Common Variable Immunodeficiency

Complex MONDO:0015517 Pathograph 31 Show in embeddings browser Primary Immunodeficiency Antibody Deficiency Disorder

Common variable immunodeficiency (CVID) is the most prevalent symptomatic primary immunodeficiency, characterized by defective B cell differentiation, hypogammaglobulinemia, and failure of antibody production. Patients present with recurrent bacterial infections, particularly of the respiratory and gastrointestinal tracts, and have increased susceptibility to autoimmune manifestations, granulomatous disease, and lymphoproliferative disorders. CVID is best understood as an umbrella diagnosis with heterogeneous genetic and immunologic etiologies spanning monogenic, digenic, and polygenic models.

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Classifications

IUIS Category

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Subtypes

Common variable immunodeficiency 1 (ICOS) MONDO:0011864

ICOS hgnc:5351

Homozygous ICOS deletion. With CVID11 it is one of the two subtypes here whose primary lesion is in follicular helper T-cell function rather than in the B cell itself: loss of the inducible costimulator removes the T-cell signal that drives germinal-centre B-cell help, while T-cell subsets, activation, cytokine production and proliferation are preserved.

Show evidence (1 reference)

PMID:12577056 SUPPORT Human Clinical

"we found four of 32 patients to lack ICOS, the "inducible costimulator" on activated T cells, due to an inherited homozygous deletion in the ICOS gene."

The four patients with homozygous ICOS deletion who define this subtype.

Common variable immunodeficiency 2 (TNFRSF13B/TACI) MONDO:0009413

TNFRSF13B hgnc:18153

The TACI form, and the one that most resists a simple subtype reading. The common heterozygous alleles C104R and A181E occur in healthy relatives and in the general population and are modelled in this entry as susceptibility, while ClinGen's Definitive classification for this MONDO term is recorded against biallelic, autosomal recessive genotypes.

Show evidence (1 reference)

PMID:16007086 SUPPORT Human Clinical

"We found that 4 of 19 unrelated individuals with common variable immunodeficiency (CVID) and 1 of 16 individuals with IgA deficiency (IgAD) had a missense mutation in one allele of TNFRSF13B (encoding TACI)."

The original cohort finding behind this subtype, and the reason the dismech typing is susceptibility: the reported variants are heterozygous.

Common variable immunodeficiency 3 (CD19) MONDO:0013283

CD19 hgnc:1633

Biallelic CD19 loss. With CVID6 and CVID7 it disables the B-cell coreceptor complex of CD19, CD21 (CR2), CD81 and CD225 through three of its components; CVID5 (CD20) is grouped with them on the same pathophysiology node for its effect on B-cell receptor signalling, not as a fourth subunit of that complex.

Show evidence (1 reference)

PMID:16672701 SUPPORT Human Clinical

"All four patients had homozygous mutations in the CD19 gene."

The four patients from two unrelated families who define this subtype.

Common variable immunodeficiency 4 (TNFRSF13C/BAFF-R) MONDO:0013284

TNFRSF13C hgnc:17755

Homozygous BAFF-R deletion, arresting B-cell development at the transitional stage. Only one of the two originally reported siblings had recurrent infections, so this subtype carries an immunological phenotype that does not always become a clinical immunodeficiency.

Show evidence (1 reference)

PMID:19666484 SUPPORT Human Clinical

"Analyzing BAFF-R expression and BAFF-binding to B cells in common variable immunodeficiency (CVID) patients, we identified two siblings carrying a homozygous deletion in the BAFF-R gene."

The two siblings with a homozygous TNFRSF13C deletion who define this subtype.

Common variable immunodeficiency 5 (MS4A1/CD20) MONDO:0013285

MS4A1 hgnc:7315

CD20 deficiency, reported in one patient. ClinGen classifies the relationship as Limited and records that a later report concluded the patient did not completely fulfil CVID diagnostic criteria, so this row carries the MONDO concept rather than a settled disease entity.

Show evidence (1 reference)

CGGV:assertion_eba48c0f-53fa-48c9-8f4e-9892d095b515-2022-03-02T185714.677Z SUPPORT Other

"MS4A1 | HGNC:7315 | immunodeficiency, common variable, 5 | MONDO:0013285 | AR | Limited | SOP8 | Antibody Deficiencies Gene Curation Expert Panel | 2022-03-02T18:57:14.677Z"

ClinGen's Limited classification against this exact MONDO term, which is the caveat this row records.

Common variable immunodeficiency 6 (CD81) MONDO:0013286

CD81 hgnc:1701

CD81 deficiency, reported in one patient with severe nephropathy. CD19 surface expression depends on CD81, so this subtype reaches the CVID3 phenotype through a different subunit of the same coreceptor complex. ClinGen classifies the relationship as Limited.

Show evidence (1 reference)

PMID:20237408 SUPPORT Human Clinical

"In this study, we present what we believe to be the first antibody deficiency syndrome caused by a mutation in the CD81 gene and consequent disruption of the CD19 complex on B cells."

The single report that defines this subtype, and the mechanism shared with CVID3.

Common variable immunodeficiency 7 (CR2/CD21) MONDO:0013862

CR2 hgnc:2336

CD21 deficiency. Loss of the complement C3d receptor removes the C3d costimulus that lowers the B-cell activation threshold. The humoral defect is narrower than in CD19 deficiency: protein-antigen vaccine responses were normal in the index patient and only the pneumococcal polysaccharide response was impaired.

Show evidence (1 reference)

PMID:22035880 SUPPORT Human Clinical

"Genetic CD21 deficiency adds to the molecular defects observed in human subjects with hypogammaglobulinemia."

The authors' own conclusion placing CD21 deficiency among the molecular causes of hypogammaglobulinemia.

Common variable immunodeficiency 10 (NFKB2) MONDO:0014260

NFKB2 hgnc:7795

Heterozygous C-terminal truncating NFKB2 variants that leave the non-canonical precursor p100 unprocessable. Frequently accompanied by ACTH deficiency, the combination known as DAVID syndrome, which MONDO carries as a separate term filed under this one. The 50-case cohort analysis cited on the paired genetic record argues this is a distinct entity that exceeds the CVID spectrum rather than a variant within it.

Show evidence (1 reference)

PMID:30941118 SUPPORT Human Clinical

"We conclude that heterozygous damaging mutations in NFKB2 represent a distinct PID entity exceeding the usual clinical spectrum of CVID."

The cohort's own conclusion, which is why this row records the subtype as broader than the umbrella it sits under.

Common variable immunodeficiency 11 (IL21) MONDO:0014338

IL21 hgnc:6005

The most doubtful row in this list. MONDO makes this term a direct child of common variable immunodeficiency and keeps CVID11 as a synonym, but its primary label names infantile inflammatory bowel disease, and ClinGen's Primary Immune Regulatory Disorders panel recurated the gene-disease relationship as Limited in January 2026 on one reported case. It is carried here so the MONDO concept is addressable alongside the other numbered subtypes, with the reservation stated rather than hidden.

Show evidence (1 reference)

CGGV:assertion_82664dca-783a-4ed9-abe5-c77b082a0684-2026-01-20T100000.000Z SUPPORT Other

"IL21 | HGNC:6005 | IL21-related infantile inflammatory bowel disease | MONDO:0014338 | AR | Limited | SOP11 | Primary Immune Regulatory Disorders Gene Curation Expert Panel | 2026-01-20T10:00:00.000Z"

The most recent expert-panel assessment of this pair: Limited, curated against a disease name that is not CVID.

Common variable immunodeficiency 12 (NFKB1) MONDO:0014697

NFKB1 hgnc:7794

NF-kB1 p50 haploinsufficiency, reported as the most common monogenic cause of CVID in Europeans. Note that frequency and evidence strength differ here: ClinGen's 2025 recuration returns Moderate, not Definitive.

Show evidence (1 reference)

PMID:26279205 SUPPORT Human Clinical

"we conclude that the CVID phenotype in these families is caused by NF-κB1 p50 haploinsufficiency."

The conclusion that defines this subtype.

Common variable immunodeficiency 13 (IKZF1/IKAROS) MONDO:0014810

IKZF1 hgnc:13176

IKAROS haploinsufficiency, defined by progressive loss of circulating B cells with reduced early B-cell precursors in marrow. MONDO names this term after the pancytopenia and carries CVID13 only as a synonym, so the CVID identity of the concept is invisible to a label search; the term is nonetheless a direct child of common variable immunodeficiency and ClinGen's Antibody Deficiencies panel classifies the relationship as Definitive.

Show evidence (1 reference)

PMID:33122583 SUPPORT Human Clinical

"IKZF1 mutation must be kept in mind if neonatal AIHA, common variable immunodeficiency, and pancytopenia are observed."

Pairs the CVID phenotype with the pancytopenia MONDO names the term after, which is why one row carries both.

Common variable immunodeficiency due to APRIL deficiency (TNFSF13) MONDO:0800149

TNFSF13 hgnc:11928

The APRIL form, and the only row here that MONDO names after a protein rather than by number. ClinGen's Limited classification for TNFSF13 is recorded against the general common variable immunodeficiency term rather than against this APRIL-specific one.

Show evidence (1 reference)

CGGV:assertion_c181d44b-5c48-441b-95ad-b4d06572596d-2022-09-20T160000.000Z SUPPORT Other

ClinGen's row for TNFSF13, showing both the Limited strength and that the curation is against MONDO:0015517 rather than the APRIL-specific term this row binds.

Common variable immunodeficiency 14 (IRF2BP2) MONDO:0054691

IRF2BP2 hgnc:21729

IRF2BP2 is a transcriptional corepressor, and this is the only subtype here whose reported phenotype is dominated by gastrointestinal and inflammatory disease alongside the antibody defect. MONDO records no causal gene edge on this term, which is why it did not appear in the knowledge-graph gap list that prompted this pass even though the term is a direct child of common variable immunodeficiency.

Show evidence (1 reference)

PMID:40090425 SUPPORT Human Clinical

"IRF2BP2 deficiency causes a complex immunodeficiency including gastrointestinal and inflammatory disorders as well as impaired B-cell maturation."

The conclusion of the 34-subject cohort that defines this subtype's phenotype.

Common variable immunodeficiency 15 (SEC61A1) MONDO:0958013

SEC61A1 hgnc:18276

The most narrowly defined subtype in this list: heterozygous SEC61A1 variants give an intrinsic failure of B cells to become plasma cells, with peripheral B- and T-cell subpopulations otherwise normal. MONDO files this term both under common variable immunodeficiency and under SEC61A1 deficiency, and carries no causal gene edge on the CVID child, so it too was absent from the gap list; ClinGen's Moderate classification for the gene is likewise recorded against the SEC61A1-deficiency term rather than this one.

Show evidence (1 reference)

PMID:28782633 SUPPORT Human Clinical

"We describe a monogenic defect leading to a specific PC deficiency in human subjects, expanding our knowledge about the pathogenesis of antibody deficiencies."

The authors' statement of what this subtype is: a monogenic plasma-cell deficiency among the antibody deficiencies.

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Pathophysiology

Defective B Cell Differentiation and Class-Switch Recombination

The hallmark of CVID is a failure of B cells to differentiate into immunoglobulin-secreting plasma cells. Defective class-switch recombination leads to impaired production of IgG, IgA, and often IgM. Most patients show reduced switched memory B cells (CD27+IgD-IgM-). Defects in B cell receptor signaling, BAFF/APRIL axis, and NF-kB signaling all converge on impaired germinal center output.

B cell CL:0000236 Plasma cell CL:0000786

SEC61A1 hgnc:18276 IRF2BP2 hgnc:21729

Immunoglobulin Production GO:0002377 ↓ DECREASED Isotype Switching GO:0045190 ↓ DECREASED B Cell Activation GO:0042113

Downstream

Hypogammaglobulinemia Defective B-cell differentiation and class switching impair antibody production, producing hypogammaglobulinemia.

Decreased Circulating IgG Impaired class-switch recombination reduces IgG production.

Decreased Circulating IgA Impaired class-switch recombination reduces IgA production.

Recurrent Infections Antibody-production failure predisposes CVID patients to recurrent infections.

Show evidence (4 references)

DOI:10.3390/jcm13061717 SUPPORT Human Clinical

"The pathogenesis of CVID involves complex immunological dysregulation, including defects in B cell development, antibody class switching, and plasma cell differentiation. These abnormalities contribute to an impaired humoral immune response against viral agents, predisposing individuals with..."

This 2024 review confirms that CVID pathogenesis centers on defective B cell development, class switching, and plasma cell differentiation.

PMID:16007086 SUPPORT Human Clinical

"B cells from individuals with TACI mutations expressed TACI but did not produce IgG and IgA in response to the TACI ligand APRIL, probably reflecting impaired isotype switching."

Demonstrates that TACI mutations in CVID patients lead to impaired isotype switching, a key mechanism of defective class-switch recombination.

PMID:28782633 SUPPORT In Vitro

"On in vitro stimulation, B cells showed an intrinsic deficiency to develop into PCs."

Places SEC61A1 on this node, and at its most specific point: the block is B-cell-intrinsic and is in the step to plasma cell, which is the cell type bound above.

+ 1 more reference

Early B Cell Lymphopoiesis Failure

A lesion upstream of, and distinct from, the germinal-centre failure the node above describes. IKAROS is a lymphoid transcription factor, and the six reported mutations all fall in its DNA-binding domain, producing a progressive loss of circulating B cells with markedly reduced early B-cell precursors in marrow. Plasma cells were still present in the marrow of the reported patients, which is why this is modelled as its own node rather than added to the differentiation-and-class-switch node: the hypogammaglobulinemia follows from having too few B cells rather than from B cells that cannot finish differentiating.

precursor B cell CL:0000817

IKZF1 hgnc:13176

B cell differentiation GO:0030183 ↓ DECREASED

Downstream

Hypogammaglobulinemia Progressive loss of the B-cell compartment reduces serum immunoglobulins, reported as falling together in affected family members.

Show evidence (3 references)

PMID:26981933 SUPPORT Human Clinical

"Heterozygous mutations in the transcription factor IKAROS caused an autosomal dominant form of CVID that is associated with a striking decrease in B-cell numbers."

The conclusion of the 29-person, six-family series: the CVID phenotype attributable to IKZF1 is defined by loss of B cells, which is what this node asserts.

PMID:26981933 SUPPORT Human Clinical

"Bone marrow aspirates in two patients had markedly decreased early B-cell precursors, but plasma cells were present."

The marrow finding that locates the lesion at early B-cell development rather than at plasma-cell differentiation, and so the reason this is a separate node.

PMID:26981933 SUPPORT Human Clinical

"Studies in family members showed progressive loss of B cells and serum immunoglobulins."

Pairs the B-cell loss with the fall in serum immunoglobulins, which is the downstream edge below.

B Cell Coreceptor Complex Failure

Three of the numbered CVID subtypes disable the same structure: the B-cell coreceptor complex of CD19, CD21 (CR2), CD81 and CD225, which lowers the activation threshold of the B-cell antigen receptor. CD19 carries the signalling function, CD81 is required for CD19 to reach the surface, and CD21 supplies the C3d costimulus. MS4A1 (CD20) is not a subunit of that complex; it is grouped on this node because ClinGen's assessment records that CD20 regulates signalling through the B-cell receptor, and because the reported patient's defect was in antibody formation rather than in B-cell development. Across these subtypes B-cell development is largely preserved and what fails is the response to antigen, which is why they present as CVID rather than as agammaglobulinemia.

B cell CL:0000236

CD19 hgnc:1633 CD81 hgnc:1701 CR2 hgnc:2336 MS4A1 hgnc:7315

B cell receptor signaling pathway GO:0050853 ↓ DECREASED

Downstream

Defective B Cell Differentiation and Class-Switch Recombination Loss of coreceptor signalling removes the antigen-driven activation that germinal-centre entry and class switching depend on.

Show evidence (6 references)

PMID:16672701 SUPPORT BACKGROUND Human Clinical

"The CD19 protein forms a complex with CD21, CD81, and CD225 in the membrane of mature B cells. Together with the B-cell antigen receptor, this complex signals the B cell to decrease its threshold for activation by the antigen."

Defines the complex this node is about and the function it serves. Taken from the study's background section rather than from its own results, hence the BACKGROUND quote role.

PMID:16672701 SUPPORT In Vitro

"The response of the patients' B cells to in vitro stimulation through the B-cell receptor was impaired"

The bound GO process measured directly: patient B cells stimulated through the B-cell receptor in culture respond poorly.

PMID:16672701 SUPPORT Human Clinical

"in all four patients, the antibody response to rabies vaccination was poor"

The clinical counterpart of the same defect in the same four patients, split from the in-vitro measurement so each item carries one evidence type.

+ 3 more references

BAFF/APRIL Receptor Signaling Deficiency

The TNF-family survival axis of the B-cell compartment, represented here by the two receptors BAFF-R (TNFRSF13C) and TACI (TNFRSF13B) and by the ligand TNFSF13, which MONDO names APRIL in the subtype term it defines. Loss of BAFF-R arrests B-cell development at the transitional stage; TACI variants were found in 4 of 19 unrelated CVID patients in the original report, in heterozygous form, and are modelled in this entry as risk alleles rather than determinants. TNFSF12 is deliberately not placed on this node: this entry has no source connecting it to either receptor, and grouping it here on family membership alone would assert a relationship it cannot support.

B cell CL:0000236

TNFRSF13C hgnc:17755 TNFRSF13B hgnc:18153 TNFSF13 hgnc:11928

tumor necrosis factor-mediated signaling pathway GO:0033209 ↓ DECREASED

Downstream

Defective B Cell Differentiation and Class-Switch Recombination Loss of BAFF/APRIL survival and costimulatory signalling arrests B-cell maturation before the switched memory and plasma-cell stages.

Show evidence (2 references)

PMID:19666484 SUPPORT Human Clinical

"Without BAFF-R, B-cell development is arrested at the stage of transitional B cells and the numbers of all subsequent B-cell stages are severely reduced."

The developmental consequence of losing this signalling axis in humans, and the direct basis for the downstream edge below.

PMID:16007086 SUPPORT Human Clinical

Places TACI on this node, in the heterozygous form in which it is usually found - which is why the gene is typed as susceptibility in this entry.

NF-kB Pathway Signaling Deficiency

Two CVID subtypes sit on the two arms of NF-kB signalling. NFKB1 haploinsufficiency reduces the canonical p50 subunit and is reported as the commonest monogenic cause of CVID in Europeans; NFKB2 C-terminal truncating variants leave the non-canonical precursor p100 unprocessable, so the mature p52 subunit is not made. The two are grouped on one node because both converge on impaired B-cell differentiation, and separated in the bound processes because the pathways themselves are distinct.

NFKB1 hgnc:7794 NFKB2 hgnc:7795

canonical NF-kappaB signal transduction GO:0007249 ↓ DECREASED non-canonical NF-kappaB signal transduction GO:0038061 ↓ DECREASED

Downstream

Defective B Cell Differentiation and Class-Switch Recombination Both NF-kB arms are required for the germinal-centre and plasma-cell transcriptional programme, so their loss reports as failed B-cell differentiation.

Immune Dysregulation and Autoimmunity Autoimmunity is prominent in the NFKB2 cohort and is predominantly T cell-mediated, but the route from the signalling defect to the autoimmune phenotype is not established, so the edge is typed as indirect with unknown intermediates.

Show evidence (3 references)

PMID:26279205 SUPPORT Human Clinical

"we conclude that the CVID phenotype in these families is caused by NF-κB1 p50 haploinsufficiency."

Supports the canonical arm of this node: loss of one p50 dose produces the CVID phenotype.

PMID:30941118 SUPPORT Human Clinical

"In contrast, impaired B-cell differentiation and hypogammaglobinemia were consistent features of NFKB2-associated disease."

Supports the non-canonical arm and the downstream edge: impaired B-cell differentiation was consistent across the NFKB2 cohort.

PMID:30941118 SUPPORT Human Clinical

"Despite the heterogeneity of the different mutations all previously described C-terminal mutations have universally been reported to result in normal expression and cytoplasmic localization of mutant, non-processable p100 precursors and thus in p52 haploinsufficiency"

The molecular consequence bound as decreased non-canonical NF-kB signal transduction: the C-terminal NFKB2 variants leave p100 unprocessable, so mature p52 is halved.

T Cell Dysregulation

Many CVID patients exhibit T cell abnormalities including reduced naive CD4+ T cells, expanded CD21low B cells, impaired T cell proliferation, and skewed T helper cell responses. T follicular helper cell dysfunction contributes to impaired germinal center reactions and defective B cell help. ICOS deficiency specifically impairs T cell help for late B cell differentiation and memory B cell generation. IL-21, a cytokine of the same follicular helper compartment, is grouped here for the same reason: its loss removes the T-cell-derived signal for B-cell differentiation rather than damaging the B cell itself.

