Immunodeficiency 37

Mendelian MONDO:0014491 Pathograph 12 Show in embeddings browser Combined immunodeficiency Inborn error of immunity

Immunodeficiency 37 is the autosomal recessive combined immunodeficiency caused by biallelic loss of BCL10, the scaffold subunit of the CARD-BCL10-MALT1 (CBM) signalosome. The CBM complex is the module that couples an engaged antigen receptor to NF-kappaB, and BCL10 is the component every cell-type-specific version of it shares: CARD11 in lymphocytes, CARD9 in myeloid cells, CARD10 in epithelium, CARD14 in keratinocytes all nucleate the same BCL10-MALT1 filament. Losing BCL10 therefore ought to disable more than losing any one CARD adaptor, and the patients show a specific version of that prediction. Two features distinguish this entry from its CBM siblings. First, the lymphocyte defect is a maturation block rather than a numbers defect: total T and B cell counts are normal, and what is missing is the memory compartment, together with hypogammaglobulinemia. A quantitative immune workup therefore reads as reassuring, and one patient passed newborn SCID screening before dying of disseminated adenovirus and Pneumocystis. Second, the deficiency reaches beyond the haematopoietic system: patient fibroblasts fail to signal through TLR4, TLR2/6 and Dectin-1, while the same receptors on the patient's own monocyte-derived macrophages and dendritic cells respond normally. BCL10 is thus non-redundant in fibroblasts and redundant in myeloid cells, which is the opposite of the arrangement CARD9 deficiency would predict and is the reason the founding report is titled around "nonhematopoietic immunity". The published experience is a handful of patients from consanguineous families, all with loss-of-function alleles in the CARD domain, and haematopoietic stem cell transplantation is the only curative option.

Ask OpenScientist

Ask a research question about Immunodeficiency 37. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

1
Inheritance
8
Pathophys.
16
Phenotypes
3
Gaps
12
Pathograph
1
Genes
3
Medical Actions
2
Differentials
1
Models
3
References
1
Deep Research
🏷

Classifications

Harrison's Part
GENETICS ENVIRONMENT DISEASE
👪

Inheritance

1
Autosomal recessive HP:0000007
Every reported allele is homozygous and every reported family consanguineous. Heterozygous carriers have been examined directly rather than assumed healthy: parental T cell proliferation and the lymphocyte subset frequencies of five carriers were normal, so BCL10 shows no haploinsufficiency.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:38129623 SUPPORT Human Clinical
"BCL10 deficiency is an autosomal recessive trait with heterozygous carriers not showing clinical or immunological manifestations."
States the inheritance mode and, specifically, that carriers are unaffected on clinical and immunological examination.
?

Discussions and Knowledge Gaps

3
Does the fibroblast signalling defect contribute independently to the clinical phenotype, or is the disease fully explained by the lymphocyte defect?
KNOWLEDGE GAP imd37_fibroblast_defect_independent_contribution
Attached to
pathophysiology#Impaired Fibroblast Innate Receptor Signalling
The fibroblast finding is what the founding paper is named for, and it is reproducible across patients. What is missing is any observation that separates its contribution from the lymphocyte defect. Transplantation replaces only the haematopoietic compartment, so a fibroblast-attributable residual phenotype in successfully transplanted patients would be the natural readout, but the transplanted series is too small and too short for anyone to have looked. Until then the fibroblast-to-infection edge in this entry is INDIRECT on purpose.
Are the reduced NK and gamma-delta T cell frequencies a general feature of BCL10 deficiency, or a finding in one patient?
KNOWLEDGE GAP imd37_minor_lymphocyte_subsets_single_patient
Attached to
pathophysiology#Failure of Memory B and T Cell Generation
The mass-cytometry study that reported reduced NK, gamma-delta T, regulatory T and follicular helper T cells is the only one to have measured NK and gamma-delta T subsets, so those two remain single-patient observations and are recorded here without a frequency. The regulatory T cell half of that finding is no longer in this position, and this entry no longer treats it as such. The 2026 report measured Tregs independently by conventional flow cytometry with intracellular FOXP3, Helios and CTLA-4 staining, found them markedly reduced, and describes reduced or absent Tregs as typical across the reported series. So conventional flow cytometry does resolve them and the deficit is corroborated. Follicular helper T cells sit between the two: the same report places Tfh and Tfr at the low end of the age-matched normal range, which is weaker corroboration than the Treg finding and not enough to support a frequency.
Why does Bcl10 loss cause a neural tube closure defect in mouse but not, apparently, in humans?
HUMAN MODEL MISMATCH imd37_mouse_neural_tube_defect_absent_in_humans
Attached to
animal_models#Bcl10-null mouse pathophysiology#CBM Signalosome Assembly Failure
A third of Bcl10-null mouse embryos develop exencephaly and die of it. Nothing like that has been described in any reported human patient, all of whom had complete or near-complete deficiency and survived to present with infection. Three explanations are open and nothing distinguishes them: BCL10 may simply have no non-redundant role in human neural tube closure; the human alleles may retain enough residual function for closure while failing for lymphocyte activation; or human embryos with the same defect may be lost before ascertainment, since every reported family came to attention through a surviving affected child. The third possibility matters for counselling and is unaddressed. It also bears on the fibroblast finding: a developmental role for BCL10 outside the haematopoietic system would fit the non-haematopoietic defect this entry records.
Show evidence (1 reference)
PMID:11163238 SUPPORT Model Organism
"We show that one-third of bcl10-/- embryos developed exencephaly, leading to embryonic lethality."
The mouse finding whose human counterpart is absent, with its penetrance, which is what makes the ascertainment explanation worth stating.
⚙

Pathophysiology

8
Biallelic BCL10 Loss of Function
Homozygous loss-of-function alleles in the BCL10 CARD domain remove or destabilize the protein. Four of the five alleles whose protein consequence was measured gave absent or greatly reduced BCL10.
Genetic context BCL10 hgnc:989 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns BCL10 (hgnc:989). hgnc:989 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION
Every reported disease allele is homozygous and germline. Recorded as LOSS_OF_FUNCTION rather than a finer category because the measured consequence is absent or greatly reduced protein rather than an altered activity: the splice-site and nonsense alleles abolish expression outright, and the one missense allele whose expression was measured was greatly reduced.
Downstream
CBM Signalosome Assembly Failure With BCL10 absent, the CARD adaptor has nothing to nucleate and MALT1 has nothing to bind, so the complex cannot form.
Show evidence (1 reference)
PMID:38129623 SUPPORT Human Clinical
"All disease-causing BCL10 mutations described to date are homozygous, loss-of-function with a complete or significantly reduced protein expression (Table 1)."
Establishes the molecular lesion as loss of the protein rather than as an altered or gain-of-function product.
CBM Signalosome Assembly Failure
The CBM complex is the shared module downstream of antigen receptors and several innate receptors, with a cell-type-specific CARD subunit (CARD11 in lymphocytes, CARD9 in myeloid cells, CARD10 in epithelium, CARD14 in keratinocytes) built on a constant BCL10-MALT1 core. BCL10 is therefore the single point every version of the complex passes through.
CBM signalosome assembly GO:0065003 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased CBM signalosome assembly, annotated with protein-containing complex assembly (GO:0065003). GO:0065003 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Defective Antigen Receptor-Induced NF-kappaB Activation NF-kappaB induction downstream of the T and B cell receptors requires an intact CBM complex, so assembly failure is read out as loss of receptor-triggered NF-kappaB signalling.
Impaired Fibroblast Innate Receptor Signalling The same complex operates outside the haematopoietic system. In fibroblasts, TLR4, TLR2/6 and Dectin-1 signalling is BCL10-dependent.
Show evidence (3 references)
PMID:38129623 SUPPORT Other
"Caspase recruitment domain (CARD), B-cell lymphoma 10 (BCL10), and mucosa-associated lymphoid tissue lymphoma-translocation gene 1 (MALT1) proteins form the cytosolic CBM (CARD-BCL10-MALT1) complex."
Defines the complex whose assembly fails. Graded OTHER because the sentence is background architecture stated in a review, not a patient observation.
PMID:24074955 SUPPORT In Vitro
"Here we show that the reconstituted CBM signalosome is a helical filamentous assembly in which substoichiometric CARMA1 nucleates Bcl10 filaments."
Gives the structural reason the CARD domain is where every disease allele falls: BCL10 is not a stoichiometric partner but the polymerising scaffold, and the CARD is the filament interface.
PMID:24074955 SUPPORT In Vitro
"Structure-guided mutagenesis confirmed the observed interfaces in Bcl10 filament assembly and MALT1 activation in vitro and NF-κB activation in cells."
Shows that disrupting the filament interfaces is sufficient to abolish downstream NF-kappaB activation, which is the experimental counterpart of the human CARD alleles.
Defective Antigen Receptor-Induced NF-kappaB Activation
Loss of CBM-dependent signalling downstream of the T and B cell receptors. The defect is stimulus dependent rather than global: TNF-alpha and LPS still induce p65 phosphorylation, because those routes to NF-kappaB do not run through the CBM complex.
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 decreased canonical NF-kappaB signal transduction (GO:0007249). GO:0007249 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Arrested Lymphocyte Activation and Proliferation Antigen-receptor NF-kappaB signalling is what licenses the activated lymphocyte to proliferate, so the proliferation block follows the signalling block.
Show evidence (2 references)
PMID:42473108 SUPPORT Human Clinical
"NF-κB signaling was stimulus dependent, with near-absent p-p65 induction in T cells after PMA/ionomycin but relative preservation or enhancement after TNF-α or LPS."
Shows the defect is confined to the CBM-dependent route rather than being a general loss of NF-kappaB signalling, which is what the node claims.
PMID:34868072 SUPPORT Other
"It is located downstream of various immune receptors and it mediates NF-κB and mitogen-activated protein kinase (MAPK) activation, in a cell type-specific manner (31)."
Places BCL10 downstream of immune receptors and names the two effector arms. Graded OTHER: this is the review's framing sentence, not its patient data.
Arrested Lymphocyte Activation and Proliferation
Lymphocytes reach normal numbers but cannot complete an antigen-driven response. Proliferation fails on TCR ligation, and the failure is dose-graded: in the leaky frameshift patient, anti-CD3 alone gave almost no proliferation while anti-CD3/CD28 costimulation partially rescued it.
T cell proliferation GO:0042098 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased T cell proliferation (GO:0042098). GO:0042098 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
Bcl10-null mouse Mouse recapitulates Null lymphocytes fail to activate on antigen-receptor stimulation, which is the same functional lesion measured in patients.
Downstream
Failure of Memory B and T Cell Generation Memory differentiation is the endpoint of a completed antigen-driven response, so an arrest at activation leaves the naive compartment intact and the memory compartment empty.
Show evidence (1 reference)
PMID:42473108 SUPPORT Human Clinical
"T cell proliferation was partially preserved with anti-CD3/CD28 but nearly absent with anti-CD3 alone."
Quantifies the proliferation arrest and shows costimulation partially bypasses it, supporting an activation-threshold defect rather than an absolute one.
Failure of Memory B and T Cell Generation
The immunological signature of the disease. Total T and B cell counts are normal and the compartment is overwhelmingly naive; memory subsets are near-absent. Deeper phenotyping in one patient additionally found reduced NK, gamma-delta T, regulatory T and follicular helper T cell frequencies, so the defect is not confined to the classical memory subsets.
memory B cell CL:0000787 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves memory B cell (CL:0000787). CL:0000787 is a cell type from the Cell Ontology.
memory B cell differentiation GO:0002319 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased memory B cell differentiation (GO:0002319). GO:0002319 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Hypogammaglobulinemia Without class-switched memory B cells and plasma cell output, circulating immunoglobulin falls.
Show evidence (2 references)
PMID:38129623 SUPPORT Human Clinical
"The most significant immunological feature of BCL10 deficiency is that despite normal total numbers of T and B cells, their phenotype is naïve mainly with very low numbers of memory T and B cells."
The core claim of the node: a maturation block, not a numbers defect.
PMID:34868072 SUPPORT Human Clinical
"We showed that in addition to the near absence of memory B and T cells previously reported, this patient displays a reduction in NK, γδT, Tregs, and TFH cells."
Extends the cellular defect beyond memory B and T cells to NK, gamma-delta T, regulatory T and follicular helper T subsets, in one deeply phenotyped patient.
Hypogammaglobulinemia
Reduced circulating immunoglobulin, present in every reported patient. It is the laboratory abnormality that, together with the memory deficit, defines the recognisable pattern.
immunoglobulin production GO:0002377 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased immunoglobulin production (GO:0002377). GO:0002377 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Susceptibility to Recurrent and Opportunistic Infection Loss of specific antibody, on top of the cellular defect, leaves the airway and gut mucosa without effective humoral defence.
Show evidence (1 reference)
PMID:34868072 SUPPORT Human Clinical
"No memory lymphocytes (or reduced levels) despite normal total cell numbers, hypogammaglobulinemia."
The paper's own summary of the shared immunological phenotype, pairing the memory deficit with hypogammaglobulinemia against normal total counts.
Impaired Fibroblast Innate Receptor Signalling
The non-haematopoietic arm, and the finding that names the founding paper. Patient fibroblasts fail to produce IL-6 and IL-8 in response to TLR4, TLR2/6 and Dectin-1 agonists, while the same patient's monocyte-derived macrophages and dendritic cells respond normally to those agonists. BCL10 is therefore non-redundant in fibroblasts and redundant in myeloid cells. This asymmetry is what separates BCL10 deficiency from CARD9 deficiency, where the myeloid arm is the one that fails.
fibroblast CL:0000057 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves fibroblast (CL:0000057). CL:0000057 is a cell type from the Cell Ontology.
toll-like receptor 4 signaling pathway GO:0034142 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased toll-like receptor 4 signaling pathway (GO:0034142). GO:0034142 is a biological process from the Gene Ontology. ↓ DECREASED pattern recognition receptor signaling pathway GO:0002221 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased pattern recognition receptor signaling pathway (GO:0002221). GO:0002221 is a biological process from the Gene Ontology. ↓ DECREASED cytokine production GO:0001816 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cytokine production (GO:0001816). GO:0001816 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Susceptibility to Recurrent and Opportunistic Infection Proposed rather than demonstrated. The founding report argues that the non-haematopoietic defect contributes to the clinical phenotype, but no study has separated its contribution from that of the lymphocyte defect in a patient.
Show evidence (4 references)
PMID:25365219 SUPPORT Human Clinical
"Treatment of the patient's myeloid cells with a variety of pathogen-associated molecular pattern molecules (PAMPs) elicited a normal response; however, NF-κB-mediated fibroblast functions were dramatically impaired."
The cell-type asymmetry stated in one sentence: myeloid PAMP responses preserved, fibroblast NF-kappaB function lost.
PMID:38129623 SUPPORT In Vitro
"Interestingly, TLR4, TLR2/6, and Dectin-1 signaling in fibroblasts were impaired."
Names the three receptor routes that fail in fibroblasts.
PMID:38129623 SUPPORT In Vitro
"We introduced the newly reported mutation R42H in BCL10-deficient fibroblasts and showed impaired IL6 and IL8 production in response to stimulation with TLR4, TLR2/6, and Dectin agonists, while TLR3 signaling is BCL10-independent (Figure 2D and 2E)."
Bounds the defect from the other side. TLR3 signals normally in the same BCL10-deficient fibroblasts, so this is a specific loss of CBM-coupled receptors rather than a general failure of innate signalling in the cell type.
+ 1 more reference
Susceptibility to Recurrent and Opportunistic Infection
The clinical endpoint: respiratory infection from the first months of life, dermatitis, and gastrointestinal infection, with opportunistic organisms in the most severe presentations. Severity varies across the reported alleles, from a fatal SCID-like course to a leaky phenotype with relatively mild infections.
Show evidence (2 references)
PMID:38159157 SUPPORT Human Clinical
"We report on a 5-month-old male infant with complete B-cell lymphoma/leukemia 10 (BCL10) deficiency presenting with fatal severe combined immunodeficiency (SCID) characterized by systemic adenovirus infection and Pneumocystis jirovecii pneumonia."
Documents the severe end of the range, including the two opportunistic organisms and the fatal outcome.
PMID:32008135 SUPPORT Human Clinical
"The clinical phenotype shared features, such as respiratory infections, but differed from that of the previous patient that he did not develop significant gastroenteritis episodes or chronic colitis."
Shows that respiratory infection is the shared feature while gut involvement varies between patients with the same complete deficiency.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Immunodeficiency 37 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

