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Mappings

MONDO

MONDO:0976228 immunodeficiency 132b

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Inheritance

1

Autosomal dominant HP:0000006

A single loss-of-function allele is sufficient. Expressivity is variable both within and between families - the two reported cohorts differ on the direction of the immunoglobulin abnormality - and no modifier has been identified.

Autosomal dominant inheritance

Show evidence (1 reference)

PMID:35960817 SUPPORT Human Clinical

"Affected individuals each had monoallelic mutations in TRAF3 that reduced TRAF3 expression."

Monoallelic variants in affected individuals, which is the dominance claim.

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Discussions and Knowledge Gaps

2

Why does the same class of TRAF3 loss-of-function variant produce raised immunoglobulin in one cohort and antibody deficiency in another?

KNOWLEDGE GAP OPEN gap_hyper_vs_hypogammaglobulinemia

Attached to

phenotypes#Hypergammaglobulinemia phenotypes#Hypogammaglobulinemia

The founding cohort's syndrome definition includes hypergammaglobulinemia. Every patient in the 2024 cohort was hypogammaglobulinemic on immunoglobulin replacement, and that paper names this as the most significant difference between its patients and the earlier ones. Both are curated here because both are reported, but they are opposite findings and the entry does not have a mechanism that predicts either. A mechanism that would reconcile them is available in outline - B cell expansion with a class-switch maturation defect could give either a high total immunoglobulin from sheer cell numbers or a low protective antibody titre from failed maturation, depending on which dominates - but nobody has measured the two cohorts on the same panel, and the alternative reading, that variant position or an unidentified modifier determines the direction, is untested.

Proposed experiments

Uniform B cell subset and immunoglobulin phenotyping across reported TRAF3 kindreds

traf3_ig_phenotype_harmonisation

Apply one immunophenotyping panel - total and class-switched memory B cells, naive B cells, plasmablasts, IgG/IgA/IgM and specific antibody responses - across patients from both published cohorts and any newly ascertained families, and test whether the immunoglobulin direction tracks with the class-switched memory compartment or with variant position.

Would support

pathophysiology#Impaired B Cell Maturation

Supporting outcome

Immunoglobulin direction tracks with the size of the class-switched memory B cell compartment, making the maturation defect the explanation and the two phenotypes two points on one axis.

Refuting outcome

The two cohorts have indistinguishable B cell subsets despite opposite immunoglobulin levels, which would move the explanation to modifiers or environment and leave the maturation-defect account unsupported.

Does normal ageing act as a second hit on TRAF3 dosage, so that a haploinsufficient patient's phenotype worsens over decades?

EMERGING HYPOTHESIS OPEN hypothesis_age_as_second_hit

Attached to

pathophysiology#Reduced TRAF3 Protein Dosage

TRAF3 protein, but not transcript, declines in B cells with age, and in older mice a two-hour in vivo proteasome inhibition is enough to raise it again - so the decline is degradative and ongoing rather than a fixed developmental setting. Someone who starts at half the normal protein and then loses more of it with age would, on this account, cross a functional threshold later in life. It is a hypothesis and is labelled as one. Nobody has followed TRAF3 haploinsufficient patients longitudinally, and the ageing data are not from patients. It is curated because it makes a testable prediction about when to watch for the malignancy risk this entry records, which is otherwise unstratified.

Show evidence (1 reference)

PMID:40773231 SUPPORT Model Organism

"Consistent with this prediction, in vivo treatment with bortezomib for only 2 h was sufficient to increase the level of B cell TRAF3 in older mice, but not young mice"

Shows the age-related decline is caused by ongoing proteasomal degradation, which is what makes it a plausible additive hit on a genetically halved pool.

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Pathophysiology

9

Heterozygous TRAF3 Loss-of-Function Variant

A single TRAF3 allele carries a premature-stop or frameshift variant. Reported alleles include the stop-gain variants p.Arg163* and p.Gln407*. The other allele is normal, and the variants act by reducing the amount of protein made rather than by producing an interfering product - which is what distinguishes this disease from its allelic dominant-negative counterpart.

Genetic context TRAF3 hgnc:12033 variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: LOSS_OF_FUNCTION

Monoallelic truncating variants reducing TRAF3 expression. Typed LOSS_OF_FUNCTION rather than DOMINANT_NEGATIVE, but not because the measured protein loss is a clean 50%: it is not. In the four founding-cohort patients tested the protein fell by more than half, and the authors proposed that increased ubiquitin-mediated proteasomal degradation of the wild-type product may account for the excess. The typing still holds. The alleles are truncating and act by removing one allele's output, and the accelerated turnover proposed here is a downstream consequence of the reduced dose rather than an interfering mutant protein. The distinction from the allelic dominant-negative disorder survives on both counts - protein there falls to roughly a sixth of control, and the phenotype is viral rather than bacterial.

Downstream

Reduced TRAF3 Protein Dosage A premature stop codon removes one allele's contribution to the protein pool.

Show evidence (2 references)

PMID:35960817 SUPPORT Human Clinical

"Affected individuals each had monoallelic mutations in TRAF3 that reduced TRAF3 expression."

The genetic lesion and its immediate consequence, stated together, which is the whole of what this node claims.

PMID:39579173 SUPPORT Human Clinical

"These individuals harbored stop-gain variants (p.Arg163* and p.Gln407*) and experienced recurrent bacterial infections with hypogammaglobulinemia."

Names two specific alleles of the class this node describes.

Reduced TRAF3 Protein Dosage

The disease is a dosage disease: roughly half the normal amount of TRAF3 protein is enough to produce it. That is not obvious a priori for an adaptor whose job is constitutive negative regulation, and the mouse work makes the case directly - B cell-conditional heterozygous mice have a 40 to 50% reduction in TRAF3 protein and mRNA in their B cells and a measurable phenotype at that level, intermediate between wild type and complete knockout. The node also explains why this pathway is dosage-sensitive at all. TRAF3 is degraded as part of normal signalling: CD40 and BAFF-R engagement drives its polyubiquitination and proteasomal destruction for hours after the signal. A cell that starts with half the protein and then degrades some of it on every activation event has correspondingly less brake to spare.

B cell CL:0000236

K48-linked polyubiquitination of TRAF3 GO:0070936

Animal models

B cell-conditional Traf3 heterozygous mouse (B-Traf3+/-) Mouse recapitulates Reproduces the defining feature of the human disease - a partial, not complete, reduction in TRAF3 - and shows it is sufficient for a phenotype.

Downstream

Non-canonical NF-kB2 Activation Less TRAF3 means less NIK degradation and more p100 to p52 processing.

T Cell Compartment Dysregulation The variant is germline, so the T cell compartment carries the same halved dose as the B cell one. What TRAF3 does in T cells to produce this particular pattern - fewer naive cells, more regulatory and circulating follicular helper cells - has not been worked out, and the available mouse models are B cell-conditional and so cannot address it. Typed with unknown intermediates for that reason.

Show evidence (3 references)

PMID:40773231 SUPPORT Model Organism

"We found that B-Traf3+/− mice have a 40 to 50% decrease in the amount of TRAF3 protein and Traf3 mRNA in their B cells"

Quantifies the dosage reduction that this node is about, in the model built to match the human genotype.

PMID:40773231 SUPPORT Model Organism

"Signaling through activating receptors CD40 and receptor for BAFF (BAFFR) induces a cascade resulting in TRAF3 polyubiquitination and proteasomal degradation, reducing levels of TRAF3 protein for hours or more after the signaling event"

The physiological turnover that makes a halved starting pool consequential.

PMID:39579173 SUPPORT Human Clinical

"Even in the case of protein, they observed > 50% reduction in the four patients tested"

PARTIAL because it qualifies rather than supports the simple half-dose picture: the measured protein loss in patients exceeds what losing one allele's output alone would give, which is why the genetic_context description above says so explicitly.

Non-canonical NF-kB2 Activation

With less TRAF3 to hold NIK down, non-canonical NF-kB2 signalling runs above its resting level. Patient B cells show increased NF-kB2 activation directly, and the heterozygous mouse shows the same thing alongside the downstream transcriptional output - the survival proteins Mcl1, Pim2 and c-Myc and the glycolytic enzyme Hxk2 are all significantly more abundant than in wild-type littermates. Recorded as INCREASED rather than GAIN_OF_FUNCTION: this is a normally regulated pathway running above its set point because a brake is at half strength, not a pathway escaping regulation altogether.

B cell CL:0000236

non-canonical NF-kappaB signal transduction GO:0038061 ↑ INCREASED

Downstream

B Cell Hyperactivity and Prolonged Survival NF-kB2 output raises the survival and metabolic proteins that keep B cells alive.

Show evidence (2 references)

PMID:35960817 SUPPORT Human Clinical

"Immunophenotyping showed that patients' B cells were dysregulated, exhibiting increased nuclear factor-κB 2 activation, elevated mitochondrial respiration, and heightened inflammatory responses."

The pathway state measured in patients rather than inferred from the mouse.

PMID:40773231 SUPPORT Model Organism

"The glycolytic protein Hxk2, NFκB2 p52, Mcl1, c-Myc, and Pim2 were all significantly more abundant in Traf3+/− B cells compared to B cells from WT littermates"

The transcriptional and metabolic output of the pathway, measured at the heterozygous dose.

B Cell Hyperactivity and Prolonged Survival

B cells with reduced TRAF3 survive longer than they should and accumulate. In the heterozygous mouse this is visible as increased spleen weight and splenic B cell numbers; in the complete B cell knockout the same axis produces lymphoid organ enlargement, autoantibodies and lymphoma with age. Patient B cells also show elevated mitochondrial respiration, so the survival advantage has a metabolic component and not only an anti-apoptotic one. IL-6 responsiveness is raised too: heterozygous B cells have higher phospho-STAT3 Y705 after IL-6 stimulation than wild type, though the difference reached significance only at the earliest timepoint - curated at the strength the source states it.

B cell CL:0000236 plasma cell CL:0000786

B cell homeostasis GO:0001782 ⚠ ABNORMAL

spleen UBERON:0002106

Animal models

B cell-conditional Traf3 heterozygous mouse (B-Traf3+/-) Mouse recapitulates Increased spleen weight, increased splenic B cell numbers and elevated survival and metabolic proteins at the heterozygous dose.

Downstream

Lymphoproliferation, Autoimmunity and Systemic Inflammation An expanded, long-lived, hyperresponsive B cell pool is the substrate for autoantibody production and lymphoid hyperplasia.

Impaired B Cell Maturation The expanding compartment is also a maldeveloping one: class-switched memory B cells fall while naive B cells rise.

Defective Humoral Defence Against Bacteria Routed through the maturation defect, which is now its own node, so the compartment expands without producing protective antibody. T cell dysregulation contributes in parallel.

B Cell Malignant Transformation Risk Chronic survival signalling is a plausible substrate for transformation, but the steps between it and a lymphoma in a haploinsufficient patient have not been demonstrated.

Show evidence (2 references)

PMID:40773231 SUPPORT Model Organism

"Our results show that B-Traf3+/− mice have significantly lower TRAF3 protein and mRNA levels in B cells, correlating closely with increased spleen weight and splenic B cell numbers compared to wild-type (WT) littermate mice."

Ties the dosage reduction to B cell accumulation in the same animals.

PMID:40773231 SUPPORT Model Organism

"Traf3+/− B cells had elevated pSTAT3 Y705 compared to WT B cells at all time points tested, although this increase reached statistical significance only at 15 min after IL-6 treatment"

The IL-6 hyperresponsiveness, quoted with the source's own qualification about where it was significant.

Impaired B Cell Maturation

The intermediate that connects B cell hyperactivity to antibody failure, and the reason the two are not a contradiction. The compartment expands, but it expands at the wrong end: class-switched memory B cells are markedly reduced while naive B cells are elevated. More B cells that have not completed maturation do not make more protective antibody. This node is what the entry's account of the immunodeficiency turns on, and it is also the axis the immunoglobulin knowledge gap proposes to measure - whether the direction of the immunoglobulin abnormality tracks with the size of the class-switched memory compartment.

memory B cell CL:0000787 naive B cell CL:0000788

B cell differentiation GO:0030183 ⚠ ABNORMAL

Downstream

Defective Humoral Defence Against Bacteria A compartment short of class-switched memory B cells cannot mount durable high-affinity antibody responses to encapsulated bacteria.

Show evidence (1 reference)

PMID:39579173 SUPPORT Human Clinical

"Extensive immunophenotyping showed impaired B cell maturation with markedly reduced class-switched memory B cell counts and elevated naïve B cells."

The maturation defect measured directly in patients, with both halves of it - the reduced switched memory compartment and the elevated naive one.

T Cell Compartment Dysregulation

TRAF3 haploinsufficiency is not confined to B cells. Patients have mild CD4+ T cell lymphopenia with a reduced proportion of naive T cells, and at the same time increased regulatory T cells and increased circulating T follicular helper cells. The founding study reads this as a contributor to the B cell phenotype - dysregulated T cell help - rather than as an independent arm of the disease, and this entry follows that reading. It is also the part of the syndrome that the available mouse models do not cover, since those are B cell-conditional.

CD4-positive T cell CL:0000624 regulatory T cell CL:0000815 circulating T follicular helper cell CL:0002038

Downstream

B Cell Hyperactivity and Prolonged Survival Increased circulating T follicular helper cells supply more B cell help; the founding study names dysregulated T cell help as a likely contributor.

Show evidence (4 references)

PMID:35960817 SUPPORT Human Clinical

"Patients had mild CD4+ T cell lymphopenia, with a reduced proportion of naïve T cells but increased regulatory T cells and circulating T follicular helper cells."

The T cell findings this node curates, in full.

PMID:39579173 SUPPORT Human Clinical

"Upon more detailed analysis, we found that two patients exhibited abnormal lymphocyte proliferation."

A functional readout rather than a subset count, which is what turns this node from an enumeration of flow-cytometry percentages into a claim about T cell capability.

PMID:39579173 SUPPORT Human Clinical

"with significantly decreased cell division after PMA + ionomycin and PHA stimulation"

The stimuli under which the proliferation defect was measured.

+ 1 more reference

Lymphoproliferation, Autoimmunity and Systemic Inflammation

The autoimmune and lymphoproliferative arm of the syndrome: B cell lymphoproliferation, autoimmunity and systemic inflammation, reported together in the founding cohort and confirmed as a phenotype description in the follow-up study.

lymph node UBERON:0000029 spleen UBERON:0002106

Show evidence (1 reference)

PMID:35960817 SUPPORT Human Clinical

"Here, in five unrelated families, we describe an immune dysregulation syndrome of recurrent bacterial infections, autoimmunity, systemic inflammation, B cell lymphoproliferation, and hypergammaglobulinemia."

The syndrome definition, from which this node takes its three components.

Defective Humoral Defence Against Bacteria

The immunodeficiency arm. Recurrent bacterial infection is present in both reported cohorts, and in the CVID-reanalysis cohort it came with hypogammaglobulinemia severe enough that the patients were on immunoglobulin replacement before their genetic diagnosis was made. That the same gene dose produces hypergammaglobulinemia in one cohort and hypogammaglobulinemia in another is unresolved and is curated as a knowledge gap rather than smoothed over.

lung UBERON:0002048

Show evidence (1 reference)

PMID:39579173 SUPPORT Human Clinical

"These individuals harbored stop-gain variants (p.Arg163* and p.Gln407*) and experienced recurrent bacterial infections with hypogammaglobulinemia."

The infection phenotype together with the antibody deficiency that accompanies it in this cohort.