CD4+ T Cell CL:0000624

ICOS hgnc:5351 IL21 hgnc:6005

T Cell Activation GO:0042110

Downstream

Defective B Cell Differentiation and Class-Switch Recombination Loss of follicular helper T-cell signalling - ICOS costimulation or IL-21 - leaves B cells without the help that germinal-centre differentiation and class switching require. In both the ICOS-deficient and IL21-deficient patients, switched memory B cells were reduced while T-cell subsets were preserved.

Show evidence (4 references)

PMID:12577056 SUPPORT Human Clinical

"we found four of 32 patients to lack ICOS, the "inducible costimulator" on activated T cells, due to an inherited homozygous deletion in the ICOS gene. T cells from these individuals were normal with regard to subset distribution, activation, cytokine production and proliferation. In contrast,..."

Demonstrates that ICOS deficiency causes CVID through impaired T cell costimulation for B cell differentiation, with reduced naive, switched, and memory B cells despite normal T cell subsets.

DOI:10.1007/s10875-023-01618-0 SUPPORT Human Clinical

"Levels of microRNA-34a correlated with 11 proteins such as CXCL9, TNF, and IL10, which were predicted to be biologically connected. Moreover, there was a negative correlation between mir-34 levels and the number of naïve CD4 T cells in CVID."

Demonstrates reduced naive CD4 T cells in CVID correlating with inflammatory markers, supporting T cell dysregulation as a key pathophysiological feature.

CGGV:assertion_82664dca-783a-4ed9-abe5-c77b082a0684-2026-01-20T100000.000Z SUPPORT Other

"IL21 is a type I cytokine produced primarily by natural killer T cells, T follicular helper cells and TH17 cells."

Places IL21 on this node rather than on a B-cell node: the cytokine is made by the follicular helper compartment this node describes.

+ 1 more reference

Immune Dysregulation and Autoimmunity

Approximately 25-50% of CVID patients develop autoimmune complications, most commonly autoimmune cytopenias (immune thrombocytopenia and autoimmune hemolytic anemia). This reflects a breakdown of peripheral tolerance and defective regulatory T cell function, particularly through the CTLA-4/LRBA checkpoint axis. Expansion of autoreactive CD21low B cells contributes to antibody-mediated autoimmunity. IKZF1 (IKAROS) is bound here as a second placement, not as its primary mechanism: its CVID lesion is the loss of the B-cell compartment modelled on the Early B Cell Lymphopoiesis Failure node, and it appears again here because autoimmune cytopenias are a recurrent part of the IKAROS phenotype rather than an incidental feature of one case.

Regulatory T cell CL:0000815

CTLA4 hgnc:2505 LRBA hgnc:1742 IKZF1 hgnc:13176

Immune Response GO:0006955

Downstream

Autoimmune Hemolytic Anemia Immune dysregulation in CVID can manifest as autoimmune cytopenias, including autoimmune hemolytic anemia.

Autoimmune Thrombocytopenia Immune dysregulation in CVID can manifest as autoimmune thrombocytopenia.

Splenomegaly CVID immune dysregulation can present with hepatosplenomegaly.

Show evidence (3 references)

PMID:25213377 SUPPORT Human Clinical

"human CTLA4 haploinsufficiency caused dysregulation of FoxP3(+) regulatory T (Treg) cells, hyperactivation of effector T cells, and lymphocytic infiltration of target organs. Patients also exhibited progressive loss of circulating B cells, associated with an increase of predominantly..."

Shows that CTLA4 haploinsufficiency, found in a subset of CVID patients, causes Treg dysfunction, expansion of autoreactive CD21low B cells, and immune dysregulation, explaining autoimmune manifestations in CVID.

DOI:10.1097/aci.0000000000000947 SUPPORT Human Clinical

"On the other hand, patients with defects in CTLA-4 or LRBA gene present with life-threatening immune dysregulation, autoimmunity and lymphocytic infiltration of multiple organs."

Places LRBA alongside CTLA4 on this node: the two produce the same dysregulation and lymphocytic infiltration phenotype.

PMID:33122583 SUPPORT Human Clinical

"Clinical features of a 3-month-old male infant who underwent hematopoietic stem cell transplantation because of an IKZF1 mutation-associated common variable immunodeficiency, AIHA, and pancytopenia are described."

Places IKZF1 on this node: the reported CVID case carried autoimmune haemolytic anaemia, one of the autoimmune cytopenias this node explains.

Granulomatous Disease and GLILD

CVID-associated granulomatous and lymphocytic interstitial lung disease (GLILD) involves poorly organized granulomas with abundant T and B cells. Key features include Th1 polarization with elevated IFN-gamma and sIL-2R, B cell abnormalities with elevated BAFF and CD21low B cells, and innate immune alterations including M2 macrophage skewing and neutrophil dysregulation.

B cell CL:0000236 Macrophage CL:0000235

Inflammatory Response GO:0006954

Downstream

Granulomatous Disease CVID-associated granulomatous inflammation produces the granulomatous disease phenotype.

Granulomatous-Lymphocytic Interstitial Lung Disease The same granulomatous and lymphocytic immune pathology can manifest as GLILD.

Show evidence (1 reference)

DOI:10.1097/aci.0000000000001032 SUPPORT Human Clinical

"Histological analysis shows that T and B cells are abundantly present in the granulomas that are less well organized and are frequently associated with lymphoid hyperplasia. Increased presence of activation markers such as soluble IL-2 receptor (sIL-2R) and IFN-ɣ, suggest increased Th1-cell..."

This 2024 review describes the immunopathology of CVID-associated granulomatous disease, demonstrating T and B cell involvement, Th1 polarization, and BAFF/CD21low B cell expansion.

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Pathograph

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

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Phenotypes

Blood 7

Hypogammaglobulinemia VERY_FREQUENT Decreased circulating immunoglobulin concentration HP:0004313

Show evidence (1 reference)

DOI:10.3390/jcm13061717 SUPPORT Human Clinical

"Common Variable Immunodeficiency (CVID) is a heterogeneous primary immunodeficiency disorder characterised by impaired antibody production, leading to recurrent infections and an increased susceptibility to viral pathogens."

Confirms hypogammaglobulinemia as the defining feature of CVID.

Decreased Circulating IgG VERY_FREQUENT Decreased circulating IgG concentration HP:0004315

Show evidence (1 reference)

PMID:22180439 SUPPORT Human Clinical

"Median immunoglobulin levels were IgG, 246 mg/dL; IgA, 8 mg/dL; and IgM, 21 mg/dL; 22.6% had an IgG less than 100 mg/dL."

The 473-patient New York cohort quantifies the reduced serum IgG (median 246 mg/dL, with 22.6% below 100 mg/dL), supporting the defining VERY_FREQUENT IgG deficit.

Decreased Circulating IgA VERY_FREQUENT Decreased circulating IgA concentration HP:0002720

Show evidence (1 reference)

PMID:22180439 SUPPORT Human Clinical

"Median immunoglobulin levels were IgG, 246 mg/dL; IgA, 8 mg/dL; and IgM, 21 mg/dL; 22.6% had an IgG less than 100 mg/dL."

The same cohort's median serum IgA of 8 mg/dL documents the profound IgA reduction that accompanies the IgG deficit in CVID.

Autoimmune Hemolytic Anemia HP:0001890

Show evidence (1 reference)

PMID:25213377 SUPPORT Human Clinical

"Patient B.I.1, previously diagnosed with common variable immunodeficiency (CVID), had hepatosplenomegaly, autoimmune hemolytic anemia (AIHA), autoimmune thrombocytopenia, pulmonary nodules, and cerebral infiltrative lesions."

Documents autoimmune hemolytic anemia as a feature in a CVID patient with CTLA4 haploinsufficiency.

Autoimmune Thrombocytopenia HP:0001973

Show evidence (2 references)

PMID:25213377 SUPPORT Human Clinical

Documents autoimmune thrombocytopenia in a CVID patient with CTLA4 haploinsufficiency.

PMID:40079712 SUPPORT Human Clinical

"The most frequent autoimmune manifestations were cytopenia (autoimmune thrombocytopenia followed by hemolytic anemia)"

Confirms autoimmune thrombocytopenia as the most frequent autoimmune cytopenia in a CVID cohort.

Granulomatous Disease OCCASIONAL Granulomatosis HP:0002955

Show evidence (3 references)

DOI:10.1097/aci.0000000000001032 SUPPORT Human Clinical

"This review describes the current knowledge on the pathogenesis of granuloma formation in CVID and the biological basis of the current treatment options."

A 2024 review dedicated to granulomatous disease in CVID, confirming it as a major complication.

PMID:22180439 SUPPORT Human Clinical

"granulomatous disease, 9.7%; liver diseases and hepatitis, 9.1%; lymphoma, 8.2%; or other cancers, 7.0%"

The New York cohort reports granulomatous disease in 9.7% of 473 patients, a derived-count basis for the OCCASIONAL band.

PMID:38792965 SUPPORT Human Clinical

"39 patients (25.5%) developed bronchiectasis, and 16 (10.5%) granulomatous disease"

The Greek nationwide cohort independently reports granulomatous disease in 10.5%, consistent with the OCCASIONAL band.

Lymphoma OCCASIONAL HP:0002665

Show evidence (3 references)

PMID:22180439 SUPPORT Human Clinical

"granulomatous disease, 9.7%; liver diseases and hepatitis, 9.1%; lymphoma, 8.2%; or other cancers, 7.0%"

The New York cohort reports lymphoma in 8.2% of 473 CVID patients (OCCASIONAL band) with other cancers in a further 7.0%.

PMID:22180439 SUPPORT Human Clinical

"Mortality was associated with lymphoma, any form of hepatitis, functional or structural lung impairment, and gastrointestinal disease with or without malabsorption"

Identifies lymphoma among the complications associated with mortality in CVID.

PMID:38792965 SUPPORT Human Clinical

"Cancer was a common complication in our cohort (25 patients, 16.3%), with B-cell malignancies representing the most common neoplasms (56.7%)."

The Greek nationwide antibody-deficiency cohort (predominantly CVID) confirms cancer as a common complication with B-cell malignancies predominating.

Cardiovascular 2

Splenomegaly HP:0001744

Show evidence (1 reference)

PMID:40079712 SUPPORT Human Clinical

"The most recurrent lymphoproliferative manifestations were chronic lymphadenopathies and splenomegaly."

In the pediatric CVID cohort, splenomegaly was one of the two most recurrent lymphoproliferative manifestations.

Lymphadenopathy HP:0002716

Show evidence (2 references)

PMID:40079712 SUPPORT Human Clinical

"The most recurrent lymphoproliferative manifestations were chronic lymphadenopathies and splenomegaly."

Chronic lymphadenopathies were among the most recurrent lymphoproliferative manifestations in the pediatric CVID cohort.

PMID:38792965 SUPPORT Human Clinical

"Remarkable findings included an increased prevalence of lymphoproliferation (60.1%)"

The Greek nationwide antibody-deficiency cohort (predominantly CVID) found lymphoproliferation in 60.1% of patients; the figure covers lymphoproliferation as a whole rather than lymphadenopathy alone, so no frequency band is asserted from it.

Digestive 1

CVID Enteropathy Chronic diarrhea HP:0002028

Show evidence (1 reference)

DOI:10.1097/aci.0000000000001040 SUPPORT Human Clinical

"Common variable immunodeficiency enteropathy (CVID-E) is a noninfectious complication of CVID caused by chronic inflammation of the gastrointestinal (GI) tract."

Defines CVID enteropathy as a recognized noninfectious gastrointestinal complication; chronic diarrhea is the closest curated HPO phenotype term.

Immune 1

Recurrent Infections VERY_FREQUENT HP:0002719

Show evidence (2 references)

DOI:10.3390/jcm13061717 SUPPORT Human Clinical

Confirms recurrent infections as a cardinal feature of CVID driven by impaired antibody production.

PMID:22180439 SUPPORT Human Clinical

"Ninety-four percent of patients had a history of infections; 68% also had noninfectious complications"

The 473-patient cohort quantifies the infection history at 94%, supporting the VERY_FREQUENT band.

Respiratory 2

Bronchiectasis OCCASIONAL HP:0002110

Show evidence (2 references)

PMID:22180439 SUPPORT Human Clinical

"hematologic or organ-specific autoimmunity, 28.6%; chronic lung disease, 28.5%; bronchiectasis, 11.2%; gastrointestinal inflammatory disease, 15.4%"

The New York cohort reports bronchiectasis in 11.2% of 473 CVID patients, a derived-count basis for the OCCASIONAL band.

PMID:38792965 SUPPORT Human Clinical

"39 patients (25.5%) developed bronchiectasis, and 16 (10.5%) granulomatous disease"

The Greek nationwide antibody-deficiency cohort (123/153 patients had CVID) reports bronchiectasis in 25.5%, the upper end of the range noted in the description.

Granulomatous-Lymphocytic Interstitial Lung Disease Abnormal pulmonary interstitial morphology HP:0006530

Show evidence (1 reference)

DOI:10.1097/aci.0000000000001032 SUPPORT Human Clinical

"Our review links the biological context of CVID with granulomatous disease or GLILD to currently prescribed therapies and potential targeted treatments."

Confirms GLILD as a recognized CVID-associated interstitial lung complication that should be represented alongside the existing pathophysiology node.

🧬

Genetic Associations

TNFRSF13B (TACI) Mutations (Predisposing)

Gene: TNFRSF13B hgnc:18153 gene page relationship_type: SUSCEPTIBILITY

Show evidence (2 references)

PMID:16007086 SUPPORT Human Clinical

Landmark study identifying TACI mutations in approximately 20% of CVID patients studied, establishing TACI as a risk factor for CVID.

CGGV:assertion_3049236b-8132-4dfa-8cda-2a328962a0a4-2021-01-20T170000.000Z SUPPORT Other

ClinGen's gene-disease validity row, recording Definitive validity against autosomal recessive inheritance - the distinction the notes rely on.

ICOS Deficiency (Causative)

Gene: ICOS hgnc:5351 relationship_type: CAUSATIVE

Show evidence (2 references)

CGGV:assertion_51864ec9-27d9-4a94-9524-d6828b17361d-2022-11-29T170000.000Z SUPPORT Other

ClinGen classifies the ICOS-common variable immunodeficiency gene-disease relationship as definitive with autosomal recessive inheritance.

PMID:12577056 SUPPORT Human Clinical

"we found four of 32 patients to lack ICOS, the "inducible costimulator" on activated T cells, due to an inherited homozygous deletion in the ICOS gene."

First identification of ICOS deficiency as a monogenic cause of CVID, demonstrating homozygous ICOS deletion in affected patients.

NFKB1 Haploinsufficiency (Causative)

Gene: NFKB1 hgnc:7794 gene page relationship_type: CAUSATIVE

Show evidence (3 references)

PMID:26279205 SUPPORT Human Clinical

"we conclude that the CVID phenotype in these families is caused by NF-κB1 p50 haploinsufficiency."

Identifies NFKB1 haploinsufficiency as a cause of CVID through degradation of the altered protein with loss of p50 transcription factor.

PMID:29477724 SUPPORT Human Clinical

"Loss-of-function nuclear factor κB subunit 1 (NFKB1) variants are the most common monogenic cause of common variable immunodeficiency in Europeans."

Large-scale study confirming NFKB1 as the most common monogenic cause of CVID in European populations.

CGGV:assertion_e922c85d-f51a-4394-8906-cf01978d8154-2025-04-14T170000.000Z SUPPORT Other

ClinGen's 2025 recuration of NFKB1 - CVID12 returns Moderate rather than Definitive, which is worth recording next to the claim that NFKB1 is the most common monogenic cause of CVID in Europeans: the two statements are about frequency and about evidence strength respectively.

CTLA4 Haploinsufficiency (Causative)

Gene: CTLA4 hgnc:2505 gene page relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:25213377 SUPPORT Human Clinical

"We identified germline heterozygous mutations in CTLA4 in subjects with severe immune dysregulation from four unrelated families."

Identifies CTLA4 haploinsufficiency as a cause of CVID-like immune dysregulation with hypogammaglobulinemia, autoimmune cytopenias, and lymphocytic organ infiltration.

LRBA Deficiency (Causative)

Gene: LRBA hgnc:1742 gene page relationship_type: CAUSATIVE

Show evidence (1 reference)

DOI:10.1097/aci.0000000000000947 SUPPORT Human Clinical

"On the other hand, patients with defects in CTLA-4 or LRBA gene present with life-threatening immune dysregulation, autoimmunity and lymphocytic infiltration of multiple organs."

This 2023 review highlights LRBA defects as a monogenic CVID-like form marked by severe immune dysregulation, autoimmunity, and multisystem organ infiltration.

BAFF-R (TNFRSF13C) Mutations (Predisposing)

Gene: TNFRSF13C hgnc:17755 gene page relationship_type: SUSCEPTIBILITY

Show evidence (3 references)

PMID:19666484 SUPPORT Human Clinical

"Analyzing BAFF-R expression and BAFF-binding to B cells in common variable immunodeficiency (CVID) patients, we identified two siblings carrying a homozygous deletion in the BAFF-R gene."

Establishes the gene-disease link: biallelic TNFRSF13C deletion was found by screening a CVID patient cohort, with arrest of B-cell development at the transitional B-cell stage and reduced IgG and IgM.

PMID:19666484 SUPPORT Human Clinical

"Therefore, deletion of the BAFF-R gene in humans causes a characteristic immunological phenotype but it does not necessarily lead to a clinically manifest immunodeficiency."

Supports the SUSCEPTIBILITY rather than CAUSATIVE typing. The authors explicitly state that BAFF-R deletion does not necessarily produce clinically manifest immunodeficiency, so this locus predisposes to the CVID phenotype rather than determining it.

CGGV:assertion_1408411b-9d28-4308-b2bc-dbada3660898-2021-04-13T003359.028Z SUPPORT Other

"In summary, only the case of the homozygous c.265_288del variant is considered informative at this time, as such there is limited evidence to support this gene-disease relationship."

ClinGen reaches the same conclusion as the SUSCEPTIBILITY typing here by a different route: only the homozygous deletion family is counted as informative, and the recurrent P21R allele is treated as a risk factor.

CTNNBL1 (Limited evidence)

Gene: CTNNBL1 hgnc:15879 relationship_type: SUSCEPTIBILITY

Show evidence (1 reference)

CGGV:assertion_4e151724-c8a5-4f3e-a7ac-bd0b1d180fae-2022-05-17T160000.000Z SUPPORT Other

ClinGen classifies the CTNNBL1-common variable immunodeficiency gene-disease relationship as limited with autosomal recessive inheritance.

TNFSF12 (Limited evidence)

Gene: TNFSF12 hgnc:11927 relationship_type: SUSCEPTIBILITY

Show evidence (1 reference)

CGGV:assertion_b943345a-024d-401d-a147-470c0ea0381c-2022-07-22T160000.000Z SUPPORT Other

ClinGen classifies the TNFSF12-common variable immunodeficiency gene-disease relationship as limited with autosomal dominant inheritance.

TNFSF13 (Limited evidence)

Gene: TNFSF13 hgnc:11928 gene page relationship_type: SUSCEPTIBILITY

Show evidence (1 reference)

CGGV:assertion_c181d44b-5c48-441b-95ad-b4d06572596d-2022-09-20T160000.000Z SUPPORT Other

ClinGen classifies the TNFSF13-common variable immunodeficiency gene-disease relationship as limited with autosomal recessive inheritance.

CD19 Deficiency (Causative)

Gene: CD19 hgnc:1633 gene page relationship_type: CAUSATIVE

Show evidence (3 references)

PMID:16672701 SUPPORT Human Clinical

"All four patients had homozygous mutations in the CD19 gene."

The four patients from two unrelated families in whom homozygous CD19 mutations were found, which is the human basis for this record.

PMID:16672701 SUPPORT Human Clinical

"Mutation of the CD19 gene causes a type of hypogammaglobulinemia in which the response of mature B cells to antigenic stimulation is defective."

States the mechanism this record asserts: hypogammaglobulinemia arising from a defective mature B-cell response to antigen.

CGGV:assertion_a6576337-703e-4d76-9120-5f6800730774-2022-05-24T160000.000Z SUPPORT Other

"CD19 | HGNC:1633 | immunodeficiency, common variable, 3 | MONDO:0013283 | AR | Definitive | SOP8 | Antibody Deficiencies Gene Curation Expert Panel | 2022-05-24T16:00:00.000Z"

ClinGen classifies the CD19 - CVID3 relationship as Definitive with autosomal recessive inheritance, which is the basis for typing this record CAUSATIVE.

CD81 Deficiency (Limited evidence)

Gene: CD81 hgnc:1701 relationship_type: UNKNOWN

Show evidence (2 references)

PMID:20237408 SUPPORT Human Clinical

"The patient had normal CD19 alleles but carried a homozygous CD81 mutation resulting in a complete lack of CD81 expression on blood leukocytes."

The single reported patient and the homozygous CD81 variant that is the whole of the human case-level evidence for this pair.