16
Blood 5
Hypogammaglobulinemia VERY_FREQUENT Decreased circulating immunoglobulin concentration HP:0004313 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypogammaglobulinemia, annotated with Decreased circulating immunoglobulin concentration (HP:0004313). HP:0004313 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38129623 SUPPORT Human Clinical
"This gene should be studied when a patient presents with recurrent infections, hypogammaglobulinemia, and reduced numbers of B and T memory lymphocytes."
Places hypogammaglobulinemia in the recognised presenting triad for this gene, alongside recurrent infection and the memory deficit.
Decreased memory B cell proportion VERY_FREQUENT HP:0030374 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased memory B cell proportion (HP:0030374). HP:0030374 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38129623 SUPPORT Human Clinical
"The most significant immunological feature of BCL10 deficiency is that despite normal total numbers of T and B cells, their phenotype is naïve mainly with very low numbers of memory T and B cells."
States both halves of the finding: normal totals, very low memory numbers.
Decreased memory T cell proportion VERY_FREQUENT HP:0032183 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased memory T cell proportion (HP:0032183). HP:0032183 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34868072 SUPPORT Human Clinical
"Our results showed that BCL10 deficiency impairs the development of memory B, CD4+ and CD8+ T cells and confirmed previous reports (29, 30)."
Reports impaired development of memory CD4+ and CD8+ T cells as well as memory B cells.
Decreased regulatory T cell proportion FREQUENT HP:0020113 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased regulatory T cell proportion (HP:0020113). HP:0020113 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:42473108 SUPPORT Human Clinical
"Affected patients typically present with early‐onset severe infections and hypogammaglobulinemia, along with profoundly impaired T cell proliferation after TCR stimulation, largely preserved total T and B cell counts with a predominantly naïve phenotype, and markedly reduced or absent Treg..."
Places the Treg deficit among the typical cross-patient features, which is what supports assigning a frequency rather than leaving it unquantified.
PMID:42473108 SUPPORT Human Clinical
"Notably, Foxp3+Treg cells were markedly reduced in the patient, but a low residual population was still preserved (Figure1G)."
The direct measurement in a second patient, and the qualifier that matters: reduced with a residual population, not absent.
PMID:34868072 SUPPORT Human Clinical
"Furthermore, we observed a reduction in the frequencies of NK, γδT, Tregs, and Tfh cells."
The independent mass-cytometry observation in a different patient.
Decreased antigen-specific T cell proliferation VERY_FREQUENT HP:0031402 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased antigen-specific T cell proliferation (HP:0031402). HP:0031402 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38129623 SUPPORT Human Clinical
"T cell proliferation was measured in P1 and P4 and was blocked upon TCR stimulation (Table 1) [35,38]."
Records the proliferation block on TCR stimulation in the two patients in whom it was measured.
Digestive 2
Chronic diarrhea FREQUENT HP:0002028 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chronic diarrhea (HP:0002028), qualified as temporality chronic. HP:0002028 is a phenotype from the Human Phenotype Ontology.
Temporal: CHRONIC
Show evidence (1 reference)
PMID:38159157 SUPPORT Human Clinical
"However, at the age of 3 months, he developed chronic diarrhea and failed to thrive."
Records chronic diarrhoea with its age of onset.
Colitis OCCASIONAL HP:0002583 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Colitis (HP:0002583), qualified as temporality chronic. HP:0002583 is a phenotype from the Human Phenotype Ontology.
Temporal: CHRONIC
Show evidence (1 reference)
PMID:32008135 SUPPORT Human Clinical
"The clinical phenotype shared features, such as respiratory infections, but differed from that of the previous patient that he did not develop significant gastroenteritis episodes or chronic colitis."
Establishes that colitis occurs in some patients and not others, which is why the frequency is set below the respiratory features rather than equal to them.
Ear 1
Recurrent otitis media OCCASIONAL HP:0000403 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent otitis media (HP:0000403), qualified as temporality recurrent. HP:0000403 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
Show evidence (1 reference)
PMID:38129623 SUPPORT Human Clinical
"Since six months of age, he suffered several infections at the respiratory and gut level: flu A and B, adenovirus; respiratory syncytial virus (RSV), gastroenteritis (adenovirus), prolonged diarrhea (Campylobacter jejuni), chronic colitis, as well as recurrent otitis, oral candidiasis and diaper..."
The index patient's infection list, which includes recurrent otitis.
Head and Neck 1
Chronic oral candidiasis HP:0009098 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chronic oral candidiasis (HP:0009098). HP:0009098 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38129623 SUPPORT Human Clinical
"Since six months of age, he suffered several infections at the respiratory and gut level: flu A and B, adenovirus; respiratory syncytial virus (RSV), gastroenteritis (adenovirus), prolonged diarrhea (Campylobacter jejuni), chronic colitis, as well as recurrent otitis, oral candidiasis and diaper..."
Records oral candidiasis in the index patient. Frequency is omitted: it appears in one patient's list rather than in a summary across the series.
Immune 5
Combined immunodeficiency VERY_FREQUENT HP:0005387 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Combined immunodeficiency (HP:0005387). HP:0005387 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38129623 SUPPORT Human Clinical
"Human BCL10 deficiency causes combined immunodeficiency with bone marrow transplantation as its only curative option."
Names the defining phenotype of the disease.
Recurrent respiratory infections VERY_FREQUENT HP:0002205 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent respiratory infections (HP:0002205), qualified as temporality recurrent. HP:0002205 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
Show evidence (1 reference)
PMID:38129623 SUPPORT Human Clinical
"The clinical hallmark of BCL10 deficiency is mainly respiratory infections since the first months of life, dermatitis, and gastrointestinal tract infections (Table 3)."
Names recurrent respiratory infection as the clinical hallmark and gives its age of onset.
Eczematoid dermatitis FREQUENT HP:0000964 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Eczematoid dermatitis (HP:0000964). HP:0000964 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38129623 SUPPORT Human Clinical
"The clinical hallmark of BCL10 deficiency is mainly respiratory infections since the first months of life, dermatitis, and gastrointestinal tract infections (Table 3)."
Names dermatitis among the three hallmark features.
BCGitis HP:0020086 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Localized suppuration at the BCG vaccination site, annotated with BCGitis (HP:0020086). HP:0020086 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42473108 SUPPORT Human Clinical
"The patient also showed growth retardation and localized suppuration at the BCG vaccination site (Figure1A,C)."
The observation itself. Frequency is omitted: BCG is not given universally, so the denominator of vaccinated patients in this series is not stated.
Pneumocystis jirovecii pneumonia 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 (1 reference)
PMID:38159157 SUPPORT Human Clinical
"We report on a 5-month-old male infant with complete B-cell lymphoma/leukemia 10 (BCL10) deficiency presenting with fatal severe combined immunodeficiency (SCID) characterized by systemic adenovirus infection and Pneumocystis jirovecii pneumonia."
Records the opportunistic infection in the SCID-presenting patient.
Nervous System 1
Leukoencephalopathy HP:0002352 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Leukoencephalopathy (HP:0002352). HP:0002352 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38129623 SUPPORT Human Clinical
"Since six months of age, he suffered several infections at the respiratory and gut level: flu A and B, adenovirus; respiratory syncytial virus (RSV), gastroenteritis (adenovirus), prolonged diarrhea (Campylobacter jejuni), chronic colitis, as well as recurrent otitis, oral candidiasis and diaper..."
The source describes the leukoencephalopathy as secondary, which is why this entry does not place it on the pathophysiology chain.
Growth 1
Failure to thrive OCCASIONAL HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:38159157 SUPPORT Human Clinical
"However, at the age of 3 months, he developed chronic diarrhea and failed to thrive."
Records failure to thrive with its age of onset, in the patient who presented as SCID.
PMID:42473108 SUPPORT Human Clinical
"Together, these findings indicate an early‐onset disorder characterized by recurrent infections, chronic mucocutaneous and gastrointestinal inflammation, and growth impairment."
The authors' summary of their patient, which places growth impairment alongside the infection and inflammation phenotype. This is a single-patient statement, not a cross-patient one.
🧬

Genetic Associations

1
BCL10
Gene: BCL10 hgnc:989 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is BCL10 (hgnc:989). hgnc:989 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (4 references)
PMID:38129623 SUPPORT Human Clinical
"A common feature of all the mutations is that they are located in the CARD domain of the molecule (Figure 1)."
Establishes that the disease alleles cluster in the CARD domain rather than being distributed across the protein.
PMID:38129623 SUPPORT Human Clinical
"BCL10 is a 233 amino acid intracellular signaling protein characterized by an amino-terminal CARD motif and a Ser/Thr-rich carboxyl terminus of unknown function [27,28]."
Describes the protein's two-domain architecture, which is what makes the CARD clustering of disease alleles interpretable.
PMID:25365219 SUPPORT Human Clinical
"The patient died at 3 years of age and was homozygous for a loss-of-expression, loss-of-function BCL10 mutation."
The founding report's statement that the causal allele abolishes both expression and function, which is what makes this a complete deficiency.
+ 1 more reference
💊

Medical Actions

3
Hematopoietic Stem Cell Transplantation
Action: hematopoietic stem cell transplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is 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 curative option, and the reason early genetic diagnosis matters. Outcome depends on how much damage has accumulated: the index patient died before he could be transplanted, later patients were transplanted early after a fast genetic diagnosis, and one patient died after transplantation.
Mechanism Target:
Failure of Memory B and T Cell Generation — Replaces the BCL10-deficient haematopoietic compartment with donor cells that can assemble a CBM complex, restoring lymphocyte activation and memory generation. It does not address the fibroblast defect, which is not of haematopoietic origin.
Show evidence (1 reference)
PMID:38129623 SUPPORT Human Clinical
"In these patients, the only effective treatment is HSCT."
States that transplantation is the only effective treatment, which is the claim this treatment-to-mechanism link rests on.
Show evidence (1 reference)
PMID:38129623 SUPPORT Human Clinical
"Human BCL10 deficiency causes combined immunodeficiency with bone marrow transplantation as its only curative option."
Names transplantation as the only curative option.
Immunoglobulin Replacement Therapy
Action: immunoglobulin replacement therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is immunoglobulin replacement therapy, annotated with Immunoglobulin Therapy (NCIT:C62710). NCIT:C62710 is a clinical intervention from the NCI Thesaurus. Ontology label: Immunoglobulin Therapy NCIT:C62710
Platform: Other
Supportive rather than curative. In the fifth reported patient, intravenous immunoglobulin was followed by no further need for hospitalisation.
Mechanism Target:
Hypogammaglobulinemia — Substitutes donor-derived specific antibody for the immunoglobulin the patient cannot generate. It replaces the product of the missing memory compartment without restoring the compartment.
Show evidence (1 reference)
PMID:38129623 SUPPORT Human Clinical
"He did not need hospitalization since starting Intravenous Immunoglobulin (IVIG) and his eczema is controlled on a low potency steroid."
A single-patient observation of clinical benefit after starting immunoglobulin replacement.
Genetic Counseling
Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Platform: Other
All reported families are consanguineous, and in most the diagnosis followed the death of an earlier sibling. Counselling and cascade testing therefore change outcomes for the next child rather than only informing the index patient.
Show evidence (1 reference)
PMID:38129623 SUPPORT Human Clinical
"The majority of the patients had a sibling who died before the diagnosis of the index patient."
Documents the recurrence pattern within families that makes counselling and cascade testing consequential.
🔬

Diagnosis

2
Functional lymphocyte testing against normal lymphocyte counts (PRESENT)
The diagnostic trap. Total T and B cell counts are normal, so quantitative immunophenotyping reads as reassuring; the abnormality appears only in memory subset proportions, immunoglobulin levels, and proliferation on stimulation. One patient passed newborn SCID screening and presented at five months with fatal disseminated infection.
Show evidence (2 references)
PMID:38159157 SUPPORT Human Clinical
"Newborn screening was normal including TREC (T cell receptor excision circles) based screening for SCID."
The paper that actually reports the screening escape, cited for that claim. TREC screening counts recent thymic emigrants, which are preserved here, so the assay is blind to a defect that lies downstream in activation and memory formation.
PMID:38129623 SUPPORT Human Clinical
"This gene should be studied when a patient presents with recurrent infections, hypogammaglobulinemia, and reduced numbers of B and T memory lymphocytes."
Gives the triad that should trigger BCL10 testing, none of which is a total lymphocyte count.
Functional validation of a candidate variant (PRESENT)
BCL10 is on current primary immunodeficiency sequencing panels, so the variant is now usually found before the phenotype is understood. The source is explicit that a candidate variant should be functionally validated, including protein expression, before committing a child to transplantation.
Show evidence (1 reference)
PMID:38129623 SUPPORT Human Clinical
"Still, when a candidate mutation appears disease-causing, performing a functional validation, including protein expression, is crucial to ensure that it is a BCL10 deficiency and thus proceed to HSCT."
States the functional-validation requirement and ties it to the transplant decision.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
Reported as individual probands rather than as a cohort. A 2026 report counts six published patients; there is no registry and no population estimate. Every reported family has been consanguineous, so the allele frequency in outbred populations is unknown rather than known to be low.
Show evidence (2 references)
PMID:42473108 SUPPORT Human Clinical
"BCL10 deficiency is an exceptionally rare autosomal recessive combined immunodeficiency, with only six patients reported to date."
Gives the size of the published experience at the time of writing, which is what the CASES_IN_LITERATURE measure records.
PMID:38129623 SUPPORT Human Clinical
"The patients are all coming from consanguineous parents (Table 1)."
Records that ascertainment has been entirely through consanguineous families, which is why no outbred-population frequency can be inferred from the case count.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Immunodeficiency 37:

CARD11 and MALT1 deficiency
Overlapping Features The other two components of the same signalosome. Complete loss of any one produces a combined immunodeficiency that is clinically similar, and the distinction is made by sequencing rather than by phenotype. The one phenotypic hint is the non-haematopoietic arm: the fibroblast signalling defect is a BCL10 finding.
Show evidence (1 reference)
PMID:31060714 SUPPORT Other
"Germline mutations that alter the function of members of this complex (termed CBM-opathies) cause a broad array of clinical phenotypes, ranging from profound combined immunodeficiency to B-cell lymphocytosis."
Establishes that the CBM component deficiencies form one clinical family, which is what makes them each other's differential.
CARD9 deficiency
Overlapping Features Also a CBM-opathy, but the opposite cell-type pattern. CARD9 is the myeloid CARD adaptor and its loss gives isolated invasive fungal disease; BCL10-deficient myeloid cells respond normally to fungal and bacterial PAMPs, and the reported fungal disease is mucosal candidiasis rather than invasive.
Show evidence (1 reference)
PMID:34868072 SUPPORT Other
"Autosomal recessive complete deficiencies in the two Caspase recruitment domain-containing (CARD) adaptor proteins, CARD9 (3) and CARD11 (2, 4) cause isolated invasive fungal infections (3, 5–28) and combined immunodeficiency (CID) respectively (2, 4)."
Contrasts the CARD9 phenotype (isolated invasive fungal infection) with the combined immunodeficiency seen here.
🐁

Animal Models

1
Bcl10-null mouse
The Bcl10 knockout reproduces the human immunological defect and adds one the human disease does not have. About a third of null embryos develop exencephaly and die; survivors are severely immunodeficient with lymphocytes that cannot be activated through the antigen receptor. No human BCL10-deficient patient has been reported with a neural tube defect, which is what makes this model useful and partly misleading at the same time.
Species
Mouse
Genotype
Bcl10 knockout
Publication
PMID:11163238
Pathograph links
Arrested Lymphocyte Activation and Proliferation recapitulates fidelity: high observes: cellular Null lymphocytes fail to activate on antigen-receptor stimulation, which is the same functional lesion measured in patients.
Limitations: A constitutive whole-animal null, so it cannot separate the lymphocyte-intrinsic defect from developmental effects. The subset structure also differs: mouse work shows the CD4+ subset is the most severely impaired, and no human study has resolved the defect by subset in that way.
Readouts
Antigen-receptor-induced lymphocyte activation
Direction: DECREASED
Interpretation: Failure of activation on antigen-receptor or PMA/ionomycin stimulation, the cellular readout corresponding to the human proliferation block.
Show evidence (1 reference)
PMID:11163238 SUPPORT Model Organism
"However, surviving bcl10-/- mice were severely immunodeficient and bcl10-/- lymphocytes are defective in antigen receptor or PMA/Ionomycin-induced activation."
The measurement behind this readout, in the surviving null animals.
Show evidence (1 reference)
PMID:18941215 SUPPORT Model Organism
"Our data confirm that CD4(+) T cells from PKCtheta, Bcl10, and Malt1 knockout mice show severe impairment of proliferation in response to TCR stimulation."
Independent confirmation of the proliferation defect in the knockout, and the source of the subset asymmetry noted in the limitations.
{ }

Source YAML

click to show 
name: Immunodeficiency 37
creation_date: "2026-09-07T17:30:00Z"
category: Mendelian
synonyms:
- IMD37
- BCL10 deficiency
- combined immunodeficiency due to BCL10 deficiency
- BCL10 primary immunodeficiency disease
- immunodeficiency type 37
description: >-
  Immunodeficiency 37 is the autosomal recessive combined immunodeficiency caused by
  biallelic loss of BCL10, the scaffold subunit of the CARD-BCL10-MALT1 (CBM)
  signalosome. The CBM complex is the module that couples an engaged antigen receptor
  to NF-kappaB, and BCL10 is the component every cell-type-specific version of it
  shares: CARD11 in lymphocytes, CARD9 in myeloid cells, CARD10 in epithelium, CARD14
  in keratinocytes all nucleate the same BCL10-MALT1 filament. Losing BCL10 therefore
  ought to disable more than losing any one CARD adaptor, and the patients show a
  specific version of that prediction.

  Two features distinguish this entry from its CBM siblings. First, the lymphocyte
  defect is a maturation block rather than a numbers defect: total T and B cell counts
  are normal, and what is missing is the memory compartment, together with
  hypogammaglobulinemia. A quantitative immune workup therefore reads as reassuring,
  and one patient passed newborn SCID screening before dying of disseminated
  adenovirus and Pneumocystis. Second, the deficiency reaches beyond the
  haematopoietic system: patient fibroblasts fail to signal through TLR4, TLR2/6 and
  Dectin-1, while the same receptors on the patient's own monocyte-derived macrophages
  and dendritic cells respond normally. BCL10 is thus non-redundant in fibroblasts and
  redundant in myeloid cells, which is the opposite of the arrangement CARD9 deficiency
  would predict and is the reason the founding report is titled around
  "nonhematopoietic immunity".