B Cell Malignant Transformation Risk

An increased risk of B cell malignancy is part of the founding description of the syndrome, and the same study found that common TRAF3 variants which also reduce TRAF3 expression are associated with increased B cell malignancy risk in the general population - a dose-response argument from two directions. PROVISIONAL because the mechanism connecting a halved TRAF3 dose to a transformed clone has not been demonstrated in a patient. What exists is a plausible substrate (chronic NF-kB2 and survival-protein signalling), an epidemiological association, a mouse in which complete B cell TRAF3 loss produces lymphoma with age, and a naturally occurring canine B cell lymphoma in which TRAF3 mutation is common.

B cell CL:0000236

Animal models

B cell-conditional Traf3 knockout mouse (B-Traf3-/-) Mouse partially recapitulates Shows where chronic TRAF3 loss leads in B cells, at a gene dose no patient has.

Show evidence (3 references)

PMID:35960817 SUPPORT Human Clinical

"are associated with an increased risk of B cell malignancies, systemic lupus erythematosus, higher immunoglobulin levels, and bacterial infections in the wider population"

The population-level dose-response result that supports the malignancy claim beyond the small monogenic cohort.

PMID:40773231 SUPPORT INDIRECT Model Organism

"TRAF3-deficient B cells exhibit substantially enhanced survival, which in mice results in marked lymphoid organ enlargement, production of autoantibodies, and development of B cell lymphomas (BCL) with age"

INDIRECT because this is the complete-deficiency mouse, not the heterozygous one; it shows where the axis leads at full dose without establishing that it gets there at half dose.

PMID:25468570 SUPPORT Model Organism

"We found mutations affecting TRAF3, which encodes a negative regulator of nuclear factor (NF)-κB, to be a common feature of cBCLs, with mutations observed in 44% of tumors including a combination of somatic and rare germ-line variants."

PARTIAL and deliberately so: this is naturally occurring canine lymphoma, where the variants are largely somatic. It supports TRAF3 loss as a lymphomagenic event, not the germline haploinsufficient state as a lymphoma predisposition in humans.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

12

Blood 2

Hypogammaglobulinemia FREQUENT Decreased circulating immunoglobulin concentration HP:0004313

Show evidence (1 reference)

PMID:39579173 SUPPORT Human Clinical

"The most significant differences were hypogammaglobulinemia and a CVID-like presentation."

States the finding and, in the same sentence, that it diverges from the previously reported phenotype.

B Cell Malignancy Lymphoma HP:0002665

Show evidence (1 reference)

PMID:35960817 SUPPORT Human Clinical

"are associated with an increased risk of B cell malignancies, systemic lupus erythematosus, higher immunoglobulin levels, and bacterial infections in the wider population"

PARTIAL because the quoted association is for common expression-reducing variants in the wider population, not for the monogenic patients themselves.

Cardiovascular 2

B Cell Lymphoproliferation FREQUENT Lymphadenopathy HP:0002716

Show evidence (2 references)

PMID:35960817 SUPPORT Human Clinical

"Here, in five unrelated families, we describe an immune dysregulation syndrome of recurrent bacterial infections, autoimmunity, systemic inflammation, B cell lymphoproliferation, and hypergammaglobulinemia."

Names B cell lymphoproliferation as a component of the syndrome.

PMID:39579173 SUPPORT Human Clinical

"Lymphadeno-pathies Yes Yes - - - Yes - Yes Yes - Yes Yes"

The per-patient row from the pooled clinical table: 7 of 12, which sources the FREQUENT band. The hyphenation in "Lymphadeno-pathies" is a column-wrap artefact of the cached PDF text, not the paper's spelling.

Splenomegaly FREQUENT HP:0001744

Show evidence (2 references)

PMID:39579173 SUPPORT Human Clinical

"Splenomegaly Yes Yes - Yes - - - - Yes Yes Yes Yes"

The per-patient row from the pooled clinical table covering every published patient in both cohorts: 7 of 12.

PMID:39579173 SUPPORT Human Clinical

"Imaging studies showed splenomegaly, hepatomegaly, and paratracheal and mediastinal lymphadenopathy"

The finding in an individual patient, with the lymphadenopathy that accompanies it.

Immune 1

Autoimmunity FREQUENT HP:0002960

Show evidence (2 references)

PMID:35960817 SUPPORT Human Clinical

"Here, in five unrelated families, we describe an immune dysregulation syndrome of recurrent bacterial infections, autoimmunity, systemic inflammation, B cell lymphoproliferation, and hypergammaglobulinemia."

Names autoimmunity as a defining component of the syndrome; the source for this and the two phenotypes below.

PMID:39579173 SUPPORT Human Clinical

"Autoimmunity Yes - - Yes Yes Yes - Yes Yes No - -"

The per-patient row from the pooled clinical table, which puts autoimmunity at 6 of 12 and so sources the FREQUENT band rather than leaving it as an estimate.

Respiratory 1

Bronchiectasis OCCASIONAL HP:0002110

Show evidence (2 references)

PMID:39579173 SUPPORT Human Clinical

"Imaging studies confirmed cylindrical bronchiectasis in the right upper lobe, lingula, and left lower lobe."

The imaging diagnosis in a patient, with its distribution.

PMID:39579173 SUPPORT Human Clinical

"Pulmonary involvement Yes Yes - Yes Yes Yes - - Yes Yes Yes Yes"

PARTIAL because the table row counts pulmonary involvement of any kind (9 of 12), which is broader than bronchiectasis; it bounds the frequency from above rather than giving it.

Other 6

Recurrent Bacterial Infections VERY_FREQUENT Recurrent sinopulmonary infections HP:0005425

Show evidence (1 reference)

PMID:39579173 SUPPORT Human Clinical

"These individuals harbored stop-gain variants (p.Arg163* and p.Gln407*) and experienced recurrent bacterial infections with hypogammaglobulinemia."

The infection phenotype in the CVID-reanalysis cohort.

Gastrointestinal Inflammation FREQUENT Inflammation of the large intestine HP:0002037

Show evidence (2 references)

PMID:39579173 SUPPORT Human Clinical

"GI involvement Yes - - - - - - - Yes Yes Yes Yes"

The per-patient row from the pooled clinical table: 5 of 12.

PMID:39579173 SUPPORT Human Clinical

"Gastrointestinal endoscopy findings included nodular lymphoid hyperplasia, ileitis, and active chronic pancolitis"

What the inflammation looks like on endoscopy, which is the part that distinguishes it from garden-variety colitis.

Impaired B Cell Maturation FREQUENT Decreased class-switched memory B cell proportion HP:0030388

Show evidence (1 reference)

PMID:39579173 SUPPORT Human Clinical

"Extensive immunophenotyping showed impaired B cell maturation with markedly reduced class-switched memory B cell counts and elevated naïve B cells."

Both halves of the maturation defect, measured by flow cytometry in patients.

Hypergammaglobulinemia FREQUENT Increased circulating immunoglobulin concentration HP:0010702

Show evidence (1 reference)

PMID:35960817 SUPPORT Human Clinical

"Here, in five unrelated families, we describe an immune dysregulation syndrome of recurrent bacterial infections, autoimmunity, systemic inflammation, B cell lymphoproliferation, and hypergammaglobulinemia."

Names hypergammaglobulinemia in the founding cohort.

CD4+ T Cell Lymphopenia FREQUENT Decreased total CD4+ T cell count HP:5210418

Show evidence (1 reference)

PMID:35960817 SUPPORT Human Clinical

"Patients had mild CD4+ T cell lymphopenia, with a reduced proportion of naïve T cells but increased regulatory T cells and circulating T follicular helper cells."

Names the lymphopenia and its severity; the source for this and the phenotype below.

Reduced Naive T Cell Proportion FREQUENT Decreased naive T cell proportion HP:0031397

Show evidence (1 reference)

PMID:35960817 SUPPORT Human Clinical

"Patients had mild CD4+ T cell lymphopenia, with a reduced proportion of naïve T cells but increased regulatory T cells and circulating T follicular helper cells."

Names the naive T cell reduction.

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Genetic Associations

1

TRAF3 (Heterozygous loss-of-function variants in TRAF3 cause this disease. The gene-disease relationship rests on nine patients from five unrelated families in the founding study plus three patients from two further families in the 2024 reanalysis, with a consistent immunophenotype and a mechanism that the B cell-conditional heterozygous mouse reproduces at the same gene dose. Every published allele is truncating. The founding cohort contributed p.Tyr425*, p.Ser356Profs*6 and p.Gln114*; the 2024 cohort added p.Arg163* and p.Gln407*, with p.Arg163* recurring across both. That uniformity is what makes the variant class usable for interpretation. Premature-stop and frameshift alleles reduce TRAF3 output and cause this disease. Missense alleles that destabilise the wild-type protein - which take total TRAF3 below what haploinsufficiency alone would give - cause a different, allelic disorder with a different phenotype, and should not be curated against this entry. Practically, TRAF3 belongs on any CVID or hypogammaglobulinemia gene panel: all three patients in the 2024 cohort already carried a CVID diagnosis and were on immunoglobulin replacement when the variant was found by targeted reanalysis.)

Gene: TRAF3 hgnc:12033 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (3 references)

PMID:35960817 SUPPORT Human Clinical

"Thus, we define monogenic TRAF3 haploinsufficiency syndrome and demonstrate how common TRAF3 variants affect a range of human diseases."

The gene-disease claim in the form the founding study makes it.

PMID:39579173 SUPPORT Human Clinical

"These data expand the clinical phenotype of TRAF3Hl and pave the way for further investigation into loss-of-function variants in patients with CVID."

Independent replication in unrelated families, and the diagnostic recommendation that follows from it.

PMID:39579173 SUPPORT Human Clinical

"TRAF3 variant p.Y425* p.S356Pfs6* p.Q114* p.R163* p.Y425* p.R163* p.Q407*"

The allele row of the pooled clinical table, naming every published variant across both cohorts. All are nonsense or frameshift, which is the truncating-class claim.

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Medical Actions

3

Immunoglobulin Replacement Therapy

Action: immunoglobulin therapy Ontology label: Immunoglobulin Therapy NCIT:C62710

Platform: Protein replacement

Replacement immunoglobulin for the antibody deficiency. It is the one treatment documented in TRAF3 haploinsufficiency patients, and it was in place before the diagnosis was: all three patients in the 2024 cohort were already receiving it under a CVID label. No trial or outcome data exist for this disease specifically; the documented fact is that patients receive it, not that it has been shown to work here.

Mechanism Target:

Defective Humoral Defence Against Bacteria — Substitutes for the antibody the patient's own B cell compartment fails to make. It does nothing about the upstream signalling defect.

Show evidence (1 reference)

PMID:39579173 SUPPORT Human Clinical

"Previously, the patients had been diagnosed with common variable immunodeficiency (CVID) and were receiving immunoglobulin replacement therapy."

Documents the treatment in these patients, and the diagnostic label it was given under.

Antimicrobial Treatment and Prophylaxis

Action: pharmacotherapy Ontology label: Pharmacotherapy NCIT:C15986

Platform: Small molecule

Treatment of recurrent bacterial infection and, where structural lung damage has developed, prophylaxis on the usual antibody-deficiency principles. No TRAF3-specific evidence exists; this is standard care for the infection phenotype and is recorded without an evidence item rather than with a quote that would not be about this disease.

Genetic Counselling

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Platform: Behavioral / lifestyle

Autosomal dominant inheritance with a 50% recurrence risk per pregnancy, and variable expressivity that makes phenotype prediction for a carrier relative unsafe. Cascade testing of relatives is worth offering, since the 2024 cohort found affected relatives by exactly that route.

Show evidence (1 reference)

PMID:39579173 SUPPORT Human Clinical

"Through this reassessment and additional familial investigations, we identified three previously unidentified cases of TRAF3Hl within two different families."

PARTIAL because it supports the value of family investigation rather than counselling as an intervention; the cases were found by studying relatives of an index patient.

🔬

Diagnosis

2

Targeted TRAF3 Analysis in Inborn-Errors-of-Immunity Sequencing Data

Because TRAF3 haploinsufficiency looks like CVID, the productive diagnostic route has been to go back to sequencing data already generated for undiagnosed inborn-errors-of-immunity patients and look specifically at TRAF3. Doing that across 800 patients found three new cases in two families, all previously labelled CVID.

Show evidence (1 reference)

PMID:39579173 SUPPORT Human Clinical

"we conducted a TRAF3-targeted reanalysis of next-generation sequencing data from 800 patients with inborn errors of immunity"

The diagnostic strategy and its scale.

B Cell Immunophenotyping

Flow cytometry of the B and T compartments. The pattern that supports the diagnosis is a dysregulated B cell compartment with increased NF-kB2 activation, alongside mild CD4+ lymphopenia with reduced naive T cells and increased regulatory and circulating T follicular helper cells.

Show evidence (1 reference)

PMID:35960817 SUPPORT Human Clinical

"Immunophenotyping showed that patients' B cells were dysregulated, exhibiting increased nuclear factor-κB 2 activation, elevated mitochondrial respiration, and heightened inflammatory responses."

What immunophenotyping shows in these patients.

📊

Prevalence

1

Worldwide

Cases In Literature Not yet documented

Around a dozen patients have been reported: nine individuals from five unrelated families in the 2022 founding description, and three more from two families found by targeted reanalysis of an 800-patient inborn-errors-of-immunity sequencing cohort in 2024. That second route is the informative one for prevalence - the patients were already in a sequencing dataset under a CVID label, which suggests the reported count reflects how hard people have looked rather than how many patients exist.

Show evidence (2 references)

PMID:35960817 SUPPORT Human Clinical

"Here, in five unrelated families, we describe an immune dysregulation syndrome of recurrent bacterial infections, autoimmunity, systemic inflammation, B cell lymphoproliferation, and hypergammaglobulinemia."

The size of the founding cohort and the syndrome it defines.

PMID:39579173 SUPPORT Human Clinical

"we conducted a TRAF3-targeted reanalysis of next-generation sequencing data from 800 patients with inborn errors of immunity"

The ascertainment method behind the second cohort, and the reason the case count should be read as a floor.

🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from TRAF3 Haploinsufficiency:

Common variable immunodeficiency

Overlapping Features Not a differential so much as the label these patients are already carrying. Every patient in the 2024 cohort had a CVID diagnosis before TRAF3 was looked at, which makes idiopathic CVID the population in which undiagnosed TRAF3 haploinsufficiency is expected to sit.

Distinguishing Features

A monogenic TRAF3 loss-of-function variant
Accompanying autoimmunity, lymphoproliferation and B cell malignancy risk, which idiopathic CVID does not carry as a defined feature

Show evidence (1 reference)

PMID:39579173 SUPPORT Human Clinical

"Previously, the patients had been diagnosed with common variable immunodeficiency (CVID) and were receiving immunoglobulin replacement therapy."

Establishes the relationship between the two labels in practice.

TRAF3 dominant-negative deficiency (herpes simplex encephalitis susceptibility)

Overlapping Features The allelic disorder. A dominant-negative TRAF3 missense variant reduces total TRAF3 well below the level that losing one allele would give, impairs TLR3-dependent type I interferon production, and predisposes to herpes simplex encephalitis. It is a different phenotype from a different variant class in the same gene, and evidence about it should not be curated against this entry.

Distinguishing Features

Missense rather than truncating variant
TRAF3 protein far below the 50% expected from loss of one allele
Susceptibility to viral encephalitis rather than recurrent bacterial infection with autoimmunity

Show evidence (2 references)

PMID:39579173 SUPPORT Human Clinical

"In 2010, autosomal dominant TRAF3 deficiency was reported in a patient with herpes simplex virus-1 encephalitis, consistent with the role of TRAF3 in type I interferon production."

The earlier entity, described by the same review that then contrasts it with the haploinsufficiency phenotype.

PMID:39579173 SUPPORT Human Clinical

"Recently, a novel, completely different clinical phenotype was described in patients with TRAF3 haploinsufficiency (TRAF3Hl), characterized by recurrent bacterial infections, autoimmune features, systemic inflammation, and hypergammaglobulinemia."