CGGV:assertion_e2092b4c-a8ff-4b40-bc09-17fbe33aa3e7-2021-04-29T210806.386Z SUPPORT Other

"CD81 | HGNC:1701 | immunodeficiency, common variable, 6 | MONDO:0013286 | AR | Limited | SOP8 | Antibody Deficiencies Gene Curation Expert Panel | 2021-04-29T21:08:06.386Z"

ClinGen's Limited classification, which is why this record is typed UNKNOWN rather than CAUSATIVE.

CR2 (CD21) Deficiency (Causative)

Gene: CR2 hgnc:2336 relationship_type: CAUSATIVE

Show evidence (3 references)

PMID:22035880 SUPPORT Human Clinical

"Sequence analysis revealed a compound heterozygous deleterious mutation in the CD21 gene."

The compound heterozygous CR2/CD21 genotype in the index patient.

PMID:22035880 SUPPORT Human Clinical

"A 28-year-old man presented with recurrent infections, reduced class-switched memory B cells, and hypogammaglobulinemia."

The CVID-pattern presentation - recurrent infection, reduced switched memory B cells, hypogammaglobulinemia - in the CD21-deficient patient.

CGGV:assertion_9153b41e-f2ef-453d-883b-187565cf4593-2021-08-03T130056.511Z SUPPORT Other

"CR2 | HGNC:2336 | immunodeficiency, common variable, 7 | MONDO:0013862 | AR | Definitive | SOP8 | Antibody Deficiencies Gene Curation Expert Panel | 2021-08-03T13:00:56.511Z"

ClinGen classifies the CR2 - CVID7 relationship as Definitive with autosomal recessive inheritance.

MS4A1 (CD20) Deficiency (Limited evidence)

Gene: MS4A1 hgnc:7315 relationship_type: UNKNOWN

Show evidence (2 references)

PMID:20038800 SUPPORT Human Clinical

"Key evidence to support this conclusion was provided by the observation that although antigen-independent B cells developed normally in the absence of CD20 expression, antibody formation, particularly after vaccination with TI antigens, was strongly impaired in the patient."

The specific humoral defect in the one reported CD20-deficient patient: normal B-cell development with impaired T cell-independent antibody formation.

CGGV:assertion_eba48c0f-53fa-48c9-8f4e-9892d095b515-2022-03-02T185714.677Z SUPPORT Other

"To date, this is the only patient that has been reported with a loss-of-function variant in MS4A1 and a positive disease association."

ClinGen's statement that the evidence rests on one patient, which is the basis for the UNKNOWN typing here.

NFKB2 Deficiency (Causative)

Gene: NFKB2 hgnc:7795 relationship_type: CAUSATIVE

Show evidence (3 references)

PMID:30941118 SUPPORT Human Clinical

"Heterozygous mutations in NFKB2 have recently been established as a molecular cause of common variable immunodeficiency (CVID) and DAVID-syndrome, a rare condition combining deficiency of anterior pituitary hormone with CVID."

States the gene-disease relationship this record asserts and the pituitary extension of the phenotype.

PMID:30941118 SUPPORT Human Clinical

"Cohort analysis extended to all 35 previously published NFKB2-cases revealed occurrence of early-onset PID in 46/50 patients (mean age of onset 5.9 years, median 4.0 years). ACTH-deficiency occurred in 44%."

The cohort size and the onset and ACTH-deficiency figures behind the statement in the notes that this entity is earlier-onset than typical CVID.

CGGV:assertion_61b546f1-5683-4588-a5bc-030ebbd5b401-2021-10-13T132601.192Z SUPPORT Other

ClinGen classifies the NFKB2 - CVID10 relationship as Definitive with autosomal dominant inheritance.

IKZF1 (IKAROS) Haploinsufficiency (Causative)

Gene: IKZF1 hgnc:13176 gene page relationship_type: CAUSATIVE

Show evidence (4 references)

PMID:26981933 SUPPORT Human Clinical

"Six different heterozygous mutations in IKZF1, the gene encoding the transcription factor IKAROS, were identified in 29 persons from six families."

The series that establishes this gene-disease relationship: six mutations across six families, all in the IKAROS DNA-binding domain.

PMID:26981933 SUPPORT Human Clinical

"Heterozygous mutations in the transcription factor IKAROS caused an autosomal dominant form of CVID that is associated with a striking decrease in B-cell numbers."

States the disease this record asserts - an autosomal dominant form of CVID - and the B-cell loss that defines it.

PMID:33122583 SUPPORT Human Clinical

A single patient in whom the IKZF1 variant produced CVID together with the autoimmune cytopenia and pancytopenia that MONDO names the entity after.

+ 1 more reference

IL21 Deficiency (Limited evidence)

Gene: IL21 hgnc:6005 gene page relationship_type: UNKNOWN

Show evidence (2 references)

PMID:24746753 SUPPORT Human Clinical

"Our study uncovers IL-21 deficiency as a novel cause of early-onset IBD in human subjects accompanied by defects in B-cell development similar to those found in patients with common variable immunodeficiency."

The authors' own framing: early-onset IBD with B-cell development defects resembling CVID, which is why MONDO files the entity under CVID and why the record sits here.

CGGV:assertion_82664dca-783a-4ed9-abe5-c77b082a0684-2026-01-20T100000.000Z SUPPORT Other

"In summary, there is a single reported case with a rare and distinct phenotype (infantile onset IBD and immunodeficiency), and an ultra-rare, biallelic, IL21 loss-of-function variant."

ClinGen's summary of the case-level evidence, which is the basis for the UNKNOWN typing and the caveat recorded in the notes.

IRF2BP2 Deficiency (Causative)

Gene: IRF2BP2 hgnc:21729 relationship_type: CAUSATIVE

Show evidence (3 references)

PMID:40090425 SUPPORT Human Clinical

"To deepen the understanding of the clinical implications of IRF2BP2 variants, we sought to clinically characterize and functionally test 34 individuals with IRF2BP2 variants."

The size of the cohort behind this record, which is the reason the typing here departs from ClinGen's 2021 Limited classification.

PMID:40090425 SUPPORT Human Clinical

"Most subjects had immunodeficiency (91%, n = 30 of 33) with variable gastrointestinal (65%, n = 20 of 31) and inflammatory or autoimmune features (57%, n = 17 of 30), including chronic abdominal pain, colitis, diarrhea, constipation, vitiligo, alopecia, and migratory rashes."

The penetrance of the immunodeficiency and of the gastrointestinal and inflammatory features across that cohort.

CGGV:assertion_025487e5-9447-4c7b-88ad-f650103e09cf-2021-03-16T125403.252Z SUPPORT Other

ClinGen's 2021 assessment, cited so that the departure from it in this record's typing is visible rather than silent. Note the autosomal dominant inheritance, which the cohort above also reports.

SEC61A1 Deficiency (Causative)

Gene: SEC61A1 hgnc:18276 relationship_type: CAUSATIVE

Show evidence (4 references)

PMID:28782633 SUPPORT Human Clinical

"Genetic analysis and targeted sequencing identified novel heterozygous missense (c.254T>A, p.V85D) and nonsense (c.1325G>T, p.E381*) mutations in SEC61A1, segregating with the disease phenotype."

The two segregating SEC61A1 variants that establish this gene-disease relationship.

PMID:28782633 SUPPORT Human Clinical

"We identified a novel genetic defect and studied its pathologic mechanism in 11 patients from 2 unrelated families with PADs."

The cohort size in the report that first tied SEC61A1 to a primary antibody deficiency.

CGGV:assertion_1ff61d15-19f9-42a2-8dc4-0a4071b562eb-2021-07-27T154837.287Z SUPPORT Other

ClinGen's assessment of this gene, curated by the Antibody Deficiencies panel against the SEC61A1-deficiency term rather than against CVID15.

+ 1 more reference

💊

Medical Actions

Immunoglobulin Replacement Therapy

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

Agent: therapeutic immune globulin NCIT:C2701

Platform: Protein replacement

Lifelong intravenous (IVIG) or subcutaneous (SCIG) immunoglobulin replacement is the cornerstone of CVID treatment, reducing the frequency and severity of infections. It does not address the non-infectious (autoimmune, granulomatous, lymphoproliferative) manifestations, which now pose the greatest therapeutic challenge.

Mechanism Target:

BYPASSES Defective B Cell Differentiation and Class-Switch Recombination — Passive polyclonal IgG substitutes for the antibody the defective B-cell compartment cannot make; it bypasses rather than corrects the underlying differentiation defect, which is why non-infectious complications persist on treatment.

Show evidence (2 references)

DOI:10.3390/jcm13061717 SUPPORT Other

"It assesses the efficacy of prophylactic measures for COVID-19, including vaccination and immunoglobulin replacement therapy, as well as trialled therapies."

Establishes that immunoglobulin replacement is used in CVID, but only in the narrow context of COVID-19 prophylaxis. It does NOT support the broader claim that lifelong IgG replacement is the cornerstone of CVID management, for which this item was previously cited as SUPPORT; that claim is carried by the general CVID review below.

PMID:41045774 SUPPORT Human Clinical

"Infections usually improve significantly after the initiation of immunoglobulin replacement therapy and other preventive measures, with non-infectious manifestations now posing the greatest therapeutic challenge."

A general CVID review carrying the core management claim: initiating immunoglobulin replacement significantly improves the infectious burden, which is why it is the cornerstone of CVID treatment. The review also frames the residual therapeutic problem as the non-infectious manifestations, i.e. those that IgG replacement does not address.

Antibiotic Prophylaxis and Treatment

Action: antibiotic therapy Ontology label: Antibiotic Therapy NCIT:C15620

Platform: Small molecule

Prophylactic and therapeutic antibiotics are used to manage recurrent bacterial infections, particularly sinopulmonary infections.

Immunosuppressive Therapy for Autoimmune Complications

Action: immunosuppressive therapy Ontology label: Pharmacotherapy NCIT:C15986

Corticosteroids, rituximab, and other immunosuppressants are used to manage autoimmune cytopenias and granulomatous disease. Treatment selection is increasingly aligned to biological mechanisms: rituximab for B cell hyperplasia and sirolimus for mTOR/Th1 programs.

Show evidence (1 reference)

DOI:10.1097/aci.0000000000001032 SUPPORT Human Clinical

"Therapeutic regimens include glucocorticoids, DMARDs, and biologicals like rituximab."

Confirms the use of glucocorticoids, DMARDs, and rituximab for granulomatous disease in CVID.

Abatacept

Action: Pharmacotherapy NCIT:C15986

Agent: abatacept NCIT:C28898

Abatacept is a CTLA-4-Ig fusion protein used as targeted immunomodulation for CVID subsets with CTLA4/LRBA-driven immune dysregulation, particularly enteropathy, autoimmunity, and GLILD.

Show evidence (1 reference)

DOI:10.1097/aci.0000000000000947 SUPPORT Human Clinical

"Abatacept, a soluble cytotoxic T lymphocyte antigen 4 (CTLA-4) fusion protein that acts as a costimulation modulator, has been widely implemented for affected patients with good results as bridge treatment."

Supports abatacept as a mechanistically targeted therapy for CTLA4/LRBA-associated CVID-like immune dysregulation.

🔬

Diagnosis

Quantitative immunoglobulins with functional antibody assessment (ESID criteria)

Per the ESID registry criteria, the laboratory diagnosis requires low IgG together with low IgA or IgM, plus at least one of a poor antibody response to vaccines or low switched memory B cells. The diagnosis can be made after the fourth year of life, although symptoms may begin earlier. Secondary causes of hypogammaglobulinemia must be excluded.

diagnostic procedure NCIT:C18020

Markers: Serum IgG, IgA, IgM; vaccine antibody responses; switched memory B cells

Results: Low IgG with low IgA or IgM, plus impaired vaccine response or low switched memory B cells

Show evidence (2 references)

PMID:40079712 SUPPORT Human Clinical

"laboratory criteria are low IgG and IgA or IgM and at least one between poor antibody vaccine response or low switched memory B cells"

States the ESID registry laboratory criteria recorded in this item.

PMID:40079712 SUPPORT Human Clinical

"The diagnosis of CVID can be made after the 4th year of life"

Supports the minimum-age criterion for the CVID diagnosis.

Genetic testing for monogenic causes

Exome-based genetic testing identifies a monogenic cause in a minority of CVID patients (2-30% across cohorts, enriched in early-onset, familial, autoimmune and lymphoproliferative presentations). A genetic diagnosis reclassifies the patient — often to an IEI in a different IUIS table — and carries prognostic, therapeutic, and genetic-counseling implications.

genetic testing NCIT:C15709

Results: Monogenic cause identified in a minority; reclassification when found

Show evidence (3 references)

PMID:40079712 SUPPORT Human Clinical

"allowing the identification of monogenic genetic variants from 2% to 30% of CVID patients in different cohorts"

Quantifies the monogenic yield of genetic testing across CVID cohorts.

PMID:41045774 SUPPORT Human Clinical

"Identifying a genetic cause allows for the reclassification of patients, it has prognostic and therapeutic implications, and enables genetic counseling for family members."

States the clinical consequences of finding a genetic cause.

PMID:40079712 SUPPORT Human Clinical

"The evaluation of a patient with suspected IEIs is neither complete nor accurate without the inclusion of genetic testing."

Supports genetic testing as a standard component of the CVID diagnostic work-up.

Multidisciplinary organ assessment and diagnostic delay

Because CVID affects multiple organ systems, patients should undergo extensive immunological evaluation and regular multi-organ assessment by multidisciplinary immunodeficiency teams. Diagnosis is typically delayed by years after symptom onset — a median of 9 years in a nationwide Greek antibody-deficiency cohort.

diagnostic procedure NCIT:C18020

Show evidence (2 references)

PMID:41045774 SUPPORT Human Clinical

"Patients with CVID should undergo extensive immunological evaluations and regular assessment of the multiple organs that may be affected, ideally by multidisciplinary teams specialized in immunodeficiencies."

The review's recommendation for multidisciplinary organ surveillance.

PMID:38792965 SUPPORT Human Clinical

"We demonstrated a remarkable delay in PAD diagnosis, several years after the onset of related symptoms (median: 9.0 years, range: 0-43.0)."

Quantifies the diagnostic delay in a predominantly-CVID national cohort.

📈

Progression

Onset and diagnosis, typically in adulthood

Age: Most diagnoses in the second to fourth decade; pediatric onset occurs

Recurrent infection is the usual presenting problem. In the New York cohort, males were diagnosed at a median age of 30 years and females at 33.5 years.

Show evidence (1 reference)

PMID:22180439 SUPPORT Human Clinical

"Males were diagnosed earlier (median age, 30 years) than females (median age, 33.5 years"

Cohort medians for age at diagnosis.

Chronic course dominated by non-infectious complications

On immunoglobulin replacement the infectious burden falls substantially, and the long-term course is instead shaped by the non-infectious complications — autoimmunity, chronic lung disease and bronchiectasis, gastrointestinal inflammatory disease, granulomatous disease, liver disease, and lymphoid malignancy — which develop in about two-thirds of patients and drive most mortality.

Show evidence (2 references)

PMID:22180439 SUPPORT Human Clinical

"Ninety-four percent of patients had a history of infections; 68% also had noninfectious complications"

Two-thirds of the cohort developed non-infectious complications.

PMID:41045774 SUPPORT Human Clinical

Frames the treated disease course: infections controlled, non-infectious manifestations dominant.

📊

Prevalence

Worldwide

Point Prevalence 3.0 per 100,000 (2.0–4.0) 1–9 per 100,000

Estimated prevalence 1 in 25,000 to 1 in 50,000, i.e. 2-4 per 100,000; the midpoint is recorded as the point value. CVID is nonetheless the most frequent symptomatic primary humoral immunodeficiency.

Show evidence (2 references)

PMID:40079712 SUPPORT Human Clinical

"affecting both children and adults worldwide with an estimated prevalence of 1:25,000–1:50,000"

States the worldwide prevalence estimate for CVID recorded here.

PMID:40079712 SUPPORT Human Clinical

"Common variable immunodeficiency (CVID) is the most frequent symptomatic primary humoral immunodeficiency"

Supports characterising CVID as the most frequent symptomatic primary humoral immunodeficiency despite the low absolute prevalence.

⚖️

Clinical Burden

High

Lifelong immunoglobulin replacement with multidisciplinary organ surveillance is required, and survival remains significantly reduced: 19.6% of the four-decade New York cohort died, with an 11-fold higher risk of death in the majority subgroup with non-infectious complications. Mortality is driven by lymphoma, hepatitis, structural or functional lung impairment, and gastrointestinal disease rather than by acute infection.

Show evidence (2 references)

PMID:22180439 SUPPORT Human Clinical

"19.6% of patients died, a significantly shorter survival than age- and sex-matched population controls"

Documents the reduced survival relative to population controls.

PMID:22180439 SUPPORT Human Clinical

"The risk of death was 11 times higher for patients with noninfectious complications"

Identifies non-infectious complications as the dominant mortality driver, the basis for the HIGH burden level.

🔀

Differential Diagnoses

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

Congenital agammaglobulinemia (XLA and autosomal forms) Not Yet Curated MONDO:0015977

Overlapping Features The agammaglobulinemias share hypogammaglobulinemia and recurrent sinopulmonary infection, but the developmental block leaves essentially no circulating B cells, whereas B cells are present in CVID. Curated separately in dismech as X-linked_Agammaglobulinemia and Autosomal_Agammaglobulinemia.

Distinguishing Features

CD19+ B cells are absent or below 1-2% of lymphocytes, versus present (usually normal numbers) in CVID
Onset in infancy after maternal IgG wanes, versus typical adult diagnosis in CVID
IgM is absent along with IgG and IgA, and a causative single-gene variant (BTK or a pre-BCR gene) is identifiable

Secondary hypogammaglobulinemia

Overlapping Features Hypogammaglobulinemia acquired from B-cell-depleting therapy (rituximab and other anti-CD20 agents), other immunosuppressants, protein loss, or lymphoid malignancy can reproduce the CVID laboratory phenotype and must be excluded before CVID is diagnosed.

Distinguishing Features

History of B-cell depletion immunotherapy, immunosuppression, protein-losing state, or hematologic malignancy
Onset after a documented period of normal immunoglobulin levels
No requirement for a primary immune defect; immunoglobulins may recover after the cause is removed

Show evidence (1 reference)

PMID:38792965 SUPPORT Human Clinical

"12 patients with "secondary" hypogammaglobulinemia due to a previous B-cell depletion immunotherapy for autoimmune or malignant disease several years ago"

The Greek nationwide cohort separated a secondary-hypogammaglobulinemia group with a typical CVID phenotype from true CVID, demonstrating the need for this exclusion.

Monogenic inborn errors of immunity presenting as CVID

Overlapping Features Genetic work-up reassigns a subset of clinically diagnosed CVID patients to distinct IEIs classified in other IUIS tables — for example activated PI3K-delta syndrome, LRBA deficiency, and CTLA4 haploinsufficiency — with different prognoses and targeted treatments. See also the cvid_umbrella_cuts_across_the_iuis_tables discussion in the Predominantly Antibody Deficiencies IEIs grouping.

Distinguishing Features

Early onset, positive family history, marked autoimmunity or lymphoproliferation raise the prior for a monogenic cause
A pathogenic variant in a non-CVID IUIS gene reclassifies the diagnosis
Targeted therapy may be available (e.g. abatacept for CTLA4/LRBA disease, PI3K-delta inhibitors for APDS)

Show evidence (1 reference)

PMID:40079712 SUPPORT Human Clinical

"This discovery led us to consider a possible metamorphosis of CVID, which, once studied from a genetic perspective, actually reveals very different IEIs."

States that genetically resolved CVID frequently proves to be a different IEI, the premise of this differential.

📊

Related Datasets

Transcriptome regulation in T-cells and monocytes in patients with Common Variable Immunodeficiency geo:GSE299706

A large subgroup of Common Variable Immunodeficiency (CVID) patients has autoimmune and inflammatory complications, associated with T cell and monocyte pathology, but the molecular mechanism for this CVID-subgroup is still elusive. To identify novel molecular pathways impacted in CVID T cells and monocytes, we examined the transcriptomic profiles in these cells from healthy control and the CVID patients in the subgroup with inflammatory complications.

human BULK RNA SEQ n=20

PMID:41991796

Identified by GEO DataSets index search for Common Variable Immunodeficiency (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.

