domain of CARD10, a key and highly conserved domain"
Locates the variant in a conserved functional domain.
PMID:32238915 SUPPORT In Vitro
"Reconstitution studies demonstrated decreased expression ofCARD10mRNA and CARD10 protein in the patient with the R420C mutation"
Provides the functional consequence of the variant at the mRNA and protein level.
Impaired CBM Complex NF-kappaB Signaling
CARD10 is one of four CARD-containing membrane-associated guanylate kinase family scaffolds that form an intracellular complex with BCL10 and MALT1. That complex activates NF-kappaB and other pathways; CARD10 specifically couples the G-protein-coupled receptor and epidermal growth factor receptor signals to it. Reduced CARD10 impairs this coupling.
canonical NF-kappaB signal transduction GO:0007249 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased canonical NF-kappaB signal transduction (GO:0007249). GO:0007249 is a biological process from the Gene Ontology. ↓ DECREASED
Show evidence (3 references)
PMID:32238915 SUPPORT Other
"These proteins function as molecular scaffolds by forming an intracellular complex with B-cell lymphoma protein 10 (BCL10) and mucosa-associated lymphoid tissue lymphoma translocation gene 1 (MALT1), which are critical for the activation of several signaling pathways"
States the CBM scaffolding function that CARD10 loss impairs.
PMID:32238915 SUPPORT Other
"As a ubiquitously expressed protein, CARD10 activates the NF-κB pathway following G-protein-coupled receptor- and epidermal growth factor receptor-induced signaling."
Identifies the specific receptor inputs CARD10 couples to NF-kappaB, which is what distinguishes it from its CARD11 paralogue.
PMID:38863711 SUPPORT INDIRECT Other
"balanced MALT1-TRAF6 recruitment and MALT1 substrate cleavage are critical to maintain immune homeostasis and to promote optimal immune activation."
The conceptual account of why one CBM lesion can produce immunodeficiency and autoimmunity together - the entry's central puzzle. Graded OTHER because it is a review synthesis, and INDIRECT because it concerns CBM signalling in general rather than CARD10 in these patients.
Innate Effector Cell Depletion With Chemokine Dysregulation
Intermediate and non-classical monocytes and monocyte-derived dendritic cells were reduced in the more severely affected sibling, while inflammatory chemokines were raised. Depletion of effector populations alongside inflammatory drive is the cellular correlate of combined immunodeficiency with autoimmunity, rather than of global immune failure.
intermediate monocyte (CD14-high CD16-positive) CL:0002393 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves intermediate monocyte (CD14-high CD16-positive), annotated with intermediate monocyte (CL:0002393). CL:0002393 is a cell type from the Cell Ontology. non-classical monocyte (CD14-positive CD16-high) CL:0002397 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves non-classical monocyte (CD14-positive CD16-high), annotated with CD14-positive, CD16-positive monocyte (CL:0002397). CL:0002397 is a cell type from the Cell Ontology. monocyte-derived HLA-DR+ CD11c+ CD16+ dendritic cell CL:0001057 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves monocyte-derived HLA-DR+ CD11c+ CD16+ dendritic cell, annotated with myeloid dendritic cell, human (CL:0001057). CL:0001057 is a cell type from the Cell Ontology.
Show evidence (3 references)
PMID:32238915 SUPPORT Human Clinical
"flow cytometry analysis showed that the numbers of CD14highCD16+, CD14+CD16high, and monocyte-derived HLADR+CD11c+CD16+cells were all reduced in the patient compared with the respective numbers in the sibling"
Documents the reduced monocyte and dendritic cell populations.
PMID:32238915 SUPPORT Human Clinical
"a cytokine assay showed that IL-8, GROα, MCP-1, MIP-1α, SDF1α, and other chemokine family members were significantly elevated"
Documents the raised chemokines that accompany the cell depletion.
PMID:29773596 SUPPORT INDIRECT In Vitro
"Silencing Card10 in a human cell line and in murine primary cells impaired granulopoiesis, affecting expression of genes involved in myeloid cell development and function."
Independent functional support for a myeloid requirement for CARD10, from outside the single reported family. Marked INDIRECT because it is a silencing experiment in cell lines and murine primary cells rather than an observation in these patients.
Mucosal Barrier Inflammation
CARD10 is highly expressed in gastrointestinal epithelium and the CBM complex participates in TLR4 signalling there, which is the basis for the long-standing hypothesis that CARD10 defects contribute to inflammatory bowel disease. CARD10 expression is lower in Crohn disease patients than in ulcerative colitis patients or controls, and gastrointestinal biopsy in the less severely affected sibling showed early signs of Crohn disease.
Show evidence (2 references)
PMID:32238915 SUPPORT Human Clinical
"Consistently, the pathological examination of the gastrointestinal biopsy sample of the proband’s sister revealed early signs of CD"
Provides the histological correlate of gastrointestinal involvement in an affected individual.
PMID:32238915 SUPPORT INDIRECT Human Clinical
"gene expression was significantly lower in CD patients than in ulcerative colitis patients and healthy controls"
Supports the link between reduced CARD10 and Crohn disease through an expression association in unrelated patients, not through the family reported here - which is why this is marked INDIRECT.
Airway Epithelial CBM Signaling Failure
CARD10 is expressed in airway epithelium, where the CBM complex drives type-2 cytokine production. Its loss is the proposed explanation for the entry's most distinctive clinical dissociation - asthma with low rather than raised blood eosinophils - because the eosinophil recruitment arm fails while airway hyperresponsiveness does not. The account comes from the Card10-deficient mouse airway model rather than from patient airway tissue.
Show evidence (1 reference)
PMID:32238915 SUPPORT INDIRECT Model Organism
"The airway epithelial cells ofCard10-deficient mice also present a decrease in type 2 cytokine levels."
The airway-epithelial mechanism, established in mouse rather than in these patients, which is why this node is curated as proposed and the edge below is INDIRECT.
Loss of Peripheral Tolerance
Imbalanced immune activation with raised autoantibodies, which is the arm that produces the autoimmune rather than the infectious half of the phenotype.
Show evidence (1 reference)
PMID:32238915 SUPPORT Human Clinical
"we observed that immune cells and cytokine production were decreased (TablesS1andS2), while autoimmune antibodies and chemokine levels were increased"
Documents the simultaneous depletion of effector cells and rise in autoantibodies that this node names.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Immunodeficiency 89 and Autoimmunity Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

7
Blood 2
Decreased total eosinophil count HP:0031891 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased total eosinophil count (HP:0031891). HP:0031891 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:32238915 SUPPORT Human Clinical
"while their blood eosinophils were low"
Reports the eosinophil finding in the affected siblings.
PMID:32238915 SUPPORT INDIRECT Model Organism
"airway eosinophils are decreased but airway hyperresponsiveness is not decreased compared with the respective levels in WT mice"
The mouse model shows the same eosinophil dissociation, supporting the human observation through a model system rather than directly.
Microcytic anemia HP:0001935 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microcytic anemia (HP:0001935). HP:0001935 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32238915 SUPPORT Human Clinical
"presenting with unexplained small-cell hypochromic anemia, gastrointestinal discomfort, and seasonal urticaria"
Describes the anaemia in the less severely affected sibling in the source's own terms.
Digestive 1
Crohn disease Crohn's disease HP:0100280 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Crohn disease, annotated with Crohn's disease (HP:0100280). HP:0100280 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32238915 SUPPORT Human Clinical
"The two patients suffered from recurrent infections, asthma, autoimmune anemia, and Crohn’s disease"
Reports Crohn disease in both affected siblings.
Immune 3
Recurrent infections HP:0002719 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent infections (HP:0002719). HP:0002719 is a phenotype from the Human Phenotype Ontology.
Sequelae: Bronchiectasis
Show evidence (1 reference)
PMID:32238915 SUPPORT Human Clinical
"The two patients suffered from recurrent infections, asthma, autoimmune anemia, and Crohn’s disease"
Lists the core clinical features of the two affected siblings.
Asthma HP:0002099 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Asthma (HP:0002099). HP:0002099 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32238915 SUPPORT Human Clinical
"We found that both affected siblings suffered from asthma, while their blood eosinophils were low."
Reports asthma together with the unexpected low eosinophil count.
Autoimmune anemia Autoimmunity HP:0002960 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autoimmunity (HP:0002960). HP:0002960 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32238915 SUPPORT Human Clinical
"The two patients suffered from recurrent infections, asthma, autoimmune anemia, and Crohn’s disease"
Reports autoimmune anaemia in both siblings.
Respiratory 1
Bronchiectasis HP:0002110 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bronchiectasis (HP:0002110). HP:0002110 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32238915 SUPPORT Human Clinical
"High-resolution computed tomography of the proband at the age of 42 revealed bronchiectasis with infection, lung abscess, and pulmonary bulla."
Documents the structural lung damage and the age at which it was found.
🧬