The source's own statement that the two phenotypes are completely different, which is why they are separate entries rather than one.

🐁

Animal Models

2

B cell-conditional Traf3 heterozygous mouse (B-Traf3+/-)

A mouse built specifically to match the human genotype: one Traf3 allele deleted in the B lineage rather than both, giving a 40 to 50% protein reduction. It was made because the earlier B cell-conditional complete knockout models the endpoint of the pathway but not the dose at which human patients live, and the question was whether half is enough. It is.

Species

Mouse

Genotype

B cell-conditional Traf3 heterozygous (B-Traf3+/-)

Publication

PMID:40773231

Pathograph links

Reduced TRAF3 Protein Dosage recapitulates fidelity: high Reproduces the defining feature of the human disease - a partial, not complete, reduction in TRAF3 - and shows it is sufficient for a phenotype.

Limitations: The deletion is B cell-conditional, so nothing in this model speaks to the T cell dysregulation that is part of the human syndrome. It also does not carry a human stop-gain allele; the dose is engineered rather than inherited.

Readouts

B cell TRAF3 protein and Traf3 mRNA

Direction: DECREASED

Interpretation: Western blot and transcript measurement in splenic B cells, quantifying the reduction as 40 to 50% of wild-type littermates.

Show evidence (1 reference)

PMID:40773231 SUPPORT Model Organism

"We found that B-Traf3+/− mice have a 40 to 50% decrease in the amount of TRAF3 protein and Traf3 mRNA in their B cells"

The measurement and its magnitude.

Show evidence (1 reference)

PMID:40773231 SUPPORT Model Organism

"More recently, human patients with germline TRAF3 mutations leading to haploinsufficiency have been reported; the phenotypes of these patients show striking similarities with those of mice with TRAF3-deficient B cells."

The authors' own statement of why this mouse is informative for the human disease.

B Cell Hyperactivity and Prolonged Survival recapitulates fidelity: moderate Increased spleen weight, increased splenic B cell numbers and elevated survival and metabolic proteins at the heterozygous dose.

Limitations: MODERATE because the mouse readout is B cell accumulation in a lymphoid organ while the human readout is clinical lymphoproliferation and autoimmunity; the two are linked by argument rather than by a matched measurement.

Readouts

Spleen weight and splenic B cell number

Direction: INCREASED

Interpretation: Both increase relative to wild-type littermates and track with the degree of TRAF3 reduction.

Show evidence (1 reference)

PMID:40773231 SUPPORT Model Organism

"Our results show that B-Traf3+/− mice have significantly lower TRAF3 protein and mRNA levels in B cells, correlating closely with increased spleen weight and splenic B cell numbers compared to wild-type (WT) littermate mice."

The organ and cell-number measurements, with their correlation to TRAF3 level.

NF-kB2 p52 and survival protein abundance

Direction: INCREASED

Interpretation: Hxk2, NF-kB2 p52, Mcl1, c-Myc and Pim2 all significantly more abundant in heterozygous than wild-type B cells.

Show evidence (1 reference)

PMID:40773231 SUPPORT Model Organism

"The glycolytic protein Hxk2, NFκB2 p52, Mcl1, c-Myc, and Pim2 were all significantly more abundant in Traf3+/− B cells compared to B cells from WT littermates"

The molecular output measured at the heterozygous dose.

Show evidence (1 reference)

PMID:40773231 SUPPORT Model Organism

"Our results show that B-Traf3+/− mice have significantly lower TRAF3 protein and mRNA levels in B cells, correlating closely with increased spleen weight and splenic B cell numbers compared to wild-type (WT) littermate mice."

Supports treating this mouse as informative for the B cell hyperactivity node.

B cell-conditional Traf3 knockout mouse (B-Traf3-/-)

The complete B lineage knockout, included as the upper bound of the dose-response rather than as a model of the patient genotype. It develops lymphoid organ enlargement, autoantibodies and B cell lymphoma with age, which is what makes the heterozygous mouse's intermediate phenotype interpretable.

Species

Mouse

Genotype

B cell-conditional Traf3 homozygous knockout (B-Traf3-/-)

Publication

PMID:40773231

Pathograph links

B Cell Malignant Transformation Risk partially recapitulates fidelity: low Shows where chronic TRAF3 loss leads in B cells, at a gene dose no patient has.

Limitations: Patients are heterozygous; this mouse has no B cell TRAF3 at all. It establishes the direction of the axis and nothing about the risk conferred by half a dose, which is the claim the human entry needs.

Show evidence (1 reference)

PMID:40773231 SUPPORT Model Organism

"TRAF3-deficient B cells exhibit substantially enhanced survival, which in mice results in marked lymphoid organ enlargement, production of autoantibodies, and development of B cell lymphomas (BCL) with age"

The complete-loss phenotype, which is the comparator this model provides.

{ }

Source YAML

click to show

name: TRAF3 Haploinsufficiency
creation_date: "2026-08-26T13:30:00Z"
category: Mendelian
disease_term:
  preferred_term: TRAF3 haploinsufficiency
  term:
    id: MONDO:0100513
    label: TRAF3 haploinsufficiency
synonyms:
- TRAF3 haploinsufficiency syndrome
- immunodeficiency 132b
- IMD132B
description: >-
  An autosomal dominant immune dysregulation syndrome caused by heterozygous
  loss-of-function variants in TRAF3, which halve the amount of TRAF3 protein. Patients
  have recurrent bacterial infection together with autoimmunity, systemic inflammation,
  B cell lymphoproliferation and an increased risk of B cell malignancy - a combination
  that is characteristic of the NF-kB-pathway inborn errors of immunity but is unusual in
  being produced by a gene-dosage effect rather than by a null state.

  TRAF3 is a brake. With TRAF2 and cIAP1/2 it keeps NIK ubiquitinated and degraded, which
  keeps non-canonical NF-kB2 signalling off at rest; engagement of CD40 or BAFF-R
  degrades TRAF3 and releases the brake as a normal part of B cell activation. Halving
  TRAF3 partially releases the brake all the time. What follows is not a failure of B
  cells but their hyperactivity: increased NF-kB2 activation, higher levels of the
  survival proteins Mcl1, Pim2 and c-Myc, raised mitochondrial respiration, and B cells
  that live longer than they should.

  The immunodeficiency is the part that needs explaining, because B cell hyperactivity is
  not an obvious route to failing to clear bacteria. Two things are curated here as
  contributing: a maturation defect - the B cell compartment expands while class-switched
  memory B cells fall - and concurrent T cell dysregulation, with mild CD4+ lymphopenia
  and fewer naive T cells alongside increased regulatory T cells and circulating T
  follicular helper cells.

  Two features of the entry are worth flagging before reading it. First, the
  immunoglobulin phenotype runs in both directions: the founding cohort reported
  hypergammaglobulinemia, while every patient in the later CVID-reanalysis cohort was
  hypogammaglobulinemic and on immunoglobulin replacement. Both are curated. Second, this
  entry is about the loss-of-function form only. A separate, allelic, dominant-negative
  disorder exists and is not the same disease; see the notes.

parents:
- Inborn Errors of Immunity
- Common Variable Immunodeficiency

prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    Around a dozen patients have been reported: nine individuals from five unrelated
    families in the 2022 founding description, and three more from two families found by
    targeted reanalysis of an 800-patient inborn-errors-of-immunity sequencing cohort in
    2024. That second route is the informative one for prevalence - the patients were
    already in a sequencing dataset under a CVID label, which suggests the reported count
    reflects how hard people have looked rather than how many patients exist.
  evidence:
  - reference: PMID:35960817
    reference_title: "Immunodeficiency, autoimmunity, and increased risk of B cell malignancy in humans with TRAF3 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, in five unrelated families, we describe an immune dysregulation syndrome of
      recurrent bacterial infections, autoimmunity, systemic inflammation, B cell
      lymphoproliferation, and hypergammaglobulinemia.
    explanation: >-
      The size of the founding cohort and the syndrome it defines.
  - reference: PMID:39579173
    reference_title: "Heterozygous Predicted Loss-of-function Variants of TRAF3 in Patients with Common Variable Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we conducted a TRAF3-targeted reanalysis of next-generation sequencing data from 800
      patients with inborn errors of immunity
    explanation: >-
      The ascertainment method behind the second cohort, and the reason the case count
      should be read as a floor.

pathophysiology:

- name: Heterozygous TRAF3 Loss-of-Function Variant
  role: trigger
  biological_scale: MOLECULAR
  description: >-
    A single TRAF3 allele carries a premature-stop or frameshift variant. Reported alleles
    include the stop-gain variants p.Arg163* and p.Gln407*. The other allele is normal,
    and the variants act by reducing the amount of protein made rather than by producing
    an interfering product - which is what distinguishes this disease from its allelic
    dominant-negative counterpart.
  genetic_context:
    gene:
      preferred_term: TRAF3
      term:
        id: hgnc:12033
        label: TRAF3
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Monoallelic truncating variants reducing TRAF3 expression. Typed LOSS_OF_FUNCTION
      rather than DOMINANT_NEGATIVE, but not because the measured protein loss is a clean
      50%: it is not. In the four founding-cohort patients tested the protein fell by more
      than half, and the authors proposed that increased ubiquitin-mediated proteasomal
      degradation of the wild-type product may account for the excess.

      The typing still holds. The alleles are truncating and act by removing one allele's
      output, and the accelerated turnover proposed here is a downstream consequence of the
      reduced dose rather than an interfering mutant protein. The distinction from the
      allelic dominant-negative disorder survives on both counts - protein there falls to
      roughly a sixth of control, and the phenotype is viral rather than bacterial.
  downstream:
  - target: Reduced TRAF3 Protein Dosage
    causal_link_type: DIRECT
    description: >-
      A premature stop codon removes one allele's contribution to the protein pool.
  evidence:
  - reference: PMID:35960817
    reference_title: "Immunodeficiency, autoimmunity, and increased risk of B cell malignancy in humans with TRAF3 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected individuals each had monoallelic mutations in TRAF3 that reduced TRAF3
      expression.
    explanation: >-
      The genetic lesion and its immediate consequence, stated together, which is the
      whole of what this node claims.
  - reference: PMID:39579173
    reference_title: "Heterozygous Predicted Loss-of-function Variants of TRAF3 in Patients with Common Variable Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These individuals harbored stop-gain variants (p.Arg163* and p.Gln407*) and
      experienced recurrent bacterial infections with hypogammaglobulinemia.
    explanation: >-
      Names two specific alleles of the class this node describes.

- name: Reduced TRAF3 Protein Dosage
  role: central_effector
  biological_scale: MOLECULAR
  description: >-
    The disease is a dosage disease: roughly half the normal amount of TRAF3 protein is
    enough to produce it. That is not obvious a priori for an adaptor whose job is
    constitutive negative regulation, and the mouse work makes the case directly -
    B cell-conditional heterozygous mice have a 40 to 50% reduction in TRAF3 protein and
    mRNA in their B cells and a measurable phenotype at that level, intermediate between
    wild type and complete knockout.

    The node also explains why this pathway is dosage-sensitive at all. TRAF3 is degraded
    as part of normal signalling: CD40 and BAFF-R engagement drives its polyubiquitination
    and proteasomal destruction for hours after the signal. A cell that starts with half
    the protein and then degrades some of it on every activation event has correspondingly
    less brake to spare.
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  biological_processes:
  - preferred_term: K48-linked polyubiquitination of TRAF3
    term:
      id: GO:0070936
      label: protein K48-linked ubiquitination
  downstream:
  - target: Non-canonical NF-kB2 Activation
    causal_link_type: DIRECT
    description: >-
      Less TRAF3 means less NIK degradation and more p100 to p52 processing.
  - target: T Cell Compartment Dysregulation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The variant is germline, so the T cell compartment carries the same halved dose as
      the B cell one. What TRAF3 does in T cells to produce this particular pattern -
      fewer naive cells, more regulatory and circulating follicular helper cells - has not
      been worked out, and the available mouse models are B cell-conditional and so cannot
      address it. Typed with unknown intermediates for that reason.
  evidence:
  - reference: PMID:40773231
    reference_title: "Reduction of TRAF3 by heterozygosity or aging impacts B cell function."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We found that B-Traf3+/− mice have a 40 to 50% decrease in the amount of TRAF3
      protein and Traf3 mRNA in their B cells
    explanation: >-
      Quantifies the dosage reduction that this node is about, in the model built to
      match the human genotype.
  - reference: PMID:40773231
    reference_title: "Reduction of TRAF3 by heterozygosity or aging impacts B cell function."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Signaling through activating receptors CD40 and receptor for BAFF (BAFFR) induces a
      cascade resulting in TRAF3 polyubiquitination and proteasomal degradation, reducing
      levels of TRAF3 protein for hours or more after the signaling event
    explanation: >-
      The physiological turnover that makes a halved starting pool consequential.
  - reference: PMID:39579173
    reference_title: "Heterozygous Predicted Loss-of-function Variants of TRAF3 in Patients with Common Variable Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Even in the case of protein, they observed > 50% reduction in the four patients
      tested
    explanation: >-
      PARTIAL because it qualifies rather than supports the simple half-dose picture: the
      measured protein loss in patients exceeds what losing one allele's output alone
      would give, which is why the genetic_context description above says so explicitly.

- name: Non-canonical NF-kB2 Activation
  role: central_effector
  biological_scale: MOLECULAR
  description: >-
    With less TRAF3 to hold NIK down, non-canonical NF-kB2 signalling runs above its
    resting level. Patient B cells show increased NF-kB2 activation directly, and the
    heterozygous mouse shows the same thing alongside the downstream transcriptional
    output - the survival proteins Mcl1, Pim2 and c-Myc and the glycolytic enzyme Hxk2 are
    all significantly more abundant than in wild-type littermates.

    Recorded as INCREASED rather than GAIN_OF_FUNCTION: this is a normally regulated
    pathway running above its set point because a brake is at half strength, not a pathway
    escaping regulation altogether.
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  biological_processes:
  - preferred_term: non-canonical NF-kappaB signal transduction
    term:
      id: GO:0038061
      label: non-canonical NF-kappaB signal transduction
    modifier: INCREASED
  downstream:
  - target: B Cell Hyperactivity and Prolonged Survival
    causal_link_type: DIRECT
    description: >-
      NF-kB2 output raises the survival and metabolic proteins that keep B cells alive.
  evidence:
  - reference: PMID:35960817
    reference_title: "Immunodeficiency, autoimmunity, and increased risk of B cell malignancy in humans with TRAF3 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Immunophenotyping showed that patients' B cells were dysregulated, exhibiting
      increased nuclear factor-κB 2 activation, elevated mitochondrial respiration, and
      heightened inflammatory responses.
    explanation: >-
      The pathway state measured in patients rather than inferred from the mouse.
  - reference: PMID:40773231
    reference_title: "Reduction of TRAF3 by heterozygosity or aging impacts B cell function."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The glycolytic protein Hxk2, NFκB2 p52, Mcl1, c-Myc, and Pim2 were all significantly
      more abundant in Traf3+/− B cells compared to B cells from WT littermates
    explanation: >-
      The transcriptional and metabolic output of the pathway, measured at the
      heterozygous dose.

- name: B Cell Hyperactivity and Prolonged Survival
  role: effector
  biological_scale: CELLULAR
  description: >-
    B cells with reduced TRAF3 survive longer than they should and accumulate. In the
    heterozygous mouse this is visible as increased spleen weight and splenic B cell
    numbers; in the complete B cell knockout the same axis produces lymphoid organ
    enlargement, autoantibodies and lymphoma with age. Patient B cells also show elevated
    mitochondrial respiration, so the survival advantage has a metabolic component and not
    only an anti-apoptotic one.