Convergence of cytokine dysregulation and antibody deficiency in common variable immunodeficiency with inflammatory complications geo:GSE330223

Background: Noninfectious complications are the greatest cause of morbidity and mortality in common variable immunodeficiency (CVID), but their pathogenesis remains poorly defined. Objective: Using high-throughput approaches, we aimed to identify, correlate, and determine the significance of immunologic features of CVID with noninfectious complications (CVIDc). Methods: We simultaneously applied proteomics, RNA sequencing, and mass cytometry to a large cohort with primary antibody deficiency. Results: CVIDc is differentiated from uncomplicated CVID, other forms of primary antibody deficiency, and healthy controls by a distinct plasma proteomic profile.

human BULK RNA SEQ n=42

PMID:34146579

RNA-seq profiling of resting naive and CD27bright memory B cells and in vitro activated CD27bright memory B cells reveals differences in B-cell activation patterns in common variable immunodeficiency (CVID) geo:GSE307095

To investigate the transcriptional differences during resting state and B-cell activation in healthy donors and patients with CVID, we sorted naive B cells and CD27bright memory B cells from the two groups and examined the resting state and TLR9 agonist (CpG)-activated CD27bright memory B cells.

human BULK RNA SEQ n=50

PMID:41124223

COVID-19 progression and convalescence in common variable immunodeficiency patients ega:EGAS50000000368

Longitudinal analysis of single-cell RNAseq datasets of PBMCs from COVID-19 CVID patients and controls.

human SINGLE CELL RNA SEQ

European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Common Variable Immunodeficiency"); description-level mentions were not accepted. EGA study_type: Transcriptome Analysis. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.