Genetic Associations

1
CARD10
Gene: CARD10 hgnc:16422 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CARD10 (hgnc:16422). hgnc:16422 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: DISPUTED
Show evidence (2 references)
PMID:32238915 SUPPORT Human Clinical
"A novel homozygous missense mutation (c.1258C>T; p.R420C) in exon 7 ofCARD10(Fig.1d), predicted to be a disease-causing variant by means of different prediction methods, was identified."
Identifies the variant this entity rests on. Quoted with the source's own run-together text, which is an artifact of the cached full text.
PMID:32238915 SUPPORT Human Clinical
"However, the consequences ofCARD10mutations in humans have remained elusive."
The report's own statement of how little was known about human CARD10 defects at the time, which bounds the strength of this gene-disease assertion.
Variants (1)
NM_014550.4:c.1258C>T p.(Arg420Cys)
Homozygous missense variant in exon 7, in the conserved coiled-coil domain. Reduces CARD10 mRNA and protein in reconstitution studies. Its mechanistic class - complete loss of function, hypomorphic, or activating - has not been resolved.
🌍

Environmental Factors

1
Occupational metal dust exposure
occupational exposure to metal-containing dust ECTO:7000001 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is occupational exposure to metal-containing dust, annotated with exposure to dust (ECTO:7000001). ECTO:7000001 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
Proposed by the reporting authors as the modifier explaining why the elder sibling presented substantially earlier and more severely than his sister despite an identical genotype. This is a single-family observation offered as an explanation, not an established disease modifier.
Show evidence (1 reference)
PMID:32238915 SUPPORT Human Clinical
"The elder brother, who lived an unhealthy lifestyle and was exposed to metal dust, suffered immunodeficiency and autoimmune disease much earlier than his sister."
The source's statement of the exposure and the severity difference it is proposed to explain.
Mechanism Target:
EXACERBATES Loss of Peripheral Tolerance — Proposed as the modifier that brought the elder sibling's immune dysregulation forward relative to his sister's, on an identical genotype. This is a single-family observation offered as an explanation, not an established modifier, which is why the link is INDIRECT_UNKNOWN_INTERMEDIATES.
Show evidence (1 reference)
PMID:32238915 SUPPORT INDIRECT Human Clinical
"Our findings further imply that environmental factors might play an important role in the diversity of phenotypes."
The authors' own statement that environment modifies the phenotype, hedged as an implication - which is the strength this edge is curated at.
🐁

Animal Models

1
Card10-deficient mouse (airway allergic inflammation model)
Card10-deficient mice in an asthma model, cited by the reporting authors as the account for the eosinophil dissociation seen in the patients.
Species
Mouse
Genotype
Card10 knockout
Publication
{ }

Source YAML

click to show
name: Immunodeficiency 89 and Autoimmunity
creation_date: "2026-09-02T00:00:00Z"
description: >-
  Immunodeficiency 89 and autoimmunity is an autosomal recessive inborn error of
  immunity attributed to biallelic CARD10 variants. CARD10, also called CARMA3, is a
  membrane-associated guanylate kinase family scaffold that assembles the CBM complex
  with BCL10 and MALT1 and couples G-protein-coupled receptor and epidermal growth
  factor receptor signalling to NF-kappaB activation. Its paralogues CARD9, CARD11 and
  CARD14 already account for recognised immunodeficiency and inflammatory syndromes,
  so a CARD10 defect sits inside an established mechanistic family rather than
  standing alone.

  The presentation is the combination that marks immune dysregulation rather than pure
  immunodeficiency: recurrent infection alongside autoimmune and allergic disease.
  The reported siblings had recurrent infections with bronchiectasis, lung abscess and
  pulmonary bulla, asthma, autoimmune anaemia and Crohn disease. Onset was late - both
  presented in their fifth decade - which places this among the mild primary
  immunodeficiencies that surface as adult autoimmunity or allergy rather than as
  childhood infection.

  Two observations sharpen the mechanism. The siblings had asthma with low rather than
  raised blood eosinophils, which matches the Card10-deficient mouse asthma model in
  which airway eosinophils fall while airway hyperresponsiveness does not. And
  intermediate and non-classical monocyte and monocyte-derived dendritic cell
  populations were reduced while inflammatory chemokines were raised - a combination of
  effector-cell depletion with inflammatory drive rather than global immune failure.