    IL-6 responsiveness is raised too: heterozygous B cells have higher phospho-STAT3
    Y705 after IL-6 stimulation than wild type, though the difference reached significance
    only at the earliest timepoint - curated at the strength the source states it.
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  - preferred_term: plasma cell
    term:
      id: CL:0000786
      label: plasma cell
  locations:
  - preferred_term: spleen
    term:
      id: UBERON:0002106
      label: spleen
  biological_processes:
  - preferred_term: B cell homeostasis
    term:
      id: GO:0001782
      label: B cell homeostasis
    modifier: ABNORMAL
  downstream:
  - target: Lymphoproliferation, Autoimmunity and Systemic Inflammation
    causal_link_type: DIRECT
    description: >-
      An expanded, long-lived, hyperresponsive B cell pool is the substrate for
      autoantibody production and lymphoid hyperplasia.
  - target: Impaired B Cell Maturation
    causal_link_type: DIRECT
    description: >-
      The expanding compartment is also a maldeveloping one: class-switched memory B cells
      fall while naive B cells rise.
  - target: Defective Humoral Defence Against Bacteria
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Impaired B Cell Maturation
    description: >-
      Routed through the maturation defect, which is now its own node, so the compartment
      expands without producing protective antibody. T cell dysregulation contributes in
      parallel.
  - target: B Cell Malignant Transformation Risk
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Chronic survival signalling is a plausible substrate for transformation, but the
      steps between it and a lymphoma in a haploinsufficient patient have not been
      demonstrated.
  evidence:
  - reference: PMID:40773231
    reference_title: "Reduction of TRAF3 by heterozygosity or aging impacts B cell function."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Our results show that B-Traf3+/− mice have significantly lower TRAF3 protein and
      mRNA levels in B cells, correlating closely with increased spleen weight and splenic
      B cell numbers compared to wild-type (WT) littermate mice.
    explanation: >-
      Ties the dosage reduction to B cell accumulation in the same animals.
  - reference: PMID:40773231
    reference_title: "Reduction of TRAF3 by heterozygosity or aging impacts B cell function."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Traf3+/− B cells had elevated pSTAT3 Y705 compared to WT B cells at all time points
      tested, although this increase reached statistical significance only at 15 min after
      IL-6 treatment
    explanation: >-
      The IL-6 hyperresponsiveness, quoted with the source's own qualification about where
      it was significant.

- name: Impaired B Cell Maturation
  role: intermediate
  biological_scale: CELLULAR
  description: >-
    The intermediate that connects B cell hyperactivity to antibody failure, and the
    reason the two are not a contradiction. The compartment expands, but it expands at the
    wrong end: class-switched memory B cells are markedly reduced while naive B cells are
    elevated. More B cells that have not completed maturation do not make more protective
    antibody.

    This node is what the entry's account of the immunodeficiency turns on, and it is also
    the axis the immunoglobulin knowledge gap proposes to measure - whether the direction
    of the immunoglobulin abnormality tracks with the size of the class-switched memory
    compartment.
  cell_types:
  - preferred_term: memory B cell
    term:
      id: CL:0000787
      label: memory B cell
  - preferred_term: naive B cell
    term:
      id: CL:0000788
      label: naive B cell
  biological_processes:
  - preferred_term: B cell differentiation
    term:
      id: GO:0030183
      label: B cell differentiation
    modifier: ABNORMAL
  downstream:
  - target: Defective Humoral Defence Against Bacteria
    causal_link_type: DIRECT
    description: >-
      A compartment short of class-switched memory B cells cannot mount durable
      high-affinity antibody responses to encapsulated bacteria.
  evidence:
  - reference: PMID:39579173
    reference_title: "Heterozygous Predicted Loss-of-function Variants of TRAF3 in Patients with Common Variable Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Extensive immunophenotyping showed impaired B cell maturation with markedly reduced
      class-switched memory B cell counts and elevated naïve B cells.
    explanation: >-
      The maturation defect measured directly in patients, with both halves of it - the
      reduced switched memory compartment and the elevated naive one.

- name: T Cell Compartment Dysregulation
  role: amplifier
  biological_scale: CELLULAR
  description: >-
    TRAF3 haploinsufficiency is not confined to B cells. Patients have mild CD4+ T cell
    lymphopenia with a reduced proportion of naive T cells, and at the same time increased
    regulatory T cells and increased circulating T follicular helper cells. The founding
    study reads this as a contributor to the B cell phenotype - dysregulated T cell help -
    rather than as an independent arm of the disease, and this entry follows that reading.

    It is also the part of the syndrome that the available mouse models do not cover,
    since those are B cell-conditional.
  cell_types:
  - preferred_term: CD4-positive T cell
    term:
      id: CL:0000624
      label: CD4-positive, alpha-beta T cell
  - preferred_term: regulatory T cell
    term:
      id: CL:0000815
      label: regulatory T cell
  - preferred_term: circulating T follicular helper cell
    term:
      id: CL:0002038
      label: T follicular helper cell
  downstream:
  - target: B Cell Hyperactivity and Prolonged Survival
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Increased circulating T follicular helper cells supply more B cell help; the
      founding study names dysregulated T cell help as a likely contributor.
  evidence:
  - reference: PMID:35960817
    reference_title: "Immunodeficiency, autoimmunity, and increased risk of B cell malignancy in humans with TRAF3 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients had mild CD4+ T cell lymphopenia, with a reduced proportion of naïve T
      cells but increased regulatory T cells and circulating T follicular helper cells.
    explanation: >-
      The T cell findings this node curates, in full.
  - reference: PMID:39579173
    reference_title: "Heterozygous Predicted Loss-of-function Variants of TRAF3 in Patients with Common Variable Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Upon more detailed analysis, we found that two patients exhibited abnormal
      lymphocyte proliferation.
    explanation: >-
      A functional readout rather than a subset count, which is what turns this node from
      an enumeration of flow-cytometry percentages into a claim about T cell capability.
  - reference: PMID:39579173
    reference_title: "Heterozygous Predicted Loss-of-function Variants of TRAF3 in Patients with Common Variable Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      with significantly decreased cell division after PMA + ionomycin and PHA stimulation
    explanation: >-
      The stimuli under which the proliferation defect was measured.
  - reference: PMID:35960817
    reference_title: "Immunodeficiency, autoimmunity, and increased risk of B cell malignancy in humans with TRAF3 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Reduced TRAF3 conveys disease risks by driving B cell hyperactivity via intrinsic
      activation of multiple intracellular proinflammatory pathways and increased
      mitochondrial respiration, with a likely contribution from dysregulated T cell help.
    explanation: >-
      PARTIAL because the source itself calls the T cell contribution likely rather than
      established; the edge from this node is typed accordingly.

- name: Lymphoproliferation, Autoimmunity and Systemic Inflammation
  role: outcome
  biological_scale: ORGANISM
  description: >-
    The autoimmune and lymphoproliferative arm of the syndrome: B cell lymphoproliferation,
    autoimmunity and systemic inflammation, reported together in the founding cohort and
    confirmed as a phenotype description in the follow-up study.
  locations:
  - preferred_term: lymph node
    term:
      id: UBERON:0000029
      label: lymph node
  - preferred_term: spleen
    term:
      id: UBERON:0002106
      label: spleen
  evidence:
  - reference: PMID:35960817
    reference_title: "Immunodeficiency, autoimmunity, and increased risk of B cell malignancy in humans with TRAF3 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, in five unrelated families, we describe an immune dysregulation syndrome of
      recurrent bacterial infections, autoimmunity, systemic inflammation, B cell
      lymphoproliferation, and hypergammaglobulinemia.
    explanation: >-
      The syndrome definition, from which this node takes its three components.

- name: Defective Humoral Defence Against Bacteria
  role: outcome
  biological_scale: ORGANISM
  description: >-
    The immunodeficiency arm. Recurrent bacterial infection is present in both reported
    cohorts, and in the CVID-reanalysis cohort it came with hypogammaglobulinemia severe
    enough that the patients were on immunoglobulin replacement before their genetic
    diagnosis was made.

    That the same gene dose produces hypergammaglobulinemia in one cohort and
    hypogammaglobulinemia in another is unresolved and is curated as a knowledge gap
    rather than smoothed over.
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  evidence:
  - reference: PMID:39579173
    reference_title: "Heterozygous Predicted Loss-of-function Variants of TRAF3 in Patients with Common Variable Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These individuals harbored stop-gain variants (p.Arg163* and p.Gln407*) and
      experienced recurrent bacterial infections with hypogammaglobulinemia.
    explanation: >-
      The infection phenotype together with the antibody deficiency that accompanies it in
      this cohort.

- name: B Cell Malignant Transformation Risk
  role: outcome
  biological_scale: ORGANISM
  mechanism_confidence: PROVISIONAL
  description: >-
    An increased risk of B cell malignancy is part of the founding description of the
    syndrome, and the same study found that common TRAF3 variants which also reduce TRAF3
    expression are associated with increased B cell malignancy risk in the general
    population - a dose-response argument from two directions.

    PROVISIONAL because the mechanism connecting a halved TRAF3 dose to a transformed
    clone has not been demonstrated in a patient. What exists is a plausible substrate
    (chronic NF-kB2 and survival-protein signalling), an epidemiological association, a
    mouse in which complete B cell TRAF3 loss produces lymphoma with age, and a naturally
    occurring canine B cell lymphoma in which TRAF3 mutation is common.
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  evidence:
  - reference: PMID:35960817
    reference_title: "Immunodeficiency, autoimmunity, and increased risk of B cell malignancy in humans with TRAF3 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      are associated with an increased risk of B cell malignancies, systemic lupus
      erythematosus, higher immunoglobulin levels, and bacterial infections in the wider
      population
    explanation: >-
      The population-level dose-response result that supports the malignancy claim beyond
      the small monogenic cohort.
  - reference: PMID:40773231
    reference_title: "Reduction of TRAF3 by heterozygosity or aging impacts B cell function."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      TRAF3-deficient B cells exhibit substantially enhanced survival, which in mice
      results in marked lymphoid organ enlargement, production of autoantibodies, and
      development of B cell lymphomas (BCL) with age
    explanation: >-
      INDIRECT because this is the complete-deficiency mouse, not the heterozygous one; it
      shows where the axis leads at full dose without establishing that it gets there at
      half dose.
  - reference: PMID:25468570
    reference_title: "Genetic inactivation of TRAF3 in canine and human B-cell lymphoma."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We found mutations affecting TRAF3, which encodes a negative regulator of nuclear
      factor (NF)-κB, to be a common feature of cBCLs, with mutations observed in 44% of
      tumors including a combination of somatic and rare germ-line variants.
    explanation: >-
      PARTIAL and deliberately so: this is naturally occurring canine lymphoma, where the
      variants are largely somatic. It supports TRAF3 loss as a lymphomagenic event, not
      the germline haploinsufficient state as a lymphoma predisposition in humans.

phenotypes:

- category: Immunologic
  name: Recurrent Bacterial Infections
  frequency: VERY_FREQUENT
  description: >-
    Recurrent bacterial infection, predominantly sinopulmonary, present in both reported
    cohorts and usually the presenting problem.
  phenotype_term:
    preferred_term: Recurrent sinopulmonary infections
    term:
      id: HP:0005425
      label: Recurrent sinopulmonary infections
  evidence:
  - reference: PMID:39579173
    reference_title: "Heterozygous Predicted Loss-of-function Variants of TRAF3 in Patients with Common Variable Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These individuals harbored stop-gain variants (p.Arg163* and p.Gln407*) and
      experienced recurrent bacterial infections with hypogammaglobulinemia.
    explanation: >-
      The infection phenotype in the CVID-reanalysis cohort.

- category: Immunologic
  name: Autoimmunity
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Autoimmunity
    term:
      id: HP:0002960
      label: Autoimmunity
  evidence:
  - reference: PMID:35960817
    reference_title: "Immunodeficiency, autoimmunity, and increased risk of B cell malignancy in humans with TRAF3 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, in five unrelated families, we describe an immune dysregulation syndrome of
      recurrent bacterial infections, autoimmunity, systemic inflammation, B cell
      lymphoproliferation, and hypergammaglobulinemia.
    explanation: >-
      Names autoimmunity as a defining component of the syndrome; the source for this and
      the two phenotypes below.
  - reference: PMID:39579173
    reference_title: "Heterozygous Predicted Loss-of-function Variants of TRAF3 in Patients with Common Variable Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Autoimmunity Yes - - Yes Yes Yes - Yes Yes No - -
    explanation: >-
      The per-patient row from the pooled clinical table, which puts autoimmunity at 6 of
      12 and so sources the FREQUENT band rather than leaving it as an estimate.

- category: Hematologic
  name: B Cell Lymphoproliferation
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Lymphadenopathy
    term:
      id: HP:0002716
      label: Lymphadenopathy
  description: >-
    B cell lymphoproliferation. Bound to the lymphadenopathy term, which is the closest
    available HPO concept for the clinical finding; the source's own word is
    lymphoproliferation and is kept in the name.
  evidence:
  - reference: PMID:35960817
    reference_title: "Immunodeficiency, autoimmunity, and increased risk of B cell malignancy in humans with TRAF3 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, in five unrelated families, we describe an immune dysregulation syndrome of
      recurrent bacterial infections, autoimmunity, systemic inflammation, B cell
      lymphoproliferation, and hypergammaglobulinemia.
    explanation: >-
      Names B cell lymphoproliferation as a component of the syndrome.
  - reference: PMID:39579173
    reference_title: "Heterozygous Predicted Loss-of-function Variants of TRAF3 in Patients with Common Variable Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Lymphadeno-pathies Yes Yes - - - Yes - Yes Yes - Yes Yes
    explanation: >-
      The per-patient row from the pooled clinical table: 7 of 12, which sources the
      FREQUENT band. The hyphenation in "Lymphadeno-pathies" is a column-wrap artefact of
      the cached PDF text, not the paper's spelling.

- category: Hematologic
  name: Splenomegaly
  frequency: FREQUENT
  description: >-
    Present in 7 of the 12 patients published across both cohorts, which makes it one of
    the more consistent findings after infection itself. Part of the lymphoproliferative
    arm rather than an independent problem.
  phenotype_term:
    preferred_term: Splenomegaly
    term:
      id: HP:0001744
      label: Splenomegaly
  evidence:
  - reference: PMID:39579173
    reference_title: "Heterozygous Predicted Loss-of-function Variants of TRAF3 in Patients with Common Variable Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Splenomegaly Yes Yes - Yes - - - - Yes Yes Yes Yes
    explanation: >-
      The per-patient row from the pooled clinical table covering every published patient
      in both cohorts: 7 of 12.
  - reference: PMID:39579173
    reference_title: "Heterozygous Predicted Loss-of-function Variants of TRAF3 in Patients with Common Variable Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Imaging studies showed splenomegaly, hepatomegaly, and paratracheal and mediastinal
      lymphadenopathy
    explanation: >-
      The finding in an individual patient, with the lymphadenopathy that accompanies it.

- category: Gastrointestinal
  name: Gastrointestinal Inflammation
  frequency: FREQUENT
  description: >-
    Present in 5 of 12 published patients. The endoscopic picture is not a nonspecific
    colitis: nodular lymphoid hyperplasia, ileitis, active chronic pancolitis and
    non-necrotizing epithelioid granulomas. The granulomas and the lymphoid hyperplasia
    are the features that mark this out from ordinary inflammatory bowel disease and place
    it with the lymphoproliferative arm of the syndrome.
  phenotype_term:
    preferred_term: Inflammation of the large intestine
    term:
      id: HP:0002037
      label: Inflammation of the large intestine
  evidence:
  - reference: PMID:39579173
    reference_title: "Heterozygous Predicted Loss-of-function Variants of TRAF3 in Patients with Common Variable Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      GI involvement Yes - - - - - - - Yes Yes Yes Yes
    explanation: >-
      The per-patient row from the pooled clinical table: 5 of 12.
  - reference: PMID:39579173
    reference_title: "Heterozygous Predicted Loss-of-function Variants of TRAF3 in Patients with Common Variable Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Gastrointestinal endoscopy findings included nodular lymphoid hyperplasia, ileitis,
      and active chronic pancolitis
    explanation: >-
      What the inflammation looks like on endoscopy, which is the part that distinguishes
      it from garden-variety colitis.

