Immunodeficiency 60

Mendelian MONDO:0032723 Pathograph 30 Show in embeddings browser Inborn error of immunity Disease of immune dysregulation

Immunodeficiency 60 is an autosomal dominant inborn error of immunity caused by haploinsufficiency for BACH2, a BTB/POZ- and basic-leucine-zipper-domain transcriptional repressor that acts as a lineage-specification factor in both the T-cell and the B-cell arm of adaptive immunity. The International Union of Immunological Societies places it in Table 4, diseases of immune dysregulation, rather than among the predominantly antibody deficiencies, and summarises the defect as haploinsufficiency for a critical lineage specification transcription factor. The consequence is the unusual pairing that defines the entity: a humoral deficiency and a lymphocytic infiltrative disease in the same patient. Loss of one functional BACH2 allele impairs regulatory T-cell differentiation, which places the disorder among the monogenic "Tregopathies" alongside IPEX, CD25 deficiency and STAT3 gain-of-function; it also impairs memory B-cell development, which underlies the sinopulmonary infection phenotype. IUIS records progressive T-cell lymphopenia in the circulating T-cell compartment and impaired memory B-cell development in the B-cell compartment, with lymphocytic colitis and sinopulmonary infections as the associated clinical features. BACH2 defects are among the monogenic causes found when FOXP3-negative IPEX-like immune dysregulation is sequenced, and pulmonary surveillance is recommended for carriers. This entry is deliberately conservative about how much is settled. ClinGen's Antibody Deficiencies Gene Curation Expert Panel classifies the BACH2 relationship to immunodeficiency 60 as Moderate rather than Definitive or Strong, and the syndrome rests on a small number of reported families - the family reporting the second case did so six years after the founding description. The founding report (Afzali et al., Nat Immunol 2017, which named the syndrome BRIDA) is now curated from its full text, which supplies the patient-level detail the abstract withheld: the isotype pattern in each of the three subjects, the class-switch and plasmablast assays in their B cells, the per-compartment mouse phenotype, and a human RNAi system that halves BACH2 in healthy donor cells. What is still missing is numeric - the immunoglobulin concentrations themselves live in a supplementary table that is not part of the retrievable article - so the humoral phenotype is curated as a direction per isotype and not as measured values. The single most useful thing the full text settles is that the humoral picture is not uniform and is not fixed by the variant. Two of the three subjects were low in every isotype; the third, who carries the same E788K allele as her affected father, had low IgA against raised IgM and IgG. So the same allele in one family produces pan-hypogammaglobulinemia in the father and an IgA-selective picture in the daughter, and a normal or high IgG does not exclude the diagnosis. Two features of the syndrome are worth flagging because they are easy to get backwards. The dosage defect is a loss, not an interference: the mutations destabilize BACH2 by blocking homodimerization or causing aggregation, so a carrier has half the protein rather than a poisoned pathway. And BACH2 loss reduces useful antibody despite BACH2 being a repressor of immunoglobulin production, because what requires BACH2 is the class-switch and hypermutation programme rather than plasma-cell differentiation itself - Bach2-null B cells still make IgM and express BLIMP1 and XBP-1 abundantly. Abundant rather than merely preserved is the mechanistically telling word: BACH2 represses BLIMP1, so a null de-represses it, and the cell proceeds to terminal differentiation without ever switching isotype. A separate claim must be kept distinct from this one. BACH2 is also a common-variant susceptibility locus in many polygenic autoimmune diseases - type 1 diabetes, Graves disease, vitiligo, multiple sclerosis, alopecia areata, autoimmune adrenal insufficiency - and appears in this knowledge base in that role in more than a dozen entries. That is an association claim about regulatory variation in a population, not the Mendelian coding haploinsufficiency described here. Whether the two act on one BACH2 dosage axis is recorded below as an emerging hypothesis, not as a causal edge.

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1
Inheritance
6
Pathophys.
1
Histopath.
14
Phenotypes
1
Hypotheses
5
Gaps
30
Pathograph
1
Genes
1
Variants
3
Medical Actions
5
Models
13
References
🏷

Classifications

IUIS Category
immune dysregulation
👪

Inheritance

1
Autosomal dominant HP:0000006
Autosomal dominant, acting through haploinsufficiency rather than a dominant negative. IUIS and ClinGen agree on the mode of inheritance.
Autosomal dominant inheritance
Show evidence (2 references)
PMID:35748970 SUPPORT Other
"BACH2 deficiency BACH2 AD 605394 Progressive T cell lymphopenia Impaired memory B cell development Haploinsufficiency for a critical lineage specification transcription factor"
The IUIS Table 4 row records the mode of inheritance as AD and the functional defect as haploinsufficiency, which together specify dominance by gene dosage.
CGGV:assertion_2473560a-6e5c-4342-a6e2-c89e37f4cc71-2023-02-21T180000.000Z SUPPORT Other
"BACH2 | HGNC:14078 | immunodeficiency 60 | MONDO:0032723 | AD | Moderate | SOP9 | Antibody Deficiencies Gene Curation Expert Panel | 2023-02-21T18:00:00.000Z"
ClinGen independently records the mode of inheritance for this gene-disease relationship as autosomal dominant.
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Mechanistic Hypotheses

1
Common regulatory variation and rare coding haploinsufficiency at BACH2 act on one gene-dosage axis
bach2_dosage_axis EMERGING
Evidence balance 5 support
BACH2 occupies an unusual position: the same gene is a recurrent common-variant susceptibility locus across many polygenic autoimmune diseases and, separately, the cause of a Mendelian inborn error of immunity through coding haploinsufficiency. The hypothesis is that these are two ends of one dosage continuum - that regulatory variants shifting BACH2 expression modestly across a population produce autoimmune susceptibility, while a coding lesion halving it produces overt immune dysregulation with immunodeficiency. This is recorded as a hypothesis and deliberately not drawn as a causal edge. The susceptibility associations and the Mendelian mechanism are established separately; that they share a dosage mechanism is an inference, and no cached source tests it. Deciding it would need expression-level data linking the risk haplotypes to BACH2 dosage in the relevant lymphocyte compartments.
See the entry-level notes for the list of dismech entries carrying BACH2 as a susceptibility locus.
Show evidence (5 references)
PMID:28530713 SUPPORT Other
"Single-nucleotide variants in the BACH2 locus are associated with several autoimmune diseases, but BACH2 mutations that cause Mendelian monogenic primary immunodeficiency have not previously been identified."
States both ends of the proposed axis in one sentence, and is the founding report's own framing of why the Mendelian entity was worth looking for.
PMID:28530713 SUPPORT Computational
"genes that cause monogenic haploinsufficient diseases were substantially enriched for TFs and SE architecture"
The mechanism the founding report proposes for why one locus supports both a common-variant association signal and a rare dosage disease - super-enhancer architecture makes transcription-factor genes dosage-sensitive.
PMID:23728300 SUPPORT INDIRECT Model Organism
"Genetic polymorphisms within a single locus encoding the transcription factor BACH2 are associated with numerous autoimmune and allergic diseases including asthma, Crohn's disease, coeliac disease, vitiligo, multiple sclerosis and type 1 diabetes."
Enumerates the common-variant end of the axis, and names the same diseases that carry BACH2 as a susceptibility locus elsewhere in this knowledge base.
+ 2 more references
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Discussions and Knowledge Gaps

5
Which immunoglobulin isotypes fall in immunodeficiency 60, by how much, and does the picture meet criteria for common variable immunodeficiency?
KNOWLEDGE GAP OPEN bach2_imd60_humoral_phenotype_uncurated
Attached to
pathophysiology#Impaired Memory B Cell Development phenotypes#Recurrent sinopulmonary infections
Two of the three parts are now answered from the founding report's full text, and the third is not. Which isotypes: not the same ones in every patient. Two founding subjects were low in IgM, IgG, IgA and IgE together; the third, carrying the same E788K allele as her affected father, had low IgA against raised IgM and IgG. IgA is the only isotype low in all three, and a further family carrying R576L was also IgA deficient. The pattern therefore does not track the variant, which rules out the simplest reading - that each allele produces its own humoral picture - and leaves modifiers, age or ascertainment as the explanation. All of this is now curated: the isotype spread on the Immunoglobulin deficiency phenotype, IgA separately as the consistent one. CVID criteria: the authors state that all three subjects developed "a chronic variable immunodeficiency" characterised by recurrent respiratory infection with failure to respond to vaccination, and the vaccine-response failure is curated as its own phenotype. That is the authors' characterisation rather than a formal application of ESID or ICON diagnostic criteria, and this entry does not upgrade it into one. The separate question of whether the disorder belongs with the antibody deficiencies at all is tracked in the IUIS-versus-ClinGen discussion below. By how much: still open, and now for a specific and probably permanent reason. The immunoglobulin concentrations are reported in Supplementary Table 1, which is not part of the article record served by PMC, so no accessible source gives a value. Table 1 of the main article gives only Low, Normal or High per isotype. Until a further family is reported with values in the main text, this entry can record the direction of each isotype but not its magnitude, and cannot carry reference ranges for the humoral phenotype. The plasmablast and class-switch assay results named in the original version of this gap are no longer missing and are curated on the memory B-cell node.
Show evidence (2 references)
PMID:28530713 SUPPORT Human Clinical
"| IgG | Low | Low | High * |"
Table 1, the IgG row. It is the sharpest statement of the non-uniformity: the third subject's IgG is not merely normal but raised, which is why this entry does not describe BRIDA as a hypogammaglobulinemia.
PMID:28530713 NO_EVIDENCE Human Clinical
"| IgE | Low | Low | Normal |"
Cited as the boundary of what the accessible record contains. Table 1 gives each isotype as a category and never as a concentration, so the founding report - the only source that measured these patients - does not bear on the magnitude question this gap now turns on.
If BACH2 suppresses immunoglobulin production, why does losing it cause antibody deficiency rather than excess antibody?
OPEN QUESTION RESOLVED bach2_repressor_direction_paradox
Attached to
pathophysiology#Impaired Memory B Cell Development
BACH2 represses immunoglobulin production, and in normal memory B cells plasma-cell differentiation proceeds by inducing BLIMP1 and downregulating BACH2. Read naively, halving BACH2 should release antibody output rather than reduce it.
Resolution: Answered by the Bach2 knockout. Bach2-null B cells still produce IgM and still express Blimp-1 and XBP-1 abundantly, so plasmacytic differentiation itself does not require BACH2 - what fails is class switch recombination specifically. The abundance is itself informative: BACH2 represses BLIMP1, so losing BACH2 de-represses the plasma-cell programme rather than leaving it untouched, and the cell terminally differentiates without having switched isotype. BACH2 is therefore not a brake on antibody output in general; it is required for the class-switch and somatic-hypermutation programme while restraining premature terminal differentiation. Losing it yields antibody that is present but unswitched and unmutated, which is a functional humoral deficiency rather than an excess. The memory B-cell node is worded accordingly. The dose caveat this note used to end on is now closed. The resolution rested on a homozygous null mouse; the founding report's full text shows the same thing in human cells at the human gene dosage, by knocking BACH2 down about 50 percent in healthy donor B cells and finding class switching to IgG and IgA suppressed. So the class-switch dependency is a property of BACH2 dosage in human B cells, not an artifact of complete loss in mouse. One thing the full text complicates rather than settles. The null mouse showed plasmacytic differentiation intact, which is what let the answer be "switching fails, terminal differentiation does not". Patient naive B cells stimulated with IL-21 in vitro show impaired plasmablast generation as well as impaired switching. Those need not conflict - different species, different dosage, different stimulus - but the clean separation should not be over-read. This entry annotates isotype switching on the memory B-cell node and does not annotate plasma-cell differentiation, because the human plasmablast finding is a single in vitro assay and the mouse evidence points the other way.
Show evidence (2 references)
PMID:15152264 SUPPORT INDIRECT Model Organism
"When stimulated in vitro, Bach2-deficient B cells produced IgM, as did wild-type cells, and abundantly expressed Blimp-1 (refs 9, 10) and XBP-1 (ref. 11), critical regulators of the plasmacytic differentiation, indicating that Bach2 was not required for the plasmacytic differentiation itself...."
The sentence that dissolves the paradox - it separates plasmacytic differentiation, which is intact without BACH2, from class switching, which is not.
PMID:28530713 SUPPORT In Vitro
"silencing BACH2 in healthy control B cells, significantly suppressed in vitro class switch recombination towards the IgG and IgA isotypes"
Closes the dose caveat: the same dependency, in human B cells, at approximately the heterozygous dosage rather than in a homozygous null mouse.
Is BRIDA fully penetrant, and can a BACH2 carrier have the cellular phenotype without the disease?
OPEN QUESTION OPEN bach2_imd60_penetrance
Attached to
genetic#BACH2 inheritance#Autosomal dominant
In the second reported family the R576L variant was inherited from the father, who had no obvious symptoms yet showed an extreme reduction in memory B cells. That is a carrier with the laboratory phenotype and without the clinical one, which is the signature of incomplete penetrance or of a threshold effect requiring a second hit. It matters practically: it means an asymptomatic parent cannot be assumed to be a non-carrier, and it bears on how a family is counselled. One family is not enough to establish a penetrance estimate, and no source consulted here reports carrier counts, so this is a single observation rather than a quantified claim.
Show evidence (1 reference)
PMID:37148421 SUPPORT Human Clinical
"Notably, extreme reduction of memory B cells was detected in the patient's father, although he had no obvious symptoms."
The observation itself - cellular phenotype present, clinical phenotype absent, in an obligate carrier.
How wide is the BRIDA phenotype beyond immunoglobulin deficiency and colitis?
OPEN QUESTION OPEN bach2_imd60_phenotype_expansion
Attached to
disease# phenotypes#
Reports after the founding description have attached progressively more autoimmunity to heterozygous BACH2 variants - early-onset systemic lupus with juvenile dermatomyositis and IgA deficiency in one family, and autoimmune enteropathy alongside T-cell large granular lymphocytic leukemia, type 1 diabetes, pure red cell aplasia and celiac disease in another. Each is a single case, and the second carries obvious confounders: an HLA-DQ8 allele and a concurrent clonal lymphoproliferative disorder that is itself associated with autoimmunity. So these are not curated as phenotypes of this entry. The open question is whether BRIDA is a broad autoimmunity-predisposing state whose reported range is still growing, or whether single-case reports are accumulating around a gene that is also a common autoimmune susceptibility locus. Deciding it needs a case series, not more single reports.
Show evidence (2 references)
PMID:37148421 SUPPORT Human Clinical
"Here we describe a patient with BRIDA presenting with early-onset SLE, juvenile dermatomyositis, and IgA deficiency."
One reported expansion of the phenotype, in a single patient.
PMID:40386599 SUPPORT INDIRECT Human Clinical
"She carries an HLA-DQ8 allele and a germline heterozygous mutation of BACH2."
The second reported expansion, quoted with the confounding HLA allele in the same sentence because that is precisely why this entry does not curate it as a phenotype. INDIRECT for the same reason.
Should immunodeficiency 60 be grouped with the antibody deficiencies or with the diseases of immune dysregulation?
INTERPRETATION OPEN bach2_imd60_iuis_versus_clingen_panel
Attached to
disease#
The two authorities pull in different directions and both are defensible. ClinGen curated the gene through its Antibody Deficiencies Gene Curation Expert Panel, which reflects how the disorder presents - sinopulmonary infection and humoral deficiency. IUIS places it in Table 4 with the regulatory T-cell defects, which reflects the mechanism and the infiltrative colitis. This entry follows IUIS, because the Tregopathy classification is corroborated independently and because the lymphocytic colitis is not explicable as a consequence of antibody deficiency. The disagreement is recorded rather than hidden, since a reader coming from the ClinGen side will expect the other answer.
Show evidence (1 reference)
CGGV:assertion_2473560a-6e5c-4342-a6e2-c89e37f4cc71-2023-02-21T180000.000Z SUPPORT Other
"BACH2 | HGNC:14078 | immunodeficiency 60 | MONDO:0032723 | AD | Moderate | SOP9 | Antibody Deficiencies Gene Curation Expert Panel | 2023-02-21T18:00:00.000Z"
Names the ClinGen expert panel that curated the gene, which is the antibody deficiency panel rather than an immune dysregulation panel.
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Pathophysiology