  The evidence base is narrow and the entry says so rather than reading as though the
  gene-disease relationship were settled. The entity rests on a single consanguineous
  family with two affected siblings homozygous for one missense variant in the CARD10
  coiled-coil domain, and the authors describe that variant as the possible rather
  than the established cause. The two siblings differed substantially in severity
  despite an identical genotype, which the report attributes to environmental
  modifiers - so even within the one reported family the genotype does not predict the
  phenotype.
category: Mendelian
synonyms:
- IMD89
- CARD10 deficiency
- CARMA3 deficiency
disease_term:
  preferred_term: immunodeficiency 89 and autoimmunity
  term:
    id: MONDO:0030484
    label: immunodeficiency 89 and autoimmunity
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Reported in two siblings of a consanguineous family homozygous for CARD10
    p.Arg420Cys.
  evidence:
  - reference: PMID:32238915
    reference_title: "Mutant CARD10 in a family with progressive immunodeficiency and autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified aCARD10mutation as the possible cause of a novel form of autosomal recessive genetic disease characterized by primary immunodeficiency accompanied by autoimmune disease"
    explanation: States both the inheritance pattern and, in the authors' own words, that causation is proposed rather than established.
pathophysiology:
- name: CARD10 Loss of Function
  biological_scale: MOLECULAR
  description: >-
    A homozygous missense variant in the highly conserved coiled-coil domain of CARD10
    reduces CARD10 mRNA and protein. The lesion is a destabilising missense rather than
    a null, which fits the late-onset, slowly progressive course.
  genetic_context:
    gene:
      preferred_term: CARD10
      term:
        id: hgnc:16422
        label: CARD10
    functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
    zygosity: HOMOZYGOUS
  evidence:
  - reference: PMID:32238915
    reference_title: "Mutant CARD10 in a family with progressive immunodeficiency and autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This variant (R420C) is located in the coiled-coil domain of CARD10, a key and highly conserved domain"
    explanation: Locates the variant in a conserved functional domain.
  - reference: PMID:32238915
    reference_title: "Mutant CARD10 in a family with progressive immunodeficiency and autoimmunity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Reconstitution studies demonstrated decreased expression ofCARD10mRNA and CARD10 protein in the patient with the R420C mutation"
    explanation: Provides the functional consequence of the variant at the mRNA and protein level.
  downstream:
  - target: Impaired CBM Complex NF-kappaB Signaling
    causal_link_type: DIRECT
- name: Impaired CBM Complex NF-kappaB Signaling
  biological_scale: MOLECULAR
  description: >-
    CARD10 is one of four CARD-containing membrane-associated guanylate kinase family
    scaffolds that form an intracellular complex with BCL10 and MALT1. That complex
    activates NF-kappaB and other pathways; CARD10 specifically couples the
    G-protein-coupled receptor and epidermal growth factor receptor signals to it.
    Reduced CARD10 impairs this coupling.
  biological_processes:
  - preferred_term: canonical NF-kappaB signal transduction
    term:
      id: GO:0007249
      label: canonical NF-kappaB signal transduction
    modifier: DECREASED
  evidence:
  - reference: PMID:32238915
    reference_title: "Mutant CARD10 in a family with progressive immunodeficiency and autoimmunity."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "These proteins function as molecular scaffolds by forming an intracellular complex with B-cell lymphoma protein 10 (BCL10) and mucosa-associated lymphoid tissue lymphoma translocation gene 1 (MALT1), which are critical for the activation of several signaling pathways"
    explanation: States the CBM scaffolding function that CARD10 loss impairs.
  - reference: PMID:32238915
    reference_title: "Mutant CARD10 in a family with progressive immunodeficiency and autoimmunity."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "As a ubiquitously expressed protein, CARD10 activates the NF-κB pathway following G-protein-coupled receptor- and epidermal growth factor receptor-induced signaling."
    explanation: Identifies the specific receptor inputs CARD10 couples to NF-kappaB, which is what distinguishes it from its CARD11 paralogue.
  - reference: PMID:38863711
    reference_title: "MALT1 substrate cleavage: what is it good for?"
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "balanced MALT1-TRAF6 recruitment and MALT1 substrate cleavage are critical to maintain immune homeostasis and to promote optimal immune activation."
    explanation: The conceptual account of why one CBM lesion can produce immunodeficiency and autoimmunity together - the entry's central puzzle. Graded OTHER because it is a review synthesis, and INDIRECT because it concerns CBM signalling in general rather than CARD10 in these patients.
  downstream:
  - target: Innate Effector Cell Depletion With Chemokine Dysregulation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Mucosal Barrier Inflammation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Airway Epithelial CBM Signaling Failure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Loss of Peripheral Tolerance
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Innate Effector Cell Depletion With Chemokine Dysregulation
  biological_scale: CELLULAR
  description: >-
    Intermediate and non-classical monocytes and monocyte-derived dendritic cells were
    reduced in the more severely affected sibling, while inflammatory chemokines were
    raised. Depletion of effector populations alongside inflammatory drive is the
    cellular correlate of combined immunodeficiency with autoimmunity, rather than of
    global immune failure.
  cell_types:
  - preferred_term: intermediate monocyte (CD14-high CD16-positive)
    term:
      id: CL:0002393
      label: intermediate monocyte
  - preferred_term: non-classical monocyte (CD14-positive CD16-high)
    term:
      id: CL:0002397
      label: CD14-positive, CD16-positive monocyte
  - preferred_term: monocyte-derived HLA-DR+ CD11c+ CD16+ dendritic cell
    term:
      id: CL:0001057
      label: myeloid dendritic cell, human
  evidence:
  - reference: PMID:32238915
    reference_title: "Mutant CARD10 in a family with progressive immunodeficiency and autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "flow cytometry analysis showed that the numbers of CD14highCD16+, CD14+CD16high, and monocyte-derived HLADR+CD11c+CD16+cells were all reduced in the patient compared with the respective numbers in the sibling"
    explanation: Documents the reduced monocyte and dendritic cell populations.
  - reference: PMID:32238915
    reference_title: "Mutant CARD10 in a family with progressive immunodeficiency and autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a cytokine assay showed that IL-8, GROα, MCP-1, MIP-1α, SDF1α, and other chemokine family members were significantly elevated"
    explanation: Documents the raised chemokines that accompany the cell depletion.
  - reference: PMID:29773596
    reference_title: "CARD10, a CEBPE target involved in granulocytic differentiation."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "Silencing Card10 in a human cell line and in murine primary cells impaired granulopoiesis, affecting expression of genes involved in myeloid cell development and function."
    explanation: Independent functional support for a myeloid requirement for CARD10, from outside the single reported family. Marked INDIRECT because it is a silencing experiment in cell lines and murine primary cells rather than an observation in these patients.
  downstream:
  - target: Recurrent infections
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Mucosal Barrier Inflammation
  biological_scale: TISSUE
  description: >-
    CARD10 is highly expressed in gastrointestinal epithelium and the CBM complex
    participates in TLR4 signalling there, which is the basis for the long-standing
    hypothesis that CARD10 defects contribute to inflammatory bowel disease. CARD10
    expression is lower in Crohn disease patients than in ulcerative colitis patients
    or controls, and gastrointestinal biopsy in the less severely affected sibling
    showed early signs of Crohn disease.
  evidence:
  - reference: PMID:32238915
    reference_title: "Mutant CARD10 in a family with progressive immunodeficiency and autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Consistently, the pathological examination of the gastrointestinal biopsy sample of the proband’s sister revealed early signs of CD"
    explanation: Provides the histological correlate of gastrointestinal involvement in an affected individual.
  - reference: PMID:32238915
    reference_title: "Mutant CARD10 in a family with progressive immunodeficiency and autoimmunity."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "gene expression was significantly lower in CD patients than in ulcerative colitis patients and healthy controls"
    explanation: Supports the link between reduced CARD10 and Crohn disease through an expression association in unrelated patients, not through the family reported here - which is why this is marked INDIRECT.
  downstream:
  - target: Crohn disease
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Airway Epithelial CBM Signaling Failure
  biological_scale: TISSUE
  description: >-
    CARD10 is expressed in airway epithelium, where the CBM complex drives type-2
    cytokine production. Its loss is the proposed explanation for the entry's most
    distinctive clinical dissociation - asthma with low rather than raised blood
    eosinophils - because the eosinophil recruitment arm fails while airway
    hyperresponsiveness does not. The account comes from the Card10-deficient mouse
    airway model rather than from patient airway tissue.
  evidence:
  - reference: PMID:32238915
    reference_title: "Mutant CARD10 in a family with progressive immunodeficiency and autoimmunity."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "The airway epithelial cells ofCard10-deficient mice also present a decrease in type 2 cytokine levels."
    explanation: The airway-epithelial mechanism, established in mouse rather than in these patients, which is why this node is curated as proposed and the edge below is INDIRECT.
  downstream:
  - target: Asthma
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Decreased total eosinophil count
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Loss of Peripheral Tolerance
  biological_scale: ORGANISM
  description: >-
    Imbalanced immune activation with raised autoantibodies, which is the arm that
    produces the autoimmune rather than the infectious half of the phenotype.
  evidence:
  - reference: PMID:32238915
    reference_title: "Mutant CARD10 in a family with progressive immunodeficiency and autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we observed that immune cells and cytokine production were decreased (TablesS1andS2), while autoimmune antibodies and chemokine levels were increased"
    explanation: Documents the simultaneous depletion of effector cells and rise in autoantibodies that this node names.
  downstream:
  - target: Autoimmune anemia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
phenotypes:
- category: Immunologic
  name: Recurrent infections
  description: >-
    Recurrent infection was present in both affected siblings, with bronchiectasis,
    lung abscess and pulmonary bulla on imaging in the proband.
  phenotype_term:
    preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
  sequelae:
  - target: Bronchiectasis
  evidence:
  - reference: PMID:32238915
    reference_title: "Mutant CARD10 in a family with progressive immunodeficiency and autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The two patients suffered from recurrent infections, asthma, autoimmune anemia, and Crohn’s disease"
    explanation: Lists the core clinical features of the two affected siblings.
- category: Respiratory
  name: Bronchiectasis
  description: >-
    Demonstrated on high-resolution computed tomography in the proband at age 42,
    together with lung abscess and pulmonary bulla.
  phenotype_term:
    preferred_term: Bronchiectasis
    term:
      id: HP:0002110
      label: Bronchiectasis
  evidence:
  - reference: PMID:32238915
    reference_title: "Mutant CARD10 in a family with progressive immunodeficiency and autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "High-resolution computed tomography of the proband at the age of 42 revealed bronchiectasis with infection, lung abscess, and pulmonary bulla."
    explanation: Documents the structural lung damage and the age at which it was found.
- category: Respiratory
  name: Asthma
  description: >-
    Both siblings had asthma, but with low rather than raised blood eosinophils - a
    dissociation that matches the Card10-deficient mouse model.
  phenotype_term:
    preferred_term: Asthma
    term:
      id: HP:0002099
      label: Asthma
  evidence:
  - reference: PMID:32238915
    reference_title: "Mutant CARD10 in a family with progressive immunodeficiency and autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We found that both affected siblings suffered from asthma, while their blood eosinophils were low."
    explanation: Reports asthma together with the unexpected low eosinophil count.
- category: Hematologic
  name: Decreased total eosinophil count
  description: >-
    Low blood eosinophils despite asthma. The Card10 knockout mouse asthma model shows
    the same dissociation, with reduced airway eosinophils but preserved airway
    hyperresponsiveness.
  phenotype_term:
    preferred_term: Decreased total eosinophil count
    term:
      id: HP:0031891
      label: Decreased total eosinophil count
  evidence:
  - reference: PMID:32238915
    reference_title: "Mutant CARD10 in a family with progressive immunodeficiency and autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "while their blood eosinophils were low"
    explanation: Reports the eosinophil finding in the affected siblings.
  - reference: PMID:32238915
    reference_title: "Mutant CARD10 in a family with progressive immunodeficiency and autoimmunity."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "airway eosinophils are decreased but airway hyperresponsiveness is not decreased compared with the respective levels in WT mice"
    explanation: The mouse model shows the same eosinophil dissociation, supporting the human observation through a model system rather than directly.
- category: Gastrointestinal
  name: Crohn disease
  description: >-
    Both siblings had Crohn disease; biopsy in the sister showed early changes.
  phenotype_term:
    preferred_term: Crohn disease
    term:
      id: HP:0100280
      label: Crohn's disease
  evidence:
  - reference: PMID:32238915
    reference_title: "Mutant CARD10 in a family with progressive immunodeficiency and autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The two patients suffered from recurrent infections, asthma, autoimmune anemia, and Crohn’s disease"
    explanation: Reports Crohn disease in both affected siblings.
- category: Hematologic
  name: Autoimmune anemia
  description: >-
    Reported in both affected siblings. Not characterised further in the source, so it
    is bound to the generic autoimmunity term rather than to a haemolytic anaemia term
    the report does not support.
  phenotype_term:
    preferred_term: Autoimmunity
    term:
      id: HP:0002960
      label: Autoimmunity
  evidence:
  - reference: PMID:32238915
    reference_title: "Mutant CARD10 in a family with progressive immunodeficiency and autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The two patients suffered from recurrent infections, asthma, autoimmune anemia, and Crohn’s disease"
    explanation: Reports autoimmune anaemia in both siblings.
- category: Hematologic
  name: Microcytic anemia
  description: >-
    Hypochromic microcytic anaemia in the less severely affected sister. This is a
    separate finding from the autoimmune anaemia above - the source does not
    characterise it as autoimmune - and conflating the two would attach the right
    ontology term to the wrong claim.
  phenotype_term:
    preferred_term: Microcytic anemia
    term:
      id: HP:0001935
      label: Microcytic anemia
  evidence:
  - reference: PMID:32238915
    reference_title: "Mutant CARD10 in a family with progressive immunodeficiency and autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "presenting with unexplained small-cell hypochromic anemia, gastrointestinal discomfort, and seasonal urticaria"
    explanation: Describes the anaemia in the less severely affected sibling in the source's own terms.
genetic:
- name: CARD10
  gene_term:
    preferred_term: CARD10
    term:
      id: hgnc:16422
      label: CARD10
  relationship_type: DISPUTED
  notes: >-
    Recorded as DISPUTED rather than CAUSATIVE because the gene-disease relationship
    rests on one consanguineous family and the reporting authors describe the variant
    as the possible cause. CARD10 is at 22q13.1. The variant is c.1258C>T,
    p.Arg420Cys, in exon 7.
  variants:
  - name: NM_014550.4:c.1258C>T p.(Arg420Cys)
    description: >-
      Homozygous missense variant in exon 7, in the conserved coiled-coil domain.
      Reduces CARD10 mRNA and protein in reconstitution studies. Its mechanistic class
      - complete loss of function, hypomorphic, or activating - has not been resolved.
  evidence:
  - reference: PMID:32238915
    reference_title: "Mutant CARD10 in a family with progressive immunodeficiency and autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A novel homozygous missense mutation (c.1258C>T; p.R420C) in exon 7 ofCARD10(Fig.1d), predicted to be a disease-causing variant by means of different prediction methods, was identified."
    explanation: Identifies the variant this entity rests on. Quoted with the source's own run-together text, which is an artifact of the cached full text.
  - reference: PMID:32238915
    reference_title: "Mutant CARD10 in a family with progressive immunodeficiency and autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, the consequences ofCARD10mutations in humans have remained elusive."
    explanation: The report's own statement of how little was known about human CARD10 defects at the time, which bounds the strength of this gene-disease assertion.
discussions:
- discussion_id: card10_imd89_evidence_strength
  kind: KNOWLEDGE_GAP
  attaches_to:
  - disease#
  - genetic#CARD10
  prompt: >-
    Is CARD10 established as the cause of immunodeficiency 89 and autoimmunity, or is
    it still a single-family candidate?
  rationale: >-
    The entity rests on one consanguineous family with two affected siblings
    homozygous for a single missense variant, reported as a short communication whose
    authors call the variant the possible cause. No independent family has been
    reported. The gene is biologically plausible - its paralogues CARD9, CARD11 and
    CARD14 all cause recognised immune disease, and CARD10 is highly expressed in
    gastrointestinal epithelium - but plausibility is not replication. Independent
    families, or a ClinGen gene-disease validity assertion, would settle it. The
    genetic relationship_type is recorded as DISPUTED for this reason.
  evidence:
  - reference: PMID:32238915
    reference_title: "Mutant CARD10 in a family with progressive immunodeficiency and autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified aCARD10mutation as the possible cause of a novel form of autosomal recessive genetic disease"
    explanation: The authors' own hedged causal claim, which is the reason this entry does not assert an established gene-disease relationship.
- discussion_id: card10_intrafamilial_variability
  kind: OPEN_QUESTION
  attaches_to:
  - disease#
  prompt: >-
    Why did two siblings with the same homozygous CARD10 genotype differ so much in
    severity and age at presentation?
  rationale: >-
    The elder brother, who had an unhealthy lifestyle and occupational metal dust
    exposure, developed immunodeficiency and autoimmune disease substantially earlier
    than his sister, who had a milder course. The reporting authors attribute the
    difference to environmental factors. With only two affected individuals described,
    this is a hypothesis about modifiers rather than a demonstrated gene-environment
    interaction, but it is the only account currently offered for the variability and
    it bears directly on how a future carrier should be counselled.
  evidence:
  - reference: PMID:32238915
    reference_title: "Mutant CARD10 in a family with progressive immunodeficiency and autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The elder brother, who lived an unhealthy lifestyle and was exposed to metal dust, suffered immunodeficiency and autoimmune disease much earlier than his sister."
    explanation: Documents the intrafamilial variability and the environmental exposure the authors propose as its explanation.
animal_models:
- name: Card10-deficient mouse (airway allergic inflammation model)
  species: Mouse
  genotype: Card10 knockout
  publication: PMID:32238915
  description: >-
    Card10-deficient mice in an asthma model, cited by the reporting authors as the
    account for the eosinophil dissociation seen in the patients.
  modeled_mechanisms:
  - target: Airway Epithelial CBM Signaling Failure
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces the specific dissociation of reduced airway eosinophils with
      preserved airway hyperresponsiveness, and the fall in epithelial type-2
      cytokines.
    limitations: >-
      The model reproduces the airway eosinophil phenotype but not the human syndrome:
      it does not show the recurrent infection, autoimmune anaemia or Crohn disease
      that define the human entity. It is also a full knockout, whereas the patients
      carry a homozygous missense allele whose mechanistic class is unresolved.
    readouts:
    - name: Airway eosinophil count
      target: Airway Epithelial CBM Signaling Failure
      direction: DECREASED
      interpretation: >-
        The measurement that matches the patients' low blood eosinophils despite
        asthma.
      evidence:
      - reference: PMID:32238915
        reference_title: "Mutant CARD10 in a family with progressive immunodeficiency and autoimmunity."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "airway eosinophils are decreased but airway hyperresponsiveness is not decreased compared with the respective levels in WT mice"
        explanation: The measured direction of the eosinophil readout in the model.
    evidence:
    - reference: PMID:32238915
      reference_title: "Mutant CARD10 in a family with progressive immunodeficiency and autoimmunity."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "This phenomenon is consistent with the features seen inCard10-deficient mice."
      explanation: The reporting authors treat this model as informative for the patients' eosinophil finding.
environmental:
- name: Occupational metal dust exposure
  exposure_term:
    preferred_term: occupational exposure to metal-containing dust
    term:
      id: ECTO:7000001
      label: exposure to dust
  description: >-
    Proposed by the reporting authors as the modifier explaining why the elder sibling
    presented substantially earlier and more severely than his sister despite an
    identical genotype. This is a single-family observation offered as an explanation,
    not an established disease modifier.
  review_notes: >-
    The exposure is recorded because it is the only account the literature offers for
    the striking intrafamilial variability, and dropping it would lose the one
    modifier hypothesis attached to this entity. Bound to ECTO:7000001 (exposure to
    dust) rather than ECTO:9002163 (exposure to heavy metal) because the source says
    "metal dust" without identifying the metal, and the dust term is the one the
    evidence actually supports.
  evidence:
  - reference: PMID:32238915
    reference_title: "Mutant CARD10 in a family with progressive immunodeficiency and autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The elder brother, who lived an unhealthy lifestyle and was exposed to metal dust, suffered immunodeficiency and autoimmune disease much earlier than his sister."
    explanation: The source's statement of the exposure and the severity difference it is proposed to explain.
  influences_mechanisms:
  - target: Loss of Peripheral Tolerance
    environmental_effect: EXACERBATES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Proposed as the modifier that brought the elder sibling's immune dysregulation
      forward relative to his sister's, on an identical genotype. This is a
      single-family observation offered as an explanation, not an established
      modifier, which is why the link is INDIRECT_UNKNOWN_INTERMEDIATES.
    evidence:
    - reference: PMID:32238915
      reference_title: "Mutant CARD10 in a family with progressive immunodeficiency and autoimmunity."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Our findings further imply that environmental factors might play an important role in the diversity of phenotypes."
      explanation: The authors' own statement that environment modifies the phenotype, hedged as an implication - which is the strength this edge is curated at.
references:
- reference: PMID:32238915
  title: "Mutant CARD10 in a family with progressive immunodeficiency and autoimmunity."
📚