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Source YAML

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name: Common Variable Immunodeficiency
creation_date: "2026-03-06T00:00:00Z"
category: Complex
parents:
- Primary Immunodeficiency
- Antibody Deficiency Disorder
disease_term:
  preferred_term: Common Variable Immunodeficiency
  term:
    id: MONDO:0015517
    label: common variable immunodeficiency
classifications:
  iuis_category:
    classification_value: predominantly antibody deficiency
    notes: >-
      IUIS 2022 phenotypic classification Table 3 (predominantly antibody
      deficiencies).
    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: "We report the updated classification of inborn errors of immunity, compiled by the International Union of Immunological Societies Expert Committee."
      explanation: >-
        CVID is classified under IUIS Table 3 (predominantly antibody
        deficiencies) in the IUIS phenotypic IEI nosology.
    - 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: "gene defect specified (CVID) Unknown Variable Low IgG and IgA and/or IgM"
      explanation: >-
        The CVID row of IUIS 2022 Table 3 (predominantly antibody
        deficiencies), which opens section 2 (CVID phenotype). The row label
        spans two printed lines ("Common variable immune deficiency with no /
        gene defect specified (CVID)"); the quote is the second line, which
        carries the Unknown genetic-defect, Variable inheritance, and
        immunoglobulin columns.
description: >-
  Common variable immunodeficiency (CVID) is the most prevalent symptomatic
  primary immunodeficiency, characterized by defective B cell differentiation,
  hypogammaglobulinemia, and failure of antibody production. Patients present
  with recurrent bacterial infections, particularly of the respiratory and
  gastrointestinal tracts, and have increased susceptibility to autoimmune
  manifestations, granulomatous disease, and lymphoproliferative disorders.
  CVID is best understood as an umbrella diagnosis with heterogeneous genetic
  and immunologic etiologies spanning monogenic, digenic, and polygenic models.
prevalence:
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_low: 2.0
  rate_high: 4.0
  rate_per_100000: 3.0
  notes: >-
    Estimated prevalence 1 in 25,000 to 1 in 50,000, i.e. 2-4 per 100,000;
    the midpoint is recorded as the point value. CVID is nonetheless the most
    frequent symptomatic primary humoral immunodeficiency.
  evidence:
  - reference: PMID:40079712
    reference_title: "Monogenic Common Variable Immunodeficiency (Mo-CVID) Score for Optimizing the Genetic Diagnosis in Pediatric CVID Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      affecting both children and adults worldwide with an estimated prevalence of
      1:25,000–1:50,000
    explanation: >-
      States the worldwide prevalence estimate for CVID recorded here.
  - reference: PMID:40079712
    reference_title: "Monogenic Common Variable Immunodeficiency (Mo-CVID) Score for Optimizing the Genetic Diagnosis in Pediatric CVID Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Common variable immunodeficiency (CVID) is the most frequent symptomatic
      primary humoral immunodeficiency
    explanation: >-
      Supports characterising CVID as the most frequent symptomatic primary
      humoral immunodeficiency despite the low absolute prevalence.
pathophysiology:
- name: Defective B Cell Differentiation and Class-Switch Recombination
  conforms_to: "germinal_center_reaction#Germinal Center Reaction"
  genes:
  - preferred_term: SEC61A1
    term:
      id: hgnc:18276
      label: SEC61A1
  - preferred_term: IRF2BP2
    term:
      id: hgnc:21729
      label: IRF2BP2
  description: >-
    The hallmark of CVID is a failure of B cells to differentiate into
    immunoglobulin-secreting plasma cells. Defective class-switch recombination
    leads to impaired production of IgG, IgA, and often IgM. Most patients
    show reduced switched memory B cells (CD27+IgD-IgM-). Defects in B cell
    receptor signaling, BAFF/APRIL axis, and NF-kB signaling all converge
    on impaired germinal center output.
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  - preferred_term: Plasma cell
    term:
      id: CL:0000786
      label: plasma cell
  biological_processes:
  - preferred_term: Immunoglobulin Production
    term:
      id: GO:0002377
      label: immunoglobulin production
    modifier: DECREASED
  - preferred_term: Isotype Switching
    term:
      id: GO:0045190
      label: isotype switching
    modifier: DECREASED
  - preferred_term: B Cell Activation
    term:
      id: GO:0042113
      label: B cell activation
  evidence:
  - reference: DOI:10.3390/jcm13061717
    reference_title: "The Scope and Impact of Viral Infections in Common Variable Immunodeficiency (CVID) and CVID-like Disorders: A Literature Review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The pathogenesis of CVID involves complex immunological dysregulation,
      including defects in B cell development, antibody class switching, and
      plasma cell differentiation. These abnormalities contribute to an impaired
      humoral immune response against viral agents, predisposing individuals
      with CVID to a broad range of viral infections.
    explanation: >-
      This 2024 review confirms that CVID pathogenesis centers on defective
      B cell development, class switching, and plasma cell differentiation.
  - reference: PMID:16007086
    reference_title: "TACI is mutant in common variable immunodeficiency and IgA deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      B cells from individuals with TACI mutations expressed TACI but did not
      produce IgG and IgA in response to the TACI ligand APRIL, probably
      reflecting impaired isotype switching.
    explanation: >-
      Demonstrates that TACI mutations in CVID patients lead to impaired
      isotype switching, a key mechanism of defective class-switch recombination.
  - reference: PMID:28782633
    reference_title: Plasma cell deficiency in human subjects with heterozygous mutations in Sec61 translocon alpha 1 subunit (SEC61A1).
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      On in vitro stimulation, B cells showed an intrinsic deficiency to develop into PCs.
    explanation: >-
      Places SEC61A1 on this node, and at its most specific point: the block is
      B-cell-intrinsic and is in the step to plasma cell, which is the cell type
      bound above.
  - reference: PMID:40090425
    reference_title: "IRF2BP2 deficiency: An important form of common variable immunodeficiency with inflammation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There was a reduced frequency of memory B cells with poor immunoglobulin production and reduced calcium flux in response to B-cell receptor stimuli.
    explanation: >-
      Places IRF2BP2 on this node: reduced memory B cells with poor
      immunoglobulin production is the defect this node describes.
  downstream:
  - target: Hypogammaglobulinemia
    causal_link_type: DIRECT
    description: Defective B-cell differentiation and class switching impair antibody production, producing hypogammaglobulinemia.
    evidence:
    - reference: DOI:10.3390/jcm13061717
      reference_title: "The Scope and Impact of Viral Infections in Common Variable Immunodeficiency (CVID) and CVID-like Disorders: A Literature Review"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Common Variable Immunodeficiency (CVID) is a heterogeneous primary
        immunodeficiency disorder characterised by impaired antibody production,
        leading to recurrent infections and an increased susceptibility to viral
        pathogens.
      explanation: The review directly connects impaired antibody production with the defining CVID phenotype.
  - target: Decreased Circulating IgG
    causal_link_type: DIRECT
    description: Impaired class-switch recombination reduces IgG production.
    evidence:
    - reference: PMID:16007086
      reference_title: "TACI is mutant in common variable immunodeficiency and IgA deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        B cells from individuals with TACI mutations expressed TACI but did not
        produce IgG and IgA in response to the TACI ligand APRIL, probably
        reflecting impaired isotype switching.
      explanation: The source directly documents impaired IgG production from B cells with a CVID-associated TACI defect.
  - target: Decreased Circulating IgA
    causal_link_type: DIRECT
    description: Impaired class-switch recombination reduces IgA production.
    evidence:
    - reference: PMID:16007086
      reference_title: "TACI is mutant in common variable immunodeficiency and IgA deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        B cells from individuals with TACI mutations expressed TACI but did not
        produce IgG and IgA in response to the TACI ligand APRIL, probably
        reflecting impaired isotype switching.
      explanation: The source directly documents impaired IgA production from B cells with a CVID-associated TACI defect.
  - target: Recurrent Infections
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Impaired antibody production reduces humoral protection against pathogens.
    description: Antibody-production failure predisposes CVID patients to recurrent infections.
    evidence:
    - reference: DOI:10.3390/jcm13061717
      reference_title: "The Scope and Impact of Viral Infections in Common Variable Immunodeficiency (CVID) and CVID-like Disorders: A Literature Review"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Common Variable Immunodeficiency (CVID) is a heterogeneous primary
        immunodeficiency disorder characterised by impaired antibody production,
        leading to recurrent infections and an increased susceptibility to viral
        pathogens.
      explanation: The review explicitly links impaired antibody production to recurrent infections and viral susceptibility.
- name: Early B Cell Lymphopoiesis Failure
  biological_scale: CELLULAR
  description: >-
    A lesion upstream of, and distinct from, the germinal-centre failure the
    node above describes. IKAROS is a lymphoid transcription factor, and the six
    reported mutations all fall in its DNA-binding domain, producing a
    progressive loss of circulating B cells with markedly reduced early B-cell
    precursors in marrow. Plasma cells were still present
    in the marrow of the reported patients, which is why this is modelled as its
    own node rather than added to the differentiation-and-class-switch node: the
    hypogammaglobulinemia follows from having too few B cells rather than from
    B cells that cannot finish differentiating.
  genes:
  - preferred_term: IKZF1
    term:
      id: hgnc:13176
      label: IKZF1
  cell_types:
  - preferred_term: precursor B cell
    term:
      id: CL:0000817
      label: precursor B cell
  biological_processes:
  - preferred_term: B cell differentiation
    modifier: DECREASED
    term:
      id: GO:0030183
      label: B cell differentiation
  evidence:
  - reference: PMID:26981933
    reference_title: Loss of B Cells in Patients with Heterozygous Mutations in IKAROS.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Heterozygous mutations in the transcription factor IKAROS caused an autosomal dominant form of CVID that is associated with a striking decrease in B-cell numbers.
    explanation: >-
      The conclusion of the 29-person, six-family series: the CVID phenotype
      attributable to IKZF1 is defined by loss of B cells, which is what this
      node asserts.
  - reference: PMID:26981933
    reference_title: Loss of B Cells in Patients with Heterozygous Mutations in IKAROS.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Bone marrow aspirates in two patients had markedly decreased early B-cell precursors, but plasma cells were present.
    explanation: >-
      The marrow finding that locates the lesion at early B-cell development
      rather than at plasma-cell differentiation, and so the reason this is a
      separate node.
  - reference: PMID:26981933
    reference_title: Loss of B Cells in Patients with Heterozygous Mutations in IKAROS.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Studies in family members showed progressive loss of B cells and serum immunoglobulins.
    explanation: >-
      Pairs the B-cell loss with the fall in serum immunoglobulins, which is the
      downstream edge below.
  downstream:
  - target: Hypogammaglobulinemia
    causal_link_type: DIRECT
    description: >-
      Progressive loss of the B-cell compartment reduces serum immunoglobulins,
      reported as falling together in affected family members.
- name: B Cell Coreceptor Complex Failure
  biological_scale: MOLECULAR
  description: >-
    Three of the numbered CVID subtypes disable the same structure: the B-cell
    coreceptor complex of CD19, CD21 (CR2), CD81 and CD225, which lowers the
    activation threshold of the B-cell antigen receptor. CD19 carries the
    signalling function, CD81 is required for CD19 to reach the surface, and
    CD21 supplies the C3d costimulus. MS4A1 (CD20) is not a subunit of that
    complex; it is grouped on this node because ClinGen's assessment records
    that CD20 regulates signalling through the B-cell receptor, and because the
    reported patient's defect was in antibody formation rather than in B-cell
    development. Across these subtypes B-cell development is largely preserved
    and what fails is the response to antigen, which is why they present as
    CVID rather than as agammaglobulinemia.
  genes:
  - preferred_term: CD19
    term:
      id: hgnc:1633
      label: CD19
  - preferred_term: CD81
    term:
      id: hgnc:1701
      label: CD81
  - preferred_term: CR2
    term:
      id: hgnc:2336
      label: CR2
  - preferred_term: MS4A1
    term:
      id: hgnc:7315
      label: MS4A1
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  biological_processes:
  - preferred_term: B cell receptor signaling pathway
    modifier: DECREASED
    term:
      id: GO:0050853
      label: B cell receptor signaling pathway
  evidence:
  - reference: PMID:16672701
    reference_title: An antibody-deficiency syndrome due to mutations in the CD19 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      The CD19 protein forms a complex with CD21, CD81, and CD225 in the membrane of mature B cells. Together with the B-cell antigen receptor, this complex signals the B cell to decrease its threshold for activation by the antigen.
    explanation: >-
      Defines the complex this node is about and the function it serves. Taken
      from the study's background section rather than from its own results,
      hence the BACKGROUND quote role.
  - reference: PMID:16672701
    reference_title: An antibody-deficiency syndrome due to mutations in the CD19 gene.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The response of the patients' B cells to in vitro stimulation through the B-cell receptor was impaired
    explanation: >-
      The bound GO process measured directly: patient B cells stimulated through
      the B-cell receptor in culture respond poorly.
  - reference: PMID:16672701
    reference_title: An antibody-deficiency syndrome due to mutations in the CD19 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      in all four patients, the antibody response to rabies vaccination was poor
    explanation: >-
      The clinical counterpart of the same defect in the same four patients,
      split from the in-vitro measurement so each item carries one evidence type.
  - reference: PMID:20237408
    reference_title: CD81 gene defect in humans disrupts CD19 complex formation and leads to antibody deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Retroviral transduction and glycosylation experiments on EBV-transformed B cells from the patient revealed that CD19 membrane expression critically depended on CD81.
    explanation: >-
      Places CD81 on this node: CD19 cannot reach the B-cell membrane without
      it, so the two genes disable one complex.
  - reference: PMID:20038800
    reference_title: CD20 deficiency in humans results in impaired T cell-independent antibody responses.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Key evidence to support this conclusion was provided by the observation that although antigen-independent B cells developed normally in the absence of CD20 expression, antibody formation, particularly after vaccination with TI antigens, was strongly impaired in the patient.
    explanation: >-
      Places MS4A1 on this node, and states the limit on that placement: normal
      B-cell development with a defect confined to T cell-independent antibody
      formation.
  - reference: CGGV:assertion_eba48c0f-53fa-48c9-8f4e-9892d095b515-2022-03-02T185714.677Z
    reference_title: MS4A1 / immunodeficiency, common variable, 5 (Limited)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      CD20 has been shown to regulate signaling through the B cell receptor (BCR).
    explanation: >-
      The source for grouping MS4A1 on a B-cell-receptor-signalling node
      despite CD20 not being a subunit of the CD19 coreceptor complex.
  downstream:
  - target: Defective B Cell Differentiation and Class-Switch Recombination
    causal_link_type: DIRECT
    description: >-
      Loss of coreceptor signalling removes the antigen-driven activation that
      germinal-centre entry and class switching depend on.
- name: BAFF/APRIL Receptor Signaling Deficiency
  biological_scale: MOLECULAR
  description: >-
    The TNF-family survival axis of the B-cell compartment, represented here by
    the two receptors BAFF-R (TNFRSF13C) and TACI (TNFRSF13B) and by the ligand
    TNFSF13, which MONDO names APRIL in the subtype term it defines. Loss of
    BAFF-R arrests B-cell development at the transitional stage; TACI variants
    were found in 4 of 19 unrelated CVID patients in the original report, in
    heterozygous form, and are modelled in this entry as risk alleles rather
    than determinants. TNFSF12 is deliberately not placed on this node: this
    entry has no source connecting it to either receptor, and grouping it here
    on family membership alone would assert a relationship it cannot support.
  genes:
  - preferred_term: TNFRSF13C
    term:
      id: hgnc:17755
      label: TNFRSF13C
  - preferred_term: TNFRSF13B
    term:
      id: hgnc:18153
      label: TNFRSF13B
  - preferred_term: TNFSF13
    term:
      id: hgnc:11928
      label: TNFSF13
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  biological_processes:
  - preferred_term: tumor necrosis factor-mediated signaling pathway
    modifier: DECREASED
    term:
      id: GO:0033209
      label: tumor necrosis factor-mediated signaling pathway
  evidence:
  - reference: PMID:19666484
    reference_title: "B-cell activating factor receptor deficiency is associated with an adult-onset antibody deficiency syndrome in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Without BAFF-R, B-cell development is arrested at the stage of transitional B cells and the numbers of all subsequent B-cell stages are severely reduced.
    explanation: >-
      The developmental consequence of losing this signalling axis in humans,
      and the direct basis for the downstream edge below.
  - reference: PMID:16007086
    reference_title: "TACI is mutant in common variable immunodeficiency and IgA deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We found that 4 of 19 unrelated individuals with common variable immunodeficiency (CVID) and 1 of 16 individuals with IgA deficiency (IgAD) had a missense mutation in one allele of TNFRSF13B (encoding TACI).
    explanation: >-
      Places TACI on this node, in the heterozygous form in which it is usually
      found - which is why the gene is typed as susceptibility in this entry.
  downstream:
  - target: Defective B Cell Differentiation and Class-Switch Recombination
    causal_link_type: DIRECT
    description: >-
      Loss of BAFF/APRIL survival and costimulatory signalling arrests B-cell
      maturation before the switched memory and plasma-cell stages.
- name: NF-kB Pathway Signaling Deficiency
  biological_scale: MOLECULAR
  description: >-
    Two CVID subtypes sit on the two arms of NF-kB signalling. NFKB1
    haploinsufficiency reduces the canonical p50 subunit and is reported as the
    commonest monogenic cause of CVID in Europeans; NFKB2 C-terminal truncating
    variants leave the non-canonical precursor p100 unprocessable, so the
    mature p52 subunit is not made. The two are grouped on one node because
    both converge on impaired B-cell differentiation, and separated in the
    bound processes because the pathways themselves are distinct.
  genes:
  - preferred_term: NFKB1
    term:
      id: hgnc:7794
      label: NFKB1
  - preferred_term: NFKB2
    term:
      id: hgnc:7795
      label: NFKB2
  biological_processes:
  - preferred_term: canonical NF-kappaB signal transduction
    modifier: DECREASED
    term:
      id: GO:0007249
      label: canonical NF-kappaB signal transduction
  - preferred_term: non-canonical NF-kappaB signal transduction
    modifier: DECREASED
    term:
      id: GO:0038061
      label: non-canonical NF-kappaB signal transduction
  evidence:
  - reference: PMID:26279205
    reference_title: "Haploinsufficiency of the NF-κB1 Subunit p50 in Common Variable Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we conclude that the CVID phenotype in these families is caused by NF-κB1 p50 haploinsufficiency.
    explanation: >-
      Supports the canonical arm of this node: loss of one p50 dose produces the
      CVID phenotype.
  - reference: PMID:30941118
    reference_title: Clinical and Immunological Phenotype of Patients With Primary Immunodeficiency Due to Damaging Mutations in NFKB2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In contrast, impaired B-cell differentiation and hypogammaglobinemia were consistent features of NFKB2-associated disease.
    explanation: >-
      Supports the non-canonical arm and the downstream edge: impaired B-cell
      differentiation was consistent across the NFKB2 cohort.
  - reference: PMID:30941118
    reference_title: Clinical and Immunological Phenotype of Patients With Primary Immunodeficiency Due to Damaging Mutations in NFKB2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Despite the heterogeneity of the different mutations all previously described C-terminal mutations have universally been reported to result in normal expression and cytoplasmic localization of mutant, non-processable p100 precursors and thus in p52 haploinsufficiency
    explanation: >-
      The molecular consequence bound as decreased non-canonical NF-kB signal
      transduction: the C-terminal NFKB2 variants leave p100 unprocessable, so
      mature p52 is halved.
  downstream:
  - target: Defective B Cell Differentiation and Class-Switch Recombination
    causal_link_type: DIRECT
    description: >-
      Both NF-kB arms are required for the germinal-centre and plasma-cell
      transcriptional programme, so their loss reports as failed B-cell
      differentiation.
  - target: Immune Dysregulation and Autoimmunity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Autoimmunity is prominent in the NFKB2 cohort and is predominantly T
      cell-mediated, but the route from the signalling defect to the autoimmune
      phenotype is not established, so the edge is typed as indirect with
      unknown intermediates.
    evidence:
    - reference: PMID:30941118
      reference_title: Clinical and Immunological Phenotype of Patients With Primary Immunodeficiency Due to Damaging Mutations in NFKB2.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In addition, 80% of patients suffered from (predominately T cell mediated) autoimmune (AI) phenomena (alopecia > various lymphocytic organ-infiltration > diarrhea > arthritis > AI-cytopenia).
      explanation: >-
        The cohort frequency and predominant mechanism of autoimmunity in
        NFKB2-associated disease, which is the observation this edge records.
- name: T Cell Dysregulation
  description: >-
    Many CVID patients exhibit T cell abnormalities including reduced naive
    CD4+ T cells, expanded CD21low B cells, impaired T cell proliferation,
    and skewed T helper cell responses. T follicular helper cell dysfunction
    contributes to impaired germinal center reactions and defective B cell help.
    ICOS deficiency specifically impairs T cell help for late B cell
    differentiation and memory B cell generation. IL-21, a cytokine of the same
    follicular helper compartment, is grouped here for the same reason: its
    loss removes the T-cell-derived signal for B-cell differentiation rather
    than damaging the B cell itself.
  genes:
  - preferred_term: ICOS
    term:
      id: hgnc:5351
      label: ICOS
  - preferred_term: IL21
    term:
      id: hgnc:6005
      label: IL21
  cell_types:
  - preferred_term: CD4+ T Cell
    term:
      id: CL:0000624
      label: CD4-positive, alpha-beta T cell
  biological_processes:
  - preferred_term: T Cell Activation
    term:
      id: GO:0042110
      label: T cell activation
  evidence:
  - reference: PMID:12577056
    reference_title: "Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we found four of 32 patients to lack ICOS, the "inducible costimulator"
      on activated T cells, due to an inherited homozygous deletion in the ICOS
      gene. T cells from these individuals were normal with regard to subset
      distribution, activation, cytokine production and proliferation. In
      contrast, naive, switched and memory B cells were reduced.
    explanation: >-
      Demonstrates that ICOS deficiency causes CVID through impaired T cell
      costimulation for B cell differentiation, with reduced naive, switched,
      and memory B cells despite normal T cell subsets.
  - reference: DOI:10.1007/s10875-023-01618-0
    reference_title: "Plasma Levels of mir-34a-5p Correlate with Systemic Inflammation and Low Naïve CD4 T Cells in Common Variable Immunodeficiency"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Levels of microRNA-34a correlated with 11 proteins such as CXCL9, TNF,
      and IL10, which were predicted to be biologically connected. Moreover,
      there was a negative correlation between mir-34 levels and the number of
      naïve CD4 T cells in CVID.
    explanation: >-
      Demonstrates reduced naive CD4 T cells in CVID correlating with
      inflammatory markers, supporting T cell dysregulation as a key
      pathophysiological feature.
  - reference: CGGV:assertion_82664dca-783a-4ed9-abe5-c77b082a0684-2026-01-20T100000.000Z
    reference_title: IL21 / IL21-related infantile inflammatory bowel disease (Limited)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      IL21 is a type I cytokine produced primarily by natural killer T cells, T follicular helper cells and TH17 cells.
    explanation: >-
      Places IL21 on this node rather than on a B-cell node: the cytokine is
      made by the follicular helper compartment this node describes.
  - reference: PMID:24746753
    reference_title: Early-onset inflammatory bowel disease and common variable immunodeficiency-like disease caused by IL-21 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Deficiency of IL-21 resulted in reduced numbers of circulating CD19(+) B cells, including IgM(+) naive and class-switched IgG memory B cells, with a concomitant increase in transitional B-cell numbers.
    explanation: >-
      The B-cell consequence of losing this T-cell-derived signal, and the basis
      for the downstream edge below.
  downstream:
  - target: Defective B Cell Differentiation and Class-Switch Recombination
    causal_link_type: DIRECT
    description: >-
      Loss of follicular helper T-cell signalling - ICOS costimulation or IL-21
      - leaves B cells without the help that germinal-centre differentiation and
      class switching require. In both the ICOS-deficient and IL21-deficient
      patients, switched memory B cells were reduced while T-cell subsets were
      preserved.
- name: Immune Dysregulation and Autoimmunity
  description: >-
    Approximately 25-50% of CVID patients develop autoimmune complications,
    most commonly autoimmune cytopenias (immune thrombocytopenia and autoimmune
    hemolytic anemia). This reflects a breakdown of peripheral tolerance and
    defective regulatory T cell function, particularly through the CTLA-4/LRBA
    checkpoint axis. Expansion of autoreactive CD21low B cells contributes
    to antibody-mediated autoimmunity. IKZF1 (IKAROS) is bound here as a second
    placement, not as its primary mechanism: its CVID lesion is the loss of the
    B-cell compartment modelled on the Early B Cell Lymphopoiesis Failure node,
    and it appears again here because autoimmune cytopenias are a recurrent part