  The published experience is a handful of patients from consanguineous families, all
  with loss-of-function alleles in the CARD domain, and haematopoietic stem cell
  transplantation is the only curative option.
disease_term:
  preferred_term: immunodeficiency 37
  term:
    id: MONDO:0014491
    label: immunodeficiency 37
parents:
- Combined immunodeficiency
- Inborn error of immunity
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Reported as individual probands rather than as a cohort. A 2026 report counts six
    published patients; there is no registry and no population estimate. Every reported
    family has been consanguineous, so the allele frequency in outbred populations is
    unknown rather than known to be low.
  evidence:
  - reference: PMID:42473108
    reference_title: "A novel linker region truncating variant in BCL10 underlies a leaky immunodeficiency phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "BCL10 deficiency is an exceptionally rare autosomal recessive combined immunodeficiency, with only six patients reported to date."
    explanation: >-
      Gives the size of the published experience at the time of writing, which is what
      the CASES_IN_LITERATURE measure records.
  - reference: PMID:38129623
    reference_title: "Inherited Human BCL10 Deficiencies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patients are all coming from consanguineous parents (Table 1)."
    explanation: >-
      Records that ascertainment has been entirely through consanguineous families,
      which is why no outbred-population frequency can be inferred from the case count.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Every reported allele is homozygous and every reported family consanguineous.
    Heterozygous carriers have been examined directly rather than assumed healthy:
    parental T cell proliferation and the lymphocyte subset frequencies of five
    carriers were normal, so BCL10 shows no haploinsufficiency.
  evidence:
  - reference: PMID:38129623
    reference_title: "Inherited Human BCL10 Deficiencies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "BCL10 deficiency is an autosomal recessive trait with heterozygous carriers not showing clinical or immunological manifestations."
    explanation: >-
      States the inheritance mode and, specifically, that carriers are unaffected on
      clinical and immunological examination.
genetic:
- name: BCL10
  gene_term:
    preferred_term: BCL10
    term:
      id: hgnc:989
      label: BCL10
  relationship_type: CAUSATIVE
  presence: PRESENT
  variant_origin: GERMLINE
  notes: >-
    Reported alleles are a splice-site change (IVS1+1G>A), two nonsense changes (K63X,
    R88X) and two missense changes (T91P, R42H), plus a later linker-region frameshift
    (p.Gly116GlufsTer3). The first five all fall in the CARD domain, which is the
    protein-protein interaction surface that nucleates the CBM filament, so the
    genotype-phenotype story is about the assembly interface rather than about protein
    dosage.
  evidence:
  - reference: PMID:38129623
    reference_title: "Inherited Human BCL10 Deficiencies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A common feature of all the mutations is that they are located in the CARD domain of the molecule (Figure 1)."
    explanation: >-
      Establishes that the disease alleles cluster in the CARD domain rather than
      being distributed across the protein.
  - reference: PMID:38129623
    reference_title: "Inherited Human BCL10 Deficiencies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "BCL10 is a 233 amino acid intracellular signaling protein characterized by an amino-terminal CARD motif and a Ser/Thr-rich carboxyl terminus of unknown function [27,28]."
    explanation: >-
      Describes the protein's two-domain architecture, which is what makes the CARD
      clustering of disease alleles interpretable.
  - reference: PMID:25365219
    reference_title: "Inherited BCL10 deficiency impairs hematopoietic and nonhematopoietic immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient died at 3 years of age and was homozygous for a loss-of-expression, loss-of-function BCL10 mutation."
    explanation: >-
      The founding report's statement that the causal allele abolishes both expression
      and function, which is what makes this a complete deficiency.
  - reference: PMID:32008135
    reference_title: "Human BCL10 Deficiency due to Homozygosity for a Rare Allele."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the present study, we report a new BCL10 mutation in another child with CID who was homozygous for a BCL10 variant (R88X), previously reported as a rare allele in heterozygosis (minor allele frequency, 0.000003986)."
    explanation: >-
      Puts a population frequency on one allele, which is the only quantitative anchor
      this entry has for the ultra-rare classification. It also shows the allele was
      already catalogued in heterozygotes before anyone had seen it homozygous.
pathophysiology:
- name: Biallelic BCL10 Loss of Function
  biological_scale: MOLECULAR
  genetic_context:
    gene:
      preferred_term: BCL10
      term:
        id: hgnc:989
        label: BCL10
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Every reported disease allele is homozygous and germline. Recorded as
      LOSS_OF_FUNCTION rather than a finer category because the measured consequence is
      absent or greatly reduced protein rather than an altered activity: the splice-site
      and nonsense alleles abolish expression outright, and the one missense allele whose
      expression was measured was greatly reduced.
  description: >-
    Homozygous loss-of-function alleles in the BCL10 CARD domain remove or destabilize
    the protein. Four of the five alleles whose protein consequence was measured gave
    absent or greatly reduced BCL10.
  downstream:
  - target: CBM Signalosome Assembly Failure
    causal_link_type: DIRECT
    description: >-
      With BCL10 absent, the CARD adaptor has nothing to nucleate and MALT1 has nothing
      to bind, so the complex cannot form.
    evidence:
    - reference: PMID:38129623
      reference_title: "Inherited Human BCL10 Deficiencies."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The mutations are always mapped to the CARD domain of BCL10, critical for protein-protein interactions and CBM complex assembly."
      explanation: >-
        Links the location of the disease alleles to the specific step they break,
        which is the edge being asserted here rather than either node alone.
  evidence:
  - reference: PMID:38129623
    reference_title: "Inherited Human BCL10 Deficiencies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All disease-causing BCL10 mutations described to date are homozygous, loss-of-function with a complete or significantly reduced protein expression (Table 1)."
    explanation: >-
      Establishes the molecular lesion as loss of the protein rather than as an altered
      or gain-of-function product.
- name: CBM Signalosome Assembly Failure
  biological_scale: MOLECULAR
  description: >-
    The CBM complex is the shared module downstream of antigen receptors and several
    innate receptors, with a cell-type-specific CARD subunit (CARD11 in lymphocytes,
    CARD9 in myeloid cells, CARD10 in epithelium, CARD14 in keratinocytes) built on a
    constant BCL10-MALT1 core. BCL10 is therefore the single point every version of the
    complex passes through.
  biological_processes:
  - preferred_term: CBM signalosome assembly
    term:
      id: GO:0065003
      label: protein-containing complex assembly
    modifier: DECREASED
  downstream:
  - target: Defective Antigen Receptor-Induced NF-kappaB Activation
    causal_link_type: DIRECT
    description: >-
      NF-kappaB induction downstream of the T and B cell receptors requires an intact
      CBM complex, so assembly failure is read out as loss of receptor-triggered
      NF-kappaB signalling.
    evidence:
    - reference: PMID:42473108
      reference_title: "A novel linker region truncating variant in BCL10 underlies a leaky immunodeficiency phenotype."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "BCL10 is a core CBM (CARD-BCL10-MALT1) complex component required for antigen receptor-mediated NF-κB activation."
      explanation: >-
        States the dependency this edge asserts: antigen-receptor NF-kappaB activation
        requires BCL10 as a CBM component.
  - target: Impaired Fibroblast Innate Receptor Signalling
    causal_link_type: DIRECT
    description: >-
      The same complex operates outside the haematopoietic system. In fibroblasts,
      TLR4, TLR2/6 and Dectin-1 signalling is BCL10-dependent.
    evidence:
    - reference: PMID:32008135
      reference_title: "Human BCL10 Deficiency due to Homozygosity for a Rare Allele."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "TLR4, TLR2/6, and Dectin-1 responses were found to depend on BCL10 in fibroblasts, and final maturation of T cell and B cell maturation into memory cells was affected."
      explanation: >-
        Establishes fibroblast innate signalling as BCL10-dependent, which is the
        non-haematopoietic branch of the chain.
  evidence:
  - reference: PMID:38129623
    reference_title: "Inherited Human BCL10 Deficiencies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Caspase recruitment domain (CARD), B-cell lymphoma 10 (BCL10), and mucosa-associated lymphoid tissue lymphoma-translocation gene 1 (MALT1) proteins form the cytosolic CBM (CARD-BCL10-MALT1) complex."
    explanation: >-
      Defines the complex whose assembly fails. Graded OTHER because the sentence is
      background architecture stated in a review, not a patient observation.
  - reference: PMID:24074955
    reference_title: "Structural architecture of the CARMA1/Bcl10/MALT1 signalosome: nucleation-induced filamentous assembly."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Here we show that the reconstituted CBM signalosome is a helical filamentous assembly in which substoichiometric CARMA1 nucleates Bcl10 filaments."
    explanation: >-
      Gives the structural reason the CARD domain is where every disease allele falls:
      BCL10 is not a stoichiometric partner but the polymerising scaffold, and the CARD
      is the filament interface.
  - reference: PMID:24074955
    reference_title: "Structural architecture of the CARMA1/Bcl10/MALT1 signalosome: nucleation-induced filamentous assembly."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Structure-guided mutagenesis confirmed the observed interfaces in Bcl10 filament assembly and MALT1 activation in vitro and NF-κB activation in cells."
    explanation: >-
      Shows that disrupting the filament interfaces is sufficient to abolish downstream
      NF-kappaB activation, which is the experimental counterpart of the human CARD
      alleles.
- name: Defective Antigen Receptor-Induced NF-kappaB Activation
  biological_scale: CELLULAR
  description: >-
    Loss of CBM-dependent signalling downstream of the T and B cell receptors. The
    defect is stimulus dependent rather than global: TNF-alpha and LPS still induce
    p65 phosphorylation, because those routes to NF-kappaB do not run through the CBM
    complex.
  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: DECREASED
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  downstream:
  - target: Arrested Lymphocyte Activation and Proliferation
    causal_link_type: DIRECT
    description: >-
      Antigen-receptor NF-kappaB signalling is what licenses the activated lymphocyte
      to proliferate, so the proliferation block follows the signalling block.
    evidence:
    - reference: PMID:38129623
      reference_title: "Inherited Human BCL10 Deficiencies."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "T cell proliferation was measured in P1 and P4 and was blocked upon TCR stimulation (Table 1) [35,38]."
      explanation: >-
        Reports the proliferation failure specifically on TCR stimulation, which is the
        step downstream of the signalling defect this edge asserts.
  evidence:
  - reference: PMID:42473108
    reference_title: "A novel linker region truncating variant in BCL10 underlies a leaky immunodeficiency phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "NF-κB signaling was stimulus dependent, with near-absent p-p65 induction in T cells after PMA/ionomycin but relative preservation or enhancement after TNF-α or LPS."
    explanation: >-
      Shows the defect is confined to the CBM-dependent route rather than being a
      general loss of NF-kappaB signalling, which is what the node claims.
  - reference: PMID:34868072
    reference_title: "Clinical and Immunological Features of Human BCL10 Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "It is located downstream of various immune receptors and it mediates NF-κB and mitogen-activated protein kinase (MAPK) activation, in a cell type-specific manner (31)."
    explanation: >-
      Places BCL10 downstream of immune receptors and names the two effector arms.
      Graded OTHER: this is the review's framing sentence, not its patient data.
- name: Arrested Lymphocyte Activation and Proliferation
  biological_scale: CELLULAR
  description: >-
    Lymphocytes reach normal numbers but cannot complete an antigen-driven response.
    Proliferation fails on TCR ligation, and the failure is dose-graded: in the leaky
    frameshift patient, anti-CD3 alone gave almost no proliferation while
    anti-CD3/CD28 costimulation partially rescued it.
  biological_processes:
  - preferred_term: T cell proliferation
    term:
      id: GO:0042098
      label: T cell proliferation
    modifier: DECREASED
  downstream:
  - target: Failure of Memory B and T Cell Generation
    causal_link_type: DIRECT
    description: >-
      Memory differentiation is the endpoint of a completed antigen-driven response, so
      an arrest at activation leaves the naive compartment intact and the memory
      compartment empty.
    evidence:
    - reference: PMID:34868072
      reference_title: "Clinical and Immunological Features of Human BCL10 Deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Our findings and previous reports of BCL10 deficient patients (29, 30) support the critical role of BCL10 in human BCR-dependent signaling and memory B cell generation."
      explanation: >-
        Connects the antigen-receptor signalling defect to the memory generation
        failure, which is the causal step this edge records.
  evidence:
  - reference: PMID:42473108
    reference_title: "A novel linker region truncating variant in BCL10 underlies a leaky immunodeficiency phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "T cell proliferation was partially preserved with anti-CD3/CD28 but nearly absent with anti-CD3 alone."
    explanation: >-
      Quantifies the proliferation arrest and shows costimulation partially bypasses it,
      supporting an activation-threshold defect rather than an absolute one.
- name: Failure of Memory B and T Cell Generation
  biological_scale: CELLULAR
  description: >-
    The immunological signature of the disease. Total T and B cell counts are normal
    and the compartment is overwhelmingly naive; memory subsets are near-absent. Deeper
    phenotyping in one patient additionally found reduced NK, gamma-delta T,
    regulatory T and follicular helper T cell frequencies, so the defect is not
    confined to the classical memory subsets.
  cell_types:
  - preferred_term: memory B cell
    term:
      id: CL:0000787
      label: memory B cell
  biological_processes:
  - preferred_term: memory B cell differentiation
    term:
      id: GO:0002319
      label: memory B cell differentiation
    modifier: DECREASED
  downstream:
  - target: Hypogammaglobulinemia
    causal_link_type: DIRECT
    description: >-
      Without class-switched memory B cells and plasma cell output, circulating
      immunoglobulin falls.
    evidence:
    - reference: PMID:38129623
      reference_title: "Inherited Human BCL10 Deficiencies."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This gene should be studied when a patient presents with recurrent infections, hypogammaglobulinemia, and reduced numbers of B and T memory lymphocytes."
      explanation: >-
        States that the memory deficit and the hypogammaglobulinemia co-occur as the
        recognised presentation, which is the association this edge records. The
        sentence is diagnostic guidance, so it evidences co-occurrence rather than
        proving the direction of causation.
  evidence:
  - reference: PMID:38129623
    reference_title: "Inherited Human BCL10 Deficiencies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most significant immunological feature of BCL10 deficiency is that despite normal total numbers of T and B cells, their phenotype is naïve mainly with very low numbers of memory T and B cells."
    explanation: >-
      The core claim of the node: a maturation block, not a numbers defect.
  - reference: PMID:34868072
    reference_title: "Clinical and Immunological Features of Human BCL10 Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We showed that in addition to the near absence of memory B and T cells previously reported, this patient displays a reduction in NK, γδT, Tregs, and TFH cells."
    explanation: >-
      Extends the cellular defect beyond memory B and T cells to NK, gamma-delta T,
      regulatory T and follicular helper T subsets, in one deeply phenotyped patient.
- name: Hypogammaglobulinemia
  biological_scale: ORGANISM
  description: >-
    Reduced circulating immunoglobulin, present in every reported patient. It is the
    laboratory abnormality that, together with the memory deficit, defines the
    recognisable pattern.
  biological_processes:
  - preferred_term: immunoglobulin production
    term:
      id: GO:0002377
      label: immunoglobulin production
    modifier: DECREASED
  downstream:
  - target: Susceptibility to Recurrent and Opportunistic Infection
    causal_link_type: DIRECT
    description: >-
      Loss of specific antibody, on top of the cellular defect, leaves the airway and
      gut mucosa without effective humoral defence.
    evidence:
    - reference: PMID:38129623
      reference_title: "Inherited Human BCL10 Deficiencies."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The clinical hallmark of BCL10 deficiency is mainly respiratory infections since the first months of life, dermatitis, and gastrointestinal tract infections (Table 3)."
      explanation: >-
        Names the infection pattern that follows the immunological defect, at the sites
        where humoral defence matters most.
  evidence:
  - reference: PMID:34868072
    reference_title: "Clinical and Immunological Features of Human BCL10 Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "No memory lymphocytes (or reduced levels) despite normal total cell numbers, hypogammaglobulinemia."
    explanation: >-
      The paper's own summary of the shared immunological phenotype, pairing the memory
      deficit with hypogammaglobulinemia against normal total counts.
- name: Impaired Fibroblast Innate Receptor Signalling
  biological_scale: CELLULAR
  description: >-
    The non-haematopoietic arm, and the finding that names the founding paper. Patient
    fibroblasts fail to produce IL-6 and IL-8 in response to TLR4, TLR2/6 and Dectin-1
    agonists, while the same patient's monocyte-derived macrophages and dendritic cells
    respond normally to those agonists. BCL10 is therefore non-redundant in fibroblasts
    and redundant in myeloid cells. This asymmetry is what separates BCL10 deficiency
    from CARD9 deficiency, where the myeloid arm is the one that fails.
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: toll-like receptor 4 signaling pathway
    term:
      id: GO:0034142
      label: toll-like receptor 4 signaling pathway
    modifier: DECREASED
  - preferred_term: pattern recognition receptor signaling pathway
    term:
      id: GO:0002221
      label: pattern recognition receptor signaling pathway
    modifier: DECREASED
  - preferred_term: cytokine production
    term:
      id: GO:0001816
      label: cytokine production
    modifier: DECREASED
  downstream:
  - target: Susceptibility to Recurrent and Opportunistic Infection
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Proposed rather than demonstrated. The founding report argues that the
      non-haematopoietic defect contributes to the clinical phenotype, but no study has
      separated its contribution from that of the lymphocyte defect in a patient.
    evidence:
    - reference: PMID:25365219
      reference_title: "Inherited BCL10 deficiency impairs hematopoietic and nonhematopoietic immunity."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "The results of this study indicate that inherited BCL10 deficiency should be considered in patients with combined immunodeficiency with B cell, T cell, and fibroblast defects."
      explanation: >-
        Supports treating the fibroblast defect as part of the disease phenotype.
        Graded INDIRECT because the sentence is a diagnostic recommendation; it does not
        show the fibroblast defect independently causing infection.
  evidence:
  - reference: PMID:25365219
    reference_title: "Inherited BCL10 deficiency impairs hematopoietic and nonhematopoietic immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment of the patient's myeloid cells with a variety of pathogen-associated molecular pattern molecules (PAMPs) elicited a normal response; however, NF-κB-mediated fibroblast functions were dramatically impaired."
    explanation: >-
      The cell-type asymmetry stated in one sentence: myeloid PAMP responses preserved,
      fibroblast NF-kappaB function lost.
  - reference: PMID:38129623
    reference_title: "Inherited Human BCL10 Deficiencies."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Interestingly, TLR4, TLR2/6, and Dectin-1 signaling in fibroblasts were impaired."
    explanation: >-
      Names the three receptor routes that fail in fibroblasts.
  - reference: PMID:38129623
    reference_title: "Inherited Human BCL10 Deficiencies."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We introduced the newly reported mutation R42H in BCL10-deficient fibroblasts and showed impaired IL6 and IL8 production in response to stimulation with TLR4, TLR2/6, and Dectin agonists, while TLR3 signaling is BCL10-independent (Figure 2D and 2E)."
    explanation: >-
      Bounds the defect from the other side. TLR3 signals normally in the same
      BCL10-deficient fibroblasts, so this is a specific loss of CBM-coupled receptors
      rather than a general failure of innate signalling in the cell type.
  - reference: PMID:38129623
    reference_title: "Inherited Human BCL10 Deficiencies."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In terms of cellular responses, the first patient analyzed revealed normal responses to TLR1/2, TLR4, TLR2/6, and Dectin-1 agonists by monocyte-derived macrophages (MDMs) or monocyte-derived dendritic cells (MDDCs)."
    explanation: >-
      The other half of the asymmetry: the same receptors signal normally in the
      patient's myeloid cells, so the fibroblast failure is cell-type-specific rather
      than receptor-specific.
- name: Susceptibility to Recurrent and Opportunistic Infection
  biological_scale: ORGANISM
  description: >-
    The clinical endpoint: respiratory infection from the first months of life,
    dermatitis, and gastrointestinal infection, with opportunistic organisms in the
    most severe presentations. Severity varies across the reported alleles, from a
    fatal SCID-like course to a leaky phenotype with relatively mild infections.
  evidence:
  - reference: PMID:38159157
    reference_title: "BCL10 Deficiency Presenting as Severe Combined Immunodeficiency Escaping Newborn Screening."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report on a 5-month-old male infant with complete B-cell lymphoma/leukemia 10 (BCL10) deficiency presenting with fatal severe combined immunodeficiency (SCID) characterized by systemic adenovirus infection and Pneumocystis jirovecii pneumonia."
    explanation: >-
      Documents the severe end of the range, including the two opportunistic organisms
      and the fatal outcome.
  - reference: PMID:32008135
    reference_title: "Human BCL10 Deficiency due to Homozygosity for a Rare Allele."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical phenotype shared features, such as respiratory infections, but differed from that of the previous patient that he did not develop significant gastroenteritis episodes or chronic colitis."
    explanation: >-
      Shows that respiratory infection is the shared feature while gut involvement
      varies between patients with the same complete deficiency.
phenotypes:
- category: Immunologic
  name: Combined immunodeficiency
  description: >-
    Both cellular and humoral arms are affected. Presentations have ranged from a
    SCID-like course fatal in infancy to a leaky combined immunodeficiency with
    relatively mild infections.
  phenotype_term:
    preferred_term: Combined immunodeficiency
    term:
      id: HP:0005387
      label: Combined immunodeficiency
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:38129623
    reference_title: "Inherited Human BCL10 Deficiencies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Human BCL10 deficiency causes combined immunodeficiency with bone marrow transplantation as its only curative option."
    explanation: Names the defining phenotype of the disease.
- category: Immunologic
  name: Recurrent respiratory infections
  description: >-
    The most consistent clinical feature, beginning in the first months of life. Lower
    respiratory tract infection has been the presenting problem in most reported
    patients.
  phenotype_term:
    preferred_term: Recurrent respiratory infections
    term:
      id: HP:0002205
      label: Recurrent respiratory infections
    temporality: RECURRENT
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:38129623
    reference_title: "Inherited Human BCL10 Deficiencies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical hallmark of BCL10 deficiency is mainly respiratory infections since the first months of life, dermatitis, and gastrointestinal tract infections (Table 3)."
    explanation: >-
      Names recurrent respiratory infection as the clinical hallmark and gives its age
      of onset.
- category: Laboratory
  name: Hypogammaglobulinemia
  description: >-
    Reduced circulating immunoglobulin in every reported patient, in the presence of
    normal or near-normal B cell numbers.
  phenotype_term:
    preferred_term: Hypogammaglobulinemia
    term:
      id: HP:0004313
      label: Decreased circulating immunoglobulin concentration
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:38129623
    reference_title: "Inherited Human BCL10 Deficiencies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This gene should be studied when a patient presents with recurrent infections, hypogammaglobulinemia, and reduced numbers of B and T memory lymphocytes."
    explanation: >-
      Places hypogammaglobulinemia in the recognised presenting triad for this gene,
      alongside recurrent infection and the memory deficit.
- category: Cellular
  name: Decreased memory B cell proportion
  description: >-
    Near-absent memory B cells against a normal total B cell count. This is the finding
    that makes a routine lymphocyte count misleading in this disease.
  phenotype_term:
    preferred_term: Decreased memory B cell proportion
    term:
      id: HP:0030374
      label: Decreased memory B cell proportion
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:38129623
    reference_title: "Inherited Human BCL10 Deficiencies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most significant immunological feature of BCL10 deficiency is that despite normal total numbers of T and B cells, their phenotype is naïve mainly with very low numbers of memory T and B cells."
    explanation: >-
      States both halves of the finding: normal totals, very low memory numbers.
- category: Cellular
  name: Decreased memory T cell proportion
  description: >-
    The T cell counterpart of the memory B cell deficit, again against normal total
    T cell numbers.
  phenotype_term:
    preferred_term: Decreased memory T cell proportion
    term:
      id: HP:0032183
      label: Decreased memory T cell proportion
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:34868072
    reference_title: "Clinical and Immunological Features of Human BCL10 Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our results showed that BCL10 deficiency impairs the development of memory B, CD4+ and CD8+ T cells and confirmed previous reports (29, 30)."
    explanation: >-
      Reports impaired development of memory CD4+ and CD8+ T cells as well as memory
      B cells.
- category: Cellular
  name: Decreased regulatory T cell proportion
  description: >-
    Reduced or absent regulatory T cells. Reported by mass cytometry in one patient and
    independently by conventional flow cytometry with intracellular FOXP3, Helios and
    CTLA-4 staining in another, where a low residual population was preserved rather
    than absent. The 2026 report also describes reduced or absent Tregs as a typical
    feature across the reported series, citing five prior cases, which is why this
    carries a frequency where the other minor subsets here do not.
  phenotype_term:
    preferred_term: Decreased regulatory T cell proportion
    term:
      id: HP:0020113
      label: Decreased regulatory T cell proportion
  frequency: FREQUENT
  evidence:
  - reference: PMID:42473108
    reference_title: "A novel linker region truncating variant in BCL10 underlies a leaky immunodeficiency phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected patients typically present with early‐onset severe infections and hypogammaglobulinemia, along with profoundly impaired T cell proliferation after TCR stimulation, largely preserved total T and B cell counts with a predominantly naïve phenotype, and markedly reduced or absent Treg cells, resulting in severe clinical courses and early death in most reported cases."
    explanation: >-
      Places the Treg deficit among the typical cross-patient features, which is what
      supports assigning a frequency rather than leaving it unquantified.
  - reference: PMID:42473108
    reference_title: "A novel linker region truncating variant in BCL10 underlies a leaky immunodeficiency phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Notably, Foxp3+Treg cells were markedly reduced in the patient, but a low residual population was still preserved (Figure1G)."
    explanation: >-
      The direct measurement in a second patient, and the qualifier that matters: reduced
      with a residual population, not absent.
  - reference: PMID:34868072
    reference_title: "Clinical and Immunological Features of Human BCL10 Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Furthermore, we observed a reduction in the frequencies of NK, γδT, Tregs, and Tfh cells."
    explanation: >-
      The independent mass-cytometry observation in a different patient.
- category: Cellular
  name: Decreased antigen-specific T cell proliferation
  description: >-
    T cells fail to proliferate on TCR stimulation. This is the functional assay that
    exposes the defect when the counts are normal.
  phenotype_term:
    preferred_term: Decreased antigen-specific T cell proliferation
    term:
      id: HP:0031402
      label: Decreased antigen-specific T cell proliferation
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:38129623
    reference_title: "Inherited Human BCL10 Deficiencies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "T cell proliferation was measured in P1 and P4 and was blocked upon TCR stimulation (Table 1) [35,38]."
    explanation: >-
      Records the proliferation block on TCR stimulation in the two patients in whom it
      was measured.
- category: Dermatologic
  name: Eczematoid dermatitis
  description: >-
    Dermatitis is one of the three hallmark clinical features. Reported presentations
    include scalp dermatitis extending to trunk and axilla, diaper dermatitis, and
    severe eczema controlled on low-potency steroid.
  phenotype_term:
    preferred_term: Eczematoid dermatitis
    term:
      id: HP:0000964
      label: Eczematoid dermatitis
  frequency: FREQUENT
  evidence:
  - reference: PMID:38129623
    reference_title: "Inherited Human BCL10 Deficiencies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical hallmark of BCL10 deficiency is mainly respiratory infections since the first months of life, dermatitis, and gastrointestinal tract infections (Table 3)."
    explanation: Names dermatitis among the three hallmark features.
- category: Growth
  name: Failure to thrive
  description: >-
    Documented in at least two of the seven reported patients: one developed chronic
    diarrhoea and failed to thrive from three months of age, and the seventh reported
    patient had growth retardation with longitudinal height and weight curves published.
    The OCCASIONAL band is a floor rather than an estimate. Growth is not systematically
    reported across this case series, so two of seven is what can be counted, not what
    is necessarily present.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:38159157
    reference_title: "BCL10 Deficiency Presenting as Severe Combined Immunodeficiency Escaping Newborn Screening."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, at the age of 3 months, he developed chronic diarrhea and failed to thrive."
    explanation: >-
      Records failure to thrive with its age of onset, in the patient who presented as
      SCID.
  - reference: PMID:42473108
    reference_title: "A novel linker region truncating variant in BCL10 underlies a leaky immunodeficiency phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Together, these findings indicate an early‐onset disorder characterized by recurrent infections, chronic mucocutaneous and gastrointestinal inflammation, and growth impairment."
    explanation: >-
      The authors' summary of their patient, which places growth impairment alongside
      the infection and inflammation phenotype. This is a single-patient statement, not
      a cross-patient one.
- category: Gastrointestinal
  name: Chronic diarrhea
  description: >-
    Prolonged or chronic diarrhoea, distinct from the colitis phenotype below: the index
    patient's prolonged diarrhoea was attributed to Campylobacter jejuni, and the
    SCID-presenting patient developed chronic diarrhoea at three months without a
    reported colitis diagnosis. Curated separately because an infectious enteritis and a
    chronic inflammatory colitis are different claims about the gut.
  phenotype_term:
    preferred_term: Chronic diarrhea
    term:
      id: HP:0002028
      label: Chronic diarrhea
    temporality: CHRONIC
  frequency: FREQUENT
  evidence:
  - reference: PMID:38159157
    reference_title: "BCL10 Deficiency Presenting as Severe Combined Immunodeficiency Escaping Newborn Screening."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, at the age of 3 months, he developed chronic diarrhea and failed to thrive."
    explanation: Records chronic diarrhoea with its age of onset.
- category: Immunologic
  name: BCGitis
  description: >-
    Localized suppuration at the BCG vaccination site in the seventh reported patient. A
    live attenuated vaccine given to a child with an as-yet-undiagnosed combined
    immunodeficiency, so this is clinically actionable rather than incidental. Note the
    source reports the suppuration and does not state culture confirmation, so the HPO
    binding names the local BCG-disease pattern rather than a proven mycobacterial
    isolate. A second patient's BCG scar flared at one month of age, which is the same
    concern.
  phenotype_term:
    preferred_term: Localized suppuration at the BCG vaccination site
    term:
      id: HP:0020086
      label: BCGitis
  evidence:
  - reference: PMID:42473108
    reference_title: "A novel linker region truncating variant in BCL10 underlies a leaky immunodeficiency phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient also showed growth retardation and localized suppuration at the BCG vaccination site (Figure1A,C)."
    explanation: >-
      The observation itself. Frequency is omitted: BCG is not given universally, so the
      denominator of vaccinated patients in this series is not stated.
- category: Gastrointestinal
  name: Colitis
  description: >-
    Chronic colitis and prolonged diarrhoea were prominent in the index patient. Gut
    involvement is not universal: the second reported patient had neither significant
    gastroenteritis nor chronic colitis despite the same complete deficiency.
  phenotype_term:
    preferred_term: Colitis
    term:
      id: HP:0002583
      label: Colitis
    temporality: CHRONIC
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:32008135
    reference_title: "Human BCL10 Deficiency due to Homozygosity for a Rare Allele."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical phenotype shared features, such as respiratory infections, but differed from that of the previous patient that he did not develop significant gastroenteritis episodes or chronic colitis."
    explanation: >-
      Establishes that colitis occurs in some patients and not others, which is why the
      frequency is set below the respiratory features rather than equal to them.
- category: Immunologic
  name: Recurrent otitis media
  description: >-
    Recurrent otitis was part of the index patient's infection burden and ear infections
    recurred in later patients.
  phenotype_term:
    preferred_term: Recurrent otitis media
    term:
      id: HP:0000403
      label: Recurrent otitis media
    temporality: RECURRENT
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:38129623
    reference_title: "Inherited Human BCL10 Deficiencies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Since six months of age, he suffered several infections at the respiratory and gut level: flu A and B, adenovirus; respiratory syncytial virus (RSV), gastroenteritis (adenovirus), prolonged diarrhea (Campylobacter jejuni), chronic colitis, as well as recurrent otitis, oral candidiasis and diaper dermatitis, secondary diffuse leukoencephalopathy, and encephalitis"
    explanation: >-
      The index patient's infection list, which includes recurrent otitis.
- category: Immunologic
  name: Chronic oral candidiasis
  description: >-
    Oral candidiasis in the index patient. Notably this is not the invasive fungal
    disease that characterises CARD9 deficiency, consistent with the preserved myeloid
    PAMP responses.
  phenotype_term:
    preferred_term: Chronic oral candidiasis
    term:
      id: HP:0009098
      label: Chronic oral candidiasis
  evidence:
  - reference: PMID:38129623
    reference_title: "Inherited Human BCL10 Deficiencies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Since six months of age, he suffered several infections at the respiratory and gut level: flu A and B, adenovirus; respiratory syncytial virus (RSV), gastroenteritis (adenovirus), prolonged diarrhea (Campylobacter jejuni), chronic colitis, as well as recurrent otitis, oral candidiasis and diaper dermatitis, secondary diffuse leukoencephalopathy, and encephalitis"
    explanation: >-
      Records oral candidiasis in the index patient. Frequency is omitted: it appears in
      one patient's list rather than in a summary across the series.
- category: Neurologic
  name: Leukoencephalopathy
  description: >-
    Diffuse leukoencephalopathy and encephalitis in the index patient, described as
    secondary to the infectious burden rather than as a primary feature of the gene
    defect.
  phenotype_term:
    preferred_term: Leukoencephalopathy
    term:
      id: HP:0002352
      label: Leukoencephalopathy
  evidence:
  - reference: PMID:38129623
    reference_title: "Inherited Human BCL10 Deficiencies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Since six months of age, he suffered several infections at the respiratory and gut level: flu A and B, adenovirus; respiratory syncytial virus (RSV), gastroenteritis (adenovirus), prolonged diarrhea (Campylobacter jejuni), chronic colitis, as well as recurrent otitis, oral candidiasis and diaper dermatitis, secondary diffuse leukoencephalopathy, and encephalitis"
    explanation: >-
      The source describes the leukoencephalopathy as secondary, which is why this entry
      does not place it on the pathophysiology chain.
- category: Immunologic
  name: Pneumocystis jirovecii pneumonia
  description: >-
    Opportunistic pneumonia in the patient who presented as SCID, alongside systemic
    adenovirus infection.
  phenotype_term:
    preferred_term: Pneumocystis jirovecii pneumonia
    term:
      id: HP:0020102
      label: Pneumocystis jirovecii pneumonia
  evidence:
  - reference: PMID:38159157
    reference_title: "BCL10 Deficiency Presenting as Severe Combined Immunodeficiency Escaping Newborn Screening."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report on a 5-month-old male infant with complete B-cell lymphoma/leukemia 10 (BCL10) deficiency presenting with fatal severe combined immunodeficiency (SCID) characterized by systemic adenovirus infection and Pneumocystis jirovecii pneumonia."
    explanation: Records the opportunistic infection in the SCID-presenting patient.
treatments:
- name: Hematopoietic Stem Cell Transplantation
  description: >-
    The only curative option, and the reason early genetic diagnosis matters. Outcome
    depends on how much damage has accumulated: the index patient died before he could
    be transplanted, later patients were transplanted early after a fast genetic
    diagnosis, and one patient died after transplantation.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: hematopoietic stem cell transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  target_mechanisms:
  - target: Failure of Memory B and T Cell Generation
    description: >-
      Replaces the BCL10-deficient haematopoietic compartment with donor cells that can
      assemble a CBM complex, restoring lymphocyte activation and memory generation. It
      does not address the fibroblast defect, which is not of haematopoietic origin.
    evidence:
    - reference: PMID:38129623
      reference_title: "Inherited Human BCL10 Deficiencies."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In these patients, the only effective treatment is HSCT."
      explanation: >-
        States that transplantation is the only effective treatment, which is the claim
        this treatment-to-mechanism link rests on.
  evidence:
  - reference: PMID:38129623
    reference_title: "Inherited Human BCL10 Deficiencies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Human BCL10 deficiency causes combined immunodeficiency with bone marrow transplantation as its only curative option."
    explanation: Names transplantation as the only curative option.
- name: Immunoglobulin Replacement Therapy
  description: >-
    Supportive rather than curative. In the fifth reported patient, intravenous
    immunoglobulin was followed by no further need for hospitalisation.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: immunoglobulin replacement therapy
    term:
      id: NCIT:C62710
      label: Immunoglobulin Therapy
  target_mechanisms:
  - target: Hypogammaglobulinemia
    description: >-
      Substitutes donor-derived specific antibody for the immunoglobulin the patient
      cannot generate. It replaces the product of the missing memory compartment without
      restoring the compartment.
    evidence:
    - reference: PMID:38129623
      reference_title: "Inherited Human BCL10 Deficiencies."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "He did not need hospitalization since starting Intravenous Immunoglobulin (IVIG) and his eczema is controlled on a low potency steroid."
      explanation: >-
        A single-patient observation of clinical benefit after starting immunoglobulin
        replacement.
- name: Genetic Counseling
  description: >-
    All reported families are consanguineous, and in most the diagnosis followed the
    death of an earlier sibling. Counselling and cascade testing therefore change
    outcomes for the next child rather than only informing the index patient.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:38129623
    reference_title: "Inherited Human BCL10 Deficiencies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The majority of the patients had a sibling who died before the diagnosis of the index patient."
    explanation: >-
      Documents the recurrence pattern within families that makes counselling and
      cascade testing consequential.
animal_models:
- name: Bcl10-null mouse
  species: Mouse
  genotype: Bcl10 knockout
  publication: PMID:11163238
  description: >-
    The Bcl10 knockout reproduces the human immunological defect and adds one the human
    disease does not have. About a third of null embryos develop exencephaly and die;
    survivors are severely immunodeficient with lymphocytes that cannot be activated
    through the antigen receptor. No human BCL10-deficient patient has been reported with
    a neural tube defect, which is what makes this model useful and partly misleading at
    the same time.
  modeled_mechanisms:
  - target: Arrested Lymphocyte Activation and Proliferation
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: CELLULAR
    description: >-
      Null lymphocytes fail to activate on antigen-receptor stimulation, which is the
      same functional lesion measured in patients.
    limitations: >-
      A constitutive whole-animal null, so it cannot separate the lymphocyte-intrinsic
      defect from developmental effects. The subset structure also differs: mouse work
      shows the CD4+ subset is the most severely impaired, and no human study has
      resolved the defect by subset in that way.
    readouts:
    - name: Antigen-receptor-induced lymphocyte activation
      target: Arrested Lymphocyte Activation and Proliferation
      direction: DECREASED
      interpretation: >-
        Failure of activation on antigen-receptor or PMA/ionomycin stimulation, the
        cellular readout corresponding to the human proliferation block.
      evidence:
      - reference: PMID:11163238
        reference_title: "Bcl10 is a positive regulator of antigen receptor-induced activation of NF-kappaB and neural tube closure."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "However, surviving bcl10-/- mice were severely immunodeficient and bcl10-/- lymphocytes are defective in antigen receptor or PMA/Ionomycin-induced activation."
        explanation: The measurement behind this readout, in the surviving null animals.
    evidence:
    - reference: PMID:18941215
      reference_title: "Loss of protein kinase C theta, Bcl10, or Malt1 selectively impairs proliferation and NF-kappa B activation in the CD4+ T cell subset."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Our data confirm that CD4(+) T cells from PKCtheta, Bcl10, and Malt1 knockout mice show severe impairment of proliferation in response to TCR stimulation."
      explanation: >-
        Independent confirmation of the proliferation defect in the knockout, and the
        source of the subset asymmetry noted in the limitations.
diagnosis:
- name: Functional lymphocyte testing against normal lymphocyte counts
  description: >-
    The diagnostic trap. Total T and B cell counts are normal, so quantitative
    immunophenotyping reads as reassuring; the abnormality appears only in memory subset
    proportions, immunoglobulin levels, and proliferation on stimulation. One patient
    passed newborn SCID screening and presented at five months with fatal disseminated
    infection.
  presence: PRESENT
  evidence:
  - reference: PMID:38159157
    reference_title: "BCL10 Deficiency Presenting as Severe Combined Immunodeficiency Escaping Newborn Screening."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Newborn screening was normal including TREC (T cell receptor excision circles) based screening for SCID."
    explanation: >-
      The paper that actually reports the screening escape, cited for that claim. TREC
      screening counts recent thymic emigrants, which are preserved here, so the assay
      is blind to a defect that lies downstream in activation and memory formation.
  - reference: PMID:38129623
    reference_title: "Inherited Human BCL10 Deficiencies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This gene should be studied when a patient presents with recurrent infections, hypogammaglobulinemia, and reduced numbers of B and T memory lymphocytes."
    explanation: >-
      Gives the triad that should trigger BCL10 testing, none of which is a total
      lymphocyte count.
- name: Functional validation of a candidate variant
  description: >-
    BCL10 is on current primary immunodeficiency sequencing panels, so the variant is
    now usually found before the phenotype is understood. The source is explicit that a
    candidate variant should be functionally validated, including protein expression,
    before committing a child to transplantation.
  presence: PRESENT
  evidence:
  - reference: PMID:38129623
    reference_title: "Inherited Human BCL10 Deficiencies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Still, when a candidate mutation appears disease-causing, performing a functional validation, including protein expression, is crucial to ensure that it is a BCL10 deficiency and thus proceed to HSCT."
    explanation: >-
      States the functional-validation requirement and ties it to the transplant
      decision.
differential_diagnoses:
- name: CARD11 and MALT1 deficiency
  description: >-
    The other two components of the same signalosome. Complete loss of any one produces
    a combined immunodeficiency that is clinically similar, and the distinction is made
    by sequencing rather than by phenotype. The one phenotypic hint is the
    non-haematopoietic arm: the fibroblast signalling defect is a BCL10 finding.
  evidence:
  - reference: PMID:31060714
    reference_title: "Germline CBM-opathies: From immunodeficiency to atopy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Germline mutations that alter the function of members of this complex (termed CBM-opathies) cause a broad array of clinical phenotypes, ranging from profound combined immunodeficiency to B-cell lymphocytosis."
    explanation: >-
      Establishes that the CBM component deficiencies form one clinical family, which is
      what makes them each other's differential.
- name: CARD9 deficiency
  description: >-
    Also a CBM-opathy, but the opposite cell-type pattern. CARD9 is the myeloid CARD
    adaptor and its loss gives isolated invasive fungal disease; BCL10-deficient myeloid
    cells respond normally to fungal and bacterial PAMPs, and the reported fungal
    disease is mucosal candidiasis rather than invasive.
  evidence:
  - reference: PMID:34868072
    reference_title: "Clinical and Immunological Features of Human BCL10 Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Autosomal recessive complete deficiencies in the two Caspase recruitment domain-containing (CARD) adaptor proteins, CARD9 (3) and CARD11 (2, 4) cause isolated invasive fungal infections (3, 5–28) and combined immunodeficiency (CID) respectively (2, 4)."
    explanation: >-
      Contrasts the CARD9 phenotype (isolated invasive fungal infection) with the
      combined immunodeficiency seen here.
discussions:
- discussion_id: imd37_fibroblast_defect_independent_contribution
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Impaired Fibroblast Innate Receptor Signalling
  prompt: >-
    Does the fibroblast signalling defect contribute independently to the clinical
    phenotype, or is the disease fully explained by the lymphocyte defect?
  rationale: >-
    The fibroblast finding is what the founding paper is named for, and it is
    reproducible across patients. What is missing is any observation that separates its
    contribution from the lymphocyte defect. Transplantation replaces only the
    haematopoietic compartment, so a fibroblast-attributable residual phenotype in
    successfully transplanted patients would be the natural readout, but the transplanted
    series is too small and too short for anyone to have looked. Until then the
    fibroblast-to-infection edge in this entry is INDIRECT on purpose.
- discussion_id: imd37_minor_lymphocyte_subsets_single_patient
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Failure of Memory B and T Cell Generation
  prompt: >-
    Are the reduced NK and gamma-delta T cell frequencies a general feature of BCL10
    deficiency, or a finding in one patient?
  rationale: >-
    The mass-cytometry study that reported reduced NK, gamma-delta T, regulatory T and
    follicular helper T cells is the only one to have measured NK and gamma-delta T
    subsets, so those two remain single-patient observations and are recorded here
    without a frequency.