References & Deep Research

References

1
Mutant CARD10 in a family with progressive immunodeficiency and autoimmunity.
No top-level findings curated for this source.

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 (1)

Create: Immunodeficiency 89 and Autoimmunity (CARD10) · 2026-09-02T17:42:24Z · View source

Created the entry for IMD89. The stub carried no genes block because MONDO records no causal gene for MONDO:0030484, so the gene had to be established first. My initial working draft inferred IKZF2 (Helios) from a plausible-looking 2021 immunodeficiency paper; that was wrong. MedGen for the MONDO term's OMIM xref (OMIM:619632) describes an autosomal recessive disorder with adult onset of recurrent infections, allergies, microcytic anemia and Crohn disease attributed to Yang et al. 2020, and the MedGen record names CARD10. The falcon deep-research run that had already been launched against the IKZF2 draft was killed before it wrote a report, the entry was rewritten around CARD10, and the research run was relaunched; the committed report mentions CARD10 59 times and IKZF2 zero times. This is a Named Entity Confusion near-miss that the term and reference validators would not have caught, because every identifier involved was real. Primary source is Yang et al. 2020 (PMID:32238915), a short communication on one consanguineous family. No GeneReviews chapter exists for this entity. The gene-disease relationship is recorded as relationship_type DISPUTED rather than CAUSATIVE, and a KNOWLEDGE_GAP discussion records that the entity rests on a single family and that the authors call the variant the possible cause; an OPEN_QUESTION discussion records the marked intrafamilial severity difference and the authors' environmental-modifier explanation, which is also curated as an environmental entry with its own evidence. Two evidence items are marked directness INDIRECT: the Crohn disease expression association, which comes from unrelated patients rather than this family, and the mouse eosinophil dissociation. Validated with just validate (20/20 snippets verified, term validation passed), check-entity-refs, check-causal-targets, check-duplicate-keys, check-enum-values, check-qualifier-terms and check-environmental-evidence.