    of the IKAROS phenotype rather than an incidental feature of one case.
  genes:
  - preferred_term: CTLA4
    term:
      id: hgnc:2505
      label: CTLA4
  - preferred_term: LRBA
    term:
      id: hgnc:1742
      label: LRBA
  - preferred_term: IKZF1
    term:
      id: hgnc:13176
      label: IKZF1
  cell_types:
  - preferred_term: Regulatory T cell
    term:
      id: CL:0000815
      label: regulatory T cell
  biological_processes:
  - preferred_term: Immune Response
    term:
      id: GO:0006955
      label: immune response
  evidence:
  - reference: PMID:25213377
    reference_title: "Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      human CTLA4 haploinsufficiency caused dysregulation of FoxP3(+) regulatory
      T (Treg) cells, hyperactivation of effector T cells, and lymphocytic
      infiltration of target organs. Patients also exhibited progressive loss of
      circulating B cells, associated with an increase of predominantly
      autoreactive CD21(lo) B cells and accumulation of B cells in nonlymphoid
      organs.
    explanation: >-
      Shows that CTLA4 haploinsufficiency, found in a subset of CVID patients,
      causes Treg dysfunction, expansion of autoreactive CD21low B cells, and
      immune dysregulation, explaining autoimmune manifestations in CVID.
  - reference: DOI:10.1097/aci.0000000000000947
    reference_title: "Monogenic forms of common variable immunodeficiency and implications on target therapeutic approaches"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      On the other hand, patients with defects in CTLA-4 or LRBA gene present
      with life-threatening immune dysregulation, autoimmunity and lymphocytic
      infiltration of multiple organs.
    explanation: >-
      Places LRBA alongside CTLA4 on this node: the two produce the same
      dysregulation and lymphocytic infiltration phenotype.
  - reference: PMID:33122583
    reference_title: "Common Variable Immunodeficiency, Autoimmune Hemolytic Anemia, and Pancytopenia Associated With a Defect in IKAROS."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical features of a 3-month-old male infant who underwent hematopoietic stem cell transplantation because of an IKZF1 mutation-associated common variable immunodeficiency, AIHA, and pancytopenia are described.
    explanation: >-
      Places IKZF1 on this node: the reported CVID case carried autoimmune
      haemolytic anaemia, one of the autoimmune cytopenias this node explains.
  downstream:
  - target: Autoimmune Hemolytic Anemia
    causal_link_type: DIRECT
    description: Immune dysregulation in CVID can manifest as autoimmune cytopenias, including autoimmune hemolytic anemia.
    evidence:
    - reference: PMID:25213377
      reference_title: "Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Patient B.I.1, previously diagnosed with common variable immunodeficiency
        (CVID), had hepatosplenomegaly, autoimmune hemolytic anemia (AIHA),
        autoimmune thrombocytopenia, pulmonary nodules, and cerebral infiltrative
        lesions.
      explanation: The CTLA4-haploinsufficiency CVID case documents autoimmune hemolytic anemia.
  - target: Autoimmune Thrombocytopenia
    causal_link_type: DIRECT
    description: Immune dysregulation in CVID can manifest as autoimmune thrombocytopenia.
    evidence:
    - reference: PMID:25213377
      reference_title: "Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Patient B.I.1, previously diagnosed with common variable immunodeficiency
        (CVID), had hepatosplenomegaly, autoimmune hemolytic anemia (AIHA),
        autoimmune thrombocytopenia, pulmonary nodules, and cerebral infiltrative
        lesions.
      explanation: The CTLA4-haploinsufficiency CVID case documents autoimmune thrombocytopenia.
  - target: Splenomegaly
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Lymphoproliferative immune dysregulation can enlarge lymphoid organs.
    description: CVID immune dysregulation can present with hepatosplenomegaly.
    evidence:
    - reference: PMID:25213377
      reference_title: "Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Patient B.I.1, previously diagnosed with common variable immunodeficiency
        (CVID), had hepatosplenomegaly, autoimmune hemolytic anemia (AIHA),
        autoimmune thrombocytopenia, pulmonary nodules, and cerebral infiltrative
        lesions.
      explanation: Hepatosplenomegaly in a CVID patient supports splenic enlargement as a downstream immune-dysregulation phenotype.
- name: Granulomatous Disease and GLILD
  description: >-
    CVID-associated granulomatous and lymphocytic interstitial lung disease
    (GLILD) involves poorly organized granulomas with abundant T and B cells.
    Key features include Th1 polarization with elevated IFN-gamma and sIL-2R,
    B cell abnormalities with elevated BAFF and CD21low B cells, and innate
    immune alterations including M2 macrophage skewing and neutrophil
    dysregulation.
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  - preferred_term: Macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: Inflammatory Response
    term:
      id: GO:0006954
      label: inflammatory response
  evidence:
  - reference: DOI:10.1097/aci.0000000000001032
    reference_title: "The biological basis for current treatment strategies for granulomatous disease in common variable immunodeficiency"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Histological analysis shows that T and B cells are abundantly present in
      the granulomas that are less well organized and are frequently associated
      with lymphoid hyperplasia. Increased presence of activation markers such
      as soluble IL-2 receptor (sIL-2R) and IFN-ɣ, suggest increased
      Th1-cell activity. Moreover, B-cell abnormalities are prominent in CVID,
      with elevated IgM, BAFF, and CD21low B cells correlating with
      granulomatous disease progression.
    explanation: >-
      This 2024 review describes the immunopathology of CVID-associated
      granulomatous disease, demonstrating T and B cell involvement, Th1
      polarization, and BAFF/CD21low B cell expansion.
  downstream:
  - target: Granulomatous Disease
    causal_link_type: DIRECT
    description: CVID-associated granulomatous inflammation produces the granulomatous disease phenotype.
    evidence:
    - reference: DOI:10.1097/aci.0000000000001032
      reference_title: "The biological basis for current treatment strategies for granulomatous disease in common variable immunodeficiency"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        This review describes the current knowledge on the pathogenesis of
        granuloma formation in CVID and the biological basis of the current
        treatment options.
      explanation: The review explicitly addresses granuloma formation in CVID.
  - target: Granulomatous-Lymphocytic Interstitial Lung Disease
    causal_link_type: DIRECT
    description: The same granulomatous and lymphocytic immune pathology can manifest as GLILD.
    evidence:
    - reference: DOI:10.1097/aci.0000000000001032
      reference_title: "The biological basis for current treatment strategies for granulomatous disease in common variable immunodeficiency"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Our review links the biological context of CVID with granulomatous
        disease or GLILD to currently prescribed therapies and potential targeted
        treatments.
      explanation: The review explicitly links CVID biological context with granulomatous disease or GLILD.
phenotypes:
- name: Hypogammaglobulinemia
  category: Immunologic
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Hypogammaglobulinemia
    term:
      id: HP:0004313
      label: Decreased circulating immunoglobulin concentration
  evidence:
  - reference: DOI:10.3390/jcm13061717
    reference_title: "The Scope and Impact of Viral Infections in Common Variable Immunodeficiency (CVID) and CVID-like Disorders: A Literature Review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Common Variable Immunodeficiency (CVID) is a heterogeneous primary
      immunodeficiency disorder characterised by impaired antibody production,
      leading to recurrent infections and an increased susceptibility to viral
      pathogens.
    explanation: >-
      Confirms hypogammaglobulinemia as the defining feature of CVID.
- name: Decreased Circulating IgG
  category: Immunologic
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Decreased Circulating IgG
    term:
      id: HP:0004315
      label: Decreased circulating IgG concentration
  evidence:
  - reference: PMID:22180439
    reference_title: "Morbidity and mortality in common variable immune deficiency over 4 decades."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Median immunoglobulin levels were IgG, 246 mg/dL; IgA, 8 mg/dL; and IgM, 21
      mg/dL; 22.6% had an IgG less than 100 mg/dL.
    explanation: >-
      The 473-patient New York cohort quantifies the reduced serum IgG (median
      246 mg/dL, with 22.6% below 100 mg/dL), supporting the defining
      VERY_FREQUENT IgG deficit.
- name: Decreased Circulating IgA
  category: Immunologic
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Decreased Circulating IgA
    term:
      id: HP:0002720
      label: Decreased circulating IgA concentration
  evidence:
  - reference: PMID:22180439
    reference_title: "Morbidity and mortality in common variable immune deficiency over 4 decades."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Median immunoglobulin levels were IgG, 246 mg/dL; IgA, 8 mg/dL; and IgM, 21
      mg/dL; 22.6% had an IgG less than 100 mg/dL.
    explanation: >-
      The same cohort's median serum IgA of 8 mg/dL documents the profound IgA
      reduction that accompanies the IgG deficit in CVID.
- name: Recurrent Infections
  category: Immunologic
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Recurrent Infections
    term:
      id: HP:0002719
      label: Recurrent infections
  evidence:
  - reference: DOI:10.3390/jcm13061717
    reference_title: "The Scope and Impact of Viral Infections in Common Variable Immunodeficiency (CVID) and CVID-like Disorders: A Literature Review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Common Variable Immunodeficiency (CVID) is a heterogeneous primary
      immunodeficiency disorder characterised by impaired antibody production,
      leading to recurrent infections and an increased susceptibility to viral
      pathogens.
    explanation: >-
      Confirms recurrent infections as a cardinal feature of CVID driven
      by impaired antibody production.
  - reference: PMID:22180439
    reference_title: "Morbidity and mortality in common variable immune deficiency over 4 decades."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ninety-four percent of patients had a history of infections; 68% also had
      noninfectious complications
    explanation: >-
      The 473-patient cohort quantifies the infection history at 94%,
      supporting the VERY_FREQUENT band.
- name: Bronchiectasis
  category: Respiratory
  frequency: OCCASIONAL
  description: >-
    Structural sequela of recurrent lower respiratory infection; reported in
    roughly 11-26% of patients across cohorts.
  phenotype_term:
    preferred_term: Bronchiectasis
    term:
      id: HP:0002110
      label: Bronchiectasis
  evidence:
  - reference: PMID:22180439
    reference_title: "Morbidity and mortality in common variable immune deficiency over 4 decades."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hematologic or organ-specific autoimmunity,
      28.6%; chronic lung disease, 28.5%; bronchiectasis, 11.2%; gastrointestinal
      inflammatory disease, 15.4%
    explanation: >-
      The New York cohort reports bronchiectasis in 11.2% of 473 CVID
      patients, a derived-count basis for the OCCASIONAL band.
  - reference: PMID:38792965
    reference_title: "A Nationwide Study of the Delayed Diagnosis and the Clinical Manifestations of Predominantly Antibody Deficiencies and CTLA4-Mediated Immune Dysregulation Syndrome in Greece."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      39 patients (25.5%) developed bronchiectasis, and 16 (10.5%) granulomatous
      disease
    explanation: >-
      The Greek nationwide antibody-deficiency cohort (123/153 patients had
      CVID) reports bronchiectasis in 25.5%, the upper end of the range noted
      in the description.
- name: CVID Enteropathy
  category: Gastrointestinal
  description: >-
    Noninfectious chronic inflammatory gastrointestinal disease in CVID,
    typically manifesting with chronic diarrhea and biopsy evidence of plasma
    cell paucity.
  phenotype_term:
    preferred_term: CVID enteropathy
    term:
      id: HP:0002028
      label: Chronic diarrhea
  evidence:
  - reference: DOI:10.1097/aci.0000000000001040
    reference_title: "Paucity of gastrointestinal plasma cells in common variable immunodeficiency"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Common variable immunodeficiency enteropathy (CVID-E) is a noninfectious
      complication of CVID caused by chronic inflammation of the
      gastrointestinal (GI) tract.
    explanation: >-
      Defines CVID enteropathy as a recognized noninfectious gastrointestinal
      complication; chronic diarrhea is the closest curated HPO phenotype term.
- name: Granulomatous-Lymphocytic Interstitial Lung Disease
  category: Respiratory
  description: >-
    CVID-associated GLILD is a noninfectious interstitial lung complication
    characterized by granulomatous and lymphocytic inflammation.
  phenotype_term:
    preferred_term: granulomatous-lymphocytic interstitial lung disease
    term:
      id: HP:0006530
      label: Abnormal pulmonary interstitial morphology
  evidence:
  - reference: DOI:10.1097/aci.0000000000001032
    reference_title: "The biological basis for current treatment strategies for granulomatous disease in common variable immunodeficiency"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our review links the biological context of CVID with granulomatous
      disease or GLILD to currently prescribed therapies and potential targeted
      treatments.
    explanation: >-
      Confirms GLILD as a recognized CVID-associated interstitial lung
      complication that should be represented alongside the existing
      pathophysiology node.
- name: Splenomegaly
  category: Immunologic
  phenotype_term:
    preferred_term: Splenomegaly
    term:
      id: HP:0001744
      label: Splenomegaly
  evidence:
  - reference: PMID:40079712
    reference_title: "Monogenic Common Variable Immunodeficiency (Mo-CVID) Score for Optimizing the Genetic Diagnosis in Pediatric CVID Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most recurrent lymphoproliferative manifestations were chronic
      lymphadenopathies and splenomegaly.
    explanation: >-
      In the pediatric CVID cohort, splenomegaly was one of the two most
      recurrent lymphoproliferative manifestations.
- name: Lymphadenopathy
  category: Immunologic
  phenotype_term:
    preferred_term: Lymphadenopathy
    term:
      id: HP:0002716
      label: Lymphadenopathy
  evidence:
  - reference: PMID:40079712
    reference_title: "Monogenic Common Variable Immunodeficiency (Mo-CVID) Score for Optimizing the Genetic Diagnosis in Pediatric CVID Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most recurrent lymphoproliferative manifestations were chronic
      lymphadenopathies and splenomegaly.
    explanation: >-
      Chronic lymphadenopathies were among the most recurrent
      lymphoproliferative manifestations in the pediatric CVID cohort.
  - reference: PMID:38792965
    reference_title: "A Nationwide Study of the Delayed Diagnosis and the Clinical Manifestations of Predominantly Antibody Deficiencies and CTLA4-Mediated Immune Dysregulation Syndrome in Greece."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Remarkable findings included an increased prevalence of lymphoproliferation
      (60.1%)
    explanation: >-
      The Greek nationwide antibody-deficiency cohort (predominantly CVID)
      found lymphoproliferation in 60.1% of patients; the figure covers
      lymphoproliferation as a whole rather than lymphadenopathy alone, so no
      frequency band is asserted from it.
- name: Autoimmune Hemolytic Anemia
  category: Hematologic
  phenotype_term:
    preferred_term: Autoimmune Hemolytic Anemia
    term:
      id: HP:0001890
      label: Autoimmune hemolytic anemia
  evidence:
  - reference: PMID:25213377
    reference_title: "Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patient B.I.1, previously diagnosed with common variable immunodeficiency
      (CVID), had hepatosplenomegaly, autoimmune hemolytic anemia (AIHA),
      autoimmune thrombocytopenia, pulmonary nodules, and cerebral infiltrative
      lesions.
    explanation: >-
      Documents autoimmune hemolytic anemia as a feature in a CVID patient
      with CTLA4 haploinsufficiency.
- name: Autoimmune Thrombocytopenia
  category: Hematologic
  phenotype_term:
    preferred_term: Autoimmune Thrombocytopenia
    term:
      id: HP:0001973
      label: Autoimmune thrombocytopenia
  evidence:
  - reference: PMID:25213377
    reference_title: "Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patient B.I.1, previously diagnosed with common variable immunodeficiency
      (CVID), had hepatosplenomegaly, autoimmune hemolytic anemia (AIHA),
      autoimmune thrombocytopenia, pulmonary nodules, and cerebral infiltrative
      lesions.
    explanation: >-
      Documents autoimmune thrombocytopenia in a CVID patient with CTLA4
      haploinsufficiency.
  - reference: PMID:40079712
    reference_title: "Monogenic Common Variable Immunodeficiency (Mo-CVID) Score for Optimizing the Genetic Diagnosis in Pediatric CVID Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most frequent autoimmune manifestations were cytopenia (autoimmune
      thrombocytopenia followed by hemolytic anemia)
    explanation: >-
      Confirms autoimmune thrombocytopenia as the most frequent autoimmune
      cytopenia in a CVID cohort.
- name: Granulomatous Disease
  category: Immunologic
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Granulomatous Disease
    term:
      id: HP:0002955
      label: Granulomatosis
  evidence:
  - reference: DOI:10.1097/aci.0000000000001032
    reference_title: "The biological basis for current treatment strategies for granulomatous disease in common variable immunodeficiency"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This review describes the current knowledge on the pathogenesis of
      granuloma formation in CVID and the biological basis of the current
      treatment options.
    explanation: >-
      A 2024 review dedicated to granulomatous disease in CVID, confirming
      it as a major complication.
  - reference: PMID:22180439
    reference_title: "Morbidity and mortality in common variable immune deficiency over 4 decades."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      granulomatous disease, 9.7%; liver diseases and hepatitis, 9.1%; lymphoma,
      8.2%; or other cancers, 7.0%
    explanation: >-
      The New York cohort reports granulomatous disease in 9.7% of 473
      patients, a derived-count basis for the OCCASIONAL band.
  - reference: PMID:38792965
    reference_title: "A Nationwide Study of the Delayed Diagnosis and the Clinical Manifestations of Predominantly Antibody Deficiencies and CTLA4-Mediated Immune Dysregulation Syndrome in Greece."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      39 patients (25.5%) developed bronchiectasis, and 16 (10.5%) granulomatous
      disease
    explanation: >-
      The Greek nationwide cohort independently reports granulomatous disease
      in 10.5%, consistent with the OCCASIONAL band.
- name: Lymphoma
  category: Oncologic
  frequency: OCCASIONAL
  description: >-
    Lymphoma — predominantly B-cell malignancy — is the most important
    malignant complication of CVID and an independent contributor to
    mortality; overall cancer risk is also increased.
  phenotype_term:
    preferred_term: Lymphoma
    term:
      id: HP:0002665
      label: Lymphoma
  evidence:
  - reference: PMID:22180439
    reference_title: "Morbidity and mortality in common variable immune deficiency over 4 decades."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      granulomatous disease, 9.7%; liver diseases and hepatitis, 9.1%; lymphoma,
      8.2%; or other cancers, 7.0%
    explanation: >-
      The New York cohort reports lymphoma in 8.2% of 473 CVID patients
      (OCCASIONAL band) with other cancers in a further 7.0%.
  - reference: PMID:22180439
    reference_title: "Morbidity and mortality in common variable immune deficiency over 4 decades."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mortality was associated with lymphoma, any form of hepatitis, functional or
      structural lung impairment, and gastrointestinal disease with or without
      malabsorption
    explanation: >-
      Identifies lymphoma among the complications associated with mortality in
      CVID.
  - reference: PMID:38792965
    reference_title: "A Nationwide Study of the Delayed Diagnosis and the Clinical Manifestations of Predominantly Antibody Deficiencies and CTLA4-Mediated Immune Dysregulation Syndrome in Greece."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cancer was a common complication in our cohort (25 patients, 16.3%),
      with B-cell malignancies representing the most common neoplasms (56.7%).
    explanation: >-
      The Greek nationwide antibody-deficiency cohort (predominantly CVID)
      confirms cancer as a common complication with B-cell malignancies
      predominating.
has_subtypes:
- name: CVID1
  display_name: Common variable immunodeficiency 1 (ICOS)
  subtype_term:
    preferred_term: immunodeficiency, common variable, 1
    term:
      id: MONDO:0011864
      label: immunodeficiency, common variable, 1
  genes:
  - preferred_term: ICOS
    term:
      id: hgnc:5351
      label: ICOS
  description: >-
    Homozygous ICOS deletion. With CVID11 it is one of the two subtypes here
    whose primary lesion is in follicular helper T-cell function rather than in
    the B cell itself: loss of the inducible costimulator removes the T-cell
    signal that drives germinal-centre B-cell help, while T-cell subsets,
    activation, cytokine production and proliferation are preserved.
  evidence:
  - reference: PMID:12577056
    reference_title: "Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we found four of 32 patients to lack ICOS, the "inducible costimulator" on activated T cells, due to an inherited homozygous deletion in the ICOS gene.
    explanation: >-
      The four patients with homozygous ICOS deletion who define this subtype.
- name: CVID2
  display_name: Common variable immunodeficiency 2 (TNFRSF13B/TACI)
  subtype_term:
    preferred_term: immunodeficiency, common variable, 2
    term:
      id: MONDO:0009413
      label: immunodeficiency, common variable, 2
  genes:
  - preferred_term: TNFRSF13B
    term:
      id: hgnc:18153
      label: TNFRSF13B
  description: >-
    The TACI form, and the one that most resists a simple subtype reading. The
    common heterozygous alleles C104R and A181E occur in healthy relatives and
    in the general population and are modelled in this entry as susceptibility,
    while ClinGen's Definitive classification for this MONDO term is recorded
    against biallelic, autosomal recessive genotypes.
  evidence:
  - reference: PMID:16007086
    reference_title: "TACI is mutant in common variable immunodeficiency and IgA deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We found that 4 of 19 unrelated individuals with common variable immunodeficiency (CVID) and 1 of 16 individuals with IgA deficiency (IgAD) had a missense mutation in one allele of TNFRSF13B (encoding TACI).
    explanation: >-
      The original cohort finding behind this subtype, and the reason the
      dismech typing is susceptibility: the reported variants are heterozygous.
- name: CVID3
  display_name: Common variable immunodeficiency 3 (CD19)
  subtype_term:
    preferred_term: immunodeficiency, common variable, 3
    term:
      id: MONDO:0013283
      label: immunodeficiency, common variable, 3
  genes:
  - preferred_term: CD19
    term:
      id: hgnc:1633
      label: CD19
  description: >-
    Biallelic CD19 loss. With CVID6 and CVID7 it disables the B-cell coreceptor
    complex of CD19, CD21 (CR2), CD81 and CD225 through three of its
    components; CVID5 (CD20) is grouped with them on the same pathophysiology
    node for its effect on B-cell receptor signalling, not as a fourth subunit
    of that complex.
  evidence:
  - reference: PMID:16672701
    reference_title: An antibody-deficiency syndrome due to mutations in the CD19 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All four patients had homozygous mutations in the CD19 gene.
    explanation: >-
      The four patients from two unrelated families who define this subtype.
- name: CVID4
  display_name: Common variable immunodeficiency 4 (TNFRSF13C/BAFF-R)
  subtype_term:
    preferred_term: immunodeficiency, common variable, 4
    term:
      id: MONDO:0013284
      label: immunodeficiency, common variable, 4
  genes:
  - preferred_term: TNFRSF13C
    term:
      id: hgnc:17755
      label: TNFRSF13C
  description: >-
    Homozygous BAFF-R deletion, arresting B-cell development at the transitional
    stage. Only one of the two originally reported siblings had recurrent
    infections, so this subtype carries an immunological phenotype that does not
    always become a clinical immunodeficiency.
  evidence:
  - reference: PMID:19666484
    reference_title: "B-cell activating factor receptor deficiency is associated with an adult-onset antibody deficiency syndrome in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Analyzing BAFF-R expression and BAFF-binding to B cells in common variable immunodeficiency (CVID) patients, we identified two siblings carrying a homozygous deletion in the BAFF-R gene.
    explanation: >-
      The two siblings with a homozygous TNFRSF13C deletion who define this
      subtype.
- name: CVID5
  display_name: Common variable immunodeficiency 5 (MS4A1/CD20)
  subtype_term:
    preferred_term: immunodeficiency, common variable, 5
    term:
      id: MONDO:0013285
      label: immunodeficiency, common variable, 5
  genes:
  - preferred_term: MS4A1
    term:
      id: hgnc:7315
      label: MS4A1
  description: >-
    CD20 deficiency, reported in one patient. ClinGen classifies the
    relationship as Limited and records that a later report concluded the
    patient did not completely fulfil CVID diagnostic criteria, so this row
    carries the MONDO concept rather than a settled disease entity.
  evidence:
  - reference: CGGV:assertion_eba48c0f-53fa-48c9-8f4e-9892d095b515-2022-03-02T185714.677Z
    reference_title: MS4A1 / immunodeficiency, common variable, 5 (Limited)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      MS4A1 | HGNC:7315 | immunodeficiency, common variable, 5 | MONDO:0013285 | AR | Limited | SOP8 | Antibody Deficiencies Gene Curation Expert Panel | 2022-03-02T18:57:14.677Z
    explanation: >-
      ClinGen's Limited classification against this exact MONDO term, which is
      the caveat this row records.
- name: CVID6
  display_name: Common variable immunodeficiency 6 (CD81)
  subtype_term:
    preferred_term: immunodeficiency, common variable, 6
    term:
      id: MONDO:0013286
      label: immunodeficiency, common variable, 6
  genes:
  - preferred_term: CD81
    term:
      id: hgnc:1701
      label: CD81
  description: >-
    CD81 deficiency, reported in one patient with severe nephropathy. CD19
    surface expression depends on CD81, so this subtype reaches the CVID3
    phenotype through a different subunit of the same coreceptor complex.
    ClinGen classifies the relationship as Limited.
  evidence:
  - reference: PMID:20237408
    reference_title: CD81 gene defect in humans disrupts CD19 complex formation and leads to antibody deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this study, we present what we believe to be the first antibody deficiency syndrome caused by a mutation in the CD81 gene and consequent disruption of the CD19 complex on B cells.
    explanation: >-
      The single report that defines this subtype, and the mechanism shared with
      CVID3.
- name: CVID7
  display_name: Common variable immunodeficiency 7 (CR2/CD21)
  subtype_term:
    preferred_term: immunodeficiency, common variable, 7
    term:
      id: MONDO:0013862
      label: immunodeficiency, common variable, 7
  genes:
  - preferred_term: CR2
    term:
      id: hgnc:2336
      label: CR2
  description: >-
    CD21 deficiency. Loss of the complement C3d receptor removes the C3d
    costimulus that lowers the B-cell activation threshold. The humoral defect