6
BACH2 Protein Destabilization
The step that explains why one mutant allele yields half-dosage rather than a poisoned pathway. The reported BRIDA mutations do not produce a dominant-negative protein; they destabilize BACH2 itself, either by interfering with homodimerization through the BTB/POZ domain or by driving the protein into aggregates. The mutant product is therefore lost rather than interfering, which is what makes the downstream defect a pure gene-dosage problem.
BACH2 hgnc:14078 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves BACH2 (hgnc:14078). hgnc:14078 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context BACH2 hgnc:14078 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns BACH2 (hgnc:14078). hgnc:14078 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: LOSS_OF_FUNCTION
Downstream
BACH2 Haploinsufficiency
Show evidence (3 references)
PMID:28530713 SUPPORT Human Clinical
"The mutations disrupted protein stability by interfering with homodimerization or by causing aggregation."
States the molecular consequence of the variants directly, and is the reason this entry records LOSS_OF_FUNCTION rather than DOMINANT_NEGATIVE.
PMID:37148421 SUPPORT Human Clinical
"Reduced BACH2 expression and deficient transcriptional repression of the BACH2 target, BLIMP1, were detected in PBMCs or lymphoblastoid cell lines of our patient."
Independent confirmation in a second family that a BRIDA variant lowers BACH2 protein and its repressor output, in patient-derived cells.
PMID:28530713 SUPPORT Human Clinical
"found it was reduced in patient CD4+, CD8+ and B lymphocytes despite normal mRNA expression"
Shows the destabilization operating in the patients themselves, and localizes it to the protein: BACH2 message is normal while BACH2 protein is low, which is what distinguishes a stability defect from reduced transcription.
BACH2 Haploinsufficiency
Loss of one functional BACH2 allele leaves insufficient BACH2 protein to specify lymphocyte lineage decisions. IUIS characterises the defect as haploinsufficiency for a critical lineage specification transcription factor, which is a dosage statement rather than a dominant-negative one: the residual wild-type allele is not poisoned, it is simply not enough. BACH2 is required in both lymphoid lineages, which is why one dosage lesion produces a T-cell and a B-cell defect at once.
BACH2 transcriptional repressor activity GO:0001227 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased BACH2 transcriptional repressor activity, annotated with DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227). GO:0001227 is a molecular function from the Gene Ontology. ↓ DECREASED
Experimental models
BACH2 RNAi knockdown in primary human T and B cells PRIMARY CELL CULTURE Reducing BACH2 by about half in healthy human lymphocytes reproduces the patients' cellular phenotype in both lineages, which is what converts the correlation between low BACH2 and the BRIDA phenotype into a causal claim.
Animal models
Bach2-heterozygous mouse (BRIDA report) Mouse recapitulates Heterozygous loss in mouse reproduces the molecular state of heterozygous loss in humans - reduced Bach2 message and protein with de-repressed Prdm1 - which is what licenses reading mouse Bach2 dosage biology onto this disorder.
Downstream
Impaired Regulatory T Cell Differentiation
Impaired Memory B Cell Development
TH1 Effector Skewing
Gut-Homing Receptor Upregulation on CD4+ T Cells
Progressive T-cell lymphopenia
Show evidence (5 references)
PMID:35748970 SUPPORT Other
"Haploinsufficiency for a critical lineage specification transcription factor"
The functional-defect column of the IUIS Table 4 row, which states both the dosage mechanism and the class of protein affected.
PMID:26235382 SUPPORT INDIRECT Other
"BACH2 is highly expressed on B cells, suppresses the production of immunoglobulins"
Background for the repressor function that is lost. Graded INDIRECT because the statement is about normal BACH2 biology in a review of autoimmune thyroid genetics, not about immunodeficiency 60.
PMID:28530713 SUPPORT Human Clinical
"Here we describe a syndrome of BACH2-related immunodeficiency and autoimmunity (BRIDA) that results from BACH2 haploinsufficiency."
The defining report's statement that the syndrome results from haploinsufficiency, and the source of the BRIDA name.
+ 2 more references
Impaired Regulatory T Cell Differentiation
BACH2 is one of the transcription factors whose loss defines the monogenic "Tregopathies" - inborn errors of immunity that act through the regulatory T-cell compartment rather than through effector immunity. Insufficient BACH2 impairs regulatory T-cell differentiation, and the resulting failure of peripheral tolerance is the arm of the disease that produces lymphocytic tissue infiltration rather than infection.
FoxP3+ regulatory T cell CL:0000815 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves FoxP3+ regulatory T cell, annotated with regulatory T cell (CL:0000815). CL:0000815 is a cell type from the Cell Ontology.
regulatory T cell differentiation GO:0045066 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased regulatory T cell differentiation (GO:0045066). GO:0045066 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
Bach2-heterozygous mouse (Igarashi line, Treg characterization) Mouse recapitulates Halving Bach2 reduces Treg frequency in mouse, matching both the gene dosage and the compartment of the human disease.
Bach2-null mouse (Igarashi line, Treg characterization) Mouse partially recapitulates Complete Bach2 loss prevents efficient Treg formation and diverts cells destined for the regulatory lineage into effector lineages, producing lethal inflammation.
Downstream
TH1 Effector Skewing
Gut-Homing Receptor Upregulation on CD4+ T Cells
Lymphadenopathy
Splenomegaly
Non-infectious fever
Pancytopenia
Show evidence (5 references)
PMID:33996698 SUPPORT Other
"Other IEIs affect the function of regulatory T (Treg) cells—so-called ‘Tregopathies'—such as immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, deficiencies of CD25 or BTB domain and CNC homolog 2 (BACH2), and gain-of-function mutations in signal transducer and..."
Places BACH2 deficiency explicitly among the inborn errors that act through regulatory T-cell function, which is the basis for this node.
PMID:23728300 SUPPORT INDIRECT Model Organism
"BACH2 was required for efficient formation of regulatory (Treg) cells and consequently for suppression of lethal inflammation in a manner that was Treg-cell-dependent."
The mechanistic basis for this node. INDIRECT because it is a mouse gene disruption rather than an observation in BRIDA patients.
PMID:23728300 SUPPORT INDIRECT Model Organism
"its absence during Treg polarization resulted in inappropriate diversion to effector lineages"
Gives the failure mode - cells destined for the regulatory lineage become effectors instead - which is what converts a Treg defect into tissue infiltration.
+ 2 more references
TH1 Effector Skewing
The effector half of the T-cell lesion. Insufficient BACH2 releases the repression that normally restrains effector lineage commitment, and the patients' CD4+ compartment is pushed towards the TH1 programme, marked by raised T-bet. This says what the surviving cells become; where they go is the separate node below.
CD4-positive helper T cell CL:0000492 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves CD4-positive helper T cell (CL:0000492). CL:0000492 is a cell type from the Cell Ontology.
T-helper 1 cell differentiation GO:0045063 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased T-helper 1 cell differentiation (GO:0045063). GO:0045063 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Lymphocytic colitis
Show evidence (1 reference)
PMID:28530713 SUPPORT Human Clinical
"increased expression of the TH1 transcription factor T-bet and two gut-homing receptors, CCR9 and β7-integrin on CD4+ T cells"
Raised T-bet on patient CD4+ T cells. The same sentence also carries the gut-homing receptors, which belong to the separate node below - the quote is shared because the source reports both in one measurement, but the two claims are curated apart.
Gut-Homing Receptor Upregulation on CD4+ T Cells
The addressing half, and what makes the tissue infiltration land in the gut. A Treg deficit on its own predicts autoimmunity without predicting where it will appear; in BRIDA the CD4+ compartment carries raised levels of the two receptors that direct a T cell to intestinal tissue, CCR9 and beta-7 integrin. The same shift is reproduced at matched gene dosage in the heterozygous mouse, which is what makes it a consequence of halving BACH2 rather than a reaction to established colitis.
CD4-positive helper T cell CL:0000492 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves CD4-positive helper T cell (CL:0000492). CL:0000492 is a cell type from the Cell Ontology.
Animal models
Bach2-heterozygous mouse (BRIDA report) Mouse recapitulates The heterozygote reproduces the patients' receptor shift - more CCR9+ and beta-7 integrin+ CD4+ T cells, alongside fewer FoxP3+ cells - at the same gene dosage.
Downstream
Lymphocytic colitis
Show evidence (2 references)
PMID:28530713 SUPPORT Human Clinical
"increased expression of the TH1 transcription factor T-bet and two gut-homing receptors, CCR9 and β7-integrin on CD4+ T cells"
Raised CCR9 and beta-7 integrin on patient CD4+ T cells. Shared with the TH1 node above because the source reports both in one measurement.
PMID:28530713 SUPPORT INDIRECT Model Organism
"but Bach2+/− mice did have a small but significant reduction in FoxP3+ cells together with significant increases in CCR9+ and β7-integrin+ cells in CD4+ T cells"
The same receptor shift at the human gene dosage in mouse. INDIRECT because it is mouse rather than patient tissue.
Impaired Memory B Cell Development
The B-cell arm of the defect. IUIS records impaired memory B-cell development as the circulating B-cell finding in BACH2 deficiency. Mechanistically BACH2 sits upstream of the memory-versus-plasma-cell decision: in normal human memory B cells, differentiation to plasma cells is driven by PRDM1/BLIMP1 induction with reciprocal downregulation of BACH2, so BACH2 is the repressor that holds the memory programme open. Insufficient BACH2 leaves that programme unable to be established, and the memory B-cell compartment that supplies durable mucosal and respiratory antibody does not accumulate. The founding report's full text resolves how far the defect goes, which earlier versions of this entry left open. The loss in patients is not only of memory B cells but specifically of class-switched ones, and activating patient naive B cells in vitro reproduces the failure directly: class-switch recombination, plasmablast generation and class-switched antibody secretion are all impaired. Isotype switching is therefore annotated here as a patient-level defect rather than a mouse inference.
memory B cell CL:0000787 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves memory B cell (CL:0000787). CL:0000787 is a cell type from the Cell Ontology. IgG class-switched memory B cell CL:0000979 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves IgG class-switched memory B cell, annotated with IgG memory B cell (CL:0000979). CL:0000979 is a cell type from the Cell Ontology.
memory B cell differentiation GO:0002319 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased memory B cell differentiation (GO:0002319). GO:0002319 is a biological process from the Gene Ontology. ↓ DECREASED immunoglobulin class switch recombination GO:0045190 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased immunoglobulin class switch recombination, annotated with isotype switching (GO:0045190). GO:0045190 is a biological process from the Gene Ontology. ↓ DECREASED
Experimental models
BACH2 RNAi knockdown in primary human T and B cells PRIMARY CELL CULTURE Halving BACH2 in healthy human B cells is sufficient to suppress class switching to IgG and IgA - the two isotypes whose deficiency dominates the patients' humoral phenotype.
Animal models
Bach2-heterozygous mouse (BRIDA report) Mouse recapitulates On immunization the heterozygote fails at exactly the step the patients fail at: it barely generates class-switched B cells or plasma cells, and its germinal centers are reduced. This is the dose-matched counterpart of the patients' impaired in vitro class switching, and it is the readout that most directly connects halving BACH2 to the humoral phenotype.
Bach2-null mouse (Igarashi line, class-switching characterization) Mouse partially recapitulates Bach2-null B cells fail to class switch efficiently while retaining IgM output and abundant Blimp-1 and XBP-1 expression, which localizes the defect to class switch recombination rather than to terminal differentiation.
Downstream
Decreased memory B cell proportion
Decreased class-switched memory B cell proportion
Immunoglobulin deficiency
Decreased circulating IgA concentration
Decreased specific antibody response to vaccination
Show evidence (6 references)
PMID:35748970 SUPPORT Other
"Impaired memory B cell development"
The circulating-B-cell column of the IUIS Table 4 row for BACH2 deficiency.
PMID:29670635 SUPPORT INDIRECT In Vitro
"human IgG+ MBCs primar - ily differentiated into PCs in response to either T-cell-dependent or T-cell-independent stimulation guided by rapid PRDM1 (BLIMP1) induction and downregulation of BACH2"
Establishes the reciprocal BACH2-BLIMP1 relationship in normal human memory B cells that this node's mechanism depends on. Graded INDIRECT because it describes normal B-cell differentiation in a review of chronic lymphocytic leukemia, not the disorder. Quoted with the source's own hyphenation artifact.
PMID:28530713 SUPPORT Human Clinical
"Affected subjects had lymphocyte-maturation defects that caused immunoglobulin deficiency and intestinal inflammation."
The defining report's statement that the maturation defect is what causes the humoral deficiency, which is the edge this node draws to immunoglobulin deficiency.
+ 3 more references
✶

Histopathology

1
Chronic colitis with crypt branching and pericryptal lymphocytic infiltrate
The colonic biopsy in the index patient shows chronic architectural change - crypt branching - together with lymphocytes massed around the crypts, and a Treg population that is reduced relative both to healthy controls and to patients with ordinary inflammatory bowel disease. That last comparison is what makes the biopsy mechanistically informative rather than merely confirmatory: the Treg deficit is not a generic consequence of colonic inflammation, so it points at the regulatory T-cell failure as the cause of the colitis rather than its result.
Show evidence (2 references)
PMID:28530713 SUPPORT Human Clinical
"A colonic biopsy demonstrated inflammatory changes with crypt branching and prominent lymphocytic infiltrates around the crypts"
The histological description itself, from the index patient's diagnostic biopsy.
PMID:28530713 SUPPORT Human Clinical
"with significantly reduced FoxP3+ regulatory T (Treg) cells compared with healthy controls or patients with classical IBD"
The controlled comparison in the same biopsy, which is what separates this histology from ordinary inflammatory bowel disease.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Immunodeficiency 60 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

14
Blood 7
Progressive T-cell lymphopenia Decreased total T cell count HP:0005403 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Progressive T-cell lymphopenia, annotated with Decreased total T cell count (HP:0005403), qualified as course progressive. HP:0005403 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (2 references)
PMID:35748970 SUPPORT Other
"Progressive T cell lymphopenia Impaired memory B cell development"
The circulating T-cell column of the IUIS Table 4 row for BACH2 deficiency. The quote runs into the adjacent circulating-B-cell column because the two cells are contiguous in the cached table text.
PMID:28530713 SUPPORT Human Clinical
"T cells from our patients have a defect in cell proliferation associated with a progressive T cell lymphopenia"
Primary-source corroboration of a phenotype this entry otherwise carried on the IUIS row alone, and it supplies the mechanism the authors attach to it: the count falls because the cells proliferate poorly, which is why the qualifier is progressive.
Immunoglobulin deficiency Decreased circulating immunoglobulin concentration HP:0004313 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Immunoglobulin deficiency, annotated with Decreased circulating immunoglobulin concentration (HP:0004313). HP:0004313 is a phenotype from the Human Phenotype Ontology.
Sequelae: Recurrent sinopulmonary infections
Show evidence (5 references)
PMID:28530713 SUPPORT Human Clinical
"Affected subjects had lymphocyte-maturation defects that caused immunoglobulin deficiency and intestinal inflammation."
States immunoglobulin deficiency as a feature of the affected subjects in the founding report.
PMID:37148421 SUPPORT Human Clinical
"BACH2-related immunodeficiency and autoimmunity (BRIDA) is an inborn error of immunity, newly reported in 2017, presenting with symptoms of immunoglobulin deficiency and ongoing colitis."
A second group's summary of the syndrome, which pairs immunoglobulin deficiency with colitis as its defining combination.
PMID:28530713 SUPPORT Human Clinical
"Fever and cytopenia improved with corticosteroids, but lymphopenia, deficiency in immunoglobulin (Ig)M, IgG, IgA and IgE, ongoing colitis, lung infiltrates and recurrent upper respiratory tract infections persisted"
The isotype-level statement for the index patient - all four measured isotypes deficient - and, in the same sentence, that the deficiency persisted after the inflammatory features had responded to steroids.
+ 2 more references
Decreased circulating IgA concentration HP:0002720 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased circulating IgA concentration (HP:0002720). HP:0002720 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28530713 SUPPORT Human Clinical
"| IgA | Low | Low | Low |"
Table 1, the IgA row: low in all three founding subjects, which is not true of any other isotype in that table.
Decreased memory B cell proportion HP:0030374 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased memory B cell proportion (HP:0030374). HP:0030374 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28530713 SUPPORT Human Clinical
"In the patient B cells, we found a marked reduction in CD19+CD27+ memory and IgG class-switched CD27+IgG+ B cells"
Reports the CD19+CD27+ memory reduction in the patients, which is this phenotype.
Decreased class-switched memory B cell proportion HP:0030388 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased class-switched memory B cell proportion (HP:0030388). HP:0030388 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28530713 SUPPORT Human Clinical
"In the patient B cells, we found a marked reduction in CD19+CD27+ memory and IgG class-switched CD27+IgG+ B cells"
The same sentence names the switched CD27+IgG+ subset as separately reduced, which is what this phenotype records.
Decreased anti-CD3/28-induced T-cell proliferation HP:0031382 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased anti-CD3/28-induced T-cell proliferation (HP:0031382). HP:0031382 is a phenotype from the Human Phenotype Ontology.
Bound to the anti-CD3/28 child term rather than the general mitogen-induced parent because the methods name the stimulus: patient T cells were cultured with anti-CD3 and anti-CD28 for five days. The parent term was the right call while only the abstract was available; the full text makes the specific one correct.
Sequelae: Progressive T-cell lymphopenia
Show evidence (3 references)
PMID:28530713 SUPPORT In Vitro
"T cells were stained with CellTrace™ Violet as per manufacturer’s instructions followed by culture in the presence of anti-CD3 and anti-CD28 (1ug/mL of each)"
Names the stimulus used for the patient proliferation assay, which is what licenses the anti-CD3/28 binding over the broader mitogen-induced term.
PMID:28530713 SUPPORT In Vitro
"Polyclonal activation of T cells resulted in reduced CD4+ T cell proliferation compared with healthy controls"
The proliferation assay itself, on patient cells in culture, which is why it is graded IN_VITRO rather than as a clinical observation.
PMID:28530713 SUPPORT Human Clinical
"T cells from our patients have a defect in cell proliferation associated with a progressive T cell lymphopenia"
Connects the proliferation defect to the lymphopenia phenotype curated above, which is why both are kept in this entry rather than only the count.
Pancytopenia HP:0001876 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pancytopenia (HP:0001876). HP:0001876 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28530713 SUPPORT Human Clinical
"with non-infectious fever, splenomegaly (21.7 cm, compared to 10–12 cm in normal adults) (Fig. 1c) and pancytopenia"
Records the pancytopenia in the index patient's presenting illness, quoted with the preceding clause so the span is self-describing.
Cardiovascular 2
Lymphadenopathy HP:0002716 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lymphadenopathy (HP:0002716). HP:0002716 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28530713 SUPPORT Human Clinical
"| Lymphadenopathy | Yes | Yes | Yes |"
Table 1, the lymphadenopathy row: recorded in each of the three founding subjects.
Splenomegaly HP:0001744 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Splenomegaly (HP:0001744). HP:0001744 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:28530713 SUPPORT Human Clinical
"with non-infectious fever, splenomegaly (21.7 cm, compared to 10–12 cm in normal adults)"
The measurement and the normal comparator in the source's own words, in the index patient's presenting illness.
PMID:28530713 SUPPORT Human Clinical
"| Splenomegaly | Yes | No | No |"
Table 1 gives the denominator: one of three subjects, which is why this is not curated as a defining feature.
Digestive 1
Lymphocytic colitis HP:0002583 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lymphocytic colitis, annotated with Colitis (HP:0002583). HP:0002583 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:35748970 SUPPORT Other
"Haploinsufficiency for a critical lineage specification transcription factor Lymphocytic colitis, sinopulmonary infections"
The associated-features column of the IUIS Table 4 row, quoted together with the preceding functional-defect cell so the span is long enough to be self-describing.
PMID:28530713 SUPPORT Human Clinical
"Affected subjects had lymphocyte-maturation defects that caused immunoglobulin deficiency and intestinal inflammation."
The defining report records intestinal inflammation in the affected subjects, which is the primary-source basis for this phenotype.
Immune 2
Recurrent sinopulmonary infections HP:0005425 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent sinopulmonary infections (HP:0005425). HP:0005425 is a phenotype from the Human Phenotype Ontology.
Sequelae: Bronchiectasis
Show evidence (1 reference)
PMID:35748970 SUPPORT Other
"Haploinsufficiency for a critical lineage specification transcription factor Lymphocytic colitis, sinopulmonary infections"
The associated-features column of the IUIS Table 4 row, quoted together with the preceding functional-defect cell so the span is long enough to be self-describing.
Decreased specific antibody response to vaccination HP:0032140 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased specific antibody response to vaccination (HP:0032140). HP:0032140 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28530713 SUPPORT Human Clinical
"All three have developed a chronic variable immunodeficiency characterized by recurrent respiratory tract infections associated with an inability to generate appropriate antibody responses to vaccination."
States the vaccine-response failure in all three subjects. Quoted in full because the same sentence carries the authors' own summary characterisation of the humoral picture, which this entry cites rather than paraphrases.
Metabolism 1
Non-infectious fever HP:0001945 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Non-infectious fever, annotated with Fever (HP:0001945). HP:0001945 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28530713 SUPPORT Human Clinical
"who became ill at 19 years old with non-infectious fever, splenomegaly"
States the fever and that it was non-infectious, which is the distinction this phenotype turns on.
Respiratory 1
Bronchiectasis HP:0002110 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bronchiectasis (HP:0002110). HP:0002110 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28530713 SUPPORT Human Clinical
"The father with the E788K mutation developed bronchiectasis later in life."
Reports the bronchiectasis and its late onset, which is what makes it a surveillance target rather than a presenting feature.
🧬

Genetic Associations

1
BACH2
Gene: BACH2 hgnc:14078 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is BACH2 (hgnc:14078). hgnc:14078 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (6 references)
PMID:28530713 SUPPORT Human Clinical
"Here we describe a syndrome of BACH2-related immunodeficiency and autoimmunity (BRIDA) that results from BACH2 haploinsufficiency."
The founding report establishing BACH2 as the causal gene for this Mendelian entity, and the mechanism as haploinsufficiency.
PMID:37148421 SUPPORT Human Clinical
"Whole exome sequencing analysis of the patient and her parents revealed a novel heterozygous point mutation in BACH2, c.G1727T, resulting in substitution of a highly conserved arginine with leucine (R576L), which is predicted to be deleterious, in the patient and her father."
Identifies the variant in the second reported family and its inheritance from an unaffected parent.
PMID:39826876 SUPPORT INDIRECT Other
"ClinGen has established guidelines to classify gene-disease relationships as definitive, strong, moderate, and limited on the basis of available scientific and clinical evidence."
Defines the tier system this entry's notes refer to, and is the curation effort that produced the Moderate call for BACH2. INDIRECT because it describes the framework rather than the BACH2 assertion itself.
+ 3 more references
Variants (1)
NM_021813.4:c.1727G>T p.(Arg576Leu)
Novel heterozygous missense variant reported in the second BRIDA family, substituting a highly conserved arginine and predicted deleterious. Patient cells showed reduced BACH2 expression and deficient repression of its target BLIMP1. Inherited from the father, who was clinically unaffected but had an extreme reduction in memory B cells - the entry's one data point on penetrance.
🗃️