    The regulatory T cell half of that finding is no longer in this position, and this
    entry no longer treats it as such. The 2026 report measured Tregs independently by
    conventional flow cytometry with intracellular FOXP3, Helios and CTLA-4 staining,
    found them markedly reduced, and describes reduced or absent Tregs as typical across
    the reported series. So conventional flow cytometry does resolve them and the deficit
    is corroborated. Follicular helper T cells sit between the two: the same report places
    Tfh and Tfr at the low end of the age-matched normal range, which is weaker
    corroboration than the Treg finding and not enough to support a frequency.
- discussion_id: imd37_mouse_neural_tube_defect_absent_in_humans
  kind: HUMAN_MODEL_MISMATCH
  attaches_to:
  - animal_models#Bcl10-null mouse
  - pathophysiology#CBM Signalosome Assembly Failure
  prompt: >-
    Why does Bcl10 loss cause a neural tube closure defect in mouse but not, apparently,
    in humans?
  rationale: >-
    A third of Bcl10-null mouse embryos develop exencephaly and die of it. Nothing like
    that has been described in any reported human patient, all of whom had complete or
    near-complete deficiency and survived to present with infection. Three explanations
    are open and nothing distinguishes them: BCL10 may simply have no non-redundant role
    in human neural tube closure; the human alleles may retain enough residual function
    for closure while failing for lymphocyte activation; or human embryos with the same
    defect may be lost before ascertainment, since every reported family came to
    attention through a surviving affected child. The third possibility matters for
    counselling and is unaddressed. It also bears on the fibroblast finding: a
    developmental role for BCL10 outside the haematopoietic system would fit the
    non-haematopoietic defect this entry records.
  evidence:
  - reference: PMID:11163238
    reference_title: "Bcl10 is a positive regulator of antigen receptor-induced activation of NF-kappaB and neural tube closure."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We show that one-third of bcl10-/- embryos developed exencephaly, leading to embryonic lethality."
    explanation: >-
      The mouse finding whose human counterpart is absent, with its penetrance, which is
      what makes the ascertainment explanation worth stating.
references:
- reference: PMID:25365219
  title: "Inherited BCL10 deficiency impairs hematopoietic and nonhematopoietic immunity."
- reference: PMID:38129623
  title: "Inherited Human BCL10 Deficiencies."
- reference: PMID:34868072
  title: "Clinical and Immunological Features of Human BCL10 Deficiency."
notes: >-
  MONDO carries a descendant of MONDO:0014491, MONDO:0979327 "combined immunodeficiency
  with low Ig due to BCL10 deficiency", which names the same disease under an
  Orphanet-style convention rather than a distinct subtype. It is deliberately not
  curated here as a has_subtypes entry: there is no second entity to describe, and
  splitting one gene's single phenotype across two records would misrepresent the
  literature.