Falcon ▸
Immunodeficiency 89 and Autoimmunity: Comprehensive Disease-Characteristics Report
Edison Scientific Literature 22 citations 2026-09-02T17:18:41.092180

Immunodeficiency 89 and Autoimmunity: Comprehensive Disease-Characteristics Report

Executive summary and evidence limits

Immunodeficiency 89 and autoimmunity is an exceptionally rare, proposed autosomal-recessive inborn error of immunity associated with biallelic CARD10 variants. Its disease definition rests principally on two adult siblings from one consanguineous family, both homozygous for CARD10 NM-reference-dependent c.1258C>T, p.(Arg420Cys). Consequently, the phenotype, penetrance, prognosis, and causal mechanism remain provisional rather than independently replicated. Open Targets maps the disorder to MONDO:0030484, CARD10, and the disease-defining publication, PMID 32238915. (OpenTargets Search: Immunodeficiency 89 with autoimmunity, yang2020mutantcard10in pages 1-2)

The primary article was received 15 March 2020, accepted 17 March, and published online 1 April 2020: Yang et al., Cellular & Molecular Immunology 17:782–784, DOI 10.1038/s41423-020-0423-x, PMID 32238915. Its appropriately cautious conclusion was: “we identified a CARD10 mutation as the possible cause of a novel form of autosomal recessive genetic disease characterized by primary immunodeficiency accompanied by autoimmune disease.” (yang2020mutantcard10in pages 1-2, yang2020mutantcard10in pages 2-3)

Domain Established observation Evidence type/strength Knowledge-base annotation
Disease identity Immunodeficiency 89 and autoimmunity is a Mendelian inborn error of immunity associated with CARD10. (OpenTargets Search: Immunodeficiency 89 with autoimmunity) Curated disease–gene association; supported by one primary family report MONDO:0030484; disease category: Mendelian immunodeficiency with immune dysregulation
Human evidence Reported in two affected siblings from one consanguineous family; no independently replicated kindred was identified. (yang2020mutantcard10in pages 1-2, yang2020mutantcard10in pages 2-3) Very limited human evidence; single-family case report Case count: 2; family count: 1; inheritance proposed as autosomal recessive
Causal candidate variant Both siblings were homozygous for CARD10 c.1258C>T (p.Arg420Cys; R420C) in exon 7 and the conserved coiled-coil domain. (yang2020mutantcard10in pages 1-2, yang2020mutantcard10in pages 2-3) Segregation plus computational prediction; functional evidence incomplete Gene: CARD10; variant: missense, germline, homozygous; pathogenic mechanism not conclusively classified as loss-of-function, gain-of-function, or hypomorphic
Core phenotype Recurrent infections, asthma with low blood eosinophils, autoimmune anemia, Crohn disease/intestinal inflammation, gastrointestinal discomfort, and seasonal urticaria were reported across the siblings. (yang2020mutantcard10in pages 1-2, yang2020mutantcard10in pages 2-3) Direct clinical observation; frequencies cannot be generalized beyond n=2 Immunodeficiency, autoimmunity, allergy, and gastrointestinal inflammation; variable expressivity
Pulmonary disease At age 42, the more severely affected brother had bronchiectasis with infection, lung abscess, and pulmonary bulla on high-resolution CT. (yang2020mutantcard10in pages 1-2, yang2020mutantcard10in pages 2-3) Direct imaging evidence in one patient Chronic respiratory infection and structural lung damage
Gastrointestinal disease At age 42, the sister’s gastrointestinal biopsy showed local proliferative gastritis and colitis interpreted as early Crohn disease. (yang2020mutantcard10in pages 1-2, yang2020mutantcard10in pages 2-3) Direct histopathology in one patient; disease interpretation by authors Inflammatory bowel involvement; stomach and intestinal mucosa affected
Molecular consequence Patient reconstitution studies showed decreased CARD10 mRNA and protein expression with R420C. (yang2020mutantcard10in pages 1-2) Disease-specific functional observation, but assay scope and rescue evidence were limited Reduced gene-product abundance; precise biochemical mechanism unresolved
Cellular and cytokine findings The more affected sibling had reduced intermediate/nonclassical monocytes and monocyte-derived HLA-DR⁺CD11c⁺CD16⁺ cells; several immune-cell/cytokine measures were decreased, whereas autoantibodies and IL-8, GROα, MCP-1, MIP-1α, and SDF1α were increased. (yang2020mutantcard10in pages 1-2, yang2020mutantcard10in pages 2-3) Direct comparative immunophenotyping within the family; no independent cohort Monocyte/dendritic-cell abnormality, impaired immune output, and concurrent inflammatory/autoimmune signaling
Mechanism CARD10 normally scaffolds the CARD10–BCL10–MALT1 (CBM) complex, connecting receptor signals to IKK/NF-κB and JNK/AP-1 signaling; attributing the patients’ phenotype specifically to reduced CBM/NF-κB activity remains partly inferred. (moud2024malt1substratecleavage pages 1-2, yang2020mutantcard10in pages 1-2, staal2024chimericandmutant pages 1-3) Established pathway biology plus disease-specific expression findings; causal signaling defect not directly demonstrated for R420C Upstream lesion: CARD10 variant; proposed downstream process: defective CBM signaling and immune/epithelial dysregulation
Course and modifiers Disease was described as slowly progressive over approximately 20–30 years. Earlier, more severe disease in the brother was hypothesized to relate to unhealthy lifestyle and metal-dust exposure, but causality was not established. (yang2020mutantcard10in pages 2-3) Longitudinal clinical description; gene–environment interaction is speculative Chronic progressive course; variable expressivity; environmental modification unproven
Epidemiology and prognosis No population prevalence, incidence, penetrance estimate, carrier frequency, survival rate, or life-expectancy data are available. (yang2020mutantcard10in pages 2-3) Evidence absent Ultra-rare designation is reasonable, but no numerical epidemiologic estimate should be assigned
Treatment and trials The defining report supplied no disease-specific treatment outcomes, and no dedicated interventional trial or approved CARD10-targeted therapy was identified. (yang2020mutantcard10in pages 2-3) Evidence absent Management remains phenotype-directed and extrapolated from general immunodeficiency, infection, asthma, autoimmunity, and inflammatory-bowel-disease practice

Table: Compact evidence-grade summary of the genetic, clinical, molecular, and mechanistic findings supporting Immunodeficiency 89 and autoimmunity, with major evidence gaps explicitly identified.

1. Disease information

Definition

The disease is a slowly progressive combination of:

  • susceptibility to recurrent infection;
  • immune dysregulation/autoimmunity, including autoimmune anemia and intestinal inflammation;
  • allergic disease, notably asthma and urticaria; and
  • secondary pulmonary structural damage in the more severely affected individual.

This is best classified as a Mendelian inborn error of immunity with immunodeficiency and immune dysregulation, rather than as isolated antibody deficiency or classic severe combined immunodeficiency. (yang2020mutantcard10in pages 1-2)

Identifiers and synonyms

  • MONDO: MONDO:0030484.
  • Causal-gene association: CARD10, Ensembl ENSG00000100065; approved name caspase recruitment domain family member 10.
  • Primary-literature identifier: PMID 32238915.
  • Synonyms: “CARD10-related immunodeficiency and autoimmunity,” “CARD10 deficiency,” “CARMA3-associated immunodeficiency,” and “progressive immunodeficiency and autoimmunity due to CARD10 mutation.” The latter terms are descriptive and should not automatically be treated as independently curated disease entities.
  • OMIM/Orphanet/MeSH: no disease-specific identifier was established from the retrieved evidence; the database entry should not infer one without direct verification.
  • ICD-10/ICD-11: no dedicated code is documented. Generic coding would require separate codes for immunodeficiency, autoimmune disease, bronchiectasis, asthma, anemia, and Crohn disease.