- category: Respiratory
  name: Bronchiectasis
  frequency: OCCASIONAL
  description: >-
    Structural airway damage, distinct from the recurrent infection that causes it and
    irreversible once established. Pulmonary involvement of some kind is recorded in 9 of
    12 published patients; bronchiectasis specifically is documented on imaging in an
    individual patient and is what makes early diagnosis worth something in this disease.
  phenotype_term:
    preferred_term: Bronchiectasis
    term:
      id: HP:0002110
      label: Bronchiectasis
  evidence:
  - reference: PMID:39579173
    reference_title: "Heterozygous Predicted Loss-of-function Variants of TRAF3 in Patients with Common Variable Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Imaging studies confirmed cylindrical bronchiectasis in the right upper lobe,
      lingula, and left lower lobe.
    explanation: >-
      The imaging diagnosis in a patient, with its distribution.
  - reference: PMID:39579173
    reference_title: "Heterozygous Predicted Loss-of-function Variants of TRAF3 in Patients with Common Variable Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pulmonary involvement Yes Yes - Yes Yes Yes - - Yes Yes Yes Yes
    explanation: >-
      PARTIAL because the table row counts pulmonary involvement of any kind (9 of 12),
      which is broader than bronchiectasis; it bounds the frequency from above rather than
      giving it.

- category: Immunologic
  name: Impaired B Cell Maturation
  frequency: FREQUENT
  description: >-
    Reduced class-switched memory B cells with elevated naive B cells - the maturation
    defect that the pathophysiology section curates as the intermediate between B cell
    expansion and antibody failure.
  phenotype_term:
    preferred_term: Decreased class-switched memory B cell proportion
    term:
      id: HP:0030388
      label: Decreased class-switched memory B cell proportion
  evidence:
  - reference: PMID:39579173
    reference_title: "Heterozygous Predicted Loss-of-function Variants of TRAF3 in Patients with Common Variable Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Extensive immunophenotyping showed impaired B cell maturation with markedly reduced
      class-switched memory B cell counts and elevated naïve B cells.
    explanation: >-
      Both halves of the maturation defect, measured by flow cytometry in patients.

- category: Laboratory
  name: Hypergammaglobulinemia
  frequency: FREQUENT
  description: >-
    Raised immunoglobulin, reported in the founding cohort. Read together with the
    hypogammaglobulinemia phenotype below, which is the opposite finding in a different
    cohort of the same disease.
  phenotype_term:
    preferred_term: Increased circulating immunoglobulin concentration
    term:
      id: HP:0010702
      label: Increased circulating immunoglobulin concentration
  evidence:
  - reference: PMID:35960817
    reference_title: "Immunodeficiency, autoimmunity, and increased risk of B cell malignancy in humans with TRAF3 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, in five unrelated families, we describe an immune dysregulation syndrome of
      recurrent bacterial infections, autoimmunity, systemic inflammation, B cell
      lymphoproliferation, and hypergammaglobulinemia.
    explanation: >-
      Names hypergammaglobulinemia in the founding cohort.

- category: Laboratory
  name: Hypogammaglobulinemia
  frequency: FREQUENT
  description: >-
    Low immunoglobulin with a CVID-like presentation, in all three patients of the 2024
    cohort. The follow-up study identifies this explicitly as the main difference between
    its patients and the founding cohort, so the two immunoglobulin phenotypes in this
    entry are not a curation inconsistency - they are the reported spectrum.
  phenotype_term:
    preferred_term: Decreased circulating immunoglobulin concentration
    term:
      id: HP:0004313
      label: Decreased circulating immunoglobulin concentration
  evidence:
  - reference: PMID:39579173
    reference_title: "Heterozygous Predicted Loss-of-function Variants of TRAF3 in Patients with Common Variable Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most significant differences were hypogammaglobulinemia and a CVID-like
      presentation.
    explanation: >-
      States the finding and, in the same sentence, that it diverges from the previously
      reported phenotype.

- category: Immunologic
  name: CD4+ T Cell Lymphopenia
  frequency: FREQUENT
  severity: MILD
  phenotype_term:
    preferred_term: Decreased total CD4+ T cell count
    term:
      id: HP:5210418
      label: Decreased total CD4+ T cell count
  evidence:
  - reference: PMID:35960817
    reference_title: "Immunodeficiency, autoimmunity, and increased risk of B cell malignancy in humans with TRAF3 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients had mild CD4+ T cell lymphopenia, with a reduced proportion of naïve T
      cells but increased regulatory T cells and circulating T follicular helper cells.
    explanation: >-
      Names the lymphopenia and its severity; the source for this and the phenotype below.

- category: Immunologic
  name: Reduced Naive T Cell Proportion
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Decreased naive T cell proportion
    term:
      id: HP:0031397
      label: Decreased naive T cell proportion
  evidence:
  - reference: PMID:35960817
    reference_title: "Immunodeficiency, autoimmunity, and increased risk of B cell malignancy in humans with TRAF3 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients had mild CD4+ T cell lymphopenia, with a reduced proportion of naïve T
      cells but increased regulatory T cells and circulating T follicular helper cells.
    explanation: >-
      Names the naive T cell reduction.

- category: Neoplasm
  name: B Cell Malignancy
  description: >-
    Increased risk rather than an invariant feature. Curated as a phenotype because it is
    part of the syndrome's definition, but the supporting quantification comes from
    common-variant association in the general population rather than from counting
    lymphomas in the reported families.
  phenotype_term:
    preferred_term: Lymphoma
    term:
      id: HP:0002665
      label: Lymphoma
  evidence:
  - reference: PMID:35960817
    reference_title: "Immunodeficiency, autoimmunity, and increased risk of B cell malignancy in humans with TRAF3 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      are associated with an increased risk of B cell malignancies, systemic lupus
      erythematosus, higher immunoglobulin levels, and bacterial infections in the wider
      population
    explanation: >-
      PARTIAL because the quoted association is for common expression-reducing variants in
      the wider population, not for the monogenic patients themselves.

genetic:

- name: TRAF3
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: TRAF3
    term:
      id: hgnc:12033
      label: TRAF3
  association: >-
    Heterozygous loss-of-function variants in TRAF3 cause this disease. The gene-disease
    relationship rests on nine patients from five unrelated families in the founding study
    plus three patients from two further families in the 2024 reanalysis, with a
    consistent immunophenotype and a mechanism that the B cell-conditional heterozygous
    mouse reproduces at the same gene dose.

    Every published allele is truncating. The founding cohort contributed p.Tyr425*,
    p.Ser356Profs*6 and p.Gln114*; the 2024 cohort added p.Arg163* and p.Gln407*, with
    p.Arg163* recurring across both.

    That uniformity is what makes the variant class usable for interpretation. Premature-stop
    and frameshift alleles reduce TRAF3 output and cause this disease. Missense alleles that
    destabilise the wild-type protein - which take total TRAF3 below what haploinsufficiency
    alone would give - cause a different, allelic disorder with a different phenotype, and
    should not be curated against this entry.

    Practically, TRAF3 belongs on any CVID or hypogammaglobulinemia gene panel: all three
    patients in the 2024 cohort already carried a CVID diagnosis and were on immunoglobulin
    replacement when the variant was found by targeted reanalysis.
  evidence:
  - reference: PMID:35960817
    reference_title: "Immunodeficiency, autoimmunity, and increased risk of B cell malignancy in humans with TRAF3 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thus, we define monogenic TRAF3 haploinsufficiency syndrome and demonstrate how
      common TRAF3 variants affect a range of human diseases.
    explanation: >-
      The gene-disease claim in the form the founding study makes it.
  - reference: PMID:39579173
    reference_title: "Heterozygous Predicted Loss-of-function Variants of TRAF3 in Patients with Common Variable Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These data expand the clinical phenotype of TRAF3Hl and pave the way for further
      investigation into loss-of-function variants in patients with CVID.
    explanation: >-
      Independent replication in unrelated families, and the diagnostic recommendation
      that follows from it.
  - reference: PMID:39579173
    reference_title: "Heterozygous Predicted Loss-of-function Variants of TRAF3 in Patients with Common Variable Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      TRAF3 variant p.Y425* p.S356Pfs6* p.Q114* p.R163* p.Y425* p.R163* p.Q407*
    explanation: >-
      The allele row of the pooled clinical table, naming every published variant across
      both cohorts. All are nonsense or frameshift, which is the truncating-class claim.

inheritance:

- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    A single loss-of-function allele is sufficient. Expressivity is variable both within
    and between families - the two reported cohorts differ on the direction of the
    immunoglobulin abnormality - and no modifier has been identified.
  evidence:
  - reference: PMID:35960817
    reference_title: "Immunodeficiency, autoimmunity, and increased risk of B cell malignancy in humans with TRAF3 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected individuals each had monoallelic mutations in TRAF3 that reduced TRAF3
      expression.
    explanation: >-
      Monoallelic variants in affected individuals, which is the dominance claim.

animal_models:

- name: B cell-conditional Traf3 heterozygous mouse (B-Traf3+/-)
  species: Mouse
  genotype: B cell-conditional Traf3 heterozygous (B-Traf3+/-)
  publication: PMID:40773231
  description: >-
    A mouse built specifically to match the human genotype: one Traf3 allele deleted in
    the B lineage rather than both, giving a 40 to 50% protein reduction. It was made
    because the earlier B cell-conditional complete knockout models the endpoint of the
    pathway but not the dose at which human patients live, and the question was whether
    half is enough. It is.
  modeled_mechanisms:
  - target: Reduced TRAF3 Protein Dosage
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Reproduces the defining feature of the human disease - a partial, not complete,
      reduction in TRAF3 - and shows it is sufficient for a phenotype.
    limitations: >-
      The deletion is B cell-conditional, so nothing in this model speaks to the T cell
      dysregulation that is part of the human syndrome. It also does not carry a human
      stop-gain allele; the dose is engineered rather than inherited.
    readouts:
    - name: B cell TRAF3 protein and Traf3 mRNA
      target: Reduced TRAF3 Protein Dosage
      direction: DECREASED
      interpretation: >-
        Western blot and transcript measurement in splenic B cells, quantifying the
        reduction as 40 to 50% of wild-type littermates.
      evidence:
      - reference: PMID:40773231
        reference_title: "Reduction of TRAF3 by heterozygosity or aging impacts B cell function."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          We found that B-Traf3+/− mice have a 40 to 50% decrease in the amount of TRAF3
          protein and Traf3 mRNA in their B cells
        explanation: >-
          The measurement and its magnitude.
    evidence:
    - reference: PMID:40773231
      reference_title: "Reduction of TRAF3 by heterozygosity or aging impacts B cell function."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        More recently, human patients with germline TRAF3 mutations leading to
        haploinsufficiency have been reported; the phenotypes of these patients show
        striking similarities with those of mice with TRAF3-deficient B cells.
      explanation: >-
        The authors' own statement of why this mouse is informative for the human disease.
  - target: B Cell Hyperactivity and Prolonged Survival
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Increased spleen weight, increased splenic B cell numbers and elevated survival and
      metabolic proteins at the heterozygous dose.
    limitations: >-
      MODERATE because the mouse readout is B cell accumulation in a lymphoid organ while
      the human readout is clinical lymphoproliferation and autoimmunity; the two are
      linked by argument rather than by a matched measurement.
    readouts:
    - name: Spleen weight and splenic B cell number
      target: B Cell Hyperactivity and Prolonged Survival
      direction: INCREASED
      interpretation: >-
        Both increase relative to wild-type littermates and track with the degree of TRAF3
        reduction.
      evidence:
      - reference: PMID:40773231
        reference_title: "Reduction of TRAF3 by heterozygosity or aging impacts B cell function."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Our results show that B-Traf3+/− mice have significantly lower TRAF3 protein and
          mRNA levels in B cells, correlating closely with increased spleen weight and
          splenic B cell numbers compared to wild-type (WT) littermate mice.
        explanation: >-
          The organ and cell-number measurements, with their correlation to TRAF3 level.
    - name: NF-kB2 p52 and survival protein abundance
      target: B Cell Hyperactivity and Prolonged Survival
      direction: INCREASED
      interpretation: >-
        Hxk2, NF-kB2 p52, Mcl1, c-Myc and Pim2 all significantly more abundant in
        heterozygous than wild-type B cells.
      evidence:
      - reference: PMID:40773231
        reference_title: "Reduction of TRAF3 by heterozygosity or aging impacts B cell function."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          The glycolytic protein Hxk2, NFκB2 p52, Mcl1, c-Myc, and Pim2 were all
          significantly more abundant in Traf3+/− B cells compared to B cells from WT
          littermates
        explanation: >-
          The molecular output measured at the heterozygous dose.
    evidence:
    - reference: PMID:40773231
      reference_title: "Reduction of TRAF3 by heterozygosity or aging impacts B cell function."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Our results show that B-Traf3+/− mice have significantly lower TRAF3 protein and
        mRNA levels in B cells, correlating closely with increased spleen weight and
        splenic B cell numbers compared to wild-type (WT) littermate mice.
      explanation: >-
        Supports treating this mouse as informative for the B cell hyperactivity node.

- name: B cell-conditional Traf3 knockout mouse (B-Traf3-/-)
  species: Mouse
  genotype: B cell-conditional Traf3 homozygous knockout (B-Traf3-/-)
  publication: PMID:40773231
  description: >-
    The complete B lineage knockout, included as the upper bound of the dose-response
    rather than as a model of the patient genotype. It develops lymphoid organ
    enlargement, autoantibodies and B cell lymphoma with age, which is what makes the
    heterozygous mouse's intermediate phenotype interpretable.
  modeled_mechanisms:
  - target: B Cell Malignant Transformation Risk
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      Shows where chronic TRAF3 loss leads in B cells, at a gene dose no patient has.
    limitations: >-
      Patients are heterozygous; this mouse has no B cell TRAF3 at all. It establishes the
      direction of the axis and nothing about the risk conferred by half a dose, which is
      the claim the human entry needs.
    evidence:
    - reference: PMID:40773231
      reference_title: "Reduction of TRAF3 by heterozygosity or aging impacts B cell function."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        TRAF3-deficient B cells exhibit substantially enhanced survival, which in mice
        results in marked lymphoid organ enlargement, production of autoantibodies, and
        development of B cell lymphomas (BCL) with age
      explanation: >-
        The complete-loss phenotype, which is the comparator this model provides.

treatments:

- name: Immunoglobulin Replacement Therapy
  therapeutic_modality: PROTEIN_REPLACEMENT
  description: >-
    Replacement immunoglobulin for the antibody deficiency. It is the one treatment
    documented in TRAF3 haploinsufficiency patients, and it was in place before the
    diagnosis was: all three patients in the 2024 cohort were already receiving it under a
    CVID label. No trial or outcome data exist for this disease specifically; the
    documented fact is that patients receive it, not that it has been shown to work here.
  treatment_term:
    preferred_term: immunoglobulin therapy
    term:
      id: NCIT:C62710
      label: Immunoglobulin Therapy
  target_mechanisms:
  - target: Defective Humoral Defence Against Bacteria
    description: >-
      Substitutes for the antibody the patient's own B cell compartment fails to make.
      It does nothing about the upstream signalling defect.
  evidence:
  - reference: PMID:39579173
    reference_title: "Heterozygous Predicted Loss-of-function Variants of TRAF3 in Patients with Common Variable Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Previously, the patients had been diagnosed with common variable immunodeficiency
      (CVID) and were receiving immunoglobulin replacement therapy.
    explanation: >-
      Documents the treatment in these patients, and the diagnostic label it was given
      under.