External Assertions

1
ClinGen BACH2 gene-disease validity assertion
ClinGen gene disease validity CGGV:assertion_2473560a-6e5c-4342-a6e2-c89e37f4cc71-2023-02-21T180000.000Z
ClinGen's Antibody Deficiencies Gene Curation Expert Panel classifies the autosomal dominant BACH2 relationship to immunodeficiency 60 (MONDO:0032723) as Moderate, curated under SOP9 on 2023-02-21. Moderate sits below the Definitive and Strong tiers that the CAUSATIVE value in this schema is defined against, so it is recorded here rather than being folded into the genetic relationship type.
Show evidence (1 reference)
CGGV:assertion_2473560a-6e5c-4342-a6e2-c89e37f4cc71-2023-02-21T180000.000Z SUPPORT Other
"BACH2 | HGNC:14078 | immunodeficiency 60 | MONDO:0032723 | AD | Moderate | SOP9 | Antibody Deficiencies Gene Curation Expert Panel | 2023-02-21T18:00:00.000Z"
The ClinGen gene-disease validity row, which fixes the gene, the disease concept, the mode of inheritance and the strength of the assertion.
💊

Medical Actions

3
Prednisone with Tofacitinib
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: prednisone CHEBI:8382 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses prednisone (CHEBI:8382). CHEBI:8382 is a therapeutic agent from Chemical Entities of Biological Interest. tofacitinib CHEBI:71200 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses tofacitinib (CHEBI:71200). CHEBI:71200 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Corticosteroid combined with JAK inhibition, which relieved the lupus features and recurrent fever in the second reported family. This is a single patient's response directed at the autoimmune arm of the disease, not an established regimen for the syndrome, and it does not address the humoral deficiency.
Mechanism Target:
Non-infectious fever — Recurrent fever was one of the two features relieved in the single patient treated this way. The lupus features it also relieved are not curated as phenotypes of this entry, so the fever is the only link this treatment can draw.
Show evidence (1 reference)
PMID:37148421 SUPPORT Human Clinical
"SLE symptoms and recurrent fever were relieved by treatment with prednisone combined with tofacitinib."
Names the recurrent fever as one of the features that responded.
Show evidence (1 reference)
PMID:37148421 SUPPORT Human Clinical
"SLE symptoms and recurrent fever were relieved by treatment with prednisone combined with tofacitinib."
Reports the response in the one patient treated this way. Quoted as the narrow claim it is - symptom relief in a single case, not a trial result.
Immunoglobulin Replacement Therapy
Action: intravenous immunoglobulin therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is intravenous immunoglobulin therapy (NCIT:C121331). NCIT:C121331 is a clinical intervention from the NCI Thesaurus. Ontology label: Intravenous Immunoglobulin Therapy NCIT:C121331
Platform: Other
Intravenous immunoglobulin, given to the two founding subjects who were deficient in every isotype. The third subject, whose IgA alone was low against raised IgM and IgG, was not on replacement - so the founding report's own practice was to treat the pan-deficient patients and not the IgA-restricted one.
Mechanism Target:
Immunoglobulin deficiency — Replacement substitutes for the antibody the failed class-switch and memory programme cannot produce. It does not act on the maturation defect itself, so it addresses the phenotype and leaves the pathophysiology node upstream of it untouched.
Show evidence (1 reference)
PMID:28530713 SUPPORT Human Clinical
"| On IvIg treatment | Yes | Yes | No |"
Table 1 records replacement in the two subjects whose isotypes were uniformly low and not in the third, which is what ties the treatment to this phenotype.
Show evidence (1 reference)
PMID:28530713 SUPPORT Human Clinical
"| On IvIg treatment | Yes | Yes | No |"
Table 1 of the founding report, the row recording immunoglobulin replacement status for each of the three subjects.
Corticosteroid Therapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: corticosteroid CHEBI:24261 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses corticosteroid, annotated with glucocorticoid (CHEBI:24261). CHEBI:24261 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Systemic corticosteroids for the inflammatory features. In the index patient they resolved the fever and the pancytopenia, and later controlled most of her autoimmune manifestations - while leaving the immunodeficiency and the pneumonitis unchanged. That split is the useful clinical fact: steroids treat the arm of the disease driven by the regulatory T-cell failure and do nothing for the arm driven by the B-cell maturation failure.
Mechanism Target:
Non-infectious fever — The fever resolved on corticosteroids, which is also what marks it as immune-mediated rather than infective.
Show evidence (1 reference)
PMID:28530713 SUPPORT Human Clinical
"Fever and cytopenia improved with corticosteroids, but lymphopenia, deficiency in immunoglobulin (Ig)M, IgG, IgA and IgE, ongoing colitis, lung infiltrates and recurrent upper respiratory tract infections persisted"
Names the fever as one of the two features that responded.
Pancytopenia — The cytopenia resolved on corticosteroids, in the same course as the fever.
Show evidence (1 reference)
PMID:28530713 SUPPORT Human Clinical
"Fever and cytopenia improved with corticosteroids, but lymphopenia, deficiency in immunoglobulin (Ig)M, IgG, IgA and IgE, ongoing colitis, lung infiltrates and recurrent upper respiratory tract infections persisted"
Names the cytopenia as the other feature that responded.
Show evidence (2 references)
PMID:28530713 SUPPORT Human Clinical
"Fever and cytopenia improved with corticosteroids, but lymphopenia, deficiency in immunoglobulin (Ig)M, IgG, IgA and IgE, ongoing colitis, lung infiltrates and recurrent upper respiratory tract infections persisted"
Both halves of the claim in one sentence: what responded, and what did not.
PMID:28530713 SUPPORT Human Clinical
"Many of the autoimmune phenomena in our patient with the L24P mutation have been successfully treated with corticosteroids although this has not reduced her chronic variable immunodeficiency nor her pneumonitis"
The longer-term result, and the explicit statement of what did not respond. It supports this treatment as described - effective against the autoimmune arm and not against the immunodeficiency or the pneumonitis - rather than supporting corticosteroids as a treatment for the disorder as a whole.
🔬

Diagnosis

1
Pulmonary surveillance in BACH2 carriers
Periodic pulmonary assessment is recommended for patients with BACH2 mutations. The recommendation follows from the sinopulmonary infection phenotype and the structural lung damage that recurrent infection produces in antibody-deficient patients, and the authors making it are explicit that the case base is small.
Recorded under diagnosis rather than treatments because it is a monitoring action, not a therapeutic one.
Show evidence (1 reference)
PMID:33864888 SUPPORT Human Clinical
"although there are limited cases reported, current evidence also supports pulmonary screening for patients with mutations in BACH2, ITCH and TOM1"
States the surveillance recommendation and, in the same sentence, the limited case base it rests on.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
Reported in single families. The 2023 SLE family described itself as the second report of the syndrome, six years after the founding description, so the published case base is in the single figures and no population estimate exists.
Show evidence (1 reference)
PMID:37148421 SUPPORT Human Clinical
"Thus, we present the second report of BRIDA and demonstrate that BACH2 may be a monogenic cause of SLE."
Fixes the size of the published case base at the time of writing - this family was only the second reported.
🧫

Experimental Models

1
BACH2 RNAi knockdown in primary human T and B cells PRIMARY_CELL_CULTURE
The dose-matched human system, and the strongest causal evidence in this entry. Every other model here is either a mouse or a patient: the mouse matches the dosage but not the species, and the patients match the species but cannot separate the BACH2 lesion from everything else in their genomes and histories. Knocking BACH2 down by about half in healthy donor cells does both at once - human cells, human gene dosage, one variable changed - and it reproduces the patients' phenotype in both lineages: PRDM1 rises, CD4+ T cells proliferate less, and class switching to IgG and IgA is suppressed.
CD4-positive helper T cell CL:0000492 Cell Ontology (CL) Relation: this experimental model uses this cell type This experimental model uses CD4-positive helper T cell (CL:0000492). CL:0000492 is a cell type from the Cell Ontology. naive B cell CL:0000788 Cell Ontology (CL) Relation: this experimental model uses this cell type This experimental model uses naive B cell (CL:0000788). CL:0000788 is a cell type from the Cell Ontology.
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Cell source
primary cells from healthy human donors
Culture
Nucleofection of BACH2-targeting siRNA/DsiRNA into purified healthy-donor CD4+ T cells or naive B cells, achieving roughly 50 percent knockdown, followed by polyclonal or class-switch-inducing stimulation.
Publication
PMID:28530713
Pathograph links
BACH2 Haploinsufficiency recapitulates fidelity: high Reducing BACH2 by about half in healthy human lymphocytes reproduces the patients' cellular phenotype in both lineages, which is what converts the correlation between low BACH2 and the BRIDA phenotype into a causal claim.
Limitations: Acute, incomplete and transient knockdown in mature cells, not a germline heterozygous state, so it cannot speak to developmental consequences or to the progressive features of the disease. Knockdown depth is reported as approximately 50 percent rather than measured per experiment.
Readouts
PRDM1 message after BACH2 knockdown in CD4+ T cells
Direction: INCREASED
Interpretation: De-repression of the direct BACH2 target, matching what is measured in patient cells.
Show evidence (1 reference)
PMID:28530713 SUPPORT In Vitro
"Silencing BACH2 in control CD4+ T cells led to a significant rise in PRDM1 mRNA"
Reports the measurement behind this readout.
Show evidence (2 references)
PMID:28530713 SUPPORT In Vitro
"we silenced BACH2 expression in healthy control T and B cells using RNAi by ~50% and carried out functional phenotyping"
States the system and the knockdown depth, which is what makes it dose-matched to a heterozygous human and therefore informative for this node.
+ 1 more reference
Impaired Memory B Cell Development recapitulates fidelity: high Halving BACH2 in healthy human B cells is sufficient to suppress class switching to IgG and IgA - the two isotypes whose deficiency dominates the patients' humoral phenotype.
Limitations: Measures class switching in culture rather than memory B-cell accumulation in vivo, so it substantiates the isotype-switching annotation on this node and not the memory-compartment annotation. Healthy donor cells, so it says what BACH2 dosage does and not what the specific BRIDA alleles do.
Readouts
In vitro class switch recombination to IgG and IgA after BACH2 knockdown
Direction: DECREASED
Interpretation: The isotype-switching step of this node, shown to depend on BACH2 dosage in human cells.
Show evidence (1 reference)
PMID:28530713 SUPPORT In Vitro
"silencing BACH2 in healthy control B cells, significantly suppressed in vitro class switch recombination towards the IgG and IgA isotypes"
Reports the measurement behind this readout.
Show evidence (1 reference)
PMID:28530713 SUPPORT In Vitro
"silencing BACH2 in healthy control B cells, significantly suppressed in vitro class switch recombination towards the IgG and IgA isotypes"
Supports treating the knockdown as informative for the class-switch arm of this node, in human cells at approximately the human heterozygous dosage.
Notes
A knockdown is not a haploinsufficiency. The reduction is transient, its depth is approximate rather than exactly one allele's worth, and it acts on mature cells rather than across development - so it shows that acutely halving BACH2 is sufficient for these defects, not that the patients' lifelong half-dosage produces them by the same route. Curated as an experimental model rather than as an animal model because the system is human primary cells; see the schema's note that whole-organism animal models never belong in this section.
🐁

Animal Models

4
Bach2-heterozygous mouse (BRIDA report)
The dose-matched model. Because BRIDA is a haploinsufficiency, a heterozygous mouse rather than a knockout is the construct that reproduces the human genetic state, and the founding report shows it produces analogous lymphocyte defects.
Species
Mouse
Genotype
Bach2 heterozygous (Bach2+/-)
Publication
PMID:28530713
Pathograph links
BACH2 Haploinsufficiency recapitulates fidelity: high Heterozygous loss in mouse reproduces the molecular state of heterozygous loss in humans - reduced Bach2 message and protein with de-repressed Prdm1 - which is what licenses reading mouse Bach2 dosage biology onto this disorder.
Limitations: The mouse is normal until it is challenged. Bulk CD4+, CD8+, B-cell and plasma-cell numbers are unchanged in unimmunized animals, whereas the patients have a progressive T-cell lymphopenia, so the heterozygote does not model the resting human phenotype and its informative readouts all come from immunization or from subset gating rather than from counts. Keeping the dose-match versus dose-dependence distinction this entry draws: dose match is a property of the construct, and every heterozygote here has it by construction. Dose dependence is a demonstrated graded response, and it needs a genotype comparison. This model now has both - the full text compares Bach2+/- against wild-type for message, protein, Prdm1, and the immunization readouts - which is why the fidelity here is HIGH rather than the MODERATE that the abstract-only record supported.
Readouts
Bach2 message and protein in heterozygous animals
Direction: DECREASED
Interpretation: The gene-dosage lesion itself, confirmed at both message and protein level.
Show evidence (1 reference)
PMID:28530713 SUPPORT Model Organism
"We found that Bach2+/− mice manifest reduced Bach2 mRNA (Fig. 6a) and protein expression (Fig. 6b) together with elevated Prdm1 mRNA"
Reports the reduced Bach2 and the de-repressed Prdm1 in one sentence, which is the same molecular signature reported in the patients.
Resting lymphocyte subset counts in heterozygous animals
Direction: UNCHANGED
Interpretation: A negative result, kept because it bounds the model: halving Bach2 does not by itself deplete the lymphoid compartments in an unchallenged animal.
Show evidence (1 reference)
PMID:28530713 SUPPORT Model Organism
"There was no difference in the numbers of CD4+ and CD8+ T cells, B cells or plasma cells in unchallenged mice"
Reports the measurement behind this readout, as a negative finding.
Show evidence (1 reference)
PMID:28530713 SUPPORT Model Organism
"We observed analogous lymphocyte defects in Bach2-heterozygous mice."
Supports treating the heterozygous mouse as informative for the human haploinsufficient state.
Impaired Memory B Cell Development recapitulates fidelity: high On immunization the heterozygote fails at exactly the step the patients fail at: it barely generates class-switched B cells or plasma cells, and its germinal centers are reduced. This is the dose-matched counterpart of the patients' impaired in vitro class switching, and it is the readout that most directly connects halving BACH2 to the humoral phenotype.
Limitations: Requires deliberate immunization to appear; unchallenged heterozygotes have normal B-cell and plasma-cell numbers. The readout is also a single model antigen (NP-CGG in alum), so it speaks to the T-dependent IgG response and not to the mucosal IgA arm that dominates the patients' isotype pattern.
Readouts
Class-switched B cells and plasma cells after immunization
Direction: DECREASED
Interpretation: The class-switch and terminal-differentiation failure at matched gene dosage.
Show evidence (1 reference)
PMID:28530713 SUPPORT Model Organism
"Immunized Bach2+/− mice exhibited minimal induction of both IgG1 class switched-B220hiCD138− B cells and B220loCD138+ plasma cells compared to WT mice"
Reports the measurement behind this readout.
Germinal center B cell proportion after immunization
Direction: DECREASED
Interpretation: Locates part of the failure upstream of switching, in the germinal center reaction that class switching and memory formation depend on.
Show evidence (1 reference)
PMID:28530713 SUPPORT Model Organism
"The proportion of germinal center B220+Ki67+Bcl6+ B cells was also reduced in Bach2+/− mice"
Reports the measurement behind this readout.
Show evidence (1 reference)
PMID:28530713 SUPPORT Model Organism
"Immunized Bach2+/− mice exhibited minimal induction of both IgG1 class switched-B220hiCD138− B cells and B220loCD138+ plasma cells compared to WT mice"
Supports treating the heterozygote as informative for the B-cell arm at the human gene dosage, which the homozygous nulls below cannot do.
Gut-Homing Receptor Upregulation on CD4+ T Cells recapitulates fidelity: moderate The heterozygote reproduces the patients' receptor shift - more CCR9+ and beta-7 integrin+ CD4+ T cells, alongside fewer FoxP3+ cells - at the same gene dosage.
Limitations: No colitis is reported in these animals, so the model supports the cellular shift without demonstrating that it is sufficient for the intestinal disease. The link targets the gut-homing node specifically because T-bet, the marker of the TH1 node, was not measured in these mice.
Readouts
Gut-homing receptor expression on CD4+ T cells
Direction: INCREASED
Interpretation: The tissue-addressing half of this node, present at halved Bach2 dosage.
Show evidence (1 reference)
PMID:28530713 SUPPORT Model Organism
"but Bach2+/− mice did have a small but significant reduction in FoxP3+ cells together with significant increases in CCR9+ and β7-integrin+ cells in CD4+ T cells"
Reports both measurements behind this readout in one sentence, including the authors' own qualification that the Treg reduction is small.
Show evidence (1 reference)
PMID:28530713 SUPPORT Model Organism
"but Bach2+/− mice did have a small but significant reduction in FoxP3+ cells together with significant increases in CCR9+ and β7-integrin+ cells in CD4+ T cells"
Supports treating the heterozygote as informative for the effector-skewing node at the human gene dosage: the same paired shift the patients show, in an animal carrying the same halved dosage.
Notes
Same line as the three model entries below, and no longer an open question: the founding report's methods state that its Bach2 animals "were generated and housed as previously described", citing the study curated here as PMID:23728300. So this heterozygote and the heterozygote in that study are one line, characterized twice. They are two experiments and not two independent observations of the line - do not count them as replication of each other.
Bach2-heterozygous mouse (Igarashi line, Treg characterization)
The best dose-matched evidence in this entry for the regulatory T-cell arm. Heterozygotes of the Igarashi null line have reduced Treg frequencies, so Treg formation is Bach2 gene-dose dependent rather than merely Bach2-dependent - which is what makes the Treg defect a plausible consequence of human haploinsufficiency rather than an artifact of complete loss.
Species
Mouse
Genotype
Bach2 heterozygous (Bach2+/-)
Publication
PMID:23728300
Pathograph links
Impaired Regulatory T Cell Differentiation recapitulates fidelity: high Halving Bach2 reduces Treg frequency in mouse, matching both the gene dosage and the compartment of the human disease.
Limitations: Mouse rather than human, and the frequency reduction is reported without the functional suppression assays that would show whether the remaining Tregs work. That caveat is about Treg function rather than Treg differentiation, so it does not weaken the model's fidelity for this node, which is a differentiation node - hence HIGH here. The dose-match versus dose-dependence distinction this entry draws applies to both heterozygote entries and no longer separates them: both are heterozygotes, so both match the human gene dosage by construction, and both now compare genotypes against wild-type, so both demonstrate a graded response rather than only a matched dose. What still separates them is which compartment each one measured. This study measured Treg frequency, which is the node here; the BRIDA report measured Bach2 message and protein, the immunization response and the CD4+ subset shifts, and is linked to those nodes instead. Same line as the null entries below and as the BRIDA heterozygote above, so none of them is an independent replication of the others.
Readouts
Regulatory T cell frequency in heterozygous animals
Direction: DECREASED
Interpretation: Treg formation responds to Bach2 gene dosage, not only to its complete absence.
Show evidence (1 reference)
PMID:23728300 SUPPORT Model Organism
"Treg cell formation was Bach2 gene-dose dependent since mice heterozygous for the KO allele had reduced frequencies of Treg cells"
Reports the measurement behind this readout.
Show evidence (1 reference)
PMID:23728300 SUPPORT Model Organism
"Treg cell formation was Bach2 gene-dose dependent since mice heterozygous for the KO allele had reduced frequencies of Treg cells"
Supports treating the heterozygote as informative for the human haploinsufficient Treg defect, at matched gene dosage.
Bach2-null mouse (Igarashi line, Treg characterization)
The Igarashi-derived Bach2 null, characterized here for the regulatory T-cell compartment. It is a null rather than a heterozygote, so it speaks to what BACH2 does, not to what halving it does.
Species
Mouse
Genotype
Bach2 knockout (homozygous null)
Publication
PMID:23728300
Pathograph links
Impaired Regulatory T Cell Differentiation partially recapitulates fidelity: moderate Complete Bach2 loss prevents efficient Treg formation and diverts cells destined for the regulatory lineage into effector lineages, producing lethal inflammation.
Limitations: Homozygous null, whereas the human disease is heterozygous; the mouse phenotype is correspondingly more severe than BRIDA and cannot be read as a dose-matched prediction.
Readouts
Regulatory T cell formation
Direction: DECREASED
Interpretation: Loss of the regulatory compartment this node describes.
Show evidence (1 reference)
PMID:23728300 SUPPORT Model Organism
"BACH2 was required for efficient formation of regulatory (Treg) cells and consequently for suppression of lethal inflammation in a manner that was Treg-cell-dependent."
Reports the measurement behind this readout.
Show evidence (1 reference)
PMID:23728300 SUPPORT Model Organism
"its absence during Treg polarization resulted in inappropriate diversion to effector lineages"
Supports treating the knockout as informative for the Treg differentiation node.
This is the same mouse line as the class-switching entry below and as the heterozygote entry above - one line from one lab, characterized in two studies. The entries are split so each publication field matches the evidence on its own links, not because the lines are independent. Do not read the three as independent replication.
Bach2-null mouse (Igarashi line, class-switching characterization)
The same Igarashi-derived Bach2 null, characterized here for the B-cell arm. This is the original report of the line; the regulatory T-cell study above used it rather than deriving its own.
Species
Mouse
Genotype
Bach2 knockout (homozygous null)
Publication
PMID:15152264
Pathograph links
Impaired Memory B Cell Development partially recapitulates fidelity: moderate Bach2-null B cells fail to class switch efficiently while retaining IgM output and abundant Blimp-1 and XBP-1 expression, which localizes the defect to class switch recombination rather than to terminal differentiation.
Limitations: Homozygous null rather than the human heterozygous dose, and the readout is class switching in mouse rather than memory B-cell counts in patients.
Readouts
Class switch recombination efficiency
Direction: DECREASED
Interpretation: The specific B-cell step that fails when BACH2 is absent.
Show evidence (1 reference)
PMID:15152264 SUPPORT Model Organism
"However, they failed to undergo efficient CSR."
Reports the measurement behind this readout.
Show evidence (1 reference)
PMID:15152264 SUPPORT Model Organism
"Genetic ablation of Bach2 in mice revealed that Bach2 was required for both T-cell-independent and T-cell-dependent IgG responses and SHM."
Supports treating the knockout as informative for the B-cell arm of this entry.
Same line as the two entries above. Curated as its own model so this publication field matches the evidence on its link, not because the line is independent.
{ }