    is narrower than in CD19 deficiency: protein-antigen vaccine responses were
    normal in the index patient and only the pneumococcal polysaccharide
    response was impaired.
  evidence:
  - reference: PMID:22035880
    reference_title: Genetic CD21 deficiency is associated with hypogammaglobulinemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genetic CD21 deficiency adds to the molecular defects observed in human subjects with hypogammaglobulinemia.
    explanation: >-
      The authors' own conclusion placing CD21 deficiency among the molecular
      causes of hypogammaglobulinemia.
- name: CVID10
  display_name: Common variable immunodeficiency 10 (NFKB2)
  subtype_term:
    preferred_term: immunodeficiency, common variable, 10
    term:
      id: MONDO:0014260
      label: immunodeficiency, common variable, 10
  genes:
  - preferred_term: NFKB2
    term:
      id: hgnc:7795
      label: NFKB2
  description: >-
    Heterozygous C-terminal truncating NFKB2 variants that leave the
    non-canonical precursor p100 unprocessable. Frequently accompanied by
    ACTH deficiency, the combination known as DAVID syndrome, which MONDO
    carries as a separate term filed under this one. The 50-case cohort analysis
    cited on the paired genetic record argues this is a distinct entity that
    exceeds the CVID spectrum rather than a variant within it.
  evidence:
  - reference: PMID:30941118
    reference_title: Clinical and Immunological Phenotype of Patients With Primary Immunodeficiency Due to Damaging Mutations in NFKB2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We conclude that heterozygous damaging mutations in NFKB2 represent a distinct PID entity exceeding the usual clinical spectrum of CVID.
    explanation: >-
      The cohort's own conclusion, which is why this row records the subtype as
      broader than the umbrella it sits under.
- name: CVID11
  display_name: Common variable immunodeficiency 11 (IL21)
  subtype_term:
    preferred_term: IL21-related infantile inflammatory bowel disease
    term:
      id: MONDO:0014338
      label: IL21-related infantile inflammatory bowel disease
  genes:
  - preferred_term: IL21
    term:
      id: hgnc:6005
      label: IL21
  description: >-
    The most doubtful row in this list. MONDO makes this term a direct child of
    common variable immunodeficiency and keeps CVID11 as a synonym, but its
    primary label names infantile inflammatory bowel disease, and ClinGen's
    Primary Immune Regulatory Disorders panel recurated the gene-disease
    relationship as Limited in January 2026 on one reported case. It is carried
    here so the MONDO concept is addressable alongside the other numbered
    subtypes, with the reservation stated rather than hidden.
  evidence:
  - reference: CGGV:assertion_82664dca-783a-4ed9-abe5-c77b082a0684-2026-01-20T100000.000Z
    reference_title: IL21 / IL21-related infantile inflammatory bowel disease (Limited)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      IL21 | HGNC:6005 | IL21-related infantile inflammatory bowel disease | MONDO:0014338 | AR | Limited | SOP11 | Primary Immune Regulatory Disorders Gene Curation Expert Panel | 2026-01-20T10:00:00.000Z
    explanation: >-
      The most recent expert-panel assessment of this pair: Limited, curated
      against a disease name that is not CVID.
- name: CVID12
  display_name: Common variable immunodeficiency 12 (NFKB1)
  subtype_term:
    preferred_term: immunodeficiency, common variable, 12
    term:
      id: MONDO:0014697
      label: immunodeficiency, common variable, 12
  genes:
  - preferred_term: NFKB1
    term:
      id: hgnc:7794
      label: NFKB1
  description: >-
    NF-kB1 p50 haploinsufficiency, reported as the most common monogenic cause
    of CVID in Europeans. Note that frequency and evidence strength differ here:
    ClinGen's 2025 recuration returns Moderate, not Definitive.
  evidence:
  - reference: PMID:26279205
    reference_title: "Haploinsufficiency of the NF-κB1 Subunit p50 in Common Variable Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we conclude that the CVID phenotype in these families is caused by NF-κB1 p50 haploinsufficiency.
    explanation: >-
      The conclusion that defines this subtype.
- name: CVID13
  display_name: Common variable immunodeficiency 13 (IKZF1/IKAROS)
  subtype_term:
    preferred_term: pancytopenia due to IKZF1 mutations
    term:
      id: MONDO:0014810
      label: pancytopenia due to IKZF1 mutations
  genes:
  - preferred_term: IKZF1
    term:
      id: hgnc:13176
      label: IKZF1
  description: >-
    IKAROS haploinsufficiency, defined by progressive loss of circulating B
    cells with reduced early B-cell precursors in marrow. MONDO names this term
    after the pancytopenia and carries CVID13 only as a synonym, so the CVID
    identity of the concept is invisible to a label search; the term is
    nonetheless a direct child of common variable immunodeficiency and ClinGen's
    Antibody Deficiencies panel classifies the relationship as Definitive.
  evidence:
  - reference: PMID:33122583
    reference_title: "Common Variable Immunodeficiency, Autoimmune Hemolytic Anemia, and Pancytopenia Associated With a Defect in IKAROS."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      IKZF1 mutation must be kept in mind if neonatal AIHA, common variable immunodeficiency, and pancytopenia are observed.
    explanation: >-
      Pairs the CVID phenotype with the pancytopenia MONDO names the term after,
      which is why one row carries both.
- name: CVID-APRIL
  display_name: Common variable immunodeficiency due to APRIL deficiency (TNFSF13)
  subtype_term:
    preferred_term: immunodeficiency, common variable, due to APRIL deficiency
    term:
      id: MONDO:0800149
      label: immunodeficiency, common variable, due to APRIL deficiency
  genes:
  - preferred_term: TNFSF13
    term:
      id: hgnc:11928
      label: TNFSF13
  description: >-
    The APRIL form, and the only row here that MONDO names after a protein
    rather than by number. ClinGen's Limited classification for TNFSF13 is
    recorded against the general common variable immunodeficiency term rather
    than against this APRIL-specific one.
  evidence:
  - reference: CGGV:assertion_c181d44b-5c48-441b-95ad-b4d06572596d-2022-09-20T160000.000Z
    reference_title: "TNFSF13 / common variable immunodeficiency (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "TNFSF13 | HGNC:11928 | common variable immunodeficiency | MONDO:0015517 | AR | Limited"
    explanation: >-
      ClinGen's row for TNFSF13, showing both the Limited strength and that the
      curation is against MONDO:0015517 rather than the APRIL-specific term this
      row binds.
- name: CVID14
  display_name: Common variable immunodeficiency 14 (IRF2BP2)
  subtype_term:
    preferred_term: immunodeficiency, common variable, 14
    term:
      id: MONDO:0054691
      label: immunodeficiency, common variable, 14
  genes:
  - preferred_term: IRF2BP2
    term:
      id: hgnc:21729
      label: IRF2BP2
  description: >-
    IRF2BP2 is a transcriptional corepressor, and this is the only subtype here
    whose reported phenotype is dominated by gastrointestinal and inflammatory
    disease alongside the antibody defect. MONDO records no causal gene edge on
    this term, which is why it did not appear in the knowledge-graph gap list
    that prompted this pass even though the term is a direct child of common
    variable immunodeficiency.
  evidence:
  - reference: PMID:40090425
    reference_title: "IRF2BP2 deficiency: An important form of common variable immunodeficiency with inflammation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      IRF2BP2 deficiency causes a complex immunodeficiency including gastrointestinal and inflammatory disorders as well as impaired B-cell maturation.
    explanation: >-
      The conclusion of the 34-subject cohort that defines this subtype's
      phenotype.
- name: CVID15
  display_name: Common variable immunodeficiency 15 (SEC61A1)
  subtype_term:
    preferred_term: immunodeficiency, common variable, 15
    term:
      id: MONDO:0958013
      label: immunodeficiency, common variable, 15
  genes:
  - preferred_term: SEC61A1
    term:
      id: hgnc:18276
      label: SEC61A1
  description: >-
    The most narrowly defined subtype in this list: heterozygous SEC61A1
    variants give an intrinsic failure of B cells to become plasma cells, with
    peripheral B- and T-cell subpopulations otherwise normal. MONDO files this
    term both under common variable immunodeficiency and under SEC61A1
    deficiency, and carries no causal gene edge on the CVID child, so it too was
    absent from the gap list; ClinGen's Moderate classification for the gene is
    likewise recorded against the SEC61A1-deficiency term rather than this one.
  evidence:
  - reference: PMID:28782633
    reference_title: Plasma cell deficiency in human subjects with heterozygous mutations in Sec61 translocon alpha 1 subunit (SEC61A1).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe a monogenic defect leading to a specific PC deficiency in human subjects, expanding our knowledge about the pathogenesis of antibody deficiencies.
    explanation: >-
      The authors' statement of what this subtype is: a monogenic plasma-cell
      deficiency among the antibody deficiencies.
genetic:
- name: TNFRSF13B (TACI) Mutations
  association: Predisposing
  relationship_type: SUSCEPTIBILITY
  subtype: CVID2
  gene_term:
    preferred_term: TNFRSF13B
    term:
      id: hgnc:18153
      label: TNFRSF13B
  notes: >-
    Heterozygous TNFRSF13B (TACI) missense variants such as C104R and A181E are
    common risk alleles rather than fully penetrant causes: they are found in
    healthy relatives and in the general population, so they are typed as
    SUSCEPTIBILITY rather than CAUSATIVE. ClinGen's Definitive classification
    for this gene is not in conflict with that typing: it is recorded against
    autosomal recessive inheritance, so it is the biallelic genotype that is
    called definitive, not the common heterozygous risk alleles this record is
    about.
  evidence:
  - reference: PMID:16007086
    reference_title: "TACI is mutant in common variable immunodeficiency and IgA deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We found that 4 of 19 unrelated individuals with common variable
      immunodeficiency (CVID) and 1 of 16 individuals with IgA deficiency
      (IgAD) had a missense mutation in one allele of TNFRSF13B (encoding
      TACI).
    explanation: >-
      Landmark study identifying TACI mutations in approximately 20% of
      CVID patients studied, establishing TACI as a risk factor for CVID.
  - reference: CGGV:assertion_3049236b-8132-4dfa-8cda-2a328962a0a4-2021-01-20T170000.000Z
    reference_title: TNFRSF13B / immunodeficiency, common variable, 2 (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      TNFRSF13B | HGNC:18153 | immunodeficiency, common variable, 2 | MONDO:0009413 | AR | Definitive | SOP8 | Antibody Deficiencies Gene Curation Expert Panel | 2021-01-20T17:00:00.000Z
    explanation: >-
      ClinGen's gene-disease validity row, recording Definitive validity against
      autosomal recessive inheritance - the distinction the notes rely on.
- name: ICOS Deficiency
  association: Causative
  relationship_type: CAUSATIVE
  subtype: CVID1
  gene_term:
    preferred_term: ICOS
    term:
      id: hgnc:5351
      label: ICOS
  evidence:
  - reference: CGGV:assertion_51864ec9-27d9-4a94-9524-d6828b17361d-2022-11-29T170000.000Z
    reference_title: "ICOS / common variable immunodeficiency (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ICOS | HGNC:5351 | common variable immunodeficiency | MONDO:0015517 | AR | Definitive"
    explanation: ClinGen classifies the ICOS-common variable immunodeficiency gene-disease relationship as definitive with autosomal recessive inheritance.
  - reference: PMID:12577056
    reference_title: "Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we found four of 32 patients to lack ICOS, the "inducible costimulator"
      on activated T cells, due to an inherited homozygous deletion in the ICOS
      gene.
    explanation: >-
      First identification of ICOS deficiency as a monogenic cause of CVID,
      demonstrating homozygous ICOS deletion in affected patients.
- name: NFKB1 Haploinsufficiency
  association: Causative
  relationship_type: CAUSATIVE
  subtype: CVID12
  gene_term:
    preferred_term: NFKB1
    term:
      id: hgnc:7794
      label: NFKB1
  evidence:
  - reference: PMID:26279205
    reference_title: "Haploinsufficiency of the NF-κB1 Subunit p50 in Common Variable Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we conclude that the CVID phenotype in these families is caused by
      NF-κB1 p50 haploinsufficiency.
    explanation: >-
      Identifies NFKB1 haploinsufficiency as a cause of CVID through
      degradation of the altered protein with loss of p50 transcription factor.
  - reference: PMID:29477724
    reference_title: "Loss-of-function nuclear factor κB subunit 1 (NFKB1) variants are the most common monogenic cause of common variable immunodeficiency in Europeans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Loss-of-function nuclear factor κB subunit 1 (NFKB1) variants are the
      most common monogenic cause of common variable immunodeficiency in
      Europeans.
    explanation: >-
      Large-scale study confirming NFKB1 as the most common monogenic cause
      of CVID in European populations.
  - reference: CGGV:assertion_e922c85d-f51a-4394-8906-cf01978d8154-2025-04-14T170000.000Z
    reference_title: NFKB1 / immunodeficiency, common variable, 12 (Moderate)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      NFKB1 | HGNC:7794 | immunodeficiency, common variable, 12 | MONDO:0014697 | AD | Moderate | SOP11 | Antibody Deficiencies Gene Curation Expert Panel | 2025-04-14T17:00:00.000Z
    explanation: >-
      ClinGen's 2025 recuration of NFKB1 - CVID12 returns Moderate rather than
      Definitive, which is worth recording next to the claim that NFKB1 is the
      most common monogenic cause of CVID in Europeans: the two statements are
      about frequency and about evidence strength respectively.
- name: CTLA4 Haploinsufficiency
  association: Causative
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: CTLA4
    term:
      id: hgnc:2505
      label: CTLA4
  evidence:
  - reference: PMID:25213377
    reference_title: "Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified germline heterozygous mutations in CTLA4 in subjects with
      severe immune dysregulation from four unrelated families.
    explanation: >-
      Identifies CTLA4 haploinsufficiency as a cause of CVID-like immune
      dysregulation with hypogammaglobulinemia, autoimmune cytopenias, and
      lymphocytic organ infiltration.
- name: LRBA Deficiency
  association: Causative
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: LRBA
    term:
      id: hgnc:1742
      label: LRBA
  evidence:
  - reference: DOI:10.1097/aci.0000000000000947
    reference_title: "Monogenic forms of common variable immunodeficiency and implications on target therapeutic approaches"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      On the other hand, patients with defects in CTLA-4 or LRBA gene present
      with life-threatening immune dysregulation, autoimmunity and lymphocytic
      infiltration of multiple organs.
    explanation: >-
      This 2023 review highlights LRBA defects as a monogenic CVID-like form
      marked by severe immune dysregulation, autoimmunity, and multisystem
      organ infiltration.
- name: BAFF-R (TNFRSF13C) Mutations
  association: Predisposing
  relationship_type: SUSCEPTIBILITY
  subtype: CVID4
  gene_term:
    preferred_term: TNFRSF13C
    term:
      id: hgnc:17755
      label: TNFRSF13C
  notes: >-
    Biallelic TNFRSF13C (BAFF-R) deficiency was identified by screening a CVID
    cohort and arrests B-cell development at the transitional stage, but the
    original siblings show a characteristic immunological phenotype without
    obligate clinical immunodeficiency (only one of the two had recurrent
    infections). Typed as SUSCEPTIBILITY rather than CAUSATIVE for that reason:
    the reduced penetrance means the gene-disease relationship does not reach
    the strength the previous `CAUSATIVE` typing implied.
  evidence:
  - reference: PMID:19666484
    reference_title: "B-cell activating factor receptor deficiency is associated with an adult-onset antibody deficiency syndrome in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Analyzing BAFF-R expression and BAFF-binding to B cells in common variable immunodeficiency (CVID) patients, we identified two siblings carrying a homozygous deletion in the BAFF-R gene."
    explanation: >-
      Establishes the gene-disease link: biallelic TNFRSF13C deletion was found
      by screening a CVID patient cohort, with arrest of B-cell development at
      the transitional B-cell stage and reduced IgG and IgM.
  - reference: PMID:19666484
    reference_title: "B-cell activating factor receptor deficiency is associated with an adult-onset antibody deficiency syndrome in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Therefore, deletion of the BAFF-R gene in humans causes a characteristic immunological phenotype but it does not necessarily lead to a clinically manifest immunodeficiency."
    explanation: >-
      Supports the SUSCEPTIBILITY rather than CAUSATIVE typing. The authors
      explicitly state that BAFF-R deletion does not necessarily produce
      clinically manifest immunodeficiency, so this locus predisposes to the
      CVID phenotype rather than determining it.
  - reference: CGGV:assertion_1408411b-9d28-4308-b2bc-dbada3660898-2021-04-13T003359.028Z
    reference_title: TNFRSF13C / immunodeficiency, common variable, 4 (Limited)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In summary, only the case of the homozygous c.265_288del variant is considered informative at this time, as such there is limited evidence to support this gene-disease relationship.
    explanation: >-
      ClinGen reaches the same conclusion as the SUSCEPTIBILITY typing here by a
      different route: only the homozygous deletion family is counted as
      informative, and the recurrent P21R allele is treated as a risk factor.
- name: CTNNBL1
  gene_term:
    preferred_term: CTNNBL1
    term:
      id: hgnc:15879
      label: CTNNBL1
  association: Limited evidence
  relationship_type: SUSCEPTIBILITY
  notes: >-
    ClinGen classifies this gene-disease relationship as LIMITED, i.e. minimal
    published evidence. Typed as SUSCEPTIBILITY rather than CAUSATIVE so the
    ClinGen strength is not silently upgraded by the dismech association value.
  evidence:
  - reference: CGGV:assertion_4e151724-c8a5-4f3e-a7ac-bd0b1d180fae-2022-05-17T160000.000Z
    reference_title: "CTNNBL1 / common variable immunodeficiency (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CTNNBL1 | HGNC:15879 | common variable immunodeficiency | MONDO:0015517 | AR | Limited"
    explanation: ClinGen classifies the CTNNBL1-common variable immunodeficiency gene-disease relationship as limited with autosomal recessive inheritance.
- name: TNFSF12
  gene_term:
    preferred_term: TNFSF12
    term:
      id: hgnc:11927
      label: TNFSF12
  association: Limited evidence
  relationship_type: SUSCEPTIBILITY
  notes: >-
    ClinGen classifies this gene-disease relationship as LIMITED, i.e. minimal
    published evidence. Typed as SUSCEPTIBILITY rather than CAUSATIVE so the
    ClinGen strength is not silently upgraded by the dismech association value.
  evidence:
  - reference: CGGV:assertion_b943345a-024d-401d-a147-470c0ea0381c-2022-07-22T160000.000Z
    reference_title: "TNFSF12 / common variable immunodeficiency (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "TNFSF12 | HGNC:11927 | common variable immunodeficiency | MONDO:0015517 | AD | Limited"
    explanation: ClinGen classifies the TNFSF12-common variable immunodeficiency gene-disease relationship as limited with autosomal dominant inheritance.
- name: TNFSF13
  gene_term:
    preferred_term: TNFSF13
    term:
      id: hgnc:11928
      label: TNFSF13
  association: Limited evidence
  relationship_type: SUSCEPTIBILITY
  subtype: CVID-APRIL
  notes: >-
    ClinGen classifies this gene-disease relationship as LIMITED, i.e. minimal
    published evidence. Typed as SUSCEPTIBILITY rather than CAUSATIVE so the
    ClinGen strength is not silently upgraded by the dismech association value.
  evidence:
  - reference: CGGV:assertion_c181d44b-5c48-441b-95ad-b4d06572596d-2022-09-20T160000.000Z
    reference_title: "TNFSF13 / common variable immunodeficiency (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "TNFSF13 | HGNC:11928 | common variable immunodeficiency | MONDO:0015517 | AR | Limited"
    explanation: ClinGen classifies the TNFSF13-common variable immunodeficiency gene-disease relationship as limited with autosomal recessive inheritance.
- name: CD19 Deficiency
  association: Causative
  relationship_type: CAUSATIVE
  subtype: CVID3
  gene_term:
    preferred_term: CD19
    term:
      id: hgnc:1633
      label: CD19
  notes: >-
    Biallelic CD19 loss removes the signal-amplifying subunit of the B-cell
    coreceptor complex. B-cell numbers are preserved; what fails is the antigen
    response, which is why this presents as a CVID phenotype rather than as
    agammaglobulinemia.
  evidence:
  - reference: PMID:16672701
    reference_title: An antibody-deficiency syndrome due to mutations in the CD19 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All four patients had homozygous mutations in the CD19 gene.
    explanation: >-
      The four patients from two unrelated families in whom homozygous CD19
      mutations were found, which is the human basis for this record.
  - reference: PMID:16672701
    reference_title: An antibody-deficiency syndrome due to mutations in the CD19 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutation of the CD19 gene causes a type of hypogammaglobulinemia in which the response of mature B cells to antigenic stimulation is defective.
    explanation: >-
      States the mechanism this record asserts: hypogammaglobulinemia arising
      from a defective mature B-cell response to antigen.
  - reference: CGGV:assertion_a6576337-703e-4d76-9120-5f6800730774-2022-05-24T160000.000Z
    reference_title: CD19 / immunodeficiency, common variable, 3 (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      CD19 | HGNC:1633 | immunodeficiency, common variable, 3 | MONDO:0013283 | AR | Definitive | SOP8 | Antibody Deficiencies Gene Curation Expert Panel | 2022-05-24T16:00:00.000Z
    explanation: >-
      ClinGen classifies the CD19 - CVID3 relationship as Definitive with
      autosomal recessive inheritance, which is the basis for typing this
      record CAUSATIVE.
- name: CD81 Deficiency
  association: Limited evidence
  relationship_type: UNKNOWN
  subtype: CVID6
  gene_term:
    preferred_term: CD81
    term:
      id: hgnc:1701
      label: CD81
  notes: >-
    Typed UNKNOWN rather than CAUSATIVE because ClinGen classifies the
    gene-disease relationship as Limited: one reported patient. Mechanistically
    the finding is coherent with CD19 deficiency, since CD19 surface expression
    depends on CD81, so the two produce the same coreceptor defect from
    different subunits.
  evidence:
  - reference: PMID:20237408
    reference_title: CD81 gene defect in humans disrupts CD19 complex formation and leads to antibody deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient had normal CD19 alleles but carried a homozygous CD81 mutation resulting in a complete lack of CD81 expression on blood leukocytes.
    explanation: >-
      The single reported patient and the homozygous CD81 variant that is the
      whole of the human case-level evidence for this pair.
  - reference: CGGV:assertion_e2092b4c-a8ff-4b40-bc09-17fbe33aa3e7-2021-04-29T210806.386Z
    reference_title: CD81 / immunodeficiency, common variable, 6 (Limited)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      CD81 | HGNC:1701 | immunodeficiency, common variable, 6 | MONDO:0013286 | AR | Limited | SOP8 | Antibody Deficiencies Gene Curation Expert Panel | 2021-04-29T21:08:06.386Z
    explanation: >-
      ClinGen's Limited classification, which is why this record is typed
      UNKNOWN rather than CAUSATIVE.
- name: CR2 (CD21) Deficiency
  association: Causative
  relationship_type: CAUSATIVE
  subtype: CVID7
  gene_term:
    preferred_term: CR2
    term:
      id: hgnc:2336
      label: CR2
  notes: >-
    CR2 encodes CD21, the complement C3d receptor of the same B-cell coreceptor
    complex as CD19 and CD81. The index patient responded normally to protein
    vaccines and only moderately poorly to pneumococcal polysaccharide, so the
    humoral defect is narrower than in CD19 deficiency.
  evidence:
  - reference: PMID:22035880
    reference_title: Genetic CD21 deficiency is associated with hypogammaglobulinemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sequence analysis revealed a compound heterozygous deleterious mutation in the CD21 gene.
    explanation: >-
      The compound heterozygous CR2/CD21 genotype in the index patient.
  - reference: PMID:22035880
    reference_title: Genetic CD21 deficiency is associated with hypogammaglobulinemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A 28-year-old man presented with recurrent infections, reduced class-switched memory B cells, and hypogammaglobulinemia.
    explanation: >-
      The CVID-pattern presentation - recurrent infection, reduced switched
      memory B cells, hypogammaglobulinemia - in the CD21-deficient patient.
  - reference: CGGV:assertion_9153b41e-f2ef-453d-883b-187565cf4593-2021-08-03T130056.511Z
    reference_title: CR2 / immunodeficiency, common variable, 7 (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      CR2 | HGNC:2336 | immunodeficiency, common variable, 7 | MONDO:0013862 | AR | Definitive | SOP8 | Antibody Deficiencies Gene Curation Expert Panel | 2021-08-03T13:00:56.511Z
    explanation: >-
      ClinGen classifies the CR2 - CVID7 relationship as Definitive with
      autosomal recessive inheritance.
- name: MS4A1 (CD20) Deficiency
  association: Limited evidence
  relationship_type: UNKNOWN
  subtype: CVID5
  gene_term:
    preferred_term: MS4A1
    term:
      id: hgnc:7315
      label: MS4A1
  notes: >-
    Typed UNKNOWN rather than CAUSATIVE: ClinGen classifies this relationship as
    Limited on a single reported patient, and records that a later report
    concluded that patient did not completely fulfil the diagnostic criteria for
    CVID. The defect is specific to T cell-independent antibody responses rather
    than to B-cell development.
  evidence:
  - reference: PMID:20038800
    reference_title: CD20 deficiency in humans results in impaired T cell-independent antibody responses.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Key evidence to support this conclusion was provided by the observation that although antigen-independent B cells developed normally in the absence of CD20 expression, antibody formation, particularly after vaccination with TI antigens, was strongly impaired in the patient.
    explanation: >-
      The specific humoral defect in the one reported CD20-deficient patient:
      normal B-cell development with impaired T cell-independent antibody
      formation.
  - reference: CGGV:assertion_eba48c0f-53fa-48c9-8f4e-9892d095b515-2022-03-02T185714.677Z
    reference_title: MS4A1 / immunodeficiency, common variable, 5 (Limited)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      To date, this is the only patient that has been reported with a loss-of-function variant in MS4A1 and a positive disease association.
    explanation: >-
      ClinGen's statement that the evidence rests on one patient, which is the
      basis for the UNKNOWN typing here.
- name: NFKB2 Deficiency
  association: Causative
  relationship_type: CAUSATIVE
  subtype: CVID10
  gene_term:
    preferred_term: NFKB2
    term:
      id: hgnc:7795
      label: NFKB2
  notes: >-
    Heterozygous C-terminal truncating NFKB2 variants leave the non-canonical
    NF-kB precursor p100 unprocessable, halving mature p52. The cohort that this record is
    built on argues the resulting entity exceeds the usual CVID spectrum -
    earlier onset, T-cell-mediated autoimmunity, and anterior pituitary hormone
    deficiency (DAVID syndrome) - so CVID10 is curated here as a subtype whose
    phenotype extends beyond the umbrella rather than as a plain CVID variant.
  evidence:
  - reference: PMID:30941118
    reference_title: Clinical and Immunological Phenotype of Patients With Primary Immunodeficiency Due to Damaging Mutations in NFKB2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Heterozygous mutations in NFKB2 have recently been established as a molecular cause of common variable immunodeficiency (CVID) and DAVID-syndrome, a rare condition combining deficiency of anterior pituitary hormone with CVID.