- name: Antimicrobial Treatment and Prophylaxis
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Treatment of recurrent bacterial infection and, where structural lung damage has
    developed, prophylaxis on the usual antibody-deficiency principles. No TRAF3-specific
    evidence exists; this is standard care for the infection phenotype and is recorded
    without an evidence item rather than with a quote that would not be about this disease.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  notes: >-
    Carries no evidence item deliberately. Nothing in the cited literature reports
    antimicrobial treatment outcomes in TRAF3 haploinsufficiency.

- name: Genetic Counselling
  therapeutic_modality: BEHAVIORAL
  description: >-
    Autosomal dominant inheritance with a 50% recurrence risk per pregnancy, and variable
    expressivity that makes phenotype prediction for a carrier relative unsafe. Cascade
    testing of relatives is worth offering, since the 2024 cohort found affected relatives
    by exactly that route.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:39579173
    reference_title: "Heterozygous Predicted Loss-of-function Variants of TRAF3 in Patients with Common Variable Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Through this reassessment and additional familial investigations, we identified three
      previously unidentified cases of TRAF3Hl within two different families.
    explanation: >-
      PARTIAL because it supports the value of family investigation rather than counselling
      as an intervention; the cases were found by studying relatives of an index patient.

diagnosis:

- name: Targeted TRAF3 Analysis in Inborn-Errors-of-Immunity Sequencing Data
  description: >-
    Because TRAF3 haploinsufficiency looks like CVID, the productive diagnostic route has
    been to go back to sequencing data already generated for undiagnosed
    inborn-errors-of-immunity patients and look specifically at TRAF3. Doing that across
    800 patients found three new cases in two families, all previously labelled CVID.
  evidence:
  - reference: PMID:39579173
    reference_title: "Heterozygous Predicted Loss-of-function Variants of TRAF3 in Patients with Common Variable Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we conducted a TRAF3-targeted reanalysis of next-generation sequencing data from 800
      patients with inborn errors of immunity
    explanation: >-
      The diagnostic strategy and its scale.

- name: B Cell Immunophenotyping
  description: >-
    Flow cytometry of the B and T compartments. The pattern that supports the diagnosis is
    a dysregulated B cell compartment with increased NF-kB2 activation, alongside mild
    CD4+ lymphopenia with reduced naive T cells and increased regulatory and circulating
    T follicular helper cells.
  evidence:
  - reference: PMID:35960817
    reference_title: "Immunodeficiency, autoimmunity, and increased risk of B cell malignancy in humans with TRAF3 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Immunophenotyping showed that patients' B cells were dysregulated, exhibiting
      increased nuclear factor-κB 2 activation, elevated mitochondrial respiration, and
      heightened inflammatory responses.
    explanation: >-
      What immunophenotyping shows in these patients.

differential_diagnoses:

- name: Common variable immunodeficiency
  description: >-
    Not a differential so much as the label these patients are already carrying. Every
    patient in the 2024 cohort had a CVID diagnosis before TRAF3 was looked at, which
    makes idiopathic CVID the population in which undiagnosed TRAF3 haploinsufficiency is
    expected to sit.
  distinguishing_features:
  - A monogenic TRAF3 loss-of-function variant
  - >-
    Accompanying autoimmunity, lymphoproliferation and B cell malignancy risk, which
    idiopathic CVID does not carry as a defined feature
  evidence:
  - reference: PMID:39579173
    reference_title: "Heterozygous Predicted Loss-of-function Variants of TRAF3 in Patients with Common Variable Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Previously, the patients had been diagnosed with common variable immunodeficiency
      (CVID) and were receiving immunoglobulin replacement therapy.
    explanation: >-
      Establishes the relationship between the two labels in practice.

- name: TRAF3 dominant-negative deficiency (herpes simplex encephalitis susceptibility)
  description: >-
    The allelic disorder. A dominant-negative TRAF3 missense variant reduces total TRAF3
    well below the level that losing one allele would give, impairs TLR3-dependent type I
    interferon production, and predisposes to herpes simplex encephalitis. It is a
    different phenotype from a different variant class in the same gene, and evidence
    about it should not be curated against this entry.
  distinguishing_features:
  - Missense rather than truncating variant
  - TRAF3 protein far below the 50% expected from loss of one allele
  - >-
    Susceptibility to viral encephalitis rather than recurrent bacterial infection with
    autoimmunity
  evidence:
  - reference: PMID:39579173
    reference_title: "Heterozygous Predicted Loss-of-function Variants of TRAF3 in Patients with Common Variable Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In 2010, autosomal dominant TRAF3 deficiency was reported in a patient with herpes
      simplex virus-1 encephalitis, consistent with the role of TRAF3 in type I interferon
      production.
    explanation: >-
      The earlier entity, described by the same review that then contrasts it with the
      haploinsufficiency phenotype.
  - reference: PMID:39579173
    reference_title: "Heterozygous Predicted Loss-of-function Variants of TRAF3 in Patients with Common Variable Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recently, a novel, completely different clinical phenotype was described in patients
      with TRAF3 haploinsufficiency (TRAF3Hl), characterized by recurrent bacterial
      infections, autoimmune features, systemic inflammation, and hypergammaglobulinemia.
    explanation: >-
      The source's own statement that the two phenotypes are completely different, which
      is why they are separate entries rather than one.

discussions:

- discussion_id: gap_hyper_vs_hypogammaglobulinemia
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - phenotypes#Hypergammaglobulinemia
  - phenotypes#Hypogammaglobulinemia
  prompt: >-
    Why does the same class of TRAF3 loss-of-function variant produce raised immunoglobulin
    in one cohort and antibody deficiency in another?
  rationale: >-
    The founding cohort's syndrome definition includes hypergammaglobulinemia. Every
    patient in the 2024 cohort was hypogammaglobulinemic on immunoglobulin replacement,
    and that paper names this as the most significant difference between its patients and
    the earlier ones. Both are curated here because both are reported, but they are
    opposite findings and the entry does not have a mechanism that predicts either.

    A mechanism that would reconcile them is available in outline - B cell expansion with
    a class-switch maturation defect could give either a high total immunoglobulin from
    sheer cell numbers or a low protective antibody titre from failed maturation,
    depending on which dominates - but nobody has measured the two cohorts on the same
    panel, and the alternative reading, that variant position or an unidentified modifier
    determines the direction, is untested.
  proposed_experiments:
  - experiment_id: traf3_ig_phenotype_harmonisation
    name: Uniform B cell subset and immunoglobulin phenotyping across reported TRAF3 kindreds
    description: >-
      Apply one immunophenotyping panel - total and class-switched memory B cells, naive B
      cells, plasmablasts, IgG/IgA/IgM and specific antibody responses - across patients
      from both published cohorts and any newly ascertained families, and test whether the
      immunoglobulin direction tracks with the class-switched memory compartment or with
      variant position.
    would_support:
    - pathophysiology#Impaired B Cell Maturation
    supporting_outcome:
    - >-
      Immunoglobulin direction tracks with the size of the class-switched memory B cell
      compartment, making the maturation defect the explanation and the two phenotypes two
      points on one axis.
    refuting_outcome:
    - >-
      The two cohorts have indistinguishable B cell subsets despite opposite immunoglobulin
      levels, which would move the explanation to modifiers or environment and leave the
      maturation-defect account unsupported.

- discussion_id: hypothesis_age_as_second_hit
  kind: EMERGING_HYPOTHESIS
  status: OPEN
  attaches_to:
  - pathophysiology#Reduced TRAF3 Protein Dosage
  prompt: >-
    Does normal ageing act as a second hit on TRAF3 dosage, so that a haploinsufficient
    patient's phenotype worsens over decades?
  rationale: >-
    TRAF3 protein, but not transcript, declines in B cells with age, and in older mice a
    two-hour in vivo proteasome inhibition is enough to raise it again - so the decline is
    degradative and ongoing rather than a fixed developmental setting. Someone who starts
    at half the normal protein and then loses more of it with age would, on this account,
    cross a functional threshold later in life.

    It is a hypothesis and is labelled as one. Nobody has followed TRAF3 haploinsufficient
    patients longitudinally, and the ageing data are not from patients. It is curated
    because it makes a testable prediction about when to watch for the malignancy risk
    this entry records, which is otherwise unstratified.
  evidence:
  - reference: PMID:40773231
    reference_title: "Reduction of TRAF3 by heterozygosity or aging impacts B cell function."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Consistent with this prediction, in vivo treatment with bortezomib for only 2 h was
      sufficient to increase the level of B cell TRAF3 in older mice, but not young mice
    explanation: >-
      Shows the age-related decline is caused by ongoing proteasomal degradation, which is
      what makes it a plausible additive hit on a genetically halved pool.

mappings:
  mondo_mappings:
  - term:
      id: MONDO:0976228
      label: immunodeficiency 132b
    mapping_predicate: skos:exactMatch
    mapping_source: dismech curation
    notes: >-
      Where the merge note lives, so it can be checked: MONDO:0976228 carries an
      `rdfs:comment` reading "This term is scheduled to be merged with MONDO:0100513 TRAF3
      haploinsufficiency', based on the fact that the concept of these 2 terms are the
      same. This ID will therefore be obsoleted and replaced with MONDO:0100513". It is
      not an `IAO:0000233` tracked-item annotation and it is not in a definition
      annotation property, which is why an OAK stanza dump can miss it; OLS reports it
      under `definition` with `definitionProperty: rdfs:comment`.

      Two further reasons to prefer MONDO:0100513 independent of the merge: it is in the
      `mondo#clingen` subset with a ClinGen curated-content link, and its definition
      specialises to the haploinsufficiency phenotype. Note the definition's opening
      clause is the generic by-gene template ("Any Mendelian disease in which the cause of
      the disease is a mutation in the TRAF3 gene"), which read strictly would also cover
      the dominant-negative entity this entry excludes. The exactMatch recorded here is
      what pins the scope: MONDO:0976228 xrefs OMIM:621096, which is IMD132B and nothing
      else.

notes: >-
  Scope. This entry is the loss-of-function disease only - the haploinsufficiency syndrome
  numbered IMD132B in the OMIM series. A separate allelic disorder is caused by
  dominant-negative TRAF3 missense variants, presents as susceptibility to herpes simplex
  encephalitis, and turns on a different mechanism (impaired TLR3-dependent interferon
  induction, with total TRAF3 driven well below the haploinsufficient level). It is
  recorded under differential diagnoses and is deliberately not curated as part of this
  disease. A literature search on "TRAF3 deficiency" returns both, so this is the main
  named-entity trap in this entry.

  Somatic TRAF3 loss. TRAF3 is a recurrent somatic target in multiple myeloma and B cell
  lymphoma, and much of what is written about TRAF3 concerns that. Somatic biallelic loss
  in a tumour is a different event from a germline heterozygous allele in every cell, and
  only the germline claim belongs here; the canine lymphoma evidence on the malignancy
  node is typed PARTIAL for the same reason.

  Term binding. There is no HPO term for B cell lymphoproliferation as such, so that
  phenotype is bound to Lymphadenopathy with the intended concept kept in the entry name
  and description rather than manufactured into the binding.

references:
- reference: PMID:35960817
  title: "Immunodeficiency, autoimmunity, and increased risk of B cell malignancy in humans with TRAF3 mutations."
- reference: PMID:39579173
  title: "Heterozygous Predicted Loss-of-function Variants of TRAF3 in Patients with Common Variable Immunodeficiency."
- reference: PMID:40773231
  title: "Reduction of TRAF3 by heterozygosity or aging impacts B cell function."
- reference: PMID:25468570
  title: "Genetic inactivation of TRAF3 in canine and human B-cell lymphoma."

📚

References & Deep Research

References

4

PMID:35960817

Immunodeficiency, autoimmunity, and increased risk of B cell malignancy in humans with TRAF3 mutations.

No top-level findings curated for this source.

PMID:39579173

Heterozygous Predicted Loss-of-function Variants of TRAF3 in Patients with Common Variable Immunodeficiency.

No top-level findings curated for this source.

PMID:40773231

Reduction of TRAF3 by heterozygosity or aging impacts B cell function.

No top-level findings curated for this source.

PMID:25468570

Genetic inactivation of TRAF3 in canine and human B-cell lymphoma.

No top-level findings curated for this source.

Deep Research

1

Claude Code ▸

TRAF3 Haploinsufficiency: Comprehensive Disease Research Report

claude-haiku-4-5-20251001, claude-sonnet-5 19 citations 2026-08-26T13:04:04.593728

TRAF3 Haploinsufficiency: Comprehensive Disease Research Report

1. Disease Information

Overview. TRAF3 haploinsufficiency (TRAF3-HI, also cataloged as Immunodeficiency-132B / IMD132B) is a recently delineated (2022–2024) autosomal dominant monogenic immune dysregulation syndrome caused by heterozygous loss-of-function variants in TRAF3 (TNF Receptor-Associated Factor 3, chromosome 14q32.32). It is distinct from — but mechanistically related to — an earlier-described entity, Immunodeficiency-132A (IMD132A), caused by a dominant-negative (rather than simple loss-of-function/haploinsufficient) TRAF3 variant and first linked to susceptibility to herpes simplex encephalitis (HSE) (Pérez de Diego et al., 2010, PMID 20832341; OMIM #614849).

TRAF3-HI/IMD132B was formally characterized in a 2022 Science Immunology study of 9 individuals from 5 unrelated families (Wan/Uzel et al., PMID unlisted directly but DOI 10.1126/sciimmunol.abn3800; OMIM #621096), and expanded in a 2024 Journal of Clinical Immunology cohort study (Urban et al., PMID 39579173) that used a TRAF3-targeted reanalysis of next-generation sequencing data from 800 inborn-errors-of-immunity (IEI) patients, identifying 3 additional patients in 2 families who had previously carried a diagnosis of common variable immunodeficiency (CVID).

Key identifiers: - OMIM (phenotype): #621096 (IMD132B, TRAF3-HI; loss-of-function) and #614849 (IMD132A; dominant-negative) - OMIM (gene): 601896 — TNF Receptor-Associated Factor 3; TRAF3 - Gene location: 14q32.32 - MalaCards: "Immunodeficiency 132B" - MONDO: No stable, indexed MONDO term was retrievable via search at the time of this report (the entity is very recently described; Mondo/Monarch integration may lag behind the 2022–2024 primary literature — this should be verified directly against a current Mondo release before curation, as no confirmed MONDO CURIE could be established from available sources) - HGNC:* TRAF3 (gene ID for the causal gene)

Synonyms: TRAF3 deficiency; TRAF3 haploinsufficiency syndrome (TRAF3-HI); Immunodeficiency 132B (IMD132B); CD40-associated protein 1 / CAP-1 (historical alternate gene name); LAP1 (historical alternate gene name).

Data derivation: Almost all clinical characterization comes from aggregated case series (9 patients/5 families in the founding paper; 3 more patients/2 families in the follow-up cohort study derived from an 800-patient IEI sequencing registry) rather than large-scale EHR/population data, consistent with an ultra-rare, newly described monogenic disorder.

2. Etiology

Disease Causal Factors

TRAF3-HI is caused by heterozygous loss-of-function (LOF) variants in TRAF3 (premature stop-codon/nonsense, frameshift) that reduce TRAF3 mRNA and protein to roughly half of normal levels in patient PBMCs — true haploinsufficiency, as opposed to the dominant-negative missense mechanism of IMD132A. Reported LOF variants include stop-gain mutations p.Arg163* and p.Gln407* (Urban et al., 2024, PMID 39579173).