Source YAML

click to show 
name: Immunodeficiency 60
creation_date: "2026-09-03T00:00:00Z"
category: Mendelian
description: >-
  Immunodeficiency 60 is an autosomal dominant inborn error of immunity caused by
  haploinsufficiency for BACH2, a BTB/POZ- and basic-leucine-zipper-domain
  transcriptional repressor that acts as a lineage-specification factor in both the
  T-cell and the B-cell arm of adaptive immunity. The International Union of
  Immunological Societies places it in Table 4, diseases of immune dysregulation,
  rather than among the predominantly antibody deficiencies, and summarises the
  defect as haploinsufficiency for a critical lineage specification transcription
  factor.

  The consequence is the unusual pairing that defines the entity: a humoral
  deficiency and a lymphocytic infiltrative disease in the same patient. Loss of one
  functional BACH2 allele impairs regulatory T-cell differentiation, which places
  the disorder among the monogenic "Tregopathies" alongside IPEX, CD25 deficiency
  and STAT3 gain-of-function; it also impairs memory B-cell development, which
  underlies the sinopulmonary infection phenotype. IUIS records progressive T-cell
  lymphopenia in the circulating T-cell compartment and impaired memory B-cell
  development in the B-cell compartment, with lymphocytic colitis and sinopulmonary
  infections as the associated clinical features. BACH2 defects are among the
  monogenic causes found when FOXP3-negative IPEX-like immune dysregulation is
  sequenced, and pulmonary surveillance is recommended for carriers.

  This entry is deliberately conservative about how much is settled. ClinGen's
  Antibody Deficiencies Gene Curation Expert Panel classifies the BACH2 relationship
  to immunodeficiency 60 as Moderate rather than Definitive or Strong, and the
  syndrome rests on a small number of reported families - the family reporting the
  second case did so six years after the founding description. The founding report
  (Afzali et al., Nat Immunol 2017, which named the syndrome BRIDA) is now curated
  from its full text, which supplies the patient-level detail the abstract withheld:
  the isotype pattern in each of the three subjects, the class-switch and plasmablast
  assays in their B cells, the per-compartment mouse phenotype, and a human RNAi
  system that halves BACH2 in healthy donor cells. What is still missing is numeric -
  the immunoglobulin concentrations themselves live in a supplementary table that is
  not part of the retrievable article - so the humoral phenotype is curated as a
  direction per isotype and not as measured values.

  The single most useful thing the full text settles is that the humoral picture is
  not uniform and is not fixed by the variant. Two of the three subjects were low in
  every isotype; the third, who carries the same E788K allele as her affected father,
  had low IgA against raised IgM and IgG. So the same allele in one family produces
  pan-hypogammaglobulinemia in the father and an IgA-selective picture in the daughter,
  and a normal or high IgG does not exclude the diagnosis.

  Two features of the syndrome are worth flagging because they are easy to get
  backwards. The dosage defect is a loss, not an interference: the mutations
  destabilize BACH2 by blocking homodimerization or causing aggregation, so a carrier
  has half the protein rather than a poisoned pathway. And BACH2 loss reduces useful
  antibody despite BACH2 being a repressor of immunoglobulin production, because what
  requires BACH2 is the class-switch and hypermutation programme rather than
  plasma-cell differentiation itself - Bach2-null B cells still make IgM and express
  BLIMP1 and XBP-1 abundantly. Abundant rather than merely preserved is the
  mechanistically telling word: BACH2 represses BLIMP1, so a null de-represses it, and
  the cell proceeds to terminal differentiation without ever switching isotype.

  A separate claim must be kept distinct from this one. BACH2 is also a common-variant
  susceptibility locus in many polygenic autoimmune diseases - type 1 diabetes,
  Graves disease, vitiligo, multiple sclerosis, alopecia areata, autoimmune adrenal
  insufficiency - and appears in this knowledge base in that role in more than a
  dozen entries. That is an association claim about regulatory variation in a
  population, not the Mendelian coding haploinsufficiency described here. Whether the
  two act on one BACH2 dosage axis is recorded below as an emerging hypothesis, not
  as a causal edge.
synonyms:
- IMD60
- BRIDA
- immunodeficiency 60 and autoimmunity
- Immunodeficiency and Autoimmunity, BACH2-Related
- BACH2 deficiency
parents:
- Inborn error of immunity
- Disease of immune dysregulation
disease_term:
  preferred_term: immunodeficiency 60
  term:
    id: MONDO:0032723
    label: immunodeficiency 60
classifications:
  iuis_category:
    classification_value: immune dysregulation
    notes: >-
      IUIS 2022 phenotypic classification Table 4 (diseases of immune dysregulation).
      The assignment is worth stating explicitly because the clinical picture -
      humoral deficiency with sinopulmonary infection and bronchiectasis - looks like
      a predominantly antibody deficiency, and ClinGen curated the gene through its
      Antibody Deficiencies expert panel. IUIS nonetheless places BACH2 deficiency
      with the regulatory T-cell defects, which matches the Tregopathy mechanism.
    evidence:
    - reference: PMID:35748970
      reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "BACH2 deficiency BACH2 AD 605394 Progressive T cell lymphopenia Impaired memory B cell development Haploinsufficiency for a critical lineage specification transcription factor Lymphocytic colitis, sinopulmonary infections"
      explanation: >-
        The complete IUIS Table 4 row for BACH2 deficiency. Table 4 is the
        immune-dysregulation table, so the row's presence there is the classification
        assertion; the row also carries the mode of inheritance, both lymphocyte
        compartment findings, the functional defect and the associated features.
external_assertions:
- name: ClinGen BACH2 gene-disease validity assertion
  source: ClinGen
  assertion_type: gene_disease_validity
  external_id: "CGGV:assertion_2473560a-6e5c-4342-a6e2-c89e37f4cc71-2023-02-21T180000.000Z"
  url: https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2473560a-6e5c-4342-a6e2-c89e37f4cc71-2023-02-21T180000.000Z
  description: >-
    ClinGen's Antibody Deficiencies Gene Curation Expert Panel classifies the
    autosomal dominant BACH2 relationship to immunodeficiency 60 (MONDO:0032723) as
    Moderate, curated under SOP9 on 2023-02-21. Moderate sits below the Definitive
    and Strong tiers that the CAUSATIVE value in this schema is defined against, so
    it is recorded here rather than being folded into the genetic relationship type.
  evidence:
  - reference: CGGV:assertion_2473560a-6e5c-4342-a6e2-c89e37f4cc71-2023-02-21T180000.000Z
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "BACH2 | HGNC:14078 | immunodeficiency 60 | MONDO:0032723 | AD | Moderate | SOP9 | Antibody Deficiencies Gene Curation Expert Panel | 2023-02-21T18:00:00.000Z"
    explanation: >-
      The ClinGen gene-disease validity row, which fixes the gene, the disease
      concept, the mode of inheritance and the strength of the assertion.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Autosomal dominant, acting through haploinsufficiency rather than a dominant
    negative. IUIS and ClinGen agree on the mode of inheritance.
  evidence:
  - reference: PMID:35748970
    reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "BACH2 deficiency BACH2 AD 605394 Progressive T cell lymphopenia Impaired memory B cell development Haploinsufficiency for a critical lineage specification transcription factor"
    explanation: >-
      The IUIS Table 4 row records the mode of inheritance as AD and the functional
      defect as haploinsufficiency, which together specify dominance by gene dosage.
  - reference: CGGV:assertion_2473560a-6e5c-4342-a6e2-c89e37f4cc71-2023-02-21T180000.000Z
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "BACH2 | HGNC:14078 | immunodeficiency 60 | MONDO:0032723 | AD | Moderate | SOP9 | Antibody Deficiencies Gene Curation Expert Panel | 2023-02-21T18:00:00.000Z"
    explanation: >-
      ClinGen independently records the mode of inheritance for this gene-disease
      relationship as autosomal dominant.
pathophysiology:
- name: BACH2 Protein Destabilization
  biological_scale: MOLECULAR
  description: >-
    The step that explains why one mutant allele yields half-dosage rather than a
    poisoned pathway. The reported BRIDA mutations do not produce a dominant-negative
    protein; they destabilize BACH2 itself, either by interfering with homodimerization
    through the BTB/POZ domain or by driving the protein into aggregates. The mutant
    product is therefore lost rather than interfering, which is what makes the
    downstream defect a pure gene-dosage problem.
  genes:
  - preferred_term: BACH2
    term:
      id: hgnc:14078
      label: BACH2
  genetic_context:
    gene:
      preferred_term: BACH2
      term:
        id: hgnc:14078
        label: BACH2
    functional_impact_category: LOSS_OF_FUNCTION
    zygosity: HETEROZYGOUS
    variant_origin: GERMLINE
  evidence:
  - reference: PMID:28530713
    reference_title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mutations disrupted protein stability by interfering with homodimerization or by causing aggregation."
    explanation: >-
      States the molecular consequence of the variants directly, and is the reason
      this entry records LOSS_OF_FUNCTION rather than DOMINANT_NEGATIVE.
  - reference: PMID:37148421
    reference_title: "An early-onset SLE patient with a novel paternal inherited BACH2 mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Reduced BACH2 expression and deficient transcriptional repression of the BACH2 target, BLIMP1, were detected in PBMCs or lymphoblastoid cell lines of our patient."
    explanation: >-
      Independent confirmation in a second family that a BRIDA variant lowers BACH2
      protein and its repressor output, in patient-derived cells.
  - reference: PMID:28530713
    reference_title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "found it was reduced in patient CD4+, CD8+ and B lymphocytes despite normal mRNA expression"
    explanation: >-
      Shows the destabilization operating in the patients themselves, and localizes it
      to the protein: BACH2 message is normal while BACH2 protein is low, which is what
      distinguishes a stability defect from reduced transcription.
  downstream:
  - target: BACH2 Haploinsufficiency
    causal_link_type: DIRECT
- name: BACH2 Haploinsufficiency
  biological_scale: MOLECULAR
  description: >-
    Loss of one functional BACH2 allele leaves insufficient BACH2 protein to
    specify lymphocyte lineage decisions. IUIS characterises the defect as
    haploinsufficiency for a critical lineage specification transcription factor,
    which is a dosage statement rather than a dominant-negative one: the residual
    wild-type allele is not poisoned, it is simply not enough. BACH2 is required in
    both lymphoid lineages, which is why one dosage lesion produces a T-cell and a
    B-cell defect at once.
  molecular_functions:
  - preferred_term: BACH2 transcriptional repressor activity
    term:
      id: GO:0001227
      label: "DNA-binding transcription repressor activity, RNA polymerase II-specific"
    modifier: DECREASED
  evidence:
  - reference: PMID:35748970
    reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Haploinsufficiency for a critical lineage specification transcription factor"
    explanation: >-
      The functional-defect column of the IUIS Table 4 row, which states both the
      dosage mechanism and the class of protein affected.
  - reference: PMID:26235382
    reference_title: "Immunogenetics of autoimmune thyroid diseases: A comprehensive review."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "BACH2 is highly expressed on B cells, suppresses the production of immunoglobulins"
    explanation: >-
      Background for the repressor function that is lost. Graded INDIRECT because the
      statement is about normal BACH2 biology in a review of autoimmune thyroid
      genetics, not about immunodeficiency 60.
  - reference: PMID:28530713
    reference_title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we describe a syndrome of BACH2-related immunodeficiency and autoimmunity (BRIDA) that results from BACH2 haploinsufficiency."
    explanation: >-
      The defining report's statement that the syndrome results from haploinsufficiency,
      and the source of the BRIDA name.
  - reference: PMID:28530713
    reference_title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The TF BACH2 is essential for T and B lymphocytes and is associated with an archetypal super-enhancer (SE)."
    explanation: >-
      States that BACH2 is required in both lymphoid lineages, which is why a single
      dosage lesion produces the paired T-cell and B-cell defects below.
  - reference: PMID:28530713
    reference_title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We found that patient naïve B cells and CD4+ T cells expressed significantly higher levels of PRDM1 mRNA compared with healthy controls suggesting a release from BACH2 repression"
    explanation: >-
      The dosage lesion read out at its immediate molecular consequence in patient
      cells. BACH2 represses PRDM1, so a de-repressed PRDM1 in both lineages is the
      direct signature of insufficient BACH2 rather than an inference from mouse work.
  downstream:
  - target: Impaired Regulatory T Cell Differentiation
    causal_link_type: DIRECT
  - target: Impaired Memory B Cell Development
    causal_link_type: DIRECT
  - target: TH1 Effector Skewing
    causal_link_type: DIRECT
  - target: Gut-Homing Receptor Upregulation on CD4+ T Cells
    causal_link_type: DIRECT
  - target: Progressive T-cell lymphopenia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Impaired Regulatory T Cell Differentiation
  biological_scale: CELLULAR
  description: >-
    BACH2 is one of the transcription factors whose loss defines the monogenic
    "Tregopathies" - inborn errors of immunity that act through the regulatory T-cell
    compartment rather than through effector immunity. Insufficient BACH2 impairs
    regulatory T-cell differentiation, and the resulting failure of peripheral
    tolerance is the arm of the disease that produces lymphocytic tissue infiltration
    rather than infection.
  cell_types:
  - preferred_term: FoxP3+ regulatory T cell
    term:
      id: CL:0000815
      label: regulatory T cell
  biological_processes:
  - preferred_term: regulatory T cell differentiation
    term:
      id: GO:0045066
      label: regulatory T cell differentiation
    modifier: DECREASED
  evidence:
  - reference: PMID:33996698
    reference_title: "Different Apples, Same Tree: Visualizing Current Biological and Clinical Insights into CTLA-4 Insufficiency and LRBA and DEF6 Deficiencies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Other IEIs affect the function of regulatory T (Treg) cells—so-called ‘Tregopathies'—such as immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, deficiencies of CD25 or BTB domain and CNC homolog 2 (BACH2), and gain-of-function mutations in signal transducer and activator of transcription 3 (STAT3)"
    explanation: >-
      Places BACH2 deficiency explicitly among the inborn errors that act through
      regulatory T-cell function, which is the basis for this node.
  - reference: PMID:23728300
    reference_title: "BACH2 represses effector programs to stabilize T(reg)-mediated immune homeostasis."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "BACH2 was required for efficient formation of regulatory (Treg) cells and consequently for suppression of lethal inflammation in a manner that was Treg-cell-dependent."
    explanation: >-
      The mechanistic basis for this node. INDIRECT because it is a mouse gene
      disruption rather than an observation in BRIDA patients.
  - reference: PMID:23728300
    reference_title: "BACH2 represses effector programs to stabilize T(reg)-mediated immune homeostasis."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "its absence during Treg polarization resulted in inappropriate diversion to effector lineages"
    explanation: >-
      Gives the failure mode - cells destined for the regulatory lineage become
      effectors instead - which is what converts a Treg defect into tissue infiltration.
  - reference: PMID:28530713
    reference_title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we found decreased expression of FoxP3 in CD4+CD25hiCD127lo regulatory T cells (Treg)"
    explanation: >-
      The node observed in the patients rather than inferred from mouse gene
      disruption. FoxP3 is measured within a gated Treg population, so the finding is
      a defect in the regulatory programme itself and not only a shortage of cells.
  - reference: PMID:28530713
    reference_title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with significantly reduced FoxP3+ regulatory T (Treg) cells compared with healthy controls or patients with classical IBD"
    explanation: >-
      The same defect in the affected tissue, and controlled against the differential
      diagnosis: the Treg deficit is present in the BRIDA colon and absent from
      ordinary inflammatory bowel disease, so it is not a generic feature of colitis.
  downstream:
  - target: TH1 Effector Skewing
    causal_link_type: DIRECT
  - target: Gut-Homing Receptor Upregulation on CD4+ T Cells
    causal_link_type: DIRECT
  - target: Lymphadenopathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Splenomegaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Non-infectious fever
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Pancytopenia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: TH1 Effector Skewing
  biological_scale: CELLULAR
  description: >-
    The effector half of the T-cell lesion. Insufficient BACH2 releases the repression
    that normally restrains effector lineage commitment, and the patients' CD4+
    compartment is pushed towards the TH1 programme, marked by raised T-bet. This says
    what the surviving cells become; where they go is the separate node below.
  cell_types:
  - preferred_term: CD4-positive helper T cell
    term:
      id: CL:0000492
      label: CD4-positive helper T cell
  biological_processes:
  - preferred_term: T-helper 1 cell differentiation
    term:
      id: GO:0045063
      label: T-helper 1 cell differentiation
    modifier: INCREASED
  evidence:
  - reference: PMID:28530713
    reference_title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "increased expression of the TH1 transcription factor T-bet and two gut-homing receptors, CCR9 and β7-integrin on CD4+ T cells"
    explanation: >-
      Raised T-bet on patient CD4+ T cells. The same sentence also carries the
      gut-homing receptors, which belong to the separate node below - the quote is
      shared because the source reports both in one measurement, but the two claims are
      curated apart.
  downstream:
  - target: Lymphocytic colitis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Gut-Homing Receptor Upregulation on CD4+ T Cells
  biological_scale: CELLULAR
  description: >-
    The addressing half, and what makes the tissue infiltration land in the gut. A Treg
    deficit on its own predicts autoimmunity without predicting where it will appear;
    in BRIDA the CD4+ compartment carries raised levels of the two receptors that
    direct a T cell to intestinal tissue, CCR9 and beta-7 integrin. The same shift is
    reproduced at matched gene dosage in the heterozygous mouse, which is what makes it
    a consequence of halving BACH2 rather than a reaction to established colitis.
  cell_types:
  - preferred_term: CD4-positive helper T cell
    term:
      id: CL:0000492
      label: CD4-positive helper T cell
  notes: >-
    Deliberately unbound. The observation is receptor expression on the cells, not a
    measurement of migration, and GO has no term for homing to intestinal tissue -
    binding T cell migration here would assert something the source does not report.
    This node was split out of a combined TH1-and-gut-homing node so that the TH1 claim
    could keep its GO binding without this one riding along under it.
  evidence:
  - reference: PMID:28530713
    reference_title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "increased expression of the TH1 transcription factor T-bet and two gut-homing receptors, CCR9 and β7-integrin on CD4+ T cells"
    explanation: >-
      Raised CCR9 and beta-7 integrin on patient CD4+ T cells. Shared with the TH1 node
      above because the source reports both in one measurement.
  - reference: PMID:28530713
    reference_title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "but Bach2+/− mice did have a small but significant reduction in FoxP3+ cells together with significant increases in CCR9+ and β7-integrin+ cells in CD4+ T cells"
    explanation: >-
      The same receptor shift at the human gene dosage in mouse. INDIRECT because it is
      mouse rather than patient tissue.
  downstream:
  - target: Lymphocytic colitis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Impaired Memory B Cell Development
  biological_scale: CELLULAR
  description: >-
    The B-cell arm of the defect. IUIS records impaired memory B-cell development as
    the circulating B-cell finding in BACH2 deficiency. Mechanistically BACH2 sits
    upstream of the memory-versus-plasma-cell decision: in normal human memory B
    cells, differentiation to plasma cells is driven by PRDM1/BLIMP1 induction with
    reciprocal downregulation of BACH2, so BACH2 is the repressor that holds the
    memory programme open. Insufficient BACH2 leaves that programme unable to be
    established, and the memory B-cell compartment that supplies durable mucosal and
    respiratory antibody does not accumulate.