  No GeneReviews chapter exists for BCL10 deficiency, so the phenotype baseline for this
  entry is the 2023 five-patient review (PMID:38129623) rather than a GeneReviews
  Clinical Characteristics section.

  Deep research. An openscientist report is committed alongside this entry. Its reference
  validation resolved 16 of 16 citations but flagged one quote as unsupported by the paper
  it was attributed to (PMID:30283440); nothing from that reference is used here. Its term
  validation reported seven label mismatches, all of which turned out to be table-cell text
  ("Laboratory abnormality", "Clinical sign") rather than proposed labels. The report's
  substantive contribution to this entry was two references the manual search had missed:
  the CBM filament structure (PMID:24074955), which explains why every disease allele sits
  in the CARD domain, and the Bcl10-null mouse (PMID:11163238), which carries a neural tube
  phenotype with no human counterpart. Every snippet here was taken from the cached
  reference text, not from the report.

  No datasets block. Searching BCL10 in expression repositories returns lymphoma studies,
  where BCL10 is famous for the MALT lymphoma translocations, and none of them concerns
  this disease. That is the Named Entity Confusion case the dataset-curation guidance
  warns about, so the block is omitted rather than filled with gene-symbol matches.
📚

References & Deep Research

References

3
PMID:25365219
Inherited BCL10 deficiency impairs hematopoietic and nonhematopoietic immunity.
No top-level findings curated for this source.
PMID:38129623
Inherited Human BCL10 Deficiencies.
No top-level findings curated for this source.
PMID:34868072
Clinical and Immunological Features of Human BCL10 Deficiency.
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 (3)

Record notes

MONDO carries a descendant of MONDO:0014491, MONDO:0979327 "combined immunodeficiency with low Ig due to BCL10 deficiency", which names the same disease under an Orphanet-style convention rather than a distinct subtype. It is deliberately not curated here as a has_subtypes entry: there is no second entity to describe, and splitting one gene's single phenotype across two records would misrepresent the literature. No GeneReviews chapter exists for BCL10 deficiency, so the phenotype baseline for this entry is the 2023 five-patient review (PMID:38129623) rather than a GeneReviews Clinical Characteristics section. Deep research. An openscientist report is committed alongside this entry. Its reference validation resolved 16 of 16 citations but flagged one quote as unsupported by the paper it was attributed to (PMID:30283440); nothing from that reference is used here. Its term validation reported seven label mismatches, all of which turned out to be table-cell text ("Laboratory abnormality", "Clinical sign") rather than proposed labels. The report's substantive contribution to this entry was two references the manual search had missed: the CBM filament structure (PMID:24074955), which explains why every disease allele sits in the CARD domain, and the Bcl10-null mouse (PMID:11163238), which carries a neural tube phenotype with no human counterpart. Every snippet here was taken from the cached reference text, not from the report. No datasets block. Searching BCL10 in expression repositories returns lymphoma studies, where BCL10 is famous for the MALT lymphoma translocations, and none of them concerns this disease. That is the Named Entity Confusion case the dataset-curation guidance warns about, so the block is omitted rather than filled with gene-symbol matches.

Review round 1: correct Treg claim, add three phenotypes · 2026-09-07T18:22:48Z · View source

Addresses the ai4c-reviewer REQUEST_CHANGES on PR #11379. Both blocking findings were verified against the cached primary sources before acting, and both held. Finding 1, failure to thrive omitted: added Failure to thrive (HP:0001508) with evidence from PMID:38159157 and PMID:42473108. Frequency set to OCCASIONAL rather than the FREQUENT band the deep-research table suggested, because it is documented in two of seven reported patients (29 percent) and growth is not systematically reported across the series; the description says the band is a floor rather than an estimate. Finding 2, the regulatory T cell claim was wrong: the entry said the Treg reduction was a single-patient mass-cytometry finding that conventional flow cytometry would not have resolved. PMID:42473108, already cited elsewhere in the same entry, contradicts both halves. It measured Tregs by conventional flow cytometry with intracellular FOXP3, Helios and CTLA-4 staining and found them markedly reduced with a preserved residual population, and it describes reduced or absent Tregs as a typical cross-patient feature citing five prior reports. The phenotype now carries frequency FREQUENT with three evidence items, and the discussion was narrowed to NK and gamma-delta T cells, which remain genuinely single-patient. Note the reviewer suggested grouping Th17 with the single-patient subsets; that was not done, because PMID:42473108 reports Th17 increased rather than reduced. All five reviewer suggestions taken in the same push: chronic diarrhea (HP:0002028) curated separately from colitis; BCGitis (HP:0020086) for the localized suppuration at the BCG vaccination site, with the description recording that the source does not state culture confirmation; the newborn-screening diagnosis claim re-pointed to PMID:38159157, which is the paper that reports it; the R88X gnomAD minor allele frequency added to the genetic section; and the TLR3-independence result added to the fibroblast node to bound the defect from the other side. Three snippets initially failed the pre-commit exact-substring check because non-ASCII characters in the cached text had been normalized during transcription (a non-breaking space in '3 months' and U+2010 hyphens in 'early-onset'). All were re-extracted programmatically from the cache. One of those edits broke the YAML by inserting a multi-line snippet; repaired and re-parsed before validating. Validated: just validate (62/62 snippets), just validate-disorders, check-entity-refs, check-causal-targets, check-duplicate-keys, check-enum-values, check-qualifier-terms, check-folded-hyphens, check-snippet-length, check-title-snippets, check-snippet-grading, check-environmental-evidence. No cache churn: every reference used was already committed in this PR.

Create: Immunodeficiency 37 (BCL10 deficiency) · 2026-09-07T17:55:25Z · View source

De novo curation of MONDO:0014491 (immunodeficiency 37), the autosomal recessive combined immunodeficiency caused by biallelic BCL10 loss of function. Pathophysiology is curated as a causal chain from the CARD-domain lesion through CBM signalosome assembly failure, loss of antigen-receptor NF-kappaB signalling, arrested lymphocyte activation, failure of memory B and T cell generation, and hypogammaglobulinemia to the infection phenotype, with a parallel non-haematopoietic branch for the fibroblast innate-signalling defect that the founding report is named for. 53 evidence snippets, all exact-quote verified against the reference cache. Deep research: one openscientist run, committed; its reference validation resolved 16/16 citations but flagged one unsupported quote (PMID:30283440), which is not used. The report contributed two references the manual literature search had missed, the CBM filament structure (PMID:24074955) and the Bcl10-null mouse (PMID:11163238); every snippet was taken from the cached reference text rather than from the report. Validated with just validate (schema, terms, references), check-entity-refs, check-causal-targets, check-duplicate-keys, check-enum-values, check-qualifier-terms, check-folded-hyphens, check-snippet-length, check-title-snippets and check-snippet-grading, all passing.

OpenScientist ▸
Immunodeficiency 37 (BCL10 Deficiency): Comprehensive Disease Characteristics Report
openscientist-autonomous 16 citations 2026-09-07T17:40:12.584633

Immunodeficiency 37 (BCL10 Deficiency): Comprehensive Disease Characteristics Report

Disease: Immunodeficiency 37 (IMD37) · OMIM: #616098 · MONDO: MONDO:0014491 · Causal gene: BCL10 (1p22.3) · Category: Mendelian, autosomal recessive combined immunodeficiency (CBM-opathy)

Summary

Immunodeficiency 37 (IMD37) is an ultra-rare autosomal recessive combined immunodeficiency caused by biallelic loss-of-function mutations in BCL10, the caspase-recruitment-domain (CARD) adaptor protein that nucleates the CARD11–BCL10–MALT1 (CBM) signalosome. The CBM complex is the molecular bridge that connects antigen-receptor engagement on B and T cells (and innate pattern-recognition receptors on other cell types) to activation of the canonical NF-κB pathway. When BCL10 is absent, antigen-receptor–induced NF-κB signaling is abolished, while proximal tyrosine phosphorylation, MAPK/AP-1, and calcium signaling remain intact. The result is a combined immunodeficiency affecting both hematopoietic (lymphocyte) and non-hematopoietic (fibroblast innate-receptor) immunity.

Clinically, IMD37 presents in infancy or early childhood with recurrent sinopulmonary infections, mucocutaneous candidiasis, gastroenteritis/enteropathy, and failure to thrive. The immunologic hallmark is a profound deficit of memory B and T cells with hypogammaglobulinemia and impaired specific antibody responses, despite frequently near-normal total lymphocyte counts. Additional reductions in NK cells, γδ T cells, and regulatory T cells have been documented. The disease is caused by homozygous (often private, consanguinity-associated) nonsense or frameshift alleles that abolish BCL10 protein expression; a single "leaky" linker-region frameshift variant produces a milder hypomorphic phenotype.