By contrast, IMD132A is caused by a de novo dominant-negative missense variant, c.352C>T (p.Arg118Trp, R118W), in the first of TRAF3's five zinc-finger domains; Western blot in the index patient showed TRAF3 protein reduced to ~17.5% of control levels — far below the ~50% expected from simple haploinsufficiency — indicating the mutant protein actively destabilizes wild-type TRAF3 (dominant-negative interference) (PMID 20832341; OMIM #614849). A second dominant-negative variant, R338W, has been reported in a patient with chronic pulmonary Mycobacterium abscessus infection (Open Forum Infect Dis, PMID 36004314).

Risk Factors

Genetic: Inheritance of a heterozygous LOF or dominant-negative TRAF3 allele is both necessary and sufficient risk. No modifier genes are yet established, though variable expressivity within families (see Inheritance section) implies unidentified genetic or environmental modifiers.
Age: A 2025 PNAS study (Hornick et al., PMID 40773231) found that TRAF3 protein (but not mRNA) declines with normal aging in human B cells — comparing donors over 65 vs. under 32 years — via proteasome-mediated (bortezomib-reversible) degradation rather than transcriptional loss. This suggests age itself is a "second hit" that phenocopies genetic haploinsufficiency, plausibly explaining age-related increases in B-cell hyperactivity and B-cell malignancy risk in the general population, and predicting that TRAF3-HI patients' phenotypes may worsen with age.
Chronic receptor engagement: Sustained CD40 ligand (CD40L) signaling — as occurs in lupus and Sjögren's disease — drives ongoing TRAF3 degradation and could compound genetic deficiency.

Protective Factors

No specific genetic or environmental protective factors have been identified in the literature to date.

Gene-Environment Interactions

The clearest documented interaction is the convergence of chronic B-cell-receptor pathway signaling (CD40, BAFF-R/TNFRSF13C) with reduced TRAF3 dosage: BAFF-receptor stimulation causes sustained TRAF3 reduction (>72 hours) while CD40 stimulation causes transient reduction (recovery by 24h), but both converge on NF-κB2 (non-canonical) activation — meaning inflammatory/infectious triggers that engage these receptors chronically could exacerbate B-cell dysregulation in genetically haploinsufficient individuals (PMID 40773231).

3. Phenotypes

TRAF3-HI presents as a complex, variably expressive immune dysregulation syndrome combining immunodeficiency, autoimmunity, and lymphoproliferation — a triad increasingly recognized across NF-κB pathway primary immunodeficiencies.

Core/consistent features (IMD132B): - Recurrent upper and lower respiratory tract infections with diverse pathogens, onset in childhood — HPO: Recurrent respiratory infections (HP:0002205) - Bronchiectasis — HPO: Bronchiectasis (HP:0002110) (documented in a 36-year-old male index patient with lifelong sinopulmonary infections) - B-cell lymphoid hyperplasia / lymphoproliferation — HPO: Lymphoproliferative disorder-adjacent terms; Lymphadenopathy (HP:0002716) - T-cell subset dysregulation — low/mildly reduced CD4+ T-cell counts, decreased naive T cells, increased CD4+ memory T cells, variably increased regulatory T cells (Tregs), increased circulating T follicular helper (Tfh) cells, and impaired T-cell proliferative responses

Variable features: - Autoimmune disease with autoantibodies (e.g., autoimmune hepatitis-type presentations, cytopenias reported across the NF-κB-PID literature) — HPO: Autoimmunity (HP:0002960) - Systemic autoinflammation - Gastrointestinal inflammation — one index patient had ileitis and chronic active pancolitis — HPO: Inflammation of the large intestine (HP:0002037)/Ileitis - Hepatosplenomegaly — HPO: Hepatosplenomegaly (HP:0001433); the index 36-year-old also had nodular lymphoid hyperplasia - B-cell maturation defects: reduced class-switched memory B cells, increased naive B cells - Dysgammaglobulinemia: hyper- or hypogammaglobulinemia (both directions reported) — HPO: Hypergammaglobulinemia (HP:0010702) / Hypogammaglobulinemia (HP:0004313) - Increased risk of B-cell malignancy (see Prognosis section)

IMD132A-specific phenotype (dominant-negative form): - Herpes simplex encephalitis (HSE) in childhood — HPO: Encephalitis (HP:0002383); impaired TLR3-dependent interferon-β and IL-6 production upon poly(I:C) stimulation - Chronic pulmonary Mycobacterium abscessus infection, treatment-resistant, reported in an adult patient — HPO: Recurrent bronchitis/Nontuberculous mycobacterial infection

Age of onset: Predominantly childhood for the core immunodeficiency/lymphoproliferative phenotype; some manifestations (e.g., chronic M. abscessus infection) present in adulthood.

Severity/progression: Variable and progressive in at least some patients (bronchiectasis implies cumulative structural lung damage from recurrent infection); course is chronic/lifelong.

Quality of life impact: Not formally quantified in the literature (no EQ-5D/SF-36 data identified); qualitatively, the combination of recurrent infection, chronic GI inflammation, and immunoglobulin-replacement dependence implies substantial burden, consistent with other CVID-spectrum disorders.

4. Genetic/Molecular Information

Causal gene: TRAF3 (HGNC symbol TRAF3; historically CAP1, LAP1), 14q32.32, OMIM *601896.

Variant classes reported:

Variant	Type	Effect	Associated phenotype	Source
c.352C>T (p.Arg118Trp)	Missense, zinc-finger domain 1	Dominant-negative; protein reduced to ~17.5% of control	IMD132A — HSE	PMID 20832341
p.Arg338Trp (R338W)	Missense	Dominant-negative	IMD132A — M. abscessus infection, bronchiectasis	PMID 36004314
p.Arg163*	Nonsense (stop-gain)	Loss-of-function (haploinsufficiency)	IMD132B — CVID-like	PMID 39579173
p.Gln407*	Nonsense (stop-gain)	Loss-of-function (haploinsufficiency)	IMD132B — CVID-like	PMID 39579173
Multiple additional LOF variants (5 families)	Various premature-stop/frameshift	Haploinsufficiency (~50% reduced protein/mRNA)	IMD132B founding cohort	Science Immunology, abn3800

Protein domain architecture: TRAF3 has an N-terminal RING-type zinc-finger domain (required for TRAF3's role in downregulating NF-κB2/p100 processing) and additional zinc fingers, followed by a C-terminal MATH/TRAF domain, which mediates receptor binding — the crystal structure of the CD40 cytoplasmic tail bound to the TRAF3 MATH domain shows the CD40 peptide binding as a hairpin loop across the domain surface.

Functional consequence: functional_impact_category-relevant — LOF variants → LOSS_OF_FUNCTION (haploinsufficiency, ~50% protein/mRNA reduction); R118W and R338W → DOMINANT_NEGATIVE (disproportionate reduction of total TRAF3 below the 50% haploinsufficiency threshold via interference with wild-type protein).

Population frequency / ClinVar: ClinVar records specific TRAF3 variants under "Herpes simplex encephalitis, susceptibility to, 3" (e.g., NM_145725.3:c.810C>T and c.651+13G>C). No large-scale gnomAD constraint or general-population carrier-frequency statistic specific to disease-causing LOF alleles was retrieved; TRAF3 is broadly conserved and intolerant of loss-of-function based on its essential immune-regulatory role (inferred from mouse knockout lethality, below).

Somatic vs. germline distinction: Germline heterozygous LOF/dominant-negative variants cause the Mendelian immunodeficiency syndrome. Separately, somatic homozygous deletions and inactivating mutations of TRAF3 are well documented as recurrent, non-germline drivers in multiple myeloma and B-cell non-Hodgkin lymphoma, where TRAF3 behaves as a bona fide tumor suppressor via constitutive non-canonical NF-κB activation. This is mechanistically related but etiologically distinct from the germline haploinsufficiency syndrome.

Epigenetics: No disease-specific DNA methylation/histone data were identified; however, the 2025 PNAS aging study shows TRAF3 protein (not mRNA) declines with age via proteasomal degradation, a post-translational rather than epigenetic mechanism.

Chromosomal abnormalities: No recurrent aneuploidy/translocation involving 14q32.32 is described for the germline syndrome (distinct from the well-known 14q32 IGH translocations in B-cell malignancy, which is a different genomic phenomenon).

5. Environmental Information

Infectious triggers: Herpes simplex virus-1 is the specific documented trigger for encephalitis in IMD132A; Mycobacterium abscessus is documented as a chronic pulmonary pathogen in TRAF3-deficient patients. Diverse unspecified bacterial/viral pathogens drive the recurrent sinopulmonary infections seen in IMD132B.
Lifestyle/toxin factors: None specifically implicated in the literature reviewed.
No infectious cause of the underlying disease itself is implicated (this is a monogenic immunodeficiency, not an infection-triggered disease); rather, infection is a downstream phenotypic consequence of the impaired antiviral/antibacterial immune signaling.

6. Mechanism / Pathophysiology

Molecular pathway

TRAF3 is a cytoplasmic adaptor that functions downstream of CD40, BAFF-receptor (BAFF-R/TNFRSF13C), other TNFR-superfamily members, TLR3/TRIF, and RIG-I-like receptors. Its central, disease-relevant role is as a negative regulator of the non-canonical (alternative) NF-κB2 pathway: together with TRAF2 and cIAP1/2, TRAF3 constitutively targets NIK (NF-κB-inducing kinase) for K48-linked polyubiquitination and proteasomal degradation, keeping NF-κB2/p100→p52 processing suppressed at baseline. Receptor engagement (CD40L, BAFF) triggers TRAF3's own K48-ubiquitination and degradation, releasing NIK, and permitting NF-κB2 (p52) activation and downstream B-cell survival/differentiation signaling. TRAF3 also participates in TLR3-TRIF-dependent type I interferon induction (IFN-β) relevant to antiviral defense (PMID 20832341) and in canonical NF-κB/MAPK regulation more broadly.

Causal chain (haploinsufficiency form, IMD132B)

Trigger: Heterozygous LOF TRAF3 variant → ~50% reduction in TRAF3 protein/mRNA in B cells and PBMCs.
Molecular consequence: Insufficient TRAF3-TRAF2-cIAP degradation of NIK → increased basal and receptor-stimulated non-canonical NF-κB2 (p52) activation — shown to be "significantly more abundant" in heterozygous mouse B cells vs. wild-type, at levels intermediate between wild-type and complete knockout.
Downstream transcriptional/metabolic effects: Dose-dependent elevation of pro-survival proteins Mcl1, Pim2, c-Myc, and the glycolytic enzyme Hxk2; increased mitochondrial respiration; heightened phospho-STAT3 (Y705) signaling downstream of IL-6 receptor engagement.
Cellular consequence: Prolonged B-cell survival in vitro (heterozygous B cells outlive wild-type through day 3 of culture before dying by day 5), increased splenic B-cell numbers and plasma cells (splenic but not bone-marrow), and altered B-cell maturation (reduced class-switched memory B cells, increased naive B cells) in humans.
Tissue/organism consequence: B-cell hyperactivity → hypergammaglobulinemia and autoimmunity (autoantibody production, lymphoid hyperplasia, GI inflammation, hepatosplenomegaly) coexisting paradoxically with impaired pathogen clearance (recurrent respiratory infection) — attributable to concurrent T-cell dysregulation (reduced naive T cells, impaired T-cell proliferation) and disrupted humoral maturation despite B-cell numeric expansion.
Malignancy risk: Chronic non-canonical NF-κB2 hyperactivation and elevated pro-survival/proliferative signaling (Mcl1, c-Myc, Pim2) create a cell-intrinsic substrate for B-cell malignant transformation, mirroring the well-established role of complete/biallelic somatic TRAF3 loss as an oncogenic driver in multiple myeloma and B-cell lymphoma.

Dominant-negative form (IMD132A)

Rather than simple dosage reduction, mutant TRAF3 protein (e.g., R118W) destabilizes the wild-type protein produced from the normal allele, driving TRAF3 levels far below the 50% haploinsufficiency threshold. This severely impairs TLR3/TRIF-dependent IFN-β and IL-6 production, compromising CNS antiviral defense against HSV-1 and predisposing to herpes simplex encephalitis; a distinct manifestation involves impaired antimycobacterial TNF-α-dependent responses, predisposing to chronic M. abscessus pulmonary infection.

Cell types and biological processes involved

Cell types (CL terms): B lymphocyte (CL:0000236), plasma cell (CL:0000786), naive B cell (CL:0000788), memory B cell (CL:0000787), CD4+ T cell (CL:0000624), regulatory T cell (CL:0000815), T follicular helper cell (CL:0002038)
Biological processes (GO terms): non-canonical NF-kappaB signal transduction (GO:0038061 / related to GO:0043123 positive regulation of NF-kB), protein K48-linked ubiquitination (GO:0070936), toll-like receptor 3 signaling pathway (GO:0034138), type I interferon production, B cell proliferation (GO:0042100), B cell differentiation, mitochondrial respiration/oxidative phosphorylation

Molecular profiling

No published transcriptomic (GEO), proteomic, or single-cell datasets specific to human TRAF3-HI patients were identified in this search; the mechanistic dataset is largely built from B-cell-conditional Traf3 knockout/heterozygous mouse models (B-Traf3+/−) combined with patient PBMC/B-cell immunophenotyping (flow cytometry, Western blot) rather than omics-scale profiling.

7. Anatomical Structures Affected

Organ level: Primary — respiratory tract (recurrent infection, bronchiectasis), lymphoid organs (spleen, lymph nodes — lymphadenopathy, splenomegaly), liver (hepatomegaly, possible autoimmune hepatitis-type involvement), gastrointestinal tract (ileitis, pancolitis). CNS involvement (encephalitis) specific to the IMD132A/HSE phenotype.
Body systems: Immune system (primary), respiratory system, hepatobiliary system, gastrointestinal system, and secondarily the central nervous system in the dominant-negative HSE-associated form.
Tissue/cell level: Lymphoid tissue (nodular lymphoid hyperplasia), B-lymphocyte and T-lymphocyte compartments specifically.
Subcellular: Cytoplasmic signalosome complexes (TRAF3-TRAF2-cIAP1/2-NIK) at the plasma membrane/receptor complex; proteasome-mediated degradation machinery.
UBERON-relevant sites: spleen (UBERON:0002106), lymph node (UBERON:0000029), lung (UBERON:0002048), liver (UBERON:0002107), large intestine (UBERON:0000059), ileum (UBERON:0002116).

8. Temporal Development

Onset: Predominantly childhood for the core immunodeficiency phenotype (recurrent respiratory infections, bronchiectasis by adulthood implies childhood onset); HSE onset also in childhood (IMD132A); M. abscessus pulmonary infection described in an adult (51-year-old woman).
Progression: Chronic, apparently progressive in respiratory (structural bronchiectasis) and possibly hepatic/GI domains; not described as episodic overall, though autoimmune flares may be episodic in nature (consistent with other autoimmune-lymphoproliferative PIDs).
Course: Lifelong/chronic — no spontaneous remission described. The 2025 aging data suggest phenotype severity could plausibly worsen with advancing age due to superimposed age-related TRAF3 protein decline, though this has not been formally studied longitudinally in patients.

9. Inheritance and Population

Epidemiology: Ultra-rare; only ~12 patients (9 in the founding cohort + 3 in the follow-up CVID-reanalysis cohort) are documented in the literature reviewed for the haploinsufficiency (IMD132B) form as of this report, plus a small number of additional IMD132A (dominant-negative) cases (HSE and M. abscessus presentations). No formal prevalence/incidence estimate exists.
Inheritance pattern: Autosomal dominant for both IMD132A and IMD132B.
Penetrance/expressivity: Variable expressivity is evident — patients within and across families present with differing combinations of infection, autoimmunity, and lymphoproliferation; some previously carried alternate diagnoses (e.g., CVID) before TRAF3 variants were identified via targeted reanalysis, suggesting either incomplete ascertainment of the syndrome's distinctive features or genuinely variable presentation.
De novo occurrence: The prototypic IMD132A R118W variant arose de novo.
Founder effects/consanguinity/carrier frequency: Not reported; not applicable given autosomal dominant, non-recessive inheritance.
Sex ratio: Not explicitly reported as skewed in available sources (index patients described include both male and female).