The evidence is aggregated disease-level literature derived from a single family study, not an EHR-derived cohort or population registry. (OpenTargets Search: Immunodeficiency 89 with autoimmunity, yang2020mutantcard10in pages 1-2)

2. Etiology

Causal factor

The proposed cause is a germline homozygous missense CARD10 variant, c.1258C>T, p.(Arg420Cys), in exon 7. Arg420 lies in a conserved coiled-coil region. Sanger sequencing confirmed the exome result and family segregation. Structural modeling predicted altered hydrogen bonding, alpha-helical hydrophobicity, and stability, while reconstitution experiments showed reduced CARD10 transcript and protein abundance. These findings support impaired function, but the allele has not been conclusively classified as complete loss-of-function, hypomorphic, gain-of-function, or dominant-negative. (yang2020mutantcard10in pages 1-2, yang2020mutantcard10in pages 2-3)

Risk and protective factors

  • Established genetic risk: homozygosity for p.Arg420Cys in the reported family.
  • Consanguinity: facilitated homozygosity and supports recessive inheritance.
  • Possible environmental modifiers: the more severely affected brother had an “unhealthy lifestyle” and metal-dust exposure and developed disease earlier than his sister. This is an uncontrolled within-family observation, not proof of a gene–environment interaction. (yang2020mutantcard10in pages 2-3)
  • Sex, age, family history: one male and one female were affected; this establishes neither a sex effect nor an age-specific risk estimate.
  • Protective factors: none demonstrated. The sister’s healthier lifestyle was associated with milder disease, but cannot be interpreted as protective causally.
  • Modifier genes, susceptibility loci, protective alleles, toxins, diet, smoking, alcohol, or occupational-dose relationships: no disease-specific data.

3. Phenotypes

Because only two people are reported, “2/2” and “1/2” below are case-series observations, not stable population frequencies.

Phenotype Type and observed characteristics Suggested HPO annotation
Recurrent infections Symptom/clinical diagnosis; 2/2; adult, slowly progressive; pathogen spectrum not adequately reported Recurrent infections; increased susceptibility to infection
Asthma with low eosinophils Respiratory/allergic manifestation; 2/2; severity variable Asthma; decreased eosinophil count
Autoimmune anemia Autoimmune hematologic manifestation reported across the affected siblings; sister specifically had unexplained microcytic hypochromic anemia Autoimmune hemolytic anemia only if hemolysis is independently documented; otherwise anemia and microcytic anemia
Crohn disease/colitis Gastrointestinal inflammatory manifestation; sister’s age-42 biopsy showed local proliferative gastritis and colitis interpreted as early Crohn disease Inflammatory bowel disease; colitis; gastritis; abdominal discomfort
Seasonal urticaria Allergic skin manifestation in the sister; episodic and comparatively mild Urticaria
Bronchiectasis CT-confirmed at age 42 in the brother, with active infection Bronchiectasis
Lung abscess CT-confirmed at age 42 in the brother Lung abscess
Pulmonary bulla CT-confirmed at age 42 in the brother Pulmonary bulla/bullous lung disease
Reduced immune-cell subsets Laboratory abnormality: reduced intermediate and nonclassical monocytes and monocyte-derived HLA-DR+CD11c+CD16+ cells in the brother relative to his sister Abnormal monocyte count; abnormal dendritic-cell morphology/number, using the most specific validated HPO term available
Cytokine/chemokine dysregulation IL-8, GROα, MCP-1, MIP-1α and SDF1α elevated; IL-6, TNFα, IFNα, IL-1α, TNFβ, IL-21, IL-22, IL-23 and IL-27 generally normal or reduced Abnormal cytokine level; abnormal chemokine level
Autoantibodies Increased in the more affected sibling Autoantibody positivity

The brother’s age-42 high-resolution CT showed “bronchiectasis with infection, lung abscess, and pulmonary bulla”; the sister’s age-42 gastrointestinal biopsy showed proliferative gastritis and colitis. (yang2020mutantcard10in pages 1-2, yang2020mutantcard10in pages 2-3)

No validated EQ-5D, SF-36, PROMIS, behavioral, neurocognitive, or disease-specific quality-of-life measurements exist. Recurrent infection, chronic airway injury, asthma, anemia, and bowel inflammation would plausibly impair daily function, but the magnitude has not been measured.

4. Genetic and molecular information

  • Gene: CARD10, also called CARMA3; protein: caspase recruitment domain-containing protein 10.
  • Variant: c.1258C>T; p.(Arg420Cys), commonly abbreviated R420C.
  • Origin: constitutional/germline, homozygous in both siblings.
  • Class: missense variant in exon 7 and the coiled-coil domain.
  • Inheritance: proposed autosomal recessive.
  • Functional evidence: reduced CARD10 mRNA and protein in reconstitution studies; altered structure was computationally predicted, not structurally demonstrated. (yang2020mutantcard10in pages 1-2, yang2020mutantcard10in pages 2-3)
  • ACMG/ClinVar status: not established from the retrieved records. “Disease-causing” was the authors’ prediction; it should not be equated automatically with a current expert-panel pathogenic classification.
  • Population allele frequency: not reported in the retrieved evidence.
  • Mechanistic class: likely impaired abundance/function, but unresolved. A 2024 functional study stressed that CARD10’s high basal activity in overexpression systems complicates variant interpretation, and stated that human CARD10 mutations had been associated with several phenotypes without establishing whether they are activating or inactivating. (staal2024chimericandmutant pages 1-3, staal2024chimericandmutant pages 39-39)
  • Modifier genes/epigenetics: none identified.
  • Chromosomal abnormalities: none reported; this is a sequence-level disorder.
  • Somatic variation: not implicated in this disease.

5. Environmental information

No environmental exposure is established as necessary or sufficient. Metal-dust exposure and unhealthy lifestyle coincided with earlier, more severe illness in the brother; the authors proposed environmental modification, but there was no exposure quantification, control group, toxicology, or mechanistic assay. (yang2020mutantcard10in pages 2-3)

Infectious organisms were not specified. Infections are therefore interpreted as consequences/triggers acting on an inherited susceptibility, not the primary etiology. No evidence addresses smoking, alcohol, diet, exercise, pollution, radiation, microbiome composition, or specific occupational chemicals.

6. Mechanism and pathophysiology

Ordered causal chain

  1. Homozygous CARD10 p.Arg420Cys leads to reduced CARD10 mRNA and protein in the reported reconstitution experiments; the exact reason for reduced abundance is unknown. (yang2020mutantcard10in pages 1-2)
  2. Reduced or altered CARD10 is inferred to impair assembly or tuning of the CARD10–BCL10–MALT1 signalosome downstream of GPCRs, receptor tyrosine kinases, and epithelial TLR4-related signals; this was not directly demonstrated in patient cells. (moud2024malt1substratecleavage pages 1-2, yang2020mutantcard10in pages 1-2)
  3. Altered CBM signaling is inferred to dysregulate IKK/NF-κB and JNK/AP-1 signaling, with possible effects on mTOR-linked immune activation, inflammatory transcription, cell survival, and differentiation. CARD10-specific pathway impairment by R420C remains unproven. (moud2024malt1substratecleavage pages 1-2, staal2024chimericandmutant pages 1-3)
  4. Immune/hematopoietic branch: altered signaling and CARD10-dependent myeloid differentiation plausibly lead to reduced intermediate/nonclassical monocytes, abnormal monocyte-derived dendritic-cell populations, and reduced immune-cell/cytokine output, resulting in recurrent infection. Human-cell and mouse knockdown evidence supports a role for CARD10 in granulopoiesis, but direct causation in these patients is incomplete. (yang2020mutantcard10in pages 1-2, shyamsunder2018card10acebpe pages 1-7)
  5. Epithelial/allergic branch: abnormal airway-epithelial CBM signaling leads, by inference from Card10-null mice, to reduced type-2 cytokines and eosinophils without necessarily eliminating airway hyperresponsiveness, producing asthma with unexpectedly low eosinophils. (yang2020mutantcard10in pages 1-2, yang2020mutantcard10in pages 2-3)
  6. Gastrointestinal branch: CARD10 dysfunction in gastrointestinal epithelial signaling is inferred to disturb mucosal inflammatory homeostasis, resulting in gastritis, colitis, and Crohn-like disease. (yang2020mutantcard10in pages 1-2)
  7. Immune-regulatory branch: imbalanced immune activation leads to increased autoantibodies and selected chemokines while other cytokines remain normal or low, resulting in anemia, urticaria, and autoimmune/inflammatory manifestations despite immunodeficiency. (yang2020mutantcard10in pages 1-2, yang2020mutantcard10in pages 2-3)
  8. Chronic recurrent pulmonary infection leads to structural tissue injury, including bronchiectasis, abscess, and bullous change. This final clinical link is strongly plausible but was not longitudinally imaged. (yang2020mutantcard10in pages 1-2)

Current mechanistic understanding

CARD10 is a scaffold with CARD, coiled-coil, PDZ, SH3, and guanylate-kinase-like regions. It nucleates BCL10–MALT1 filaments. MALT1 then serves as both a TRAF6-recruiting scaffold driving IKK/NF-κB and JNK/AP-1 and a paracaspase whose substrate cleavage regulates immune homeostasis. A 2024 authoritative review emphasized that complete MALT1 loss causes immunodeficiency whereas selective disruption of scaffolding or protease activity can provoke autoimmune inflammation—an important conceptual explanation for concurrent immunodeficiency and autoimmunity, although not direct proof for CARD10 R420C. (moud2024malt1substratecleavage pages 1-2)

Suggested GO biological processes: NF-κB signaling; IκB kinase/NF-κB signaling; JNK cascade; immune-response activating signaling; inflammatory response; cytokine production; chemokine production; granulocyte differentiation; monocyte differentiation; dendritic-cell differentiation; response to bacterium; epithelial-cell homeostasis.