Prognosis is poor without allogeneic hematopoietic stem cell transplantation (HSCT), which is the only curative therapy. The index patient died at 3 years of age. Supportive care consists of immunoglobulin replacement and antimicrobial prophylaxis. Because BCL10 is also required in non-hematopoietic cells, HSCT corrects the lymphoid compartment but would not be expected to correct the fibroblast innate-immunity defect. As of 2026, only approximately six to seven patients have been reported worldwide, making this one of the rarest inborn errors of immunity known. This report synthesizes 9 confirmed findings and 31 reviewed papers across all 15 requested disease-characteristic domains.

Key Findings

Finding 1 — IMD37 is autosomal recessive complete BCL10 deficiency

Immunodeficiency 37 corresponds to OMIM entry #616098 and MONDO:0014491. It was first characterized in a landmark 2014 study by Torres and colleagues (Inherited BCL10 deficiency impairs hematopoietic and nonhematopoietic immunity, J Clin Invest). The index patient was a child homozygous for a loss-of-expression, loss-of-function BCL10 mutation who presented with a broad combined immunodeficiency and died at 3 years of age. Critically, the defect affected both hematopoietic and non-hematopoietic immunity, distinguishing BCL10 deficiency from many other inborn errors of immunity that are restricted to lymphoid cells.

"we characterized a case of autosomal-recessive, complete BCL10 deficiency in a child with a broad immunodeficiency, including defects of both hematopoietic and nonhematopoietic immunity. The patient died at 3 years of age and was homozygous for a loss-of-expression, loss-of-function BCL10 mutation." — PMID: 25365219

The disease is exceptionally rare. A 2026 report confirms the small global patient count:

"BCL10 deficiency is an exceptionally rare autosomal recessive combined immunodeficiency, with only six patients reported to date." — PMID: 42473108

The causal gene, BCL10, is located on chromosome 1p22.3, encodes a CARD-containing signaling adaptor, and carries the identifiers HGNC:989 and gene-OMIM 603517.

Finding 2 — BCL10 links antigen-receptor signaling to NF-κB via the CBM signalosome

The mechanistic role of BCL10 was defined in Ruland et al. (2001, Cell) using Bcl10-knockout mice. These animals showed complete absence of antigen-receptor–induced NF-κB activation, while early tyrosine phosphorylation, MAPK/AP-1 signaling, and calcium flux remained normal — pinpointing BCL10's specific position in the signaling network.

"antigen receptor-induced NF-kappaB activation was absent. Thus, Bcl10 functions as a positive regulator of lymphocyte proliferation that specifically connects antigen receptor signaling in B and T cells to NF-kappaB activation." — PMID: 11163238

BCL10 acts within the tripartite CARD11 (CARMA1)–BCL10–MALT1 (CBM) signalosome. CARD11 nucleates BCL10 filaments, which in turn recruit the MALT1 paracaspase; the assembled complex bridges the T-cell receptor (TCR) and B-cell receptor (BCR) — as well as the innate CARD9/CARD14 receptors — to IKK-mediated canonical NF-κB, JNK, and mTORC1 activation.

"The caspase recruitment domain family member 11 (CARD11 or CARMA1)-B cell CLL/lymphoma 10 (BCL10)-MALT1 paracaspase (MALT1) [CBM] signalosome complex serves as a molecular bridge between cell surface antigen receptor signaling and the activation of the NF-κB, JNK, and mTORC1 signaling axes." — PMID: 30283440

Finding 3 — Immunophenotype: profound memory lymphocyte defect with near-normal cell counts

Patients characteristically show near-absence of memory B and memory T cells, hypogammaglobulinemia with impaired specific antibody responses, and defective T- and B-cell proliferation to antigen-receptor stimulation — all despite frequently near-normal total lymphocyte counts. Mass cytometry of a patient homozygous for the K63X nonsense allele (Garcia-Solis et al. 2021, Front Immunol) additionally revealed reductions in NK cells, γδ T cells, and regulatory T cells.

"in addition to the near absence of memory B and T cells previously reported, this patient displays a reduction in NK, γδT, Tregs, and T" — PMID: 34868072

Importantly, the non-hematopoietic arm of the phenotype is real: BCL10-null fibroblasts show dramatically impaired NF-κB–mediated functions, while myeloid PAMP responses are largely preserved. IMD37 can present with an SCID-like picture yet escape TREC-based newborn screening, as documented in a case report titled BCL10 Deficiency Presenting as Severe Combined Immunodeficiency Escaping Newborn Screening (PMID: 38159157).

Finding 4 — Mouse model recapitulates immunodeficiency and adds a neural tube defect

Bcl10-knockout mice recapitulate the core human immunodeficiency and additionally reveal a developmental role. Approximately one-third of Bcl10−/− embryos develop exencephaly (a neural tube closure defect) leading to embryonic lethality; surviving mice are severely immunodeficient.

"We show that one-third of bcl10-/- embryos developed exencephaly, leading to embryonic lethality." — PMID: 11163238

"surviving bcl10-/- mice were severely immunodeficient and bcl10-/- lymphocytes are defective in antigen receptor or PMA/Ionomycin-induced activation" — PMID: 11163238

Subset-specific studies show that CD4+ T cells are most severely affected, whereas CD8+ T cells retain partial CBM-independent NF-κB activation (PMID: 18941215); antigen-experienced CD4+CD44hi memory T cells can even bypass BCL10 for IL-2 production (PMID: 18583339). A non-immune role is also evident: Bcl10-deficient mice are protected from angiotensin-II–dependent atherosclerosis and aortic aneurysm via the vascular CARMA3–BCL10–MALT1 axis (PMID: 20605784).

Finding 5 — Pathogenic variant spectrum: biallelic loss-of-function nonsense/frameshift alleles

All reported IMD37 patients carry biallelic loss-of-expression, loss-of-function BCL10 variants. The documented allele spectrum is summarized below.

Variant Type Effect Reference
Private frameshift (Patient 1) Frameshift Complete loss of protein Torres 2014, PMID: 25365219
K63X Nonsense Complete loss of protein Garcia-Solis 2021, PMID: 34868072
R88X Nonsense Loss-of-expression / loss-of-function; heterozygous MAF 3.99×10⁻⁶ Van Den Rym 2020, PMID: 32008135
c.345_346dup (p.Gly116GlufsTer3) Linker frameshift "Leaky" hypomorph, low-abundance truncated protein Tong 2026, PMID: 42473108

"we report a new BCL10 mutation in another child with CID who was homozygous for a BCL10 variant (R88X), previously reported as a rare allele in heterozygosis (minor allele frequency, 0.000003986). The mutant allele was a loss-of-expression and loss-of-function allele." — PMID: 32008135

"A novel homozygous BCL10 c.345_346dup (p.Gly116GlufsTer3) variant was identified in a patient with combined immunodeficiency and immune dysregulation, with relatively mild infections" — PMID: 42473108

This establishes an emerging genotype–phenotype correlation: complete-null alleles produce severe early-lethal disease, while the leaky linker-region frameshift produces a milder, later-recognized phenotype.

Finding 6 — Clinical phenotype: early-onset infections, enteropathy, and innate fibroblast defects

Onset is in infancy or early childhood. Core clinical features are recurrent respiratory (sinopulmonary) infections, candidiasis/mucocutaneous infections, gastroenteritis and chronic colitis/enteropathy, and failure to thrive. The gastrointestinal manifestations show variable expressivity — present in the index patient but absent in the R88X patient.

"The clinical phenotype shared features, such as respiratory infections, but differed from that of the previous patient that he did not develop significant gastroenteritis episodes or chronic colitis." — PMID: 32008135

The non-hematopoietic defect was mechanistically confirmed by showing that fibroblast innate-receptor responses depend on BCL10:

"TLR4, TLR2/6, and Dectin-1 responses were found to depend on BCL10 in fibroblasts, and final maturation of T cell and B cell maturation into memory cells was affected." — PMID: 32008135

Finding 7 — Treatment and prognosis: HSCT is the only curative option

Human BCL10 deficiency is managed supportively with immunoglobulin replacement (IVIG/SCIG) and antimicrobial prophylaxis, but allogeneic hematopoietic stem cell transplantation is the only curative therapy.

"Human BCL10 deficiency causes combined immunodeficiency with bone marrow transplantation as its only curative option." — PMID: 38129623

Proof-of-concept for curative HSCT in the CBM-opathy family comes from the closely related MALT1 deficiency, which was successfully treated with reduced-intensity conditioning and full immunological normalization:

"The clinical and immunological phenotype of MALT1 deficiency can be successfully treated with hematopoietic stem cell transplantation following reduced intensity conditioning." — PMID: 27109639

Prognosis is poor without HSCT — the index patient died at 3 years. No gene therapy or small-molecule therapy exists. A key caveat: HSCT corrects the hematopoietic compartment but would not correct the non-hematopoietic (fibroblast) BCL10 defect.

Finding 8 — Identifiers, inheritance, and epidemiology

Disease identifiers: Immunodeficiency 37 (IMD37); OMIM #616098; MONDO:0014491.

Gene identifiers (BCL10, "BCL10 immune signaling adaptor"): NCBI Gene 8915; HGNC:989; gene OMIM 603517; Ensembl ENSG00000142867; UniProt O95999; cytoband 1p22.3 (GRCh38 chr1:85,265,776–85,276,640, minus strand). Aliases: CARMEN, CIPER, CLAP, c-E10, mE10, IMD37. Mouse ortholog: Bcl10 (NCBI Gene 12051).

Inheritance: Autosomal recessive, with complete penetrance in biallelic loss-of-function carriers. Heterozygous carriers are healthy. Disease results from homozygous (often private, consanguinity-associated) LoF alleles.

Epidemiology: Ultra-rare — only ~6–7 patients reported worldwide as of 2026. No population prevalence or incidence has been established. Both sexes are affected (autosomal locus). Carrier alleles are extremely rare in gnomAD (e.g., R88X MAF 3.99×10⁻⁶).

"BCL10 deficiency is an exceptionally rare autosomal recessive combined immunodeficiency, with only six patients reported to date." — PMID: 42473108

Finding 9 — Structural basis: BCL10 CARD nucleates helical CBM filaments

Structural work (Qiao et al. 2013, Mol Cell) using cryo-EM, crystallography, and NMR revealed that the CBM signalosome is a helical filamentous assembly. Substoichiometric CARMA1 (CARD11) nucleates BCL10 CARD filaments; filament formation is highly cooperative and its threshold is sensitized by oligomerized CARMA1 upon receptor activation. These filaments then recruit and activate MALT1 to drive NF-κB. Structure-guided mutagenesis of the BCL10 filament interfaces abolished both MALT1 activation and cellular NF-κB activation.

"the reconstituted CBM signalosome is a helical filamentous assembly in which substoichiometric CARMA1 nucleates Bcl10 filaments. Bcl10 filament formation is a highly cooperative process whose threshold is sensitized by oligomerized CARMA1 upon receptor activation." — PMID: 24074955

This explains why complete loss of BCL10 abolishes NF-κB signaling: BCL10 is the nucleated scaffold that converts receptor engagement into a digital, threshold-gated signaling output.

Section-by-Section Disease Characterization

1. Disease Information

IMD37 is an autosomal recessive combined immunodeficiency caused by complete BCL10 deficiency. Key identifiers: OMIM #616098; MONDO:0014491; gene BCL10 OMIM 603517; HGNC:989. Synonyms/alternative names: BCL10 deficiency; immunodeficiency 37; IMD37. There is no dedicated Orphanet number widely used beyond the CBM-opathy grouping; ICD-11 would fall under primary immunodeficiency/combined immunodeficiency categories (e.g., 4A00). Information source: aggregated at the disease level from a handful of individual case reports (EHR-derived clinical data on ~6–7 patients worldwide), synthesized with model-organism and in-vitro mechanistic data.

2. Etiology

Primary cause: genetic — biallelic (homozygous) loss-of-function mutations in BCL10. Genetic risk factors: consanguinity is the dominant risk factor, as disease requires two LoF alleles that are individually extremely rare (e.g., R88X MAF 3.99×10⁻⁶). No susceptibility loci, modifier genes, or protective alleles have been established given the tiny patient count. Environmental risk/protective factors: none identified; the disease is fully penetrant Mendelian. Gene–environment interactions: the phenotype is triggered by ordinary environmental pathogen exposure acting on a defective immune system, but no specific GxE modifier is documented.

3. Phenotypes

Phenotype Type HPO term (suggested) Onset Frequency
Recurrent respiratory/sinopulmonary infections Clinical sign HP:0002783 / HP:0002205 Infancy Core, most patients
Recurrent candidiasis / mucocutaneous infection Clinical sign HP:0002728 Infancy Frequent
Chronic diarrhea / enteropathy / colitis Clinical sign HP:0002028 / HP:0002037 Infancy Variable expressivity
Failure to thrive Physical manifestation HP:0001508 Infancy Frequent
Hypogammaglobulinemia Laboratory abnormality HP:0002720 Congenital/infancy Core
Decreased memory B cells Laboratory abnormality HP:0005404 Congenital Core
Reduced/absent memory T cells Laboratory abnormality HP:0011840 Congenital Core
Impaired specific antibody response Laboratory abnormality HP:0004313 Congenital Core
Decreased NK / γδ T / Treg cells Laboratory abnormality HP:0040218 Congenital Documented (K63X patient)

Severity: severe in complete-null genotypes (early death), milder in the leaky hypomorph. Progression: progressive with recurrent infections. Quality-of-life impact: severe — chronic infection, malnutrition, and early mortality without HSCT.

4. Genetic / Molecular Information

Causal gene: BCL10 (1p22.3; OMIM 603517; HGNC:989). Pathogenic variants: all biallelic germline LoF — frameshift (private; c.345_346dup p.Gly116GlufsTer3) and nonsense (K63X, R88X). ACMG classification: pathogenic/likely pathogenic. Variant types: nonsense and frameshift predominate; no missense pathogenic alleles yet reported. Allele frequency: extremely rare in gnomAD (R88X MAF 3.99×10⁻⁶). Origin: germline. Functional consequence: complete loss of function (null) for most; hypomorphic "leaky" loss for the linker frameshift. Modifier genes/epigenetics/chromosomal abnormalities: none established for the germline disease. (Note: somatic BCL10 truncating mutations and t(1;14)(p22;q32) rearrangements occur in MALT lymphoma — PMID: 10319863, PMID: 11445840 — a distinct dysregulation context, not IMD37.)

5. Environmental Information

No environmental, lifestyle, or toxicant contributing factors are known — IMD37 is a fully penetrant monogenic disorder. Infectious agents are downstream consequences, not causes: patients suffer recurrent bacterial respiratory pathogens, Candida species (mucocutaneous candidiasis), and viral/gastrointestinal infections due to the underlying immune defect.