10. Diagnostics

Genetic testing: Diagnosis is established via NGS-based inborn-errors-of-immunity gene panels or exome/genome sequencing with TRAF3-targeted variant calling/reanalysis — explicitly how the 2024 cohort was ascertained (reanalysis of 800 existing IEI sequencing datasets). Given the gene's association with CVID-like presentations, TRAF3 should be considered in any CVID/hypogammaglobulinemia gene panel, and clinicians are encouraged to revisit "CVID of unknown cause" cohorts for TRAF3 variants.
Immunophenotyping (flow cytometry): CD4+ T-cell count and naive/memory subsets, Treg and Tfh proportions, B-cell maturation subsets (naive vs. class-switched memory), immunoglobulin levels (IgG/IgA/IgM), autoantibody panels.
Functional assays: TRAF3 protein quantification (Western blot) in PBMCs/B cells to confirm haploinsufficient (~50%) vs. dominant-negative (<50%, e.g. ~17.5%) reduction; TLR3-stimulated IFN-β/IL-6 production assays (fibroblast-based, as used in the original HSE study) for suspected IMD132A.
Imaging: Chest CT for bronchiectasis assessment; abdominal imaging for hepatosplenomegaly/lymphadenopathy.
Endoscopy/biopsy: For GI inflammation (ileitis, pancolitis) as seen in the index patient.
Differential diagnosis: Other NF-κB-pathway primary immunodeficiencies — NFKB1 haploinsufficiency (CVID-like), NFKB2 deficiency, CTLA4 haploinsufficiency, TNFAIP3/A20 haploinsufficiency (HA20), LRBA deficiency — all share overlapping combined immunodeficiency-with-autoimmunity phenotypes and should be distinguished by targeted gene panel/exome sequencing. Also distinguish idiopathic CVID (no identified monogenic cause) from monogenic TRAF3-HI, since a subset of "CVID" patients are now understood to actually have TRAF3-HI.
Screening: No population/newborn screening applicable given rarity; cascade testing of relatives is appropriate given autosomal dominant inheritance and variable expressivity.

11. Outcome/Prognosis

Malignancy risk: The founding Science Immunology study explicitly reports an increased risk of B-cell malignancy among TRAF3-HI patients, mechanistically consistent with TRAF3's established tumor-suppressor role — chronic non-canonical NF-κB2/pro-survival protein (Mcl1, Pim2, c-Myc) hyperactivation in the heterozygous state provides a plausible intermediate step toward the complete/biallelic TRAF3 loss recurrently observed as a somatic driver in multiple myeloma and B-cell lymphoma. Comparative oncology data reinforce this: germline TRAF3 mutations were found in 17.5% (11/63) of canine B-cell lymphoma cases, with 14.2% lacking any additional somatic TRAF3 mutation, suggesting inherited TRAF3 variants alone can predispose to lymphoma (PMID 25468570).
Structural/functional sequelae: Bronchiectasis represents a documented, presumably irreversible structural complication of recurrent respiratory infection.
Mortality/survival: No formal survival statistics are available given the small, recently described cohort; the historical HSE-associated case responded to antiviral treatment, while the M. abscessus-associated case was treatment-resistant, illustrating variable infection-related morbidity.
Complications: Chronic GI inflammation (ileitis, pancolitis), hepatosplenomegaly, autoimmune manifestations, and immunoglobulin abnormalities requiring ongoing management.
Prognostic factors: No validated biomarkers for stratifying disease severity/malignancy risk are yet established; age-related TRAF3 decline (independent of the germline variant) is a biologically plausible but clinically unvalidated risk-modifying factor.

12. Treatment

No disease-specific, TRAF3-HI-tailored treatment guideline yet exists (reflecting its very recent characterization); management is inferred to follow the general combined-immunodeficiency-with-autoimmunity paradigm used for related NF-κB-pathway PIDs (e.g., CVID, NFKB1-HI, CTLA4-HI):

Immunoglobulin replacement therapy (IVIG/SCIG): Documented directly — the 2024 cohort's 3 patients, having previously been diagnosed with CVID, were receiving immunoglobulin replacement therapy for hypogammaglobulinemia and recurrent infections (NCIT:C15986 Pharmacotherapy category; specific product NCIT terms would apply to the IVIG/SCIG agent used).
Antibiotic prophylaxis/treatment: Implied standard-of-care for recurrent bacterial sinopulmonary infection and bronchiectasis management, and specifically required (with resistance noted) for the M. abscessus pulmonary infection case.
Antiviral therapy: Standard HSV antiviral treatment (e.g., acyclovir) for herpes simplex encephalitis in the IMD132A phenotype; the reported HSE case "responded to treatment."
Immunomodulation for autoimmune manifestations: Not explicitly reported for TRAF3-HI patients in the sources retrieved, but by analogy to closely related NF-κB-pathway PIDs (e.g., CTLA4 haploinsufficiency, ALPS), agents such as sirolimus (mTOR inhibitor, effective for refractory autoimmune cytopenias/lymphoproliferation in related PIDs) and rituximab (anti-CD20, B-cell depletion) represent plausible off-label options for autoimmune cytopenia/lymphoproliferation, though no TRAF3-HI-specific outcome data were found.
Targeted/experimental therapeutics: Given TRAF3's role upstream of NF-κB2/NIK, NIK inhibitors or other non-canonical NF-κB pathway modulators represent a mechanistically rational but currently unvalidated therapeutic avenue; a related mouse study found Syk inhibition limited autoimmunity and abnormal B-cell phenotype/function in B-cell-specific TRAF3-deficient mice (J Immunol, academic.oup.com/jimmunol article), suggesting Syk-pathway targeting as another candidate strategy warranting translational investigation.
Malignancy surveillance: Given the demonstrated B-cell malignancy risk, ongoing hematologic/oncologic surveillance is a reasonable clinical inference, though no formal surveillance protocol has been published.
No gene therapy, cell therapy, or disease-specific clinical trials (ClinicalTrials.gov) were identified for TRAF3-HI specifically.

13. Prevention

Primary prevention: Not applicable in the classic sense (germline monogenic disease); genetic counseling for affected families is appropriate given autosomal dominant inheritance and variable expressivity, including consideration of cascade testing in relatives and reproductive counseling.
Secondary prevention: Early genetic diagnosis (via IEI panel/exome reanalysis) allows earlier initiation of immunoglobulin replacement and infection-prevention measures, potentially forestalling bronchiectasis and other structural sequelae; routine vaccination status optimization (noting that live vaccines may be contraindicated depending on the degree of immunodeficiency, as in other combined immunodeficiencies) is a standard PID consideration though not TRAF3-HI-specific in the literature reviewed.
Tertiary prevention: Malignancy surveillance (as above) to enable early detection of B-cell lymphoproliferative transformation.
No vaccine, chemoprophylactic, or public-health-level prevention strategy specific to TRAF3-HI exists, consistent with its status as an ultra-rare monogenic disorder rather than an infectious or environmentally-driven condition.

14. Other Species / Natural Disease

Dog (Canis lupus familiaris): The most clinically relevant comparative model — germline and somatic TRAF3 inactivation is a recurrent, naturally occurring feature of canine B-cell lymphoma (cBCL). Somatic TRAF3 mutations (frameshift + truncating SNVs) were found in ~30.2% of a cBCL cohort, and germline TRAF3 mutations in 17.5% (11/63) of cases, with 14.2% of cases carrying only a germline (no somatic) TRAF3 mutation — directly supporting the concept that a single inherited TRAF3 LOF allele predisposes to B-cell malignancy, paralleling concerns for human TRAF3-HI patients (PMID 25468570, Blood). This makes naturally occurring canine BCL a valuable spontaneous large-animal comparative model for the human malignancy-risk arm of TRAF3-HI.
Taxonomy: Canis lupus familiaris (NCBITaxon:9615).
Orthology: TRAF3 is highly conserved across mammals; canine TRAF3 shares the same NF-κB-regulatory function as human TRAF3.
Zoonotic potential: Not applicable — this is a non-communicable, germline genetic condition, not a transmissible disease.

15. Model Organisms

Mouse (Mus musculus), full-body Traf3 knockout: Per MGI (marker MGI:108041), homozygous Traf3-null mice show progressive runting, hypoglycemia, and depletion of peripheral white blood cells, dying by ~10 days of age; lethally irradiated mice reconstituted with mutant hematopoietic cells show impaired T-dependent antibody responses — establishing TRAF3 as essential for immune and metabolic homeostasis, and explaining why disease-causing human variants are invariably heterozygous (complete biallelic loss is likely embryonically/perinatally incompatible with survival, analogous to the mouse).
Mouse, B-cell-conditional heterozygous knockout (B-Traf3+/−): The key genetic model directly modeling human haploinsufficiency (Hornick et al., 2025, PNAS). Findings: 40–50% reduction of TRAF3 protein/mRNA in splenic B cells; dose-intermediate increases in spleen weight, splenic B-cell number, NF-κB2 (p52) activation, plasma-cell numbers (splenic, not marrow), and pro-survival protein expression (Mcl1, Pim2, c-Myc, Hxk2) relative to wild-type and full knockout; prolonged in vitro B-cell survival through day 3 (dying by day 5); elevated phospho-STAT3(Y705) after IL-6 stimulation.
Mouse, B-cell-specific complete Traf3 knockout: Used in earlier mechanistic work (e.g., leu2011309, Leukemia journal) showing that complete B-lineage Traf3 deletion drives spontaneous B-lymphoma development in mice — modeling the malignancy end of the phenotypic spectrum; Syk inhibition was shown to limit the resulting autoimmunity and abnormal B-cell phenotype in this model.
Aged wild-type mice: Used as a model of physiological TRAF3 decline — aged (≥16 months) vs. young (≤3 months) mouse B cells show reduced TRAF3 protein (mirroring the human aging data), reversible acutely by proteasome inhibition (bortezomib), directly linking normal aging biology to the same pathway disrupted genetically in TRAF3-HI.
Model limitations: Full knockout mice die neonatally and cannot model the chronic, decades-long human disease course; heterozygous B-cell-conditional mice best model the dosage-sensitive human phenotype but do not capture T-cell dysregulation, GI inflammation, or CNS (HSE-susceptibility) aspects of the human syndrome, which currently lack dedicated animal models. No zebrafish, Drosophila, C. elegans, iPSC, or organoid TRAF3-HI-specific disease models were identified in this search.
Resources: MGI (Traf3 marker MGI:108041; targeted alleles e.g. MGI:3722126 [tm1Bshp], MGI:2135257 [tm1Bal], MGI:3777325 [tm1.1Rbr]); Cyagen commercial Traf3-KO mouse model.

Summary of Key Ontology Term Suggestions

Category	Suggested terms
Causal gene	HGNC:TRAF3 (hgnc: TRAF3), Chromosome 14q32.32
GO Biological Process	non-canonical NF-kB signal transduction, protein K48-linked ubiquitination (GO:0070936), toll-like receptor 3 signaling pathway (GO:0034138), B cell proliferation (GO:0042100)
GO Molecular Function	ubiquitin-protein transferase adaptor activity
Cell types (CL)	B lymphocyte (CL:0000236), plasma cell (CL:0000786), naive/memory B cell, CD4+ T cell (CL:0000624), regulatory T cell (CL:0000815), Tfh cell (CL:0002038)
Phenotypes (HP)	Recurrent respiratory infections (HP:0002205), Bronchiectasis (HP:0002110), Lymphadenopathy (HP:0002716), Hepatosplenomegaly (HP:0001433), Hypergammaglobulinemia (HP:0010702), Hypogammaglobulinemia (HP:0004313), Encephalitis (HP:0002383), Autoimmunity (HP:0002960)
Anatomy (UBERON)	Spleen, Lymph node, Lung, Liver, Ileum, Large intestine
Treatment (NCIT)	Pharmacotherapy (NCIT:C15986) with therapeutic_agent immunoglobulin; Chemotherapy/anti-infective for M. abscessus/HSV

Notes on Evidentiary Gaps

No confirmed MONDO ID was identified for this specific entity via search; this should be independently verified in the current Mondo release before curation.
Direct primary-source full text for the founding Science Immunology paper (abn3800) and the Journal of Clinical Immunology CVID cohort paper (10.1007/s10875-024-01833-3) could not be fetched directly (paywalled/403); the information above for these two papers is drawn from search-result summaries and secondary citations rather than verified direct quotes from the primary text. Exact-quote snippets for dismech evidence items should be re-verified against the primary PMID/DOI sources (or PMC full text if available) before being entered into evidence blocks, per the project's evidence-integrity requirements.
Quantitative epidemiological data (prevalence/incidence), formal quality-of-life measures, and a validated diagnostic/treatment algorithm are not yet available in the literature, consistent with this being a very recently characterized (2022–2024), ultra-rare monogenic disorder.

Sources: - Human TRAF3 Adaptor Molecule Deficiency Leads to Impaired Toll-like Receptor 3 Response and Susceptibility to Herpes Simplex Encephalitis (PubMed, PMID 20832341) - Human TRAF3 Adaptor Molecule Deficiency... (Immunity/Cell.com full text) - Immunodeficiency, autoimmunity, and increased risk of B cell malignancy in humans with TRAF3 mutations (Science Immunology, abn3800) - Heterozygous Predicted Loss-of-function Variants of TRAF3 in Patients with Common Variable Immunodeficiency (J Clin Immunol, PMID 39579173) - Reduction of TRAF3 by heterozygosity or aging impacts B cell function (PNAS, PMID 40773231) - Reduction of TRAF3 by heterozygosity or aging impacts B cell function (PMC free full text) - OMIM #621096 — IMMUNODEFICIENCY 132B; IMD132B - OMIM #614849 — IMMUNODEFICIENCY 132A; IMD132A - OMIM *601896 — TNF RECEPTOR-ASSOCIATED FACTOR 3; TRAF3 - Dominant Negative TRAF3 Variant With Recurrent Mycobacterium abscessus Infection and Bronchiectasis (Open Forum Infectious Diseases, PMID 36004314) - Genetic inactivation of TRAF3 in canine and human B-cell lymphoma (Blood, PMID 25468570) - Specific deletion of TRAF3 in B lymphocytes leads to B-lymphoma development in mice (Leukemia) - TRAF3: A novel regulator of mitochondrial physiology and metabolic pathways in B lymphocytes (Frontiers in Oncology, PMC9911533) - Syk inhibition limits autoimmunity and abnormal B cell phenotype and function in mice with B cell-specific TRAF3 deficiency (Journal of Immunology) - Traf3 MGI Mouse Gene Detail — MGI:108041 - TRAF3 Gene — GeneCards - TNF receptor (TNFR)-associated factor (TRAF) 3 serves as an inhibitor of TRAF2/5-mediated activation of the noncanonical NF-κB pathway (PNAS) - Molecular basis for CD40 signaling mediated by TRAF3 (PNAS) - Immunodeficiency 132b — MalaCards

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TRAF3 Haploinsufficiency: Comprehensive Disease Research Report

1. Disease Information

2. Etiology

Disease Causal Factors

Risk Factors

Protective Factors

Gene-Environment Interactions

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

Molecular pathway

Causal chain (haploinsufficiency form, IMD132B)

Dominant-negative form (IMD132A)

Cell types and biological processes involved

Molecular profiling

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Summary of Key Ontology Term Suggestions

Notes on Evidentiary Gaps