    The founding report's full text resolves how far the defect goes, which earlier
    versions of this entry left open. The loss in patients is not only of memory B
    cells but specifically of class-switched ones, and activating patient naive B
    cells in vitro reproduces the failure directly: class-switch recombination,
    plasmablast generation and class-switched antibody secretion are all impaired.
    Isotype switching is therefore annotated here as a patient-level defect rather
    than a mouse inference.
  cell_types:
  - preferred_term: memory B cell
    term:
      id: CL:0000787
      label: memory B cell
  - preferred_term: IgG class-switched memory B cell
    term:
      id: CL:0000979
      label: IgG memory B cell
  biological_processes:
  - preferred_term: memory B cell differentiation
    term:
      id: GO:0002319
      label: memory B cell differentiation
    modifier: DECREASED
  - preferred_term: immunoglobulin class switch recombination
    term:
      id: GO:0045190
      label: isotype switching
    modifier: DECREASED
  evidence:
  - reference: PMID:35748970
    reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Impaired memory B cell development"
    explanation: >-
      The circulating-B-cell column of the IUIS Table 4 row for BACH2 deficiency.
  - reference: PMID:29670635
    reference_title: "Chronic Lymphocytic Leukemia B-Cell Normal Cellular Counterpart: Clues From a Functional Perspective."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "human IgG+ MBCs primar - ily differentiated into PCs in response to either T-cell-dependent or T-cell-independent stimulation guided by rapid PRDM1 (BLIMP1) induction and downregulation of BACH2"
    explanation: >-
      Establishes the reciprocal BACH2-BLIMP1 relationship in normal human memory B
      cells that this node's mechanism depends on. Graded INDIRECT because it
      describes normal B-cell differentiation in a review of chronic lymphocytic
      leukemia, not the disorder. Quoted with the source's own hyphenation artifact.
  - reference: PMID:28530713
    reference_title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected subjects had lymphocyte-maturation defects that caused immunoglobulin deficiency and intestinal inflammation."
    explanation: >-
      The defining report's statement that the maturation defect is what causes the
      humoral deficiency, which is the edge this node draws to immunoglobulin deficiency.
  - reference: PMID:15152264
    reference_title: "The transcriptional programme of antibody class switching involves the repressor Bach2."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "Here we show that Bach2 is critical for CSR and somatic hypermutation (SHM) of immunoglobulin genes."
    explanation: >-
      Identifies which step of the B-cell programme depends on BACH2. INDIRECT because
      it is a mouse knockout, and note the dose mismatch - a null, not the human
      heterozygous state.
  - reference: PMID:28530713
    reference_title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the patient B cells, we found a marked reduction in CD19+CD27+ memory and IgG class-switched CD27+IgG+ B cells"
    explanation: >-
      The compartment loss measured in the patients, and the reason this node now
      carries a class-switched memory B-cell binding: the depletion is reported for
      the switched subset specifically, not only for CD27+ memory as a whole.
  - reference: PMID:28530713
    reference_title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In vitro activation of naïve B cells from patients resulted in significantly impaired plasmablast generation, class-switch recombination and class-switched antibody secretion in the presence of IL-21"
    explanation: >-
      The functional assay behind the isotype-switching annotation, done on the
      patients' own naive B cells under defined stimulation, so the defect is
      intrinsic to the cells rather than a consequence of their in vivo environment.
      IN_VITRO because the measurement is made in culture.
  downstream:
  - target: Decreased memory B cell proportion
    causal_link_type: DIRECT
  - target: Decreased class-switched memory B cell proportion
    causal_link_type: DIRECT
  - target: Immunoglobulin deficiency
    causal_link_type: DIRECT
  - target: Decreased circulating IgA concentration
    causal_link_type: DIRECT
  - target: Decreased specific antibody response to vaccination
    causal_link_type: DIRECT
phenotypes:
- category: Immunologic
  name: Progressive T-cell lymphopenia
  description: >-
    IUIS records the circulating T-cell finding in BACH2 deficiency as progressive
    T-cell lymphopenia. The qualifier matters: the count falls over time rather than
    being low from the outset, so a normal T-cell count early does not exclude the
    diagnosis.
  phenotype_term:
    preferred_term: Progressive T-cell lymphopenia
    term:
      id: HP:0005403
      label: Decreased total T cell count
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:35748970
    reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Progressive T cell lymphopenia Impaired memory B cell development"
    explanation: >-
      The circulating T-cell column of the IUIS Table 4 row for BACH2 deficiency. The
      quote runs into the adjacent circulating-B-cell column because the two cells
      are contiguous in the cached table text.
  - reference: PMID:28530713
    reference_title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "T cells from our patients have a defect in cell proliferation associated with a progressive T cell lymphopenia"
    explanation: >-
      Primary-source corroboration of a phenotype this entry otherwise carried on the
      IUIS row alone, and it supplies the mechanism the authors attach to it: the count
      falls because the cells proliferate poorly, which is why the qualifier is
      progressive.
- category: Gastrointestinal
  name: Lymphocytic colitis
  description: >-
    Lymphocytic infiltration of the colonic mucosa, listed by IUIS as an associated
    feature of BACH2 deficiency. It is the infiltrative rather than the infectious
    half of the phenotype and is what marks the disorder as immune dysregulation
    rather than isolated antibody deficiency.
  phenotype_term:
    preferred_term: Lymphocytic colitis
    term:
      id: HP:0002583
      label: Colitis
  evidence:
  - reference: PMID:35748970
    reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Haploinsufficiency for a critical lineage specification transcription factor Lymphocytic colitis, sinopulmonary infections"
    explanation: >-
      The associated-features column of the IUIS Table 4 row, quoted together with
      the preceding functional-defect cell so the span is long enough to be
      self-describing.
  - reference: PMID:28530713
    reference_title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected subjects had lymphocyte-maturation defects that caused immunoglobulin deficiency and intestinal inflammation."
    explanation: >-
      The defining report records intestinal inflammation in the affected subjects,
      which is the primary-source basis for this phenotype.
- category: Immunologic
  name: Immunoglobulin deficiency
  description: >-
    The humoral consequence of the failed B-cell maturation programme, and the finding
    that makes the disorder look like a predominantly antibody deficiency at the
    bedside.

    Which isotypes fall is now curated from the founding report's full text, and the
    answer is that it varies between patients rather than tracking the variant. Two of
    the three founding subjects - the L24P proband and the E788K father - were low in
    IgM, IgG, IgA and IgE together. The third, the father's daughter and so a carrier
    of the same E788K allele, had low IgA against raised IgM and raised IgG. IgA is
    the only isotype low in all three. A later, unrelated family carrying R576L again
    showed IgA deficiency. So a normal or high IgG does not exclude the diagnosis, and
    the humoral phenotype should be read per isotype rather than as a single grade.

    What is still not curated is how far each isotype falls. The concentrations are
    reported in a supplementary table that is not part of the retrievable article, so
    this entry records direction and not values, and carries no reference ranges.
  phenotype_term:
    preferred_term: Immunoglobulin deficiency
    term:
      id: HP:0004313
      label: Decreased circulating immunoglobulin concentration
  sequelae:
  - target: Recurrent sinopulmonary infections
  evidence:
  - reference: PMID:28530713
    reference_title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected subjects had lymphocyte-maturation defects that caused immunoglobulin deficiency and intestinal inflammation."
    explanation: >-
      States immunoglobulin deficiency as a feature of the affected subjects in the
      founding report.
  - reference: PMID:37148421
    reference_title: "An early-onset SLE patient with a novel paternal inherited BACH2 mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "BACH2-related immunodeficiency and autoimmunity (BRIDA) is an inborn error of immunity, newly reported in 2017, presenting with symptoms of immunoglobulin deficiency and ongoing colitis."
    explanation: >-
      A second group's summary of the syndrome, which pairs immunoglobulin deficiency
      with colitis as its defining combination.
  - reference: PMID:28530713
    reference_title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fever and cytopenia improved with corticosteroids, but lymphopenia, deficiency in immunoglobulin (Ig)M, IgG, IgA and IgE, ongoing colitis, lung infiltrates and recurrent upper respiratory tract infections persisted"
    explanation: >-
      The isotype-level statement for the index patient - all four measured isotypes
      deficient - and, in the same sentence, that the deficiency persisted after the
      inflammatory features had responded to steroids.
  - reference: PMID:28530713
    reference_title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The father (proband) was deficient in all Ig sub-types; his daughter had undetectable IgA"
    explanation: >-
      The intrafamilial contrast that shows the humoral pattern is not determined by
      the variant: father and daughter carry the same E788K allele and differ from
      pan-deficiency to an IgA-restricted picture.
  - reference: PMID:28530713
    reference_title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| IgM | Low | Low | High |"
    explanation: >-
      Table 1, the IgM row across the three founding subjects. The third subject's
      raised IgM is the finding that stops this entry describing BRIDA as a uniform
      pan-hypogammaglobulinemia.
- category: Immunologic
  name: Recurrent sinopulmonary infections
  description: >-
    Recurrent infection of the upper and lower respiratory tract, listed by IUIS as
    an associated feature. It is the clinical expression of the failed memory B-cell
    compartment and is the reason the disorder presents to clinicians
    as an antibody deficiency.
  phenotype_term:
    preferred_term: Recurrent sinopulmonary infections
    term:
      id: HP:0005425
      label: Recurrent sinopulmonary infections
  sequelae:
  - target: Bronchiectasis
  evidence:
  - reference: PMID:35748970
    reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Haploinsufficiency for a critical lineage specification transcription factor Lymphocytic colitis, sinopulmonary infections"
    explanation: >-
      The associated-features column of the IUIS Table 4 row, quoted together with
      the preceding functional-defect cell so the span is long enough to be
      self-describing.
- category: Immunologic
  name: Decreased circulating IgA concentration
  description: >-
    The one isotype low in every reported subject. Both founding families and the
    later R576L family show it, including in the two individuals whose other isotypes
    are normal or raised, which makes IgA the most consistent single humoral marker in
    this disorder and the reason a normal total IgG should not close the question.
  phenotype_term:
    preferred_term: Decreased circulating IgA concentration
    term:
      id: HP:0002720
      label: Decreased circulating IgA concentration
  evidence:
  - reference: PMID:28530713
    reference_title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| IgA | Low | Low | Low |"
    explanation: >-
      Table 1, the IgA row: low in all three founding subjects, which is not true of
      any other isotype in that table.
- category: Immunologic
  name: Decreased memory B cell proportion
  description: >-
    Reduction of the CD27+ memory B-cell compartment, measured directly in the
    founding patients. It is the cellular counterpart of the antibody deficiency and,
    in the second reported family, was present in a clinically unaffected carrier -
    so it may be the earliest detectable sign in a relative.
  phenotype_term:
    preferred_term: Decreased memory B cell proportion
    term:
      id: HP:0030374
      label: Decreased memory B cell proportion
  evidence:
  - reference: PMID:28530713
    reference_title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the patient B cells, we found a marked reduction in CD19+CD27+ memory and IgG class-switched CD27+IgG+ B cells"
    explanation: >-
      Reports the CD19+CD27+ memory reduction in the patients, which is this phenotype.
- category: Immunologic
  name: Decreased class-switched memory B cell proportion
  description: >-
    The switched subset is depleted specifically, not merely in proportion to the
    memory compartment as a whole. That is the finding that points at class-switch
    recombination rather than at memory formation in general, and it is curated
    separately from the memory B-cell phenotype for that reason.
  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:28530713
    reference_title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the patient B cells, we found a marked reduction in CD19+CD27+ memory and IgG class-switched CD27+IgG+ B cells"
    explanation: >-
      The same sentence names the switched CD27+IgG+ subset as separately reduced,
      which is what this phenotype records.
- category: Immunologic
  name: Decreased specific antibody response to vaccination
  description: >-
    Failure to mount protective antibody after immunization, reported in all three
    founding subjects. It is the functional test that converts a low immunoglobulin
    concentration into a demonstrated antibody deficiency, and it is what the authors
    rest their common-variable-immunodeficiency characterisation on.
  phenotype_term:
    preferred_term: Decreased specific antibody response to vaccination
    term:
      id: HP:0032140
      label: Decreased specific antibody response to vaccination
  evidence:
  - reference: PMID:28530713
    reference_title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All three have developed a chronic variable immunodeficiency characterized by recurrent respiratory tract infections associated with an inability to generate appropriate antibody responses to vaccination."
    explanation: >-
      States the vaccine-response failure in all three subjects. Quoted in full because
      the same sentence carries the authors' own summary characterisation of the
      humoral picture, which this entry cites rather than paraphrases.
- category: Immunologic
  name: Decreased anti-CD3/28-induced T-cell proliferation
  description: >-
    Patient CD4+ T cells proliferate poorly on polyclonal stimulation. It is the
    cellular defect the authors link to the progressive T-cell lymphopenia, and it is
    reproduced by knocking BACH2 down by about half in healthy donor T cells, so it
    follows from the gene dosage rather than from chronic inflammation.
  phenotype_term:
    preferred_term: Decreased anti-CD3/28-induced T-cell proliferation
    term:
      id: HP:0031382
      label: Decreased anti-CD3/28-induced T-cell proliferation
  sequelae:
  - target: Progressive T-cell lymphopenia
  notes: >-
    Bound to the anti-CD3/28 child term rather than the general mitogen-induced parent
    because the methods name the stimulus: patient T cells were cultured with anti-CD3
    and anti-CD28 for five days. The parent term was the right call while only the
    abstract was available; the full text makes the specific one correct.
  evidence:
  - reference: PMID:28530713
    reference_title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "T cells were stained with CellTrace™ Violet as per manufacturer’s instructions followed by culture in the presence of anti-CD3 and anti-CD28 (1ug/mL of each)"
    explanation: >-
      Names the stimulus used for the patient proliferation assay, which is what licenses
      the anti-CD3/28 binding over the broader mitogen-induced term.
  - reference: PMID:28530713
    reference_title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Polyclonal activation of T cells resulted in reduced CD4+ T cell proliferation compared with healthy controls"
    explanation: >-
      The proliferation assay itself, on patient cells in culture, which is why it is
      graded IN_VITRO rather than as a clinical observation.
  - reference: PMID:28530713
    reference_title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "T cells from our patients have a defect in cell proliferation associated with a progressive T cell lymphopenia"
    explanation: >-
      Connects the proliferation defect to the lymphopenia phenotype curated above,
      which is why both are kept in this entry rather than only the count.
- category: Hematologic
  name: Lymphadenopathy
  description: >-
    Present in all three founding subjects, and the most consistent non-mucosal
    finding in the founding report. It sits with the infiltrative rather than the
    infectious arm of the disease.
  phenotype_term:
    preferred_term: Lymphadenopathy
    term:
      id: HP:0002716
      label: Lymphadenopathy
  evidence:
  - reference: PMID:28530713
    reference_title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Lymphadenopathy | Yes | Yes | Yes |"
    explanation: >-
      Table 1, the lymphadenopathy row: recorded in each of the three founding
      subjects.
- category: Hematologic
  name: Splenomegaly
  description: >-
    Massive splenomegaly, measured at 21.7 cm in the index patient against a normal
    adult spleen of 10-12 cm. Recorded in one of the three founding subjects, so it is
    a feature of the disorder rather than a diagnostic requirement.
  phenotype_term:
    preferred_term: Splenomegaly
    term:
      id: HP:0001744
      label: Splenomegaly
  evidence:
  - reference: PMID:28530713
    reference_title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with non-infectious fever, splenomegaly (21.7 cm, compared to 10–12 cm in normal adults)"
    explanation: >-
      The measurement and the normal comparator in the source's own words, in the
      index patient's presenting illness.
  - reference: PMID:28530713
    reference_title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Splenomegaly | Yes | No | No |"
    explanation: >-
      Table 1 gives the denominator: one of three subjects, which is why this is not
      curated as a defining feature.
- category: Hematologic
  name: Pancytopenia
  description: >-
    Reduction across all three blood lineages at presentation in the index patient.
    Unlike the immunoglobulin deficiency it responded to corticosteroids, which is
    what marks it as part of the inflammatory rather than the maturation arm of the
    disease.
  phenotype_term:
    preferred_term: Pancytopenia
    term:
      id: HP:0001876
      label: Pancytopenia
  evidence:
  - reference: PMID:28530713
    reference_title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with non-infectious fever, splenomegaly (21.7 cm, compared to 10–12 cm in normal adults) (Fig. 1c) and pancytopenia"
    explanation: >-
      Records the pancytopenia in the index patient's presenting illness, quoted with
      the preceding clause so the span is self-describing.
- category: Constitutional
  name: Non-infectious fever
  description: >-
    Fever without an identified infectious cause, part of the index patient's
    presenting illness at 19 years and recurrent in the later R576L family. It is an
    inflammatory feature: it responded to corticosteroids while the humoral deficiency
    did not.
  phenotype_term:
    preferred_term: Non-infectious fever
    term:
      id: HP:0001945
      label: Fever
  evidence:
  - reference: PMID:28530713
    reference_title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "who became ill at 19 years old with non-infectious fever, splenomegaly"
    explanation: >-
      States the fever and that it was non-infectious, which is the distinction this
      phenotype turns on.
- category: Respiratory
  name: Bronchiectasis
  description: >-
    Irreversible airway dilatation from recurrent sinopulmonary infection. The
    discussion attributes it to the older affected father specifically, and that is
    what this entry curates; note that the narrative introducing Family B describes
    the father and daughter together as presenting with recurrent sinopulmonary
    infections, bronchiectasis and fibrosis, while Table 1 records the daughter as not
    imaged. So the count is one confirmed of three, with a second neither confirmed nor
    excluded. It is the structural end point the entry's pulmonary surveillance
    recommendation exists to catch.
  phenotype_term:
    preferred_term: Bronchiectasis
    term:
      id: HP:0002110
      label: Bronchiectasis
  evidence:
  - reference: PMID:28530713
    reference_title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The father with the E788K mutation developed bronchiectasis later in life."
    explanation: >-
      Reports the bronchiectasis and its late onset, which is what makes it a
      surveillance target rather than a presenting feature.
histopathology:
- name: Chronic colitis with crypt branching and pericryptal lymphocytic infiltrate
  description: >-
    The colonic biopsy in the index patient shows chronic architectural change - crypt
    branching - together with lymphocytes massed around the crypts, and a Treg
    population that is reduced relative both to healthy controls and to patients with
    ordinary inflammatory bowel disease. That last comparison is what makes the biopsy
    mechanistically informative rather than merely confirmatory: the Treg deficit is
    not a generic consequence of colonic inflammation, so it points at the regulatory
    T-cell failure as the cause of the colitis rather than its result.
  diagnostic: false
  evidence:
  - reference: PMID:28530713
    reference_title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A colonic biopsy demonstrated inflammatory changes with crypt branching and prominent lymphocytic infiltrates around the crypts"
    explanation: >-
      The histological description itself, from the index patient's diagnostic biopsy.
  - reference: PMID:28530713
    reference_title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with significantly reduced FoxP3+ regulatory T (Treg) cells compared with healthy controls or patients with classical IBD"
    explanation: >-
      The controlled comparison in the same biopsy, which is what separates this
      histology from ordinary inflammatory bowel disease.
  notes: >-
    No finding_term is bound. HP has no term for crypt architectural distortion or a
    pericryptal lymphocytic infiltrate, and NCIT's Crypt-prefixed terms are all
    Cryptococcus, cryptochrome or cryptorchidism - none of them this finding. Searched
    both before leaving it unbound rather than binding an approximate term.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Reported in single families. The 2023 SLE family described itself as the second
    report of the syndrome, six years after the founding description, so the published
    case base is in the single figures and no population estimate exists.
  evidence:
  - reference: PMID:37148421
    reference_title: "An early-onset SLE patient with a novel paternal inherited BACH2 mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thus, we present the second report of BRIDA and demonstrate that BACH2 may be a monogenic cause of SLE."
    explanation: >-
      Fixes the size of the published case base at the time of writing - this family
      was only the second reported.
genetic:
- name: BACH2
  gene_term:
    preferred_term: BACH2
    term:
      id: hgnc:14078
      label: BACH2
  relationship_type: CAUSATIVE
  notes: >-
    Recorded as CAUSATIVE because the mechanism is a Mendelian autosomal dominant
    haploinsufficiency, but with an important qualification: ClinGen classifies the
    BACH2 relationship to immunodeficiency 60 as Moderate, and this schema's
    CAUSATIVE value is defined against ClinGen's Definitive and Strong tiers. There is
    no enum value for the Moderate tier, so the ClinGen classification is carried in
    external_assertions and stated here rather than being lost. BACH2 is at 6q15.