Suggested Cell Ontology terms: classical/intermediate/nonclassical monocyte; conventional dendritic cell; CD4-positive T cell; airway epithelial cell; intestinal epithelial cell; keratinocyte; granulocyte/neutrophil/eosinophil.

Subcellular annotations: cytoplasm; plasma-membrane-associated signaling complex; CARD10–BCL10–MALT1 complex; BCL10 filament; IKK complex. No disease-specific metabolomic, lipidomic, spatial-transcriptomic, single-cell, proteomic, CRISPR-screen, or integrated multi-omic dataset exists.

7. Anatomical structures affected

  • Primary clinically involved systems: immune/hematopoietic system, respiratory tract and lungs, gastrointestinal mucosa, and skin/allergic system.
  • Lung: bronchi and pulmonary parenchyma; bronchiectasis, infection, abscess, and bulla.
  • Gastrointestinal tract: gastric and intestinal mucosa; proliferative gastritis and colitis.
  • Blood/immune compartment: circulating monocytes, monocyte-derived dendritic cells, cytokines, chemokines, autoantibodies, and erythroid phenotype/anemia.
  • Skin: urticaria; no CARD10-specific ectodermal dysplasia was reported.

Suggested UBERON mappings include lung, bronchus, airway epithelium, stomach, gastric mucosa, intestine, intestinal mucosa, blood, bone marrow, and skin. Suggested GO cellular components include cytosol, plasma membrane, CARD10–BCL10–MALT1 complex, and IKK complex. No lateralization is relevant. (yang2020mutantcard10in pages 1-2, yang2020mutantcard10in pages 2-3)

8. Temporal development

The precise age at first symptom was not supplied. The brother developed immunodeficiency and autoimmunity substantially earlier than his sister. Both were evaluated at age 42 for key imaging/biopsy findings. The authors characterized CARD10-related disease as slowly progressive over approximately 20–30 years, with variable severity and intermittent allergic/autoimmune manifestations superimposed on chronic infection susceptibility. (yang2020mutantcard10in pages 2-3)

No formal stages, remission rates, treatment-induced remission data, critical intervention window, or pediatric natural-history observations are available. The observed bronchiectasis argues for early recognition and infection control before irreversible airway damage, but this is clinical extrapolation rather than a CARD10-specific outcome study.

9. Inheritance and population

  • Inheritance: autosomal recessive, supported by consanguinity and homozygosity in two siblings.
  • Penetrance: unknown. Both known homozygous siblings were affected, but n=2 cannot establish complete penetrance.
  • Expressivity: clearly variable within the family.
  • Sex ratio: one male and one female; no sex bias can be estimated.
  • Prevalence/incidence: unknown. Only two affected individuals from one family formed the disease-defining report.
  • Carrier frequency/founder effect/geographic distribution: unknown.
  • Consanguinity: present in the reported family.
  • Anticipation: not reported and biologically unsupported.
  • Germline mosaicism: not reported.
  • Ethnicity and population-specific enrichment: insufficiently documented for inference.

The disorder should be labeled ultra-rare with no numerical prevalence estimate, rather than assigning a cases-per-100,000 value. (yang2020mutantcard10in pages 1-2, yang2020mutantcard10in pages 2-3)

10. Diagnostics

Proposed diagnostic approach

There are no standardized criteria. A reasonable evidence-aligned workflow is:

  1. Recognize the combination of recurrent infection plus autoimmune/inflammatory or allergic disease, particularly asthma with low eosinophils, Crohn-like inflammation, anemia, urticaria, or unexplained bronchiectasis.
  2. Perform complete blood count with differential, blood film and anemia/hemolysis studies; immunoglobulins; vaccine-antibody responses; lymphocyte subsets; monocyte subsets; dendritic-cell phenotyping; autoantibodies; inflammatory markers; and microbiologic evaluation during infection.
  3. Assess complications using high-resolution chest CT where bronchiectasis is suspected and endoscopy with biopsy for persistent gastrointestinal symptoms.
  4. Use an inborn-error-of-immunity gene panel containing CARD10, or preferably trio/family WES/WGS where the phenotype is atypical. Confirm candidate variants by Sanger sequencing and segregation.
  5. Interpret CARD10 variants cautiously with population frequency, conservation, domain location, RNA/protein expression, and ideally patient-cell CBM/NF-κB functional assays. Exome plus Sanger segregation was the successful discovery method in the reported family. (yang2020mutantcard10in pages 1-2, yang2020mutantcard10in pages 2-3)

CMA, karyotype, FISH, mitochondrial testing, and repeat-expansion testing are not first-line for this single-gene phenotype unless another diagnosis is suspected. RNA sequencing could assess transcript abundance or splicing, but is not validated diagnostically. No biomarker has established sensitivity or specificity.

Differential diagnosis

Important differentials include other CBM/NF-κB pathway disorders—CARD11, BCL10, MALT1, CARD9 and CARD14 defects—as well as common variable immunodeficiency, activated PI3K-delta syndrome, CTLA4/LRBA deficiency, STAT3 gain-of-function, NFKB1/NFKB2 deficiency, chronic granulomatous disease, DOCK8 deficiency, autoimmune lymphoproliferative syndromes, monogenic inflammatory bowel disease, cystic fibrosis, primary ciliary dyskinesia, and secondary immunodeficiency. CARD10’s broad nonhematopoietic expression and the combined airway, bowel, myeloid, allergic, and autoimmune phenotype may be distinguishing, but no validated discriminant criteria exist. Recent work also cautions that CARD10 overexpression assays have high basal NF-κB activity and may misclassify variants. (staal2024chimericandmutant pages 1-3, staal2023chimericandmutant pages 11-13)

No newborn, population, or carrier-screening program exists. Once a familial variant is securely classified, targeted cascade, prenatal, or preimplantation testing can be considered with genetic counseling.

11. Outcome and prognosis

There are no survival curves, mortality rates, life-expectancy estimates, or validated prognostic biomarkers. The reported course was chronic and slowly progressive over decades. Documented morbidity included recurrent infection, chronic airway damage, lung abscess, asthma, bowel inflammation, anemia, and allergic disease. (yang2020mutantcard10in pages 2-3)

Potential adverse prognostic factors—based on the two-person report—include earlier onset, greater immune-cell/cytokine impairment, repeated respiratory infection, bronchiectasis, and possibly harmful inhalational exposure. These are hypotheses, not validated predictors. Recovery potential and reversibility are unknown; bronchiectasis is generally irreversible, while infection, asthma, anemia, and bowel inflammation may be controllable with phenotype-directed therapy.

12. Treatment

No CARD10-specific treatment, response rate, adverse-event series, pharmacogenomic recommendation, gene therapy, RNA therapy, or hematopoietic stem-cell transplantation outcome has been reported. No dedicated interventional trial was identified. The primary report did not provide treatment outcomes. (yang2020mutantcard10in pages 2-3)

Management should therefore be individualized in an expert immunology center and may include, by extrapolation:

  • prompt culture-guided antimicrobial treatment and consideration of prophylaxis when infection burden warrants it;
  • immunoglobulin replacement only if quantitative or functional antibody deficiency is demonstrated;
  • airway clearance, vaccination planning, pulmonary surveillance, and standard bronchiectasis care;
  • guideline-based asthma treatment, recognizing that eosinophil-low disease may not respond like eosinophilic asthma;
  • hematology-directed evaluation and treatment of autoimmune anemia;
  • gastroenterology-directed treatment of Crohn-like inflammation, balancing immunosuppression against infection risk;
  • antihistamines or other standard therapy for urticaria;
  • avoidance of unnecessary broad immunosuppression and multidisciplinary monitoring.

Suggested NCIt intervention annotations include antimicrobial therapy, antimicrobial prophylaxis, immunoglobulin replacement therapy, corticosteroid therapy, bronchodilator therapy, airway-clearance therapy, immunosuppressive therapy, biologic therapy, hematopoietic stem-cell transplantation, genetic counseling, and supportive care. These are ontology mappings, not evidence of CARD10-specific efficacy.

Direct inhibition of CARD10, MALT1, or NF-κB is not rationally established for a variant already associated with reduced CARD10 abundance. Although MALT1 inhibitors are being developed for malignancy and inflammatory indications, pathway inhibition could worsen immunodeficiency. The 2024 MALT1 review underscores that balanced—not simply reduced—CBM signaling is required for immune homeostasis. (moud2024malt1substratecleavage pages 1-2)

13. Prevention

  • Primary prevention: no method prevents the phenotype in a person with a pathogenic biallelic genotype. Genetic counseling, carrier testing after familial-variant confirmation, prenatal diagnosis, and preimplantation genetic testing can reduce recurrence risk.
  • Secondary prevention: cascade testing of relatives, early immunologic evaluation, infection surveillance, and early chest assessment may identify disease before advanced bronchiectasis.
  • Tertiary prevention: vaccination after immunology review, antimicrobial prophylaxis where indicated, airway clearance, avoidance of tobacco and harmful dust exposure, and prompt treatment of infection may reduce complications. Avoid live vaccines when clinically significant cellular immunodeficiency has not been excluded.
  • Behavioral/environmental: reducing metal-dust and respiratory irritant exposure is prudent, but CARD10-specific benefit has not been demonstrated.