6. Mechanism / Pathophysiology

Ordered causal chain:

1. Biallelic LoF mutation in BCL10 (nonsense/frameshift)
│ leads to
2. Complete absence (or, for the leaky allele, near-absence) of BCL10 protein
│ results in
3. Failure to nucleate CARD11-BCL10-MALT1 (CBM) helical filaments
   (BCL10 CARD is the nucleated scaffold; CARMA1 seeds it)  [PMID:24074955]
│ leads to
4. No recruitment/activation of MALT1 paracaspase; no IKK activation
│ results in
5. Abolished antigen-receptor-induced canonical NF-kB activation
   (proximal tyrosine-P, MAPK/AP-1, Ca2+ remain intact)     [PMID:11163238]
│ branches into
   ┌────────────────────────────┬──────────────────────────────────┐
6a. Hematopoietic arm:          6b. Non-hematopoietic arm:
   defective B/T proliferation,    fibroblast TLR4, TLR2/6, Dectin-1
   failed memory B/T generation,   responses fail (BCL10-dependent)
   hypogammaglobulinemia,          [PMID:32008135]
   reduced NK/gdT/Treg
│ leads to                        │ leads to
7. Combined immunodeficiency: impaired adaptive AND innate immunity
│ results in
8. Clinical manifestation: recurrent respiratory infections, candidiasis,
   enteropathy, failure to thrive -> early death without HSCT

Molecular pathways (KEGG/Reactome): canonical NF-κB signaling (downstream), also JNK and mTORC1 axes (PMID: 30283440). Cellular processes (GO): lymphocyte activation (GO:0046649), antigen receptor-mediated signaling (GO:0050851), I-κB kinase/NF-κB signaling (GO:0007249). Protein dysfunction: loss of the BCL10 filament scaffold; the CBM complex (GO:0032449) cannot assemble. Immune involvement: immunodeficiency, both adaptive and innate. Upstream vs downstream: the mutation → loss of scaffold → loss of NF-κB is upstream; memory-cell failure and clinical infection are downstream. Cell types (CL): T cell (CL:0000084), B cell (CL:0000236), memory B cell (CL:0000787), memory T cell (CL:0000813), NK cell (CL:0000623), γδ T cell (CL:0000798), regulatory T cell (CL:0000815), fibroblast (CL:0000057).

7. Anatomical Structures Affected

Organ/system level: immune/hematopoietic system (UBERON:0002405) is primary; secondary involvement of the respiratory tract (lung, UBERON:0002048; airways), gastrointestinal tract (intestine, UBERON:0000160; for enteropathy/colitis), and skin/mucosa (UBERON:0002097; candidiasis). Tissue/cell level: lymphoid tissue and lymphocytes; connective-tissue fibroblasts (non-hematopoietic arm). Subcellular (GO CC): cytoplasmic CBM signalosome/filament assembly signaling to the nucleus for NF-κB-dependent transcription. Lateralization: systemic/bilateral (not a focal lesion).

8. Temporal Development

Onset: congenital/neonatal-infantile immune defect, clinically manifesting in infancy/early childhood with an insidious-to-subacute course of recurrent infections. Progression: progressive without treatment; the leaky hypomorph runs a milder, later-recognized course. Duration: chronic and lifelong; fatal in early childhood without HSCT (index patient died at 3 years). Critical period: early diagnosis and HSCT before the establishment of chronic infections and end-organ (pulmonary) damage is the key intervention window.

9. Inheritance and Population

Inheritance: autosomal recessive; penetrance: complete in biallelic LoF carriers; expressivity: variable (GI features variable; leaky allele milder); carrier status: heterozygotes healthy. Consanguinity: a major contributor (homozygosity for rare private alleles). Founder effects/anticipation/mosaicism: none documented. Epidemiology: ultra-rare, ~6–7 patients worldwide as of 2026; no prevalence/incidence figures; both sexes affected; no ethnic predilection established beyond consanguineous pedigrees.

10. Diagnostics

Laboratory: immunoglobulin quantitation (hypogammaglobulinemia), specific antibody responses (impaired), lymphocyte subset immunophenotyping showing near-absent memory B/T cells with often near-normal total counts; extended flow/mass cytometry may show reduced NK, γδ T, and Treg. Functional NF-κB activation assays (impaired). Genetic testing is definitive: WES/WGS or a combined-immunodeficiency/primary-immunodeficiency gene panel including BCL10; single-gene sequencing confirms biallelic LoF variants. Newborn screening caveat: TREC-based SCID screening can miss IMD37 (PMID: 38159157). Differential diagnosis: other CBM-opathies — CARD11 deficiency (IMD11), MALT1 deficiency (IMD12) — and other combined immunodeficiencies (e.g., DOCK8 deficiency); distinguished by gene identification.

11. Outcome / Prognosis

Survival/mortality: poor without HSCT; index patient died at 3 years; another died in infancy — high early mortality. Morbidity: chronic recurrent infections, failure to thrive, potential end-organ (pulmonary) damage. Prognostic factors: genotype (complete-null vs leaky hypomorph), timing of HSCT relative to infection burden. Recovery potential: curative HSCT can restore the hematopoietic immune compartment (by analogy with MALT1 deficiency, PMID: 27109639), though the non-hematopoietic fibroblast defect would persist.

12. Treatment

  • Supportive/pharmacotherapy: immunoglobulin replacement (IVIG/SCIG; NCIT: Intravenous Immunoglobulin Therapy) and antimicrobial/antifungal prophylaxis.
  • Curative: allogeneic hematopoietic stem cell transplantation (NCIT: Allogeneic Hematopoietic Stem Cell Transplantation) — the only curative option (PMID: 38129623); reduced-intensity conditioning is effective in the related MALT1 deficiency (PMID: 27109639).
  • Advanced/experimental: no gene therapy, RNA therapy, or targeted small molecule exists; none in registered trials for IMD37 specifically.
  • Personalized medicine: genotype-guided — early HSCT for complete-null genotypes; the leaky hypomorph may permit more conservative initial management.

13. Prevention

Primary prevention: not possible (monogenic); genetic counseling for consanguineous families and carrier/cascade testing of relatives are the principal preventive measures (NSGC/ACMG framework). Prenatal/preimplantation genetic diagnosis is available for families with a known pathogenic BCL10 genotype. Secondary prevention: early molecular diagnosis and pre-emptive HSCT before infection-related organ damage. Tertiary prevention: immunoglobulin replacement and antimicrobial prophylaxis to prevent complications. Note that standard TREC newborn screening does not reliably detect IMD37.

14. Other Species / Natural Disease

Taxonomy/orthologs: mouse Bcl10 (NCBI Gene 12051; NCBI Taxon 10090) is the principal model ortholog; the gene is evolutionarily conserved. Natural disease in other species: no naturally occurring companion-animal or wildlife BCL10-deficiency disease is documented in OMIA to date. Comparative biology: the CBM/NF-κB axis is conserved across mammals; the mouse knockout adds an exencephaly/neural-tube phenotype not reported in humans, indicating species-specific developmental requirements. Zoonotic potential: not applicable (non-infectious genetic disease).

15. Model Organisms

Principal model: the Bcl10−/− mouse (Ruland et al. 2001, PMID: 11163238) — a constitutive knockout. Phenotype recapitulation: strong for the immunodeficiency (absent antigen-receptor NF-κB, defective lymphocyte activation and proliferation), providing the foundational mechanistic model. Model limitations/divergences: ~1/3 of embryos die of exencephaly (embryonic lethality), a neural-tube phenotype not seen in human patients; subset-specific studies show CD8+ T cells and memory CD4+CD44hi cells retain partial BCL10-independent function (PMID: 18941215, PMID: 18583339). In-vitro models: BCL10-null patient fibroblasts and CRISPR/reconstituted Jurkat T-cell NF-κB reporter systems (PMID: 34236636) are used to dissect CBM signaling. Resources: MGI (mouse), Cellosaurus (cell lines).

Mechanistic Model / Interpretation

IMD37 is best understood as a "CBM-opathy" — a disorder of the CARD11–BCL10–MALT1 signalosome. BCL10 occupies the central, non-redundant position in this three-protein module. Structurally, it is the nucleated filament scaffold: CARMA1 (CARD11), once oligomerized by receptor engagement, seeds the cooperative polymerization of BCL10 CARD filaments, which display MALT1 for activation. This filamentous, threshold-gated architecture converts a graded receptor input into a switch-like NF-κB output (PMID: 24074955).

Because BCL10 is the obligate scaffold, its complete loss produces a clean, specific lesion: antigen-receptor signaling still fires its proximal tyrosine kinases, MAPK, and calcium arms, but the NF-κB arm is silenced (PMID: 11163238). NF-κB is essential for the terminal differentiation and survival programs that generate immunological memory, which explains why the cardinal laboratory signature is loss of memory B and T cells with preserved naïve-cell counts.

A distinctive feature that separates BCL10 deficiency from CARD11 deficiency is the non-hematopoietic dimension. CARD11 (CARMA1) is lymphocyte-restricted, but BCL10 also partners with the broadly expressed CARMA3 (CARD10) and with CARD9/CARD14 in innate contexts. Consequently, BCL10-null fibroblasts fail to respond to TLR4, TLR2/6, and Dectin-1 stimulation (PMID: 32008135). This dual hematopoietic + non-hematopoietic defect is the key therapeutic caveat: HSCT replaces the lymphoid compartment but cannot correct the fibroblast (stromal) innate defect, which may limit long-term cure completeness even after successful transplantation.

Feature BCL10 (IMD37) CARD11 (IMD11) MALT1 (IMD12)
Cell-type breadth of defect Hematopoietic + non-hematopoietic Lymphocyte-restricted Hematopoietic + non-hematopoietic
Core immunophenotype Loss of memory B/T; hypogammaglobulinemia CID; variable CID; inflammatory features
Curative therapy HSCT only HSCT HSCT (proven, PMID: 27109639)
Global patient count ~6–7 Rare Rare

Evidence Base

PMID Title (abbreviated) Contribution
25365219 Inherited BCL10 deficiency impairs hematopoietic and nonhematopoietic immunity Defines the disease: AR complete BCL10 deficiency, dual immune defect, death at 3 y
42473108 A novel linker region truncating variant in BCL10 underlies a leaky immunodeficiency phenotype Epidemiology (~6 patients), hypomorphic genotype–phenotype correlation
11163238 Bcl10 is a positive regulator of antigen receptor-induced NF-κB and neural tube closure Core mechanism (NF-κB–specific defect) + mouse model (exencephaly)
30283440 The CBM-opathies Places BCL10 in the CBM signalosome; NF-κB/JNK/mTORC1 axes
34868072 Clinical and Immunological Features of Human BCL10 Deficiency Immunophenotype: memory loss + reduced NK/γδT/Treg
32008135 Human BCL10 Deficiency due to Homozygosity for a Rare Allele R88X allele + fibroblast innate-receptor dependence on BCL10
38129623 Inherited Human BCL10 Deficiencies HSCT as only curative option
27109639 HSCT for human MALT1 deficiency HSCT proof-of-concept for a related CBM-opathy
24074955 Structural architecture of the CARMA1/Bcl10/MALT1 signalosome Structural basis: BCL10 filament nucleation, threshold signaling
38159157 BCL10 Deficiency Escaping Newborn Screening Diagnostic caveat: TREC screening can miss IMD37
18941215 Loss of PKCθ/Bcl10/Malt1 selectively impairs CD4+ T cells CD4 > CD8 selectivity; CD8 retains partial CBM-independent NF-κB

Evidence source types: human clinical (case reports of ~6–7 patients), model organism (Bcl10−/− mouse), in vitro (patient fibroblasts, Jurkat reconstitution), and computational/structural (cryo-EM/NMR of the CBM filament).

Limitations and Knowledge Gaps

  1. Extremely small patient count (~6–7 worldwide). All clinical conclusions rest on case reports; no cohort statistics, formal prevalence/incidence, penetrance estimates, or survival curves exist.
  2. Genotype–phenotype correlation is preliminary. Only one "leaky" hypomorphic allele has been described; the full allelic and phenotypic spectrum (including any missense pathogenic variants) is unknown.
  3. HSCT outcome data are indirect. Direct long-term transplant outcomes in BCL10-deficient patients are sparse; the curative evidence is partly extrapolated from MALT1 deficiency.
  4. Non-hematopoietic contribution is unquantified. It remains unclear how much the fibroblast/stromal innate defect contributes to clinical disease, and whether it limits cure after HSCT.
  5. No natural animal disease and no established modifier genes, epigenetic mechanisms, or environmental modifiers.
  6. Newborn screening gap. Because IMD37 can escape TREC screening, true incidence may be underestimated.

Proposed Follow-up Experiments / Actions

  1. Establish an international BCL10-deficiency registry to aggregate genotypes, immunophenotypes, HSCT outcomes, and survival — the only way to move beyond single case reports.
  2. Systematic HSCT outcome study (conditioning regimen, chimerism, immune reconstitution, and whether the fibroblast defect persists post-transplant), ideally with comparison to MALT1/CARD11 CBM-opathy transplants.
  3. Genotype–function mapping: reconstitute the full allelic series (null vs leaky vs any candidate missense) in NF-κB reporter Jurkat and fibroblast systems to build a quantitative genotype–residual-signal–phenotype map.
  4. Assess the stromal/non-hematopoietic defect in vivo using conditional (tissue-specific) Bcl10 mouse models to isolate the fibroblast contribution and test whether HSCT alone is sufficient.
  5. Improve newborn detection: evaluate whether adding B-cell/KREC metrics or targeted CBM-gene panels to newborn screening captures IMD37 missed by TREC.
  6. Explore gene-correction feasibility (autologous HSC gene addition/editing of BCL10) as a future curative modality that could restore the hematopoietic compartment without allogeneic transplant risks.

Report compiled from 9 confirmed findings and 31 reviewed publications across a 5-iteration autonomous investigation. The evidence base is dominated by human case reports and the foundational Bcl10−/− mouse model; all mechanistic and clinical claims are cited to primary literature by PMID.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 16
Resolved 16
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 15
Quoted claims found in source 14
Quoted claims not found in source 1
References weighed for topical relevance 16
On topic 8
Off topic 0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

  • PMID:30283440 (abstract only): "The caspase recruitment domain family member 11 (CARD11 or CARMA1)-B cell CLL/lymphoma 10 (BCL10)-MALT1 paracaspase (MALT1) [CBM] signalosome complex serves as a molecular bridge between cell surface antigen receptor signaling and the activation of the NF-κB, JNK, and mTORC1 signaling axes."
  • closest text in source: "The caspase recruitment domain family member 11 (CARD11 or CARMA1)-B cell CLL/lymphoma 10 (BCL10)-MALT1 paracaspase (MALT1) [CBM] signalosome complex serves as a molecular bridge between cell surface antigen receptor signaling and the activation of the NF-κB, JNK, and mTORC1 signaling axes."

Term Validation

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

Outcome Count
Terms checked 29
Resolved 28
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 1
Terms whose name was checked 7
Terms named correctly 0
Terms named as a different term 7

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:

  • HP:0002728 (1 mention) - the report calls it "Clinical sign"; HP calls it Recurrent mucocutaneous candidiasis
  • HP:0001508 (1 mention) - the report calls it "Physical manifestation"; HP calls it Failure to thrive
  • HP:0002720 (1 mention) - the report calls it "Laboratory abnormality"; HP calls it Decreased circulating IgA concentration
  • HP:0005404 (1 mention) - the report calls it "Laboratory abnormality"; HP calls it Increased total B cell count
  • HP:0011840 (1 mention) - the report calls it "Laboratory abnormality"; HP calls it Abnormal T cell physiology
  • HP:0004313 (1 mention) - the report calls it "Laboratory abnormality"; HP calls it Decreased circulating immunoglobulin concentration
  • HP:0040218 (1 mention) - the report calls it "Laboratory abnormality"; HP calls it Reduced total natural killer cell count