    This entry's BACH2 record is the rare coding haploinsufficiency claim only. The
    same gene appears elsewhere in this knowledge base as a common-variant
    susceptibility locus with relationship_type SUSCEPTIBILITY in polygenic autoimmune
    entries; those records make a different claim and should not be merged with this
    one.
  variants:
  - name: "NM_021813.4:c.1727G>T p.(Arg576Leu)"
    description: >-
      Novel heterozygous missense variant reported in the second BRIDA family,
      substituting a highly conserved arginine and predicted deleterious. Patient
      cells showed reduced BACH2 expression and deficient repression of its target
      BLIMP1. Inherited from the father, who was clinically unaffected but had an
      extreme reduction in memory B cells - the entry's one data point on penetrance.
  evidence:
  - reference: PMID:28530713
    reference_title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we describe a syndrome of BACH2-related immunodeficiency and autoimmunity (BRIDA) that results from BACH2 haploinsufficiency."
    explanation: >-
      The founding report establishing BACH2 as the causal gene for this Mendelian
      entity, and the mechanism as haploinsufficiency.
  - reference: PMID:37148421
    reference_title: "An early-onset SLE patient with a novel paternal inherited BACH2 mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole exome sequencing analysis of the patient and her parents revealed a novel heterozygous point mutation in BACH2, c.G1727T, resulting in substitution of a highly conserved arginine with leucine (R576L), which is predicted to be deleterious, in the patient and her father."
    explanation: >-
      Identifies the variant in the second reported family and its inheritance from an
      unaffected parent.
  - reference: PMID:39826876
    reference_title: "Curation of gene-disease relationships in primary antibody deficiencies using the ClinGen validation framework."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "ClinGen has established guidelines to classify gene-disease relationships as definitive, strong, moderate, and limited on the basis of available scientific and clinical evidence."
    explanation: >-
      Defines the tier system this entry's notes refer to, and is the curation effort
      that produced the Moderate call for BACH2. INDIRECT because it describes the
      framework rather than the BACH2 assertion itself.
  - reference: PMID:35748970
    reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "BACH2 deficiency BACH2 AD 605394 Progressive T cell lymphopenia Impaired memory B cell development Haploinsufficiency for a critical lineage specification transcription factor Lymphocytic colitis, sinopulmonary infections"
    explanation: >-
      The IUIS Table 4 row establishes BACH2 as the causal gene for a recognised
      inborn error of immunity, with the mode of inheritance and functional mechanism.
  - reference: CGGV:assertion_2473560a-6e5c-4342-a6e2-c89e37f4cc71-2023-02-21T180000.000Z
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "BACH2 | HGNC:14078 | immunodeficiency 60 | MONDO:0032723 | AD | Moderate | SOP9 | Antibody Deficiencies Gene Curation Expert Panel | 2023-02-21T18:00:00.000Z"
    explanation: >-
      ClinGen's expert-panel assertion for this gene-disease pair, and the source of
      the Moderate classification that bounds how strongly the relationship is stated.
  - reference: PMID:33864888
    reference_title: "Molecular diagnosis of childhood immune dysregulation, polyendocrinopathy, and enteropathy, and implications for clinical management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of 123 patients with FOXP3-negative IPEX-like disease, 48 (39%) carried damaging germline mutations in 1 of the following 27 genes: AIRE, BACH2, BCL11B, CARD11, CARD14, CTLA4, IRF2BP2, ITCH, JAK1, KMT2D, LRBA, MYO5B, NFKB1, NLRC4, POLA1, POMP, RAG1, SH2D1A, SKIV2L, STAT1, STAT3, TNFAIP3, TNFRSF6/FAS, TNRSF13B/TACI, TOM1, TTC37, and XIAP."
    explanation: >-
      Independent clinical corroboration that damaging germline BACH2 variants are
      found in patients investigated for IPEX-like immune dysregulation, which is the
      diagnostic setting in which this disorder is encountered.
treatments:
- name: Prednisone with Tofacitinib
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Corticosteroid combined with JAK inhibition, which relieved the lupus features and
    recurrent fever in the second reported family. This is a single patient's response
    directed at the autoimmune arm of the disease, not an established regimen for the
    syndrome, and it does not address the humoral deficiency.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: prednisone
      term:
        id: CHEBI:8382
        label: prednisone
    - preferred_term: tofacitinib
      term:
        id: CHEBI:71200
        label: tofacitinib
  target_mechanisms:
  - target: Non-infectious fever
    description: >-
      Recurrent fever was one of the two features relieved in the single patient
      treated this way. The lupus features it also relieved are not curated as
      phenotypes of this entry, so the fever is the only link this treatment can draw.
    evidence:
    - reference: PMID:37148421
      reference_title: "An early-onset SLE patient with a novel paternal inherited BACH2 mutation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "SLE symptoms and recurrent fever were relieved by treatment with prednisone combined with tofacitinib."
      explanation: Names the recurrent fever as one of the features that responded.
  evidence:
  - reference: PMID:37148421
    reference_title: "An early-onset SLE patient with a novel paternal inherited BACH2 mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SLE symptoms and recurrent fever were relieved by treatment with prednisone combined with tofacitinib."
    explanation: >-
      Reports the response in the one patient treated this way. Quoted as the narrow
      claim it is - symptom relief in a single case, not a trial result.
  notes: >-
    Aimed at the autoimmune arm only. The founding report is explicit that steroids in
    its own index patient did not touch the immunodeficiency or the pneumonitis, so a
    response here should not be read as disease control.
- name: Immunoglobulin Replacement Therapy
  therapeutic_modality: OTHER
  description: >-
    Intravenous immunoglobulin, given to the two founding subjects who were deficient
    in every isotype. The third subject, whose IgA alone was low against raised IgM
    and IgG, was not on replacement - so the founding report's own practice was to
    treat the pan-deficient patients and not the IgA-restricted one.
  treatment_term:
    preferred_term: intravenous immunoglobulin therapy
    term:
      id: NCIT:C121331
      label: Intravenous Immunoglobulin Therapy
  target_mechanisms:
  - target: Immunoglobulin deficiency
    description: >-
      Replacement substitutes for the antibody the failed class-switch and memory
      programme cannot produce. It does not act on the maturation defect itself, so it
      addresses the phenotype and leaves the pathophysiology node upstream of it
      untouched.
    evidence:
    - reference: PMID:28530713
      reference_title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "| On IvIg treatment | Yes | Yes | No |"
      explanation: >-
        Table 1 records replacement in the two subjects whose isotypes were uniformly
        low and not in the third, which is what ties the treatment to this phenotype.
  evidence:
  - reference: PMID:28530713
    reference_title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| On IvIg treatment | Yes | Yes | No |"
    explanation: >-
      Table 1 of the founding report, the row recording immunoglobulin replacement
      status for each of the three subjects.
  notes: >-
    Recorded as observed management in three patients, not as a trial result or a
    guideline recommendation - no source consulted states a dosing regimen, a target
    trough, or an outcome under replacement for BRIDA. The modality is OTHER rather
    than PROTEIN_REPLACEMENT: IVIg is pooled plasma-derived polyclonal antibody, and
    PROTEIN_REPLACEMENT is defined in the schema as recombinant protein or enzyme
    replacement, which this is not. Earlier versions of this entry
    carried the absence of this treatment as a known gap; it was closed by Table 1 of
    the founding report, which reached the reference cache only once JATS tables were
    extracted (issue #10867).
- name: Corticosteroid Therapy
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Systemic corticosteroids for the inflammatory features. In the index patient they
    resolved the fever and the pancytopenia, and later controlled most of her
    autoimmune manifestations - while leaving the immunodeficiency and the pneumonitis
    unchanged. That split is the useful clinical fact: steroids treat the arm of the
    disease driven by the regulatory T-cell failure and do nothing for the arm driven
    by the B-cell maturation failure.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: corticosteroid
      term:
        id: CHEBI:24261
        label: glucocorticoid
  target_mechanisms:
  - target: Non-infectious fever
    description: >-
      The fever resolved on corticosteroids, which is also what marks it as
      immune-mediated rather than infective.
    evidence:
    - reference: PMID:28530713
      reference_title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Fever and cytopenia improved with corticosteroids, but lymphopenia, deficiency in immunoglobulin (Ig)M, IgG, IgA and IgE, ongoing colitis, lung infiltrates and recurrent upper respiratory tract infections persisted"
      explanation: Names the fever as one of the two features that responded.
  - target: Pancytopenia
    description: >-
      The cytopenia resolved on corticosteroids, in the same course as the fever.
    evidence:
    - reference: PMID:28530713
      reference_title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Fever and cytopenia improved with corticosteroids, but lymphopenia, deficiency in immunoglobulin (Ig)M, IgG, IgA and IgE, ongoing colitis, lung infiltrates and recurrent upper respiratory tract infections persisted"
      explanation: Names the cytopenia as the other feature that responded.
  evidence:
  - reference: PMID:28530713
    reference_title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fever and cytopenia improved with corticosteroids, but lymphopenia, deficiency in immunoglobulin (Ig)M, IgG, IgA and IgE, ongoing colitis, lung infiltrates and recurrent upper respiratory tract infections persisted"
    explanation: >-
      Both halves of the claim in one sentence: what responded, and what did not.
  - reference: PMID:28530713
    reference_title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Many of the autoimmune phenomena in our patient with the L24P mutation have been successfully treated with corticosteroids although this has not reduced her chronic variable immunodeficiency nor her pneumonitis"
    explanation: >-
      The longer-term result, and the explicit statement of what did not respond. It
      supports this treatment as described - effective against the autoimmune arm and
      not against the immunodeficiency or the pneumonitis - rather than supporting
      corticosteroids as a treatment for the disorder as a whole.
  notes: >-
    Bound to the generic Pharmacotherapy action with a CHEBI agent because the source
    names no specific steroid. NCIT:C2322 is the real Corticosteroid term but fails the
    ChemicalEntityTerm dynamic enum, so CHEBI:24261 is used instead - the same choice
    recorded in E-Cigarette_or_Vaping_Product_Use-Associated_Lung_Injury.
diagnosis:
- name: Pulmonary surveillance in BACH2 carriers
  description: >-
    Periodic pulmonary assessment is recommended for patients with BACH2 mutations.
    The recommendation follows from the sinopulmonary infection phenotype and the
    structural lung damage that recurrent infection produces in antibody-deficient
    patients, and the authors making it are explicit that the case base is small.
  evidence:
  - reference: PMID:33864888
    reference_title: "Molecular diagnosis of childhood immune dysregulation, polyendocrinopathy, and enteropathy, and implications for clinical management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "although there are limited cases reported, current evidence also supports pulmonary screening for patients with mutations in BACH2, ITCH and TOM1"
    explanation: >-
      States the surveillance recommendation and, in the same sentence, the limited
      case base it rests on.
  notes: >-
    Recorded under diagnosis rather than treatments because it is a monitoring
    action, not a therapeutic one.
animal_models:
- name: Bach2-heterozygous mouse (BRIDA report)
  species: Mouse
  genotype: Bach2 heterozygous (Bach2+/-)
  publication: PMID:28530713
  description: >-
    The dose-matched model. Because BRIDA is a haploinsufficiency, a heterozygous
    mouse rather than a knockout is the construct that reproduces the human genetic
    state, and the founding report shows it produces analogous lymphocyte defects.
  notes: >-
    Same line as the three model entries below, and no longer an open question: the
    founding report's methods state that its Bach2 animals "were generated and housed
    as previously described", citing the study curated here as PMID:23728300. So this
    heterozygote and the heterozygote in that study are one line, characterized twice.
    They are two experiments and not two independent observations of the line - do not
    count them as replication of each other.
  modeled_mechanisms:
  - target: BACH2 Haploinsufficiency
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Heterozygous loss in mouse reproduces the molecular state of heterozygous loss in
      humans - reduced Bach2 message and protein with de-repressed Prdm1 - which is
      what licenses reading mouse Bach2 dosage biology onto this disorder.
    limitations: >-
      The mouse is normal until it is challenged. Bulk CD4+, CD8+, B-cell and
      plasma-cell numbers are unchanged in unimmunized animals, whereas the patients
      have a progressive T-cell lymphopenia, so the heterozygote does not model the
      resting human phenotype and its informative readouts all come from immunization
      or from subset gating rather than from counts.