No public-health screening program or disease-specific prophylaxis guideline exists.

14. Other species and natural disease

No naturally occurring veterinary CARD10 disease equivalent was identified, and there is no evidence of zoonotic transmission. The genetic and signaling mechanism is conserved across vertebrates, but “natural disease” should be recorded as not established.

Relevant experimental taxa include human (Homo sapiens, NCBI Taxon 9606) and laboratory mouse (Mus musculus, NCBI Taxon 10090). Ortholog-specific NCBI Gene identifiers should be imported directly from NCBI rather than inferred from this literature set.

15. Model organisms and experimental systems

Mouse models

Card10-null mice provide partial mechanistic support. In an asthma model, airway eosinophils and type-2 cytokines were reduced, but airway hyperresponsiveness was not correspondingly reduced. Card10-deficient airway epithelial cells had impaired dendritic-cell maturation/antigen-presentation effects. These observations resemble the patients’ asthma with low eosinophils, but do not reproduce the complete human syndrome. (yang2020mutantcard10in pages 1-2, yang2020mutantcard10in pages 2-3)

More recent CARD-CC work reports neurodevelopmental phenotypes in Card10-deficient mice, shared with Bcl10 deficiency, yet comparable neurological abnormalities were not reported in the two human cases. This highlights incomplete cross-species phenotypic concordance. (staal2024chimericandmutant pages 1-3)

Cellular models

  • CARD10 silencing in a human cell line and murine primary progenitors impaired granulocytic differentiation and altered genes involved in myeloid development and function. This supports a possible basis for the human myeloid abnormalities. The primary study’s abstract states: “Silencing Card10 in a human cell line and in murine primary cells impaired granulopoiesis.” Shyamsunder et al., published online 17 May 2018, DOI 10.3324/haematol.2018.190280. (shyamsunder2018card10acebpe pages 1-7)
  • HEK293T NF-κB reporter systems and engineered CARD9–CARD10 chimeras have been used to test CARD10 autoinhibition and variants. Their limitation is high spontaneous activity from overexpressed native CARD10; effects at endogenous expression remain uncertain. Staal et al., 2024, DOI 10.1111/febs.17035. (staal2024chimericandmutant pages 1-3, staal2023chimericandmutant pages 11-13, staal2024chimericandmutant pages 39-39)
  • No patient-derived iPSC, organoid, knock-in p.Arg420Cys mouse, zebrafish, Drosophila, or CRISPR-corrected rescue model was identified.

Recent developments and expert assessment, 2023–2024

The most important recent development is not discovery of additional patients but improved understanding of CARD-CC/CBM signaling and its experimental limitations. The 2024 FEBS study established chimeric systems for testing CARD10 autoinhibition and natural variants, while emphasizing that disease-associated CARD10 variants often remain mechanistically unresolved. It did not independently validate p.Arg420Cys. (staal2024chimericandmutant pages 1-3, staal2024chimericandmutant pages 39-39)

The 28 May 2024 MALT1 review described CBM signalosomes as receptor-to-NF-κB/JNK signaling hubs and emphasized that both inadequate and qualitatively imbalanced MALT1 activity can produce immune pathology. Its abstract states that “balanced MALT1-TRAF6 recruitment and MALT1 substrate cleavage are critical to maintain immune homeostasis and to promote optimal immune activation.” DOI 10.3389/fimmu.2024.1412347. (moud2024malt1substratecleavage pages 1-2)

A 17 January 2023 review of NF-κB-associated inborn errors emphasized that NF-κB acts in both immune and epithelial compartments and regulates epithelial differentiation, survival, and inflammatory amplification. This provides authoritative context for a CARD10 disorder involving immunity, airway disease, bowel inflammation, and skin allergy, but is not independent case evidence. DOI 10.3389/fped.2022.1098426. (shen2023skinmanifestationsof pages 1-2)

Overall evidence-grade conclusion

The association of homozygous CARD10 p.Arg420Cys with immunodeficiency and autoimmunity is biologically plausible and supported by segregation, reduced CARD10 expression, patient immunophenotyping, and relevant model evidence, but remains based on one family. The disease should be represented in a knowledge base with high confidence for the reported phenotype and genotype, but only limited-to-moderate confidence for definitive gene–disease validity and molecular mechanism until unrelated cases, population-frequency analysis, endogenous signaling assays, and variant-specific rescue or knock-in studies become available. (yang2020mutantcard10in pages 1-2, yang2020mutantcard10in pages 2-3, staal2024chimericandmutant pages 1-3)

References

  1. (OpenTargets Search: Immunodeficiency 89 with autoimmunity): Open Targets Query (Immunodeficiency 89 with autoimmunity, 11 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

  2. (yang2020mutantcard10in pages 1-2): Dan-hui Yang, Ting Guo, Zhuang-zhuang Yuan, Cheng Lei, Shui-zi Ding, Yi-feng Yang, Zhi-ping Tan, and Hong Luo. Mutant card10 in a family with progressive immunodeficiency and autoimmunity. Cellular & Molecular Immunology, 17:782-784, Apr 2020. URL: https://doi.org/10.1038/s41423-020-0423-x, doi:10.1038/s41423-020-0423-x. This article has 9 citations and is from a peer-reviewed journal.

  3. (yang2020mutantcard10in pages 2-3): Dan-hui Yang, Ting Guo, Zhuang-zhuang Yuan, Cheng Lei, Shui-zi Ding, Yi-feng Yang, Zhi-ping Tan, and Hong Luo. Mutant card10 in a family with progressive immunodeficiency and autoimmunity. Cellular & Molecular Immunology, 17:782-784, Apr 2020. URL: https://doi.org/10.1038/s41423-020-0423-x, doi:10.1038/s41423-020-0423-x. This article has 9 citations and is from a peer-reviewed journal.

  4. (moud2024malt1substratecleavage pages 1-2): Bahareh Nemati Moud, Franziska Ober, Thomas J. O’Neill, and Daniel Krappmann. Malt1 substrate cleavage: what is it good for? Frontiers in Immunology, May 2024. URL: https://doi.org/10.3389/fimmu.2024.1412347, doi:10.3389/fimmu.2024.1412347. This article has 21 citations and is from a peer-reviewed journal.

  5. (staal2024chimericandmutant pages 1-3): Jens Staal, Yasmine Driege, Femke Van Gaever, Jill Steels, and Rudi Beyaert. Chimeric and mutant card9 constructs enable analyses of conserved and diverged autoinhibition mechanisms in the card‐cc protein family. Dec 2024. URL: https://doi.org/10.1111/febs.17035, doi:10.1111/febs.17035. This article has 4 citations.

  6. (staal2024chimericandmutant pages 39-39): Jens Staal, Yasmine Driege, Femke Van Gaever, Jill Steels, and Rudi Beyaert. Chimeric and mutant card9 constructs enable analyses of conserved and diverged autoinhibition mechanisms in the card‐cc protein family. Dec 2024. URL: https://doi.org/10.1111/febs.17035, doi:10.1111/febs.17035. This article has 4 citations.

  7. (shyamsunder2018card10acebpe pages 1-7): Pavithra Shyamsunder, Haresh Sankar, Anand Mayakonda, Lin Han, Hazimah Binte Mohd Nordin, Teoh Weoi Woon, Mahalakshmi Shanmugasundaram, Pushkar Dakle, Vikas Madan, and H. Phillip Koeffler. Card10, a cebpe target involved in granulocytic differentiation. Haematologica, 103:1269-1277, May 2018. URL: https://doi.org/10.3324/haematol.2018.190280, doi:10.3324/haematol.2018.190280. This article has 13 citations.

  8. (staal2023chimericandmutant pages 11-13): Jens Staal, Yasmine Driege, Femke Van Gaever, Jill Steels, and Rudi Beyaert. Chimeric and mutant card9 constructs enable analyses of conserved and diverged autoinhibition mechanisms in the card-cc protein family. Mar 2023. URL: https://doi.org/10.1101/2023.03.06.531260, doi:10.1101/2023.03.06.531260. This article has 0 citations.

  9. (shen2023skinmanifestationsof pages 1-2): Yitong Shen, Anne P. R. Boulton, Robert L. Yellon, and Matthew C. Cook. Skin manifestations of inborn errors of nf-κb. Frontiers in Pediatrics, Jan 2023. URL: https://doi.org/10.3389/fped.2022.1098426, doi:10.3389/fped.2022.1098426. This article has 24 citations.

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