      Keeping the dose-match versus dose-dependence distinction this entry draws: dose
      match is a property of the construct, and every heterozygote here has it by
      construction. Dose dependence is a demonstrated graded response, and it needs a
      genotype comparison. This model now has both - the full text compares Bach2+/-
      against wild-type for message, protein, Prdm1, and the immunization readouts -
      which is why the fidelity here is HIGH rather than the MODERATE that the
      abstract-only record supported.
    readouts:
    - name: Bach2 message and protein in heterozygous animals
      target: BACH2 Haploinsufficiency
      direction: DECREASED
      interpretation: >-
        The gene-dosage lesion itself, confirmed at both message and protein level.
      evidence:
      - reference: PMID:28530713
        reference_title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "We found that Bach2+/− mice manifest reduced Bach2 mRNA (Fig. 6a) and protein expression (Fig. 6b) together with elevated Prdm1 mRNA"
        explanation: >-
          Reports the reduced Bach2 and the de-repressed Prdm1 in one sentence, which is
          the same molecular signature reported in the patients.
    - name: Resting lymphocyte subset counts in heterozygous animals
      target: BACH2 Haploinsufficiency
      direction: UNCHANGED
      interpretation: >-
        A negative result, kept because it bounds the model: halving Bach2 does not by
        itself deplete the lymphoid compartments in an unchallenged animal.
      evidence:
      - reference: PMID:28530713
        reference_title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "There was no difference in the numbers of CD4+ and CD8+ T cells, B cells or plasma cells in unchallenged mice"
        explanation: Reports the measurement behind this readout, as a negative finding.
    evidence:
    - reference: PMID:28530713
      reference_title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We observed analogous lymphocyte defects in Bach2-heterozygous mice."
      explanation: >-
        Supports treating the heterozygous mouse as informative for the human
        haploinsufficient state.
  - target: Impaired Memory B Cell Development
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      On immunization the heterozygote fails at exactly the step the patients fail at:
      it barely generates class-switched B cells or plasma cells, and its germinal
      centers are reduced. This is the dose-matched counterpart of the patients'
      impaired in vitro class switching, and it is the readout that most directly
      connects halving BACH2 to the humoral phenotype.
    limitations: >-
      Requires deliberate immunization to appear; unchallenged heterozygotes have normal
      B-cell and plasma-cell numbers. The readout is also a single model antigen
      (NP-CGG in alum), so it speaks to the T-dependent IgG response and not to the
      mucosal IgA arm that dominates the patients' isotype pattern.
    readouts:
    - name: Class-switched B cells and plasma cells after immunization
      target: Impaired Memory B Cell Development
      direction: DECREASED
      interpretation: >-
        The class-switch and terminal-differentiation failure at matched gene dosage.
      evidence:
      - reference: PMID:28530713
        reference_title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Immunized Bach2+/− mice exhibited minimal induction of both IgG1 class switched-B220hiCD138− B cells and B220loCD138+ plasma cells compared to WT mice"
        explanation: Reports the measurement behind this readout.
    - name: Germinal center B cell proportion after immunization
      target: Impaired Memory B Cell Development
      direction: DECREASED
      interpretation: >-
        Locates part of the failure upstream of switching, in the germinal center
        reaction that class switching and memory formation depend on.
      evidence:
      - reference: PMID:28530713
        reference_title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "The proportion of germinal center B220+Ki67+Bcl6+ B cells was also reduced in Bach2+/− mice"
        explanation: Reports the measurement behind this readout.
    evidence:
    - reference: PMID:28530713
      reference_title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Immunized Bach2+/− mice exhibited minimal induction of both IgG1 class switched-B220hiCD138− B cells and B220loCD138+ plasma cells compared to WT mice"
      explanation: >-
        Supports treating the heterozygote as informative for the B-cell arm at the
        human gene dosage, which the homozygous nulls below cannot do.
  - target: Gut-Homing Receptor Upregulation on CD4+ T Cells
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      The heterozygote reproduces the patients' receptor shift - more CCR9+ and beta-7
      integrin+ CD4+ T cells, alongside fewer FoxP3+ cells - at the same gene dosage.
    limitations: >-
      No colitis is reported in these animals, so the model supports the cellular shift
      without demonstrating that it is sufficient for the intestinal disease. The link
      targets the gut-homing node specifically because T-bet, the marker of the TH1
      node, was not measured in these mice.
    readouts:
    - name: Gut-homing receptor expression on CD4+ T cells
      target: Gut-Homing Receptor Upregulation on CD4+ T Cells
      direction: INCREASED
      interpretation: >-
        The tissue-addressing half of this node, present at halved Bach2 dosage.
      evidence:
      - reference: PMID:28530713
        reference_title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "but Bach2+/− mice did have a small but significant reduction in FoxP3+ cells together with significant increases in CCR9+ and β7-integrin+ cells in CD4+ T cells"
        explanation: >-
          Reports both measurements behind this readout in one sentence, including the
          authors' own qualification that the Treg reduction is small.
    evidence:
    - reference: PMID:28530713
      reference_title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "but Bach2+/− mice did have a small but significant reduction in FoxP3+ cells together with significant increases in CCR9+ and β7-integrin+ cells in CD4+ T cells"
      explanation: >-
        Supports treating the heterozygote as informative for the effector-skewing node
        at the human gene dosage: the same paired shift the patients show, in an animal
        carrying the same halved dosage.
- name: Bach2-heterozygous mouse (Igarashi line, Treg characterization)
  species: Mouse
  genotype: Bach2 heterozygous (Bach2+/-)
  publication: PMID:23728300
  description: >-
    The best dose-matched evidence in this entry for the regulatory T-cell arm.
    Heterozygotes of the Igarashi null line have reduced Treg frequencies, so Treg
    formation is Bach2 gene-dose dependent rather than merely Bach2-dependent - which
    is what makes the Treg defect a plausible consequence of human haploinsufficiency
    rather than an artifact of complete loss.
  modeled_mechanisms:
  - target: Impaired Regulatory T Cell Differentiation
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Halving Bach2 reduces Treg frequency in mouse, matching both the gene dosage and
      the compartment of the human disease.
    limitations: >-
      Mouse rather than human, and the frequency reduction is reported without the
      functional suppression assays that would show whether the remaining Tregs work.
      That caveat is about Treg function rather than Treg differentiation, so it does
      not weaken the model's fidelity for this node, which is a differentiation node -
      hence HIGH here. The dose-match versus dose-dependence distinction this entry
      draws applies to both heterozygote entries and no longer separates them: both are
      heterozygotes, so both match the human gene dosage by construction, and both now
      compare genotypes against wild-type, so both demonstrate a graded response rather
      than only a matched dose. What still separates them is which compartment each one
      measured. This study measured Treg frequency, which is the node here; the BRIDA
      report measured Bach2 message and protein, the immunization response and the CD4+
      subset shifts, and is linked to those nodes instead. Same line as the null entries
      below and as the BRIDA heterozygote above, so none of them is an independent
      replication of the others.
    readouts:
    - name: Regulatory T cell frequency in heterozygous animals
      target: Impaired Regulatory T Cell Differentiation
      direction: DECREASED
      interpretation: >-
        Treg formation responds to Bach2 gene dosage, not only to its complete absence.
      evidence:
      - reference: PMID:23728300
        reference_title: "BACH2 represses effector programs to stabilize T(reg)-mediated immune homeostasis."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Treg cell formation was Bach2 gene-dose dependent since mice heterozygous for the KO allele had reduced frequencies of Treg cells"
        explanation: Reports the measurement behind this readout.
    evidence:
    - reference: PMID:23728300
      reference_title: "BACH2 represses effector programs to stabilize T(reg)-mediated immune homeostasis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Treg cell formation was Bach2 gene-dose dependent since mice heterozygous for the KO allele had reduced frequencies of Treg cells"
      explanation: >-
        Supports treating the heterozygote as informative for the human
        haploinsufficient Treg defect, at matched gene dosage.
- name: Bach2-null mouse (Igarashi line, Treg characterization)
  species: Mouse
  genotype: Bach2 knockout (homozygous null)
  publication: PMID:23728300
  description: >-
    The Igarashi-derived Bach2 null, characterized here for the regulatory T-cell
    compartment. It is a null rather than a heterozygote, so it speaks to what BACH2
    does, not to what halving it does.
  notes: >-
    This is the same mouse line as the class-switching entry below and as the
    heterozygote entry above - one line from one lab, characterized in two studies.
    The entries are split so each publication field matches the evidence on its own
    links, not because the lines are independent. Do not read the three as independent
    replication.
  modeled_mechanisms:
  - target: Impaired Regulatory T Cell Differentiation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Complete Bach2 loss prevents efficient Treg formation and diverts cells destined
      for the regulatory lineage into effector lineages, producing lethal inflammation.
    limitations: >-
      Homozygous null, whereas the human disease is heterozygous; the mouse phenotype
      is correspondingly more severe than BRIDA and cannot be read as a dose-matched
      prediction.
    readouts:
    - name: Regulatory T cell formation
      target: Impaired Regulatory T Cell Differentiation
      direction: DECREASED
      interpretation: Loss of the regulatory compartment this node describes.
      evidence:
      - reference: PMID:23728300
        reference_title: "BACH2 represses effector programs to stabilize T(reg)-mediated immune homeostasis."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "BACH2 was required for efficient formation of regulatory (Treg) cells and consequently for suppression of lethal inflammation in a manner that was Treg-cell-dependent."
        explanation: Reports the measurement behind this readout.
    evidence:
    - reference: PMID:23728300
      reference_title: "BACH2 represses effector programs to stabilize T(reg)-mediated immune homeostasis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "its absence during Treg polarization resulted in inappropriate diversion to effector lineages"
      explanation: >-
        Supports treating the knockout as informative for the Treg differentiation node.
- name: Bach2-null mouse (Igarashi line, class-switching characterization)
  species: Mouse
  genotype: Bach2 knockout (homozygous null)
  publication: PMID:15152264
  description: >-
    The same Igarashi-derived Bach2 null, characterized here for the B-cell arm. This
    is the original report of the line; the regulatory T-cell study above used it
    rather than deriving its own.
  notes: >-
    Same line as the two entries above. Curated as its own model so this publication
    field matches the evidence on its link, not because the line is independent.
  modeled_mechanisms:
  - target: Impaired Memory B Cell Development
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Bach2-null B cells fail to class switch efficiently while retaining IgM output
      and abundant Blimp-1 and XBP-1 expression, which localizes the defect to class
      switch recombination rather than to terminal differentiation.
    limitations: >-
      Homozygous null rather than the human heterozygous dose, and the readout is
      class switching in mouse rather than memory B-cell counts in patients.
    readouts:
    - name: Class switch recombination efficiency
      target: Impaired Memory B Cell Development
      direction: DECREASED
      interpretation: >-
        The specific B-cell step that fails when BACH2 is absent.
      evidence:
      - reference: PMID:15152264
        reference_title: "The transcriptional programme of antibody class switching involves the repressor Bach2."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "However, they failed to undergo efficient CSR."
        explanation: Reports the measurement behind this readout.
    evidence:
    - reference: PMID:15152264
      reference_title: "The transcriptional programme of antibody class switching involves the repressor Bach2."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Genetic ablation of Bach2 in mice revealed that Bach2 was required for both T-cell-independent and T-cell-dependent IgG responses and SHM."
      explanation: >-
        Supports treating the knockout as informative for the B-cell arm of this entry.
experimental_models:
- name: BACH2 RNAi knockdown in primary human T and B cells
  experimental_model_type: PRIMARY_CELL_CULTURE
  cell_source: primary cells from healthy human donors
  culture_system: >-
    Nucleofection of BACH2-targeting siRNA/DsiRNA into purified healthy-donor CD4+ T
    cells or naive B cells, achieving roughly 50 percent knockdown, followed by
    polyclonal or class-switch-inducing stimulation.
  publication: PMID:28530713
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: CD4-positive helper T cell
    term:
      id: CL:0000492
      label: CD4-positive helper T cell
  - preferred_term: naive B cell
    term:
      id: CL:0000788
      label: naive B cell
  description: >-
    The dose-matched human system, and the strongest causal evidence in this entry.
    Every other model here is either a mouse or a patient: the mouse matches the dosage
    but not the species, and the patients match the species but cannot separate the
    BACH2 lesion from everything else in their genomes and histories. Knocking BACH2
    down by about half in healthy donor cells does both at once - human cells, human
    gene dosage, one variable changed - and it reproduces the patients' phenotype in
    both lineages: PRDM1 rises, CD4+ T cells proliferate less, and class switching to
    IgG and IgA is suppressed.
  notes: >-
    A knockdown is not a haploinsufficiency. The reduction is transient, its depth is
    approximate rather than exactly one allele's worth, and it acts on mature cells
    rather than across development - so it shows that acutely halving BACH2 is
    sufficient for these defects, not that the patients' lifelong half-dosage produces
    them by the same route. Curated as an experimental model rather than as an animal
    model because the system is human primary cells; see the schema's note that
    whole-organism animal models never belong in this section.
  modeled_mechanisms:
  - target: BACH2 Haploinsufficiency
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Reducing BACH2 by about half in healthy human lymphocytes reproduces the
      patients' cellular phenotype in both lineages, which is what converts the
      correlation between low BACH2 and the BRIDA phenotype into a causal claim.
    limitations: >-
      Acute, incomplete and transient knockdown in mature cells, not a germline
      heterozygous state, so it cannot speak to developmental consequences or to the
      progressive features of the disease. Knockdown depth is reported as approximately
      50 percent rather than measured per experiment.
    readouts:
    - name: PRDM1 message after BACH2 knockdown in CD4+ T cells
      target: BACH2 Haploinsufficiency
      direction: INCREASED
      interpretation: >-
        De-repression of the direct BACH2 target, matching what is measured in patient
        cells.
      evidence:
      - reference: PMID:28530713
        reference_title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Silencing BACH2 in control CD4+ T cells led to a significant rise in PRDM1 mRNA"
        explanation: Reports the measurement behind this readout.
    evidence:
    - reference: PMID:28530713
      reference_title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "we silenced BACH2 expression in healthy control T and B cells using RNAi by ~50% and carried out functional phenotyping"
      explanation: >-
        States the system and the knockdown depth, which is what makes it dose-matched
        to a heterozygous human and therefore informative for this node.
    - reference: PMID:28530713
      reference_title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Thus, experimental silencing of BACH2 in healthy T and B cells recapitulated the phenotype seen in primary cells of the patients."
      explanation: >-
        The authors' own summary that the knockdown reproduces the patient phenotype,
        which is the claim this model link makes.
  - target: Impaired Memory B Cell Development
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Halving BACH2 in healthy human B cells is sufficient to suppress class switching
      to IgG and IgA - the two isotypes whose deficiency dominates the patients'
      humoral phenotype.
    limitations: >-
      Measures class switching in culture rather than memory B-cell accumulation in
      vivo, so it substantiates the isotype-switching annotation on this node and not
      the memory-compartment annotation. Healthy donor cells, so it says what BACH2
      dosage does and not what the specific BRIDA alleles do.
    readouts:
    - name: In vitro class switch recombination to IgG and IgA after BACH2 knockdown
      target: Impaired Memory B Cell Development
      direction: DECREASED
      interpretation: >-
        The isotype-switching step of this node, shown to depend on BACH2 dosage in
        human cells.
      evidence:
      - reference: PMID:28530713
        reference_title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "silencing BACH2 in healthy control B cells, significantly suppressed in vitro class switch recombination towards the IgG and IgA isotypes"
        explanation: Reports the measurement behind this readout.
    evidence:
    - reference: PMID:28530713
      reference_title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "silencing BACH2 in healthy control B cells, significantly suppressed in vitro class switch recombination towards the IgG and IgA isotypes"
      explanation: >-
        Supports treating the knockdown as informative for the class-switch arm of this
        node, in human cells at approximately the human heterozygous dosage.
mechanistic_hypotheses:
- hypothesis_group_id: bach2_dosage_axis
  hypothesis_label: >-
    Common regulatory variation and rare coding haploinsufficiency at BACH2 act on one
    gene-dosage axis
  status: EMERGING
  description: >-
    BACH2 occupies an unusual position: the same gene is a recurrent common-variant
    susceptibility locus across many polygenic autoimmune diseases and, separately,
    the cause of a Mendelian inborn error of immunity through coding
    haploinsufficiency. The hypothesis is that these are two ends of one dosage
    continuum - that regulatory variants shifting BACH2 expression modestly across a
    population produce autoimmune susceptibility, while a coding lesion halving it
    produces overt immune dysregulation with immunodeficiency.

    This is recorded as a hypothesis and deliberately not drawn as a causal edge. The
    susceptibility associations and the Mendelian mechanism are established
    separately; that they share a dosage mechanism is an inference, and no cached
    source tests it. Deciding it would need expression-level data linking the risk
    haplotypes to BACH2 dosage in the relevant lymphocyte compartments.
  evidence:
  - reference: PMID:28530713
    reference_title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Single-nucleotide variants in the BACH2 locus are associated with several autoimmune diseases, but BACH2 mutations that cause Mendelian monogenic primary immunodeficiency have not previously been identified."
    explanation: >-
      States both ends of the proposed axis in one sentence, and is the founding
      report's own framing of why the Mendelian entity was worth looking for.
  - reference: PMID:28530713
    reference_title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "genes that cause monogenic haploinsufficient diseases were substantially enriched for TFs and SE architecture"
    explanation: >-
      The mechanism the founding report proposes for why one locus supports both a
      common-variant association signal and a rare dosage disease - super-enhancer
      architecture makes transcription-factor genes dosage-sensitive.
  - reference: PMID:23728300
    reference_title: "BACH2 represses effector programs to stabilize T(reg)-mediated immune homeostasis."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "Genetic polymorphisms within a single locus encoding the transcription factor BACH2 are associated with numerous autoimmune and allergic diseases including asthma, Crohn's disease, coeliac disease, vitiligo, multiple sclerosis and type 1 diabetes."
    explanation: >-
      Enumerates the common-variant end of the axis, and names the same diseases that
      carry BACH2 as a susceptibility locus elsewhere in this knowledge base.
  - reference: PMID:22561518
    reference_title: "Genome-wide association analyses identify 13 new susceptibility loci for generalized vitiligo."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "CLNK (P = 1.56 × 10(-8)), BACH2 (P = 2.53 × 10(-8)), SLA (P = 1.58 × 10(-8))"
    explanation: >-
      One concrete instance of the common-variant end, with its association statistic.
  - reference: PMID:35748970
    reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Haploinsufficiency for a critical lineage specification transcription factor"
    explanation: >-
      Establishes the Mendelian end of the proposed axis as an explicitly
      dosage-dependent mechanism, which is what makes a shared-dosage model
      conceivable in the first place.
  notes: >-
    See the entry-level notes for the list of dismech entries carrying BACH2 as a
    susceptibility locus.
discussions:
- discussion_id: bach2_imd60_humoral_phenotype_uncurated
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Impaired Memory B Cell Development
  - phenotypes#Recurrent sinopulmonary infections
  prompt: >-
    Which immunoglobulin isotypes fall in immunodeficiency 60, by how much, and does
    the picture meet criteria for common variable immunodeficiency?
  rationale: >-
    Two of the three parts are now answered from the founding report's full text, and
    the third is not.

    Which isotypes: not the same ones in every patient. Two founding subjects were low
    in IgM, IgG, IgA and IgE together; the third, carrying the same E788K allele as her
    affected father, had low IgA against raised IgM and IgG. IgA is the only isotype
    low in all three, and a further family carrying R576L was also IgA deficient. The
    pattern therefore does not track the variant, which rules out the simplest reading
    - that each allele produces its own humoral picture - and leaves modifiers, age or
    ascertainment as the explanation. All of this is now curated: the isotype spread on
    the Immunoglobulin deficiency phenotype, IgA separately as the consistent one.

    CVID criteria: the authors state that all three subjects developed "a chronic
    variable immunodeficiency" characterised by recurrent respiratory infection with
    failure to respond to vaccination, and the vaccine-response failure is curated as
    its own phenotype. That is the authors' characterisation rather than a formal
    application of ESID or ICON diagnostic criteria, and this entry does not upgrade it
    into one. The separate question of whether the disorder belongs with the antibody
    deficiencies at all is tracked in the IUIS-versus-ClinGen discussion below.

    By how much: still open, and now for a specific and probably permanent reason. The
    immunoglobulin concentrations are reported in Supplementary Table 1, which is not
    part of the article record served by PMC, so no accessible source gives a value.
    Table 1 of the main article gives only Low, Normal or High per isotype. Until a
    further family is reported with values in the main text, this entry can record the
    direction of each isotype but not its magnitude, and cannot carry reference ranges
    for the humoral phenotype.

    The plasmablast and class-switch assay results named in the original version of
    this gap are no longer missing and are curated on the memory B-cell node.
  evidence:
  - reference: PMID:28530713
    reference_title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| IgG | Low | Low | High * |"
    explanation: >-
      Table 1, the IgG row. It is the sharpest statement of the non-uniformity: the
      third subject's IgG is not merely normal but raised, which is why this entry does
      not describe BRIDA as a hypogammaglobulinemia.
  - reference: PMID:28530713
    reference_title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
    supports: NO_EVIDENCE
    evidence_source: HUMAN_CLINICAL
    snippet: "| IgE | Low | Low | Normal |"
    explanation: >-
      Cited as the boundary of what the accessible record contains. Table 1 gives each
      isotype as a category and never as a concentration, so the founding report - the
      only source that measured these patients - does not bear on the magnitude
      question this gap now turns on.
- discussion_id: bach2_repressor_direction_paradox
  kind: OPEN_QUESTION
  status: RESOLVED
  attaches_to:
  - pathophysiology#Impaired Memory B Cell Development
  prompt: >-
    If BACH2 suppresses immunoglobulin production, why does losing it cause antibody
    deficiency rather than excess antibody?
  rationale: >-
    BACH2 represses immunoglobulin production, and in normal memory B cells plasma-cell
    differentiation proceeds by inducing BLIMP1 and downregulating BACH2. Read naively,
    halving BACH2 should release antibody output rather than reduce it.
  resolution_note: >-
    Answered by the Bach2 knockout. Bach2-null B cells still produce IgM and still
    express Blimp-1 and XBP-1 abundantly, so plasmacytic differentiation itself does
    not require BACH2 - what fails is class switch recombination specifically. The
    abundance is itself informative: BACH2 represses BLIMP1, so losing BACH2
    de-represses the plasma-cell programme rather than leaving it untouched, and the
    cell terminally differentiates without having switched isotype. BACH2 is
    therefore not a brake on antibody output in general; it is required for the
    class-switch and somatic-hypermutation programme while restraining premature
    terminal differentiation. Losing it yields antibody that is present but unswitched
    and unmutated, which is a functional humoral deficiency rather than an excess. The
    memory B-cell node is worded accordingly.

    The dose caveat this note used to end on is now closed. The resolution rested on a
    homozygous null mouse; the founding report's full text shows the same thing in
    human cells at the human gene dosage, by knocking BACH2 down about 50 percent in
    healthy donor B cells and finding class switching to IgG and IgA suppressed. So the
    class-switch dependency is a property of BACH2 dosage in human B cells, not an
    artifact of complete loss in mouse.

    One thing the full text complicates rather than settles. The null mouse showed
    plasmacytic differentiation intact, which is what let the answer be "switching
    fails, terminal differentiation does not". Patient naive B cells stimulated with
    IL-21 in vitro show impaired plasmablast generation as well as impaired switching.
    Those need not conflict - different species, different dosage, different stimulus -
    but the clean separation should not be over-read. This entry annotates isotype
    switching on the memory B-cell node and does not annotate plasma-cell
    differentiation, because the human plasmablast finding is a single in vitro assay
    and the mouse evidence points the other way.
  evidence:
  - reference: PMID:15152264
    reference_title: "The transcriptional programme of antibody class switching involves the repressor Bach2."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "When stimulated in vitro, Bach2-deficient B cells produced IgM, as did wild-type cells, and abundantly expressed Blimp-1 (refs 9, 10) and XBP-1 (ref. 11), critical regulators of the plasmacytic differentiation, indicating that Bach2 was not required for the plasmacytic differentiation itself. However, they failed to undergo efficient CSR."
    explanation: >-
      The sentence that dissolves the paradox - it separates plasmacytic
      differentiation, which is intact without BACH2, from class switching, which is not.
  - reference: PMID:28530713
    reference_title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "silencing BACH2 in healthy control B cells, significantly suppressed in vitro class switch recombination towards the IgG and IgA isotypes"
    explanation: >-
      Closes the dose caveat: the same dependency, in human B cells, at approximately
      the heterozygous dosage rather than in a homozygous null mouse.
- discussion_id: bach2_imd60_penetrance
  kind: OPEN_QUESTION
  status: OPEN
  attaches_to:
  - genetic#BACH2
  - inheritance#Autosomal dominant
  prompt: >-
    Is BRIDA fully penetrant, and can a BACH2 carrier have the cellular phenotype
    without the disease?
  rationale: >-
    In the second reported family the R576L variant was inherited from the father, who
    had no obvious symptoms yet showed an extreme reduction in memory B cells. That is
    a carrier with the laboratory phenotype and without the clinical one, which is the
    signature of incomplete penetrance or of a threshold effect requiring a second hit.
    It matters practically: it means an asymptomatic parent cannot be assumed to be a
    non-carrier, and it bears on how a family is counselled. One family is not enough
    to establish a penetrance estimate, and no source consulted here reports carrier
    counts, so this is a single observation rather than a quantified claim.
  evidence:
  - reference: PMID:37148421
    reference_title: "An early-onset SLE patient with a novel paternal inherited BACH2 mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Notably, extreme reduction of memory B cells was detected in the patient's father, although he had no obvious symptoms."
    explanation: >-
      The observation itself - cellular phenotype present, clinical phenotype absent,
      in an obligate carrier.
- discussion_id: bach2_imd60_phenotype_expansion
  kind: OPEN_QUESTION
  status: OPEN
  attaches_to:
  - disease#
  - phenotypes#
  prompt: >-
    How wide is the BRIDA phenotype beyond immunoglobulin deficiency and colitis?
  rationale: >-
    Reports after the founding description have attached progressively more
    autoimmunity to heterozygous BACH2 variants - early-onset systemic lupus with
    juvenile dermatomyositis and IgA deficiency in one family, and autoimmune
    enteropathy alongside T-cell large granular lymphocytic leukemia, type 1 diabetes,
    pure red cell aplasia and celiac disease in another. Each is a single case, and
    the second carries obvious confounders: an HLA-DQ8 allele and a concurrent
    clonal lymphoproliferative disorder that is itself associated with autoimmunity.
    So these are not curated as phenotypes of this entry. The open question is whether
    BRIDA is a broad autoimmunity-predisposing state whose reported range is still
    growing, or whether single-case reports are accumulating around a gene that is
    also a common autoimmune susceptibility locus. Deciding it needs a case series,
    not more single reports.
  evidence:
  - reference: PMID:37148421
    reference_title: "An early-onset SLE patient with a novel paternal inherited BACH2 mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we describe a patient with BRIDA presenting with early-onset SLE, juvenile dermatomyositis, and IgA deficiency."
    explanation: One reported expansion of the phenotype, in a single patient.
  - reference: PMID:40386599
    reference_title: "Autoimmune enteropathy associated with T cell large granular lymphocytic leukemia in a patient with BACH2 mutation: a case report."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "She carries an HLA-DQ8 allele and a germline heterozygous mutation of BACH2."
    explanation: >-
      The second reported expansion, quoted with the confounding HLA allele in the same
      sentence because that is precisely why this entry does not curate it as a
      phenotype. INDIRECT for the same reason.
- discussion_id: bach2_imd60_iuis_versus_clingen_panel
  kind: INTERPRETATION
  status: OPEN
  attaches_to:
  - disease#
  prompt: >-
    Should immunodeficiency 60 be grouped with the antibody deficiencies or with the
    diseases of immune dysregulation?
  rationale: >-
    The two authorities pull in different directions and both are defensible. ClinGen
    curated the gene through its Antibody Deficiencies Gene Curation Expert Panel,
    which reflects how the disorder presents - sinopulmonary infection and humoral
    deficiency. IUIS places it in Table 4 with the regulatory T-cell defects, which
    reflects the mechanism and the infiltrative colitis. This entry follows IUIS,
    because the Tregopathy classification is corroborated independently and because
    the lymphocytic colitis is not explicable as a consequence of antibody deficiency.
    The disagreement is recorded rather than hidden, since a reader coming from the
    ClinGen side will expect the other answer.
  evidence:
  - reference: CGGV:assertion_2473560a-6e5c-4342-a6e2-c89e37f4cc71-2023-02-21T180000.000Z
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "BACH2 | HGNC:14078 | immunodeficiency 60 | MONDO:0032723 | AD | Moderate | SOP9 | Antibody Deficiencies Gene Curation Expert Panel | 2023-02-21T18:00:00.000Z"
    explanation: >-
      Names the ClinGen expert panel that curated the gene, which is the antibody
      deficiency panel rather than an immune dysregulation panel.
references:
- reference: PMID:28530713
  title: "BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency."
  findings:
  - statement: >-
      The founding report. Describes the syndrome, names it BRIDA, attributes it to BACH2
      haploinsufficiency, states the immunoglobulin deficiency and intestinal inflammation,
      gives the protein-destabilization mechanism, and reports the Bach2-heterozygous
      mouse. Cached as full text, including Table 1, which carries the per-subject isotype
      pattern and immunoglobulin-replacement status. The immunoglobulin concentrations
      themselves are in Supplementary Table 1, which is not part of the retrievable article.
- reference: PMID:37148421
  title: "An early-onset SLE patient with a novel paternal inherited BACH2 mutation."
  findings:
  - statement: >-
      The second reported family. Supplies the R576L variant, reduced BACH2 expression and
      deficient BLIMP1 repression in patient cells, an unaffected carrier father with an
      extreme memory B-cell reduction, and the prednisone plus tofacitinib response.
- reference: PMID:23728300
  title: "BACH2 represses effector programs to stabilize T(reg)-mediated immune homeostasis."
  findings:
  - statement: >-
      Mouse knockout establishing that BACH2 is required for regulatory T-cell formation and
      that its absence diverts cells to effector lineages. The basis of the Treg arm.
- reference: PMID:15152264
  title: "The transcriptional programme of antibody class switching involves the repressor Bach2."
  findings:
  - statement: >-
      Mouse knockout localizing the B-cell defect to class switch recombination while showing
      plasmacytic differentiation is intact. Resolves the repressor-direction paradox.
- reference: PMID:40386599
  title: "Autoimmune enteropathy associated with T cell large granular lymphocytic leukemia in a patient with BACH2 mutation: a case report."
  findings:
  - statement: >-
      Single case of autoimmune enteropathy with T-LGL in a germline heterozygous BACH2
      carrier. Cited only in the phenotype-expansion discussion, not as a phenotype.
- reference: PMID:39826876
  title: "Curation of gene-disease relationships in primary antibody deficiencies using the ClinGen validation framework."
  findings:
  - statement: >-
      The ClinGen Antibody Deficiencies expert panel curation effort behind the Moderate
      classification, and the definition of the tier system.
- reference: PMID:35748970
  title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
  findings:
  - statement: >-
      Places BACH2 deficiency in Table 4 (diseases of immune dysregulation) with
      autosomal dominant inheritance, progressive T-cell lymphopenia, impaired memory
      B-cell development, haploinsufficiency for a lineage specification transcription
      factor, and lymphocytic colitis with sinopulmonary infections. The backbone of
      this entry.
- reference: PMID:33996698
  title: "Different Apples, Same Tree: Visualizing Current Biological and Clinical Insights into CTLA-4 Insufficiency and LRBA and DEF6 Deficiencies."
  findings:
  - statement: >-
      Lists BACH2 deficiency among the monogenic Tregopathies alongside IPEX, CD25
      deficiency and STAT3 gain-of-function, which grounds the regulatory T-cell arm of
      the mechanism.
- reference: PMID:33864888
  title: "Molecular diagnosis of childhood immune dysregulation, polyendocrinopathy, and enteropathy, and implications for clinical management."
  findings:
  - statement: >-
      Sequenced 123 patients with FOXP3-negative IPEX-like disease and found damaging
      germline variants in 27 genes including BACH2; recommends pulmonary screening for
      patients with BACH2 mutations while noting the limited case base.
- reference: CGGV:assertion_2473560a-6e5c-4342-a6e2-c89e37f4cc71-2023-02-21T180000.000Z
  title: "BACH2 / immunodeficiency 60 (Moderate)"
  findings:
  - statement: >-
      ClinGen Antibody Deficiencies Gene Curation Expert Panel classifies the autosomal
      dominant BACH2-immunodeficiency 60 relationship as Moderate (SOP9, 2023-02-21).
- reference: PMID:29670635
  title: "Chronic Lymphocytic Leukemia B-Cell Normal Cellular Counterpart: Clues From a Functional Perspective."
  findings:
  - statement: >-
      Background B-cell biology: in normal human IgG+ memory B cells, plasma-cell
      differentiation is driven by PRDM1/BLIMP1 induction with reciprocal
      downregulation of BACH2.
- reference: PMID:26235382
  title: "Immunogenetics of autoimmune thyroid diseases: A comprehensive review."
  findings:
  - statement: >-
      Background BACH2 biology: highly expressed in B cells and a suppressor of
      immunoglobulin production. Also one of the sources establishing BACH2 as a
      common-variant autoimmune susceptibility locus.
- reference: PMID:22561518
  title: "Genome-wide association analyses identify 13 new susceptibility loci for generalized vitiligo."
  findings:
  - statement: >-
      Identifies BACH2 among 13 new genome-wide significant vitiligo susceptibility
      loci; cited only to establish the common-variant end of the dosage hypothesis.
notes: >-
  Provenance, stated so a reader can calibrate the entry. The spine is the founding
  report (PMID:28530713) plus the second reported family (PMID:37148421), with the
  IUIS 2022 Table 4 row and the ClinGen gene-disease validity record supplying the
  classification and the strength of the gene-disease assertion, and two mouse studies
  (PMID:23728300, PMID:15152264) supplying the mechanism of each arm.

  PMID:28530713 was originally curated from its abstract alone, and that bounded most
  of this entry. Its full text is now in the reference cache and the entry has been
  rebuilt on it (issue #10867), which changed the following: the isotype pattern is
  curated per patient rather than as an undifferentiated deficiency, the founding
  subjects' individual phenotypes are curated, the Bach2 heterozygote carries
  per-compartment readouts instead of a single "analogous lymphocyte defects" line and
  its mouse line is identified, immunoglobulin replacement and corticosteroid therapy
  are recorded as observed management, and a human RNAi knockdown is curated as an
  experimental model. The full text was not previously reachable because of a bug in
  this repository's reference-validator patch rather than because the article is
  restricted; the fix ships with the same change.

  Two limits survive. Immunoglobulin concentrations are in Supplementary Table 1, which
  PMC does not serve, so the humoral phenotype is a direction per isotype and carries
  no values or reference ranges. And the mouse mechanism evidence for the individual
  arms is still largely homozygous-null rather than heterozygous, so it establishes
  what BACH2 does rather than what halving it does; the model links say so in their
  limitations. The dose-matched claims now rest on the heterozygous mouse and on the
  human knockdown instead.

  Named Entity Confusion warning for whoever extends this entry. Searching the
  reference cache for BACH2 returns around thirty files, and almost none of them are
  about this disorder. They divide into two unrelated groups: BACH2 as a
  common-variant susceptibility locus in polygenic autoimmune disease, and BACH2 in
  lymphoma and leukemia biology. Citing either group for the Mendelian entity would
  be exactly the entity confusion the reference SOP warns about. The two background
  sources used here (PMID:29670635 and PMID:26235382) are cited only for statements
  about normal BACH2 molecular biology that they make directly, and both are graded
  INDIRECT for that reason.

  BACH2 appears as a SUSCEPTIBILITY locus in the following dismech entries, all of
  which make the polygenic association claim rather than this Mendelian one. This is
  a snapshot taken at curation (2026-09-03), not a maintained index - re-derive it
  with a grep for the gene rather than trusting the list to be current:
  Type_I_Diabetes, Crohn_Disease, Celiac_Disease, Vitiligo, Multiple_Sclerosis,
  Asthma, Psoriasis, Systemic_Lupus_Erythematosus, Ulcerative_Colitis,
  Rheumatoid_Arthritis, Ankylosing_Spondylitis, Addisons_Disease,
  Atopic_Dermatitis.

  No mechanism module currently covers regulatory T-cell differentiation failure or
  class-switch recombination failure, so there is no conforms_to target for either
  pathophysiology node. Both are recurrent across the inborn errors of immunity and
  would be reasonable module candidates.

  On quoting Table 1. The founding report's Table 1 rows are quotable as evidence
  snippets because JATS tables are now extracted into the reference cache as
  pipe-delimited rows, the same shape as an ORPHA or ICEES row. A row quote carries no
  column headers, so an explanation citing one has to say which table and which row it
  is - the rows in this entry do. Do not quote a row without that context.
📚

References & Deep Research

References

13
PMID:28530713
BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency.
1 finding
The founding report. Describes the syndrome, names it BRIDA, attributes it to BACH2 haploinsufficiency, states the immunoglobulin deficiency and intestinal inflammation, gives the protein-destabilization mechanism, and reports the Bach2-heterozygous mouse. Cached as full text, including Table 1, which carries the per-subject isotype pattern and immunoglobulin-replacement status. The immunoglobulin concentrations themselves are in Supplementary Table 1, which is not part of the retrievable article.
PMID:37148421
An early-onset SLE patient with a novel paternal inherited BACH2 mutation.
1 finding
The second reported family. Supplies the R576L variant, reduced BACH2 expression and deficient BLIMP1 repression in patient cells, an unaffected carrier father with an extreme memory B-cell reduction, and the prednisone plus tofacitinib response.
PMID:23728300
BACH2 represses effector programs to stabilize T(reg)-mediated immune homeostasis.
1 finding
Mouse knockout establishing that BACH2 is required for regulatory T-cell formation and that its absence diverts cells to effector lineages. The basis of the Treg arm.
PMID:15152264
The transcriptional programme of antibody class switching involves the repressor Bach2.
1 finding
Mouse knockout localizing the B-cell defect to class switch recombination while showing plasmacytic differentiation is intact. Resolves the repressor-direction paradox.
PMID:40386599
Autoimmune enteropathy associated with T cell large granular lymphocytic leukemia in a patient with BACH2 mutation: a case report.
1 finding
Single case of autoimmune enteropathy with T-LGL in a germline heterozygous BACH2 carrier. Cited only in the phenotype-expansion discussion, not as a phenotype.
PMID:39826876
Curation of gene-disease relationships in primary antibody deficiencies using the ClinGen validation framework.
1 finding
The ClinGen Antibody Deficiencies expert panel curation effort behind the Moderate classification, and the definition of the tier system.
PMID:35748970
Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee.
1 finding
Places BACH2 deficiency in Table 4 (diseases of immune dysregulation) with autosomal dominant inheritance, progressive T-cell lymphopenia, impaired memory B-cell development, haploinsufficiency for a lineage specification transcription factor, and lymphocytic colitis with sinopulmonary infections. The backbone of this entry.
PMID:33996698
Different Apples, Same Tree: Visualizing Current Biological and Clinical Insights into CTLA-4 Insufficiency and LRBA and DEF6 Deficiencies.
1 finding
Lists BACH2 deficiency among the monogenic Tregopathies alongside IPEX, CD25 deficiency and STAT3 gain-of-function, which grounds the regulatory T-cell arm of the mechanism.
PMID:33864888
Molecular diagnosis of childhood immune dysregulation, polyendocrinopathy, and enteropathy, and implications for clinical management.
1 finding
Sequenced 123 patients with FOXP3-negative IPEX-like disease and found damaging germline variants in 27 genes including BACH2; recommends pulmonary screening for patients with BACH2 mutations while noting the limited case base.
1 finding
ClinGen Antibody Deficiencies Gene Curation Expert Panel classifies the autosomal dominant BACH2-immunodeficiency 60 relationship as Moderate (SOP9, 2023-02-21).
PMID:29670635
Chronic Lymphocytic Leukemia B-Cell Normal Cellular Counterpart: Clues From a Functional Perspective.
1 finding
Background B-cell biology: in normal human IgG+ memory B cells, plasma-cell differentiation is driven by PRDM1/BLIMP1 induction with reciprocal downregulation of BACH2.
PMID:26235382
Immunogenetics of autoimmune thyroid diseases: A comprehensive review.
1 finding
Background BACH2 biology: highly expressed in B cells and a suppressor of immunoglobulin production. Also one of the sources establishing BACH2 as a common-variant autoimmune susceptibility locus.
PMID:22561518
Genome-wide association analyses identify 13 new susceptibility loci for generalized vitiligo.
1 finding
Identifies BACH2 among 13 new genome-wide significant vitiligo susceptibility loci; cited only to establish the common-variant end of the dosage hypothesis.