    explanation: >-
      States the gene-disease relationship this record asserts and the pituitary
      extension of the phenotype.
  - reference: PMID:30941118
    reference_title: Clinical and Immunological Phenotype of Patients With Primary Immunodeficiency Due to Damaging Mutations in NFKB2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cohort analysis extended to all 35 previously published NFKB2-cases revealed occurrence of early-onset PID in 46/50 patients (mean age of onset 5.9 years, median 4.0 years). ACTH-deficiency occurred in 44%.
    explanation: >-
      The cohort size and the onset and ACTH-deficiency figures behind the
      statement in the notes that this entity is earlier-onset than typical
      CVID.
  - reference: CGGV:assertion_61b546f1-5683-4588-a5bc-030ebbd5b401-2021-10-13T132601.192Z
    reference_title: NFKB2 / immunodeficiency, common variable, 10 (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      NFKB2 | HGNC:7795 | immunodeficiency, common variable, 10 | MONDO:0014260 | AD | Definitive | SOP8 | Antibody Deficiencies Gene Curation Expert Panel | 2021-10-13T13:26:01.192Z
    explanation: >-
      ClinGen classifies the NFKB2 - CVID10 relationship as Definitive with
      autosomal dominant inheritance.
- name: IKZF1 (IKAROS) Haploinsufficiency
  association: Causative
  relationship_type: CAUSATIVE
  subtype: CVID13
  gene_term:
    preferred_term: IKZF1
    term:
      id: hgnc:13176
      label: IKZF1
  notes: >-
    MONDO files the IKZF1 entity under the primary label "pancytopenia due to
    IKZF1 mutations" and carries CVID13 only as a synonym, so a search on the
    CVID label alone does not find it. ClinGen's Definitive classification is
    recorded against that same pancytopenia label. The defining lesion is loss
    of the B-cell compartment - the series below found a striking decrease in
    B-cell numbers across 29 affected people - and that is where the gene is
    wired into the pathograph; the autoimmune cytopenia and pancytopenia the
    MONDO label names are the second arm of the same phenotype.
  evidence:
  - reference: PMID:26981933
    reference_title: Loss of B Cells in Patients with Heterozygous Mutations in IKAROS.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Six different heterozygous mutations in IKZF1, the gene encoding the transcription factor IKAROS, were identified in 29 persons from six families.
    explanation: >-
      The series that establishes this gene-disease relationship: six mutations
      across six families, all in the IKAROS DNA-binding domain.
  - reference: PMID:26981933
    reference_title: Loss of B Cells in Patients with Heterozygous Mutations in IKAROS.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Heterozygous mutations in the transcription factor IKAROS caused an autosomal dominant form of CVID that is associated with a striking decrease in B-cell numbers.
    explanation: >-
      States the disease this record asserts - an autosomal dominant form of
      CVID - and the B-cell loss that defines it.
  - reference: PMID:33122583
    reference_title: "Common Variable Immunodeficiency, Autoimmune Hemolytic Anemia, and Pancytopenia Associated With a Defect in IKAROS."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical features of a 3-month-old male infant who underwent hematopoietic stem cell transplantation because of an IKZF1 mutation-associated common variable immunodeficiency, AIHA, and pancytopenia are described.
    explanation: >-
      A single patient in whom the IKZF1 variant produced CVID together with the
      autoimmune cytopenia and pancytopenia that MONDO names the entity after.
  - reference: CGGV:assertion_be4b4555-477b-477b-bff9-7fcc8883806a-2022-09-13T170000.000Z
    reference_title: IKZF1 / pancytopenia due to IKZF1 mutations (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      IKZF1 | HGNC:13176 | pancytopenia due to IKZF1 mutations | MONDO:0014810 | AD | Definitive | SOP9 | Antibody Deficiencies Gene Curation Expert Panel | 2022-09-13T17:00:00.000Z
    explanation: >-
      ClinGen's Definitive, autosomal dominant classification, curated by the
      Antibody Deficiencies expert panel against the MONDO term that also
      carries CVID13 as a synonym.
- name: IL21 Deficiency
  association: Limited evidence
  relationship_type: UNKNOWN
  subtype: CVID11
  gene_term:
    preferred_term: IL21
    term:
      id: hgnc:6005
      label: IL21
  notes: >-
    The weakest of the numbered CVID entities curated here, and the one whose
    placement under this entry is most arguable. MONDO makes the IL21 term a
    direct child of common variable immunodeficiency and keeps CVID11 as a
    synonym, but names it after infantile inflammatory bowel disease, and
    ClinGen's Primary Immune Regulatory Disorders panel recurated it as Limited
    in January 2026 on a single reported case. It is retained here because the
    reporting authors describe the B-cell phenotype as resembling CVID, and
    typed UNKNOWN rather than CAUSATIVE to reflect the Limited classification.
  evidence:
  - reference: PMID:24746753
    reference_title: Early-onset inflammatory bowel disease and common variable immunodeficiency-like disease caused by IL-21 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our study uncovers IL-21 deficiency as a novel cause of early-onset IBD in human subjects accompanied by defects in B-cell development similar to those found in patients with common variable immunodeficiency.
    explanation: >-
      The authors' own framing: early-onset IBD with B-cell development defects
      resembling CVID, which is why MONDO files the entity under CVID and why
      the record sits here.
  - reference: CGGV:assertion_82664dca-783a-4ed9-abe5-c77b082a0684-2026-01-20T100000.000Z
    reference_title: IL21 / IL21-related infantile inflammatory bowel disease (Limited)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In summary, there is a single reported case with a rare and distinct phenotype (infantile onset IBD and immunodeficiency), and an ultra-rare, biallelic, IL21 loss-of-function variant.
    explanation: >-
      ClinGen's summary of the case-level evidence, which is the basis for the
      UNKNOWN typing and the caveat recorded in the notes.
- name: IRF2BP2 Deficiency
  association: Causative
  relationship_type: CAUSATIVE
  subtype: CVID14
  gene_term:
    preferred_term: IRF2BP2
    term:
      id: hgnc:21729
      label: IRF2BP2
  notes: >-
    Typed CAUSATIVE against ClinGen, which returns Limited for this pair. That
    classification is dated March 2021 and predates the 34-subject, 18-family
    cohort cited here, which reports immunodeficiency in 30 of 33 assessable
    subjects with functional confirmation of impaired NFAT repression. The
    disagreement is deliberate and recorded rather than resolved by deferring to
    the older assessment; a ClinGen recuration would be the thing to check
    before relying on either.
  evidence:
  - reference: PMID:40090425
    reference_title: "IRF2BP2 deficiency: An important form of common variable immunodeficiency with inflammation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To deepen the understanding of the clinical implications of IRF2BP2 variants, we sought to clinically characterize and functionally test 34 individuals with IRF2BP2 variants.
    explanation: >-
      The size of the cohort behind this record, which is the reason the typing
      here departs from ClinGen's 2021 Limited classification.
  - reference: PMID:40090425
    reference_title: "IRF2BP2 deficiency: An important form of common variable immunodeficiency with inflammation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most subjects had immunodeficiency (91%, n = 30 of 33) with variable gastrointestinal (65%, n = 20 of 31) and inflammatory or autoimmune features (57%, n = 17 of 30), including chronic abdominal pain, colitis, diarrhea, constipation, vitiligo, alopecia, and migratory rashes.
    explanation: >-
      The penetrance of the immunodeficiency and of the gastrointestinal and
      inflammatory features across that cohort.
  - reference: CGGV:assertion_025487e5-9447-4c7b-88ad-f650103e09cf-2021-03-16T125403.252Z
    reference_title: IRF2BP2 / immunodeficiency, common variable, 14 (Limited)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      IRF2BP2 | HGNC:21729 | immunodeficiency, common variable, 14 | MONDO:0054691 | AD | Limited | SOP8 | Antibody Deficiencies Gene Curation Expert Panel | 2021-03-16T12:54:03.252Z
    explanation: >-
      ClinGen's 2021 assessment, cited so that the departure from it in this
      record's typing is visible rather than silent. Note the autosomal dominant
      inheritance, which the cohort above also reports.
- name: SEC61A1 Deficiency
  association: Causative
  relationship_type: CAUSATIVE
  subtype: CVID15
  gene_term:
    preferred_term: SEC61A1
    term:
      id: hgnc:18276
      label: SEC61A1
  notes: >-
    ClinGen does curate this gene, but against MONDO:0100337 SEC61A1 deficiency
    rather than against the CVID15 term - searching the committed gene-validity
    download for "common variable, 15" returns nothing while searching for
    SEC61A1 returns that row, classified Moderate. MONDO makes CVID15 a child of
    both concepts, so the two are describing the same gene-disease pair under
    different names. ClinGen also records that SEC61A1 patients have been
    diagnosed with entities well outside antibody deficiency, including
    autosomal dominant tubulointerstitial kidney disease and severe congenital
    neutropenia, so the CVID presentation is one arm of a broader gene
    phenotype.
  evidence:
  - reference: PMID:28782633
    reference_title: Plasma cell deficiency in human subjects with heterozygous mutations in Sec61 translocon alpha 1 subunit (SEC61A1).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genetic analysis and targeted sequencing identified novel heterozygous missense (c.254T>A, p.V85D) and nonsense (c.1325G>T, p.E381*) mutations in SEC61A1, segregating with the disease phenotype.
    explanation: >-
      The two segregating SEC61A1 variants that establish this gene-disease
      relationship.
  - reference: PMID:28782633
    reference_title: Plasma cell deficiency in human subjects with heterozygous mutations in Sec61 translocon alpha 1 subunit (SEC61A1).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a novel genetic defect and studied its pathologic mechanism in 11 patients from 2 unrelated families with PADs.
    explanation: >-
      The cohort size in the report that first tied SEC61A1 to a primary
      antibody deficiency.
  - reference: CGGV:assertion_1ff61d15-19f9-42a2-8dc4-0a4071b562eb-2021-07-27T154837.287Z
    reference_title: SEC61A1 / SEC61A1 deficiency (Moderate)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      SEC61A1 | HGNC:18276 | SEC61A1 deficiency | MONDO:0100337 | AD | Moderate | SOP8 | Antibody Deficiencies Gene Curation Expert Panel | 2021-07-27T15:48:37.287Z
    explanation: >-
      ClinGen's assessment of this gene, curated by the Antibody Deficiencies
      panel against the SEC61A1-deficiency term rather than against CVID15.
  - reference: CGGV:assertion_1ff61d15-19f9-42a2-8dc4-0a4071b562eb-2021-07-27T154837.287Z
    reference_title: SEC61A1 / SEC61A1 deficiency (Moderate)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Patients in the literature have been described with different diagnosed entities such as Autosomal dominant tubulointerstital kidney disease, Primary antibody deficiency and severe congenital neutropenia.
    explanation: >-
      The basis for the caveat in the notes that the CVID presentation is one arm
      of a broader SEC61A1 phenotype.
treatments:
- name: Immunoglobulin Replacement Therapy
  description: >-
    Lifelong intravenous (IVIG) or subcutaneous (SCIG) immunoglobulin
    replacement is the cornerstone of CVID treatment, reducing the frequency
    and severity of infections. It does not address the non-infectious
    (autoimmune, granulomatous, lymphoproliferative) manifestations, which now
    pose the greatest therapeutic challenge.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: immunoglobulin replacement therapy
    term:
      id: NCIT:C62710
      label: Immunoglobulin Therapy
    therapeutic_agent:
    - preferred_term: therapeutic immune globulin
      term:
        id: NCIT:C2701
        label: Therapeutic Immune Globulin
  target_mechanisms:
  - target: Defective B Cell Differentiation and Class-Switch Recombination
    treatment_effect: BYPASSES
    description: >-
      Passive polyclonal IgG substitutes for the antibody the defective B-cell
      compartment cannot make; it bypasses rather than corrects the underlying
      differentiation defect, which is why non-infectious complications
      persist on treatment.
  evidence:
  - reference: DOI:10.3390/jcm13061717
    reference_title: "The Scope and Impact of Viral Infections in Common Variable Immunodeficiency (CVID) and CVID-like Disorders: A Literature Review"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      It assesses the efficacy of prophylactic measures for COVID-19, including
      vaccination and immunoglobulin replacement therapy, as well as trialled
      therapies.
    explanation: >-
      Establishes that immunoglobulin replacement is used in CVID, but only in
      the narrow context of COVID-19 prophylaxis. It does NOT support the
      broader claim that lifelong IgG replacement is the cornerstone of CVID
      management, for which this item was previously cited as SUPPORT; that
      claim is carried by the general CVID review below.
  - reference: PMID:41045774
    reference_title: "Common variable immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Infections usually improve significantly after the initiation of immunoglobulin replacement therapy and other preventive measures, with non-infectious manifestations now posing the greatest therapeutic challenge."
    explanation: >-
      A general CVID review carrying the core management claim: initiating
      immunoglobulin replacement significantly improves the infectious burden,
      which is why it is the cornerstone of CVID treatment. The review also
      frames the residual therapeutic problem as the non-infectious
      manifestations, i.e. those that IgG replacement does not address.
- name: Antibiotic Prophylaxis and Treatment
  description: >-
    Prophylactic and therapeutic antibiotics are used to manage recurrent
    bacterial infections, particularly sinopulmonary infections.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: antibiotic therapy
    term:
      id: NCIT:C15620
      label: Antibiotic Therapy
- name: Immunosuppressive Therapy for Autoimmune Complications
  description: >-
    Corticosteroids, rituximab, and other immunosuppressants are used
    to manage autoimmune cytopenias and granulomatous disease. Treatment
    selection is increasingly aligned to biological mechanisms: rituximab
    for B cell hyperplasia and sirolimus for mTOR/Th1 programs.
  treatment_term:
    preferred_term: immunosuppressive therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: DOI:10.1097/aci.0000000000001032
    reference_title: "The biological basis for current treatment strategies for granulomatous disease in common variable immunodeficiency"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Therapeutic regimens include glucocorticoids, DMARDs, and biologicals
      like rituximab.
    explanation: >-
      Confirms the use of glucocorticoids, DMARDs, and rituximab for
      granulomatous disease in CVID.
- name: Abatacept
  description: >-
    Abatacept is a CTLA-4-Ig fusion protein used as targeted immunomodulation
    for CVID subsets with CTLA4/LRBA-driven immune dysregulation, particularly
    enteropathy, autoimmunity, and GLILD.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: abatacept
      term:
        id: NCIT:C28898
        label: Abatacept
  evidence:
  - reference: DOI:10.1097/aci.0000000000000947
    reference_title: "Monogenic forms of common variable immunodeficiency and implications on target therapeutic approaches"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Abatacept, a soluble cytotoxic T lymphocyte antigen 4 (CTLA-4) fusion
      protein that acts as a costimulation modulator, has been widely
      implemented for affected patients with good results as bridge treatment.
    explanation: >-
      Supports abatacept as a mechanistically targeted therapy for
      CTLA4/LRBA-associated CVID-like immune dysregulation.
diagnosis:
- name: Quantitative immunoglobulins with functional antibody assessment (ESID criteria)
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  description: >-
    Per the ESID registry criteria, the laboratory diagnosis requires low IgG
    together with low IgA or IgM, plus at least one of a poor antibody
    response to vaccines or low switched memory B cells. The diagnosis can be
    made after the fourth year of life, although symptoms may begin earlier.
    Secondary causes of hypogammaglobulinemia must be excluded.
  markers: Serum IgG, IgA, IgM; vaccine antibody responses; switched memory B cells
  results: Low IgG with low IgA or IgM, plus impaired vaccine response or low switched memory B cells
  evidence:
  - reference: PMID:40079712
    reference_title: "Monogenic Common Variable Immunodeficiency (Mo-CVID) Score for Optimizing the Genetic Diagnosis in Pediatric CVID Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      laboratory criteria are low IgG and IgA or IgM and at least one between poor
      antibody vaccine response or low switched memory B cells
    explanation: >-
      States the ESID registry laboratory criteria recorded in this item.
  - reference: PMID:40079712
    reference_title: "Monogenic Common Variable Immunodeficiency (Mo-CVID) Score for Optimizing the Genetic Diagnosis in Pediatric CVID Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of CVID can be made after the 4th year of life
    explanation: >-
      Supports the minimum-age criterion for the CVID diagnosis.
- name: Genetic testing for monogenic causes
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: >-
    Exome-based genetic testing identifies a monogenic cause in a minority of
    CVID patients (2-30% across cohorts, enriched in early-onset, familial,
    autoimmune and lymphoproliferative presentations). A genetic diagnosis
    reclassifies the patient — often to an IEI in a different IUIS table —
    and carries prognostic, therapeutic, and genetic-counseling implications.
  results: Monogenic cause identified in a minority; reclassification when found
  evidence:
  - reference: PMID:40079712
    reference_title: "Monogenic Common Variable Immunodeficiency (Mo-CVID) Score for Optimizing the Genetic Diagnosis in Pediatric CVID Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      allowing the identification of monogenic genetic variants from 2% to 30%
      of CVID patients in different cohorts
    explanation: >-
      Quantifies the monogenic yield of genetic testing across CVID cohorts.
  - reference: PMID:41045774
    reference_title: "Common variable immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Identifying a genetic cause allows for the reclassification of
      patients, it has prognostic and therapeutic implications, and enables genetic
      counseling for family members.
    explanation: >-
      States the clinical consequences of finding a genetic cause.
  - reference: PMID:40079712
    reference_title: "Monogenic Common Variable Immunodeficiency (Mo-CVID) Score for Optimizing the Genetic Diagnosis in Pediatric CVID Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The evaluation of a patient with suspected IEIs is neither complete nor
      accurate without the inclusion of genetic testing.
    explanation: >-
      Supports genetic testing as a standard component of the CVID diagnostic
      work-up.
- name: Multidisciplinary organ assessment and diagnostic delay
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  description: >-
    Because CVID affects multiple organ systems, patients should undergo
    extensive immunological evaluation and regular multi-organ assessment by
    multidisciplinary immunodeficiency teams. Diagnosis is typically delayed
    by years after symptom onset — a median of 9 years in a nationwide Greek
    antibody-deficiency cohort.
  evidence:
  - reference: PMID:41045774
    reference_title: "Common variable immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with CVID should undergo extensive
      immunological evaluations and regular assessment of the multiple organs that may
      be affected, ideally by multidisciplinary teams specialized in
      immunodeficiencies.
    explanation: >-
      The review's recommendation for multidisciplinary organ surveillance.
  - reference: PMID:38792965
    reference_title: "A Nationwide Study of the Delayed Diagnosis and the Clinical Manifestations of Predominantly Antibody Deficiencies and CTLA4-Mediated Immune Dysregulation Syndrome in Greece."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We demonstrated a remarkable delay
      in PAD diagnosis, several years after the onset of related symptoms (median: 9.0
      years, range: 0-43.0).
    explanation: >-
      Quantifies the diagnostic delay in a predominantly-CVID national cohort.
progression:
- phase: Onset and diagnosis, typically in adulthood
  age_range: Most diagnoses in the second to fourth decade; pediatric onset occurs
  notes: >-
    Recurrent infection is the usual presenting problem. In the New York
    cohort, males were diagnosed at a median age of 30 years and females at
    33.5 years.
  evidence:
  - reference: PMID:22180439
    reference_title: "Morbidity and mortality in common variable immune deficiency over 4 decades."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Males were diagnosed earlier (median age, 30 years) than females (median age,
      33.5 years
    explanation: >-
      Cohort medians for age at diagnosis.
- phase: Chronic course dominated by non-infectious complications
  notes: >-
    On immunoglobulin replacement the infectious burden falls substantially,
    and the long-term course is instead shaped by the non-infectious
    complications — autoimmunity, chronic lung disease and bronchiectasis,
    gastrointestinal inflammatory disease, granulomatous disease, liver
    disease, and lymphoid malignancy — which develop in about two-thirds of
    patients and drive most mortality.
  evidence:
  - reference: PMID:22180439
    reference_title: "Morbidity and mortality in common variable immune deficiency over 4 decades."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ninety-four percent of patients had a history of infections; 68% also had
      noninfectious complications
    explanation: >-
      Two-thirds of the cohort developed non-infectious complications.
  - reference: PMID:41045774
    reference_title: "Common variable immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Infections usually improve significantly after the
      initiation of immunoglobulin replacement therapy and other preventive measures,
      with non-infectious manifestations now posing the greatest therapeutic
      challenge.
    explanation: >-
      Frames the treated disease course: infections controlled, non-infectious
      manifestations dominant.
clinical_burden:
  burden_level: HIGH
  rationale: >-
    Lifelong immunoglobulin replacement with multidisciplinary organ
    surveillance is required, and survival remains significantly reduced:
    19.6% of the four-decade New York cohort died, with an 11-fold higher risk
    of death in the majority subgroup with non-infectious complications.
    Mortality is driven by lymphoma, hepatitis, structural or functional lung
    impairment, and gastrointestinal disease rather than by acute infection.
  evidence:
  - reference: PMID:22180439
    reference_title: "Morbidity and mortality in common variable immune deficiency over 4 decades."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      19.6% of patients died, a significantly shorter survival than age- and
      sex-matched population controls
    explanation: >-
      Documents the reduced survival relative to population controls.
  - reference: PMID:22180439
    reference_title: "Morbidity and mortality in common variable immune deficiency over 4 decades."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The risk of death was 11 times higher for patients with noninfectious
      complications
    explanation: >-
      Identifies non-infectious complications as the dominant mortality
      driver, the basis for the HIGH burden level.
differential_diagnoses:
- name: Congenital agammaglobulinemia (XLA and autosomal forms)
  description: >-
    The agammaglobulinemias share hypogammaglobulinemia and recurrent
    sinopulmonary infection, but the developmental block leaves essentially no
    circulating B cells, whereas B cells are present in CVID. Curated
    separately in dismech as X-linked_Agammaglobulinemia and
    Autosomal_Agammaglobulinemia.
  disease_term:
    preferred_term: agammaglobulinemia
    term:
      id: MONDO:0015977
      label: agammaglobulinemia
  distinguishing_features:
  - CD19+ B cells are absent or below 1-2% of lymphocytes, versus present (usually normal numbers) in CVID
  - Onset in infancy after maternal IgG wanes, versus typical adult diagnosis in CVID
  - IgM is absent along with IgG and IgA, and a causative single-gene variant (BTK or a pre-BCR gene) is identifiable
- name: Secondary hypogammaglobulinemia
  description: >-
    Hypogammaglobulinemia acquired from B-cell-depleting therapy (rituximab
    and other anti-CD20 agents), other immunosuppressants, protein loss, or
    lymphoid malignancy can reproduce the CVID laboratory phenotype and must
    be excluded before CVID is diagnosed.
  distinguishing_features:
  - History of B-cell depletion immunotherapy, immunosuppression, protein-losing state, or hematologic malignancy
  - Onset after a documented period of normal immunoglobulin levels
  - No requirement for a primary immune defect; immunoglobulins may recover after the cause is removed
  evidence:
  - reference: PMID:38792965
    reference_title: "A Nationwide Study of the Delayed Diagnosis and the Clinical Manifestations of Predominantly Antibody Deficiencies and CTLA4-Mediated Immune Dysregulation Syndrome in Greece."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      12 patients with "secondary" hypogammaglobulinemia due to a previous
      B-cell depletion immunotherapy for autoimmune or malignant disease several
      years ago
    explanation: >-
      The Greek nationwide cohort separated a secondary-hypogammaglobulinemia
      group with a typical CVID phenotype from true CVID, demonstrating the
      need for this exclusion.
- name: Monogenic inborn errors of immunity presenting as CVID
  description: >-
    Genetic work-up reassigns a subset of clinically diagnosed CVID patients
    to distinct IEIs classified in other IUIS tables — for example activated
    PI3K-delta syndrome, LRBA deficiency, and CTLA4 haploinsufficiency — with
    different prognoses and targeted treatments. See also the
    cvid_umbrella_cuts_across_the_iuis_tables discussion in the
    Predominantly Antibody Deficiencies IEIs grouping.
  distinguishing_features:
  - Early onset, positive family history, marked autoimmunity or lymphoproliferation raise the prior for a monogenic cause
  - A pathogenic variant in a non-CVID IUIS gene reclassifies the diagnosis
  - Targeted therapy may be available (e.g. abatacept for CTLA4/LRBA disease, PI3K-delta inhibitors for APDS)
  evidence:
  - reference: PMID:40079712
    reference_title: "Monogenic Common Variable Immunodeficiency (Mo-CVID) Score for Optimizing the Genetic Diagnosis in Pediatric CVID Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This discovery led us to consider a possible metamorphosis of CVID, which,
      once studied from a genetic perspective, actually reveals very different IEIs.
    explanation: >-
      States that genetically resolved CVID frequently proves to be a
      different IEI, the premise of this differential.
datasets:
- accession: geo:GSE299706
  title: Transcriptome regulation in T-cells and monocytes in patients with Common Variable Immunodeficiency
  description: A large subgroup of Common Variable Immunodeficiency (CVID) patients has autoimmune and inflammatory complications, associated with T cell and monocyte pathology, but the molecular mechanism for this CVID-subgroup is still elusive. To identify novel molecular pathways impacted in CVID T cells and monocytes, we examined the transcriptomic profiles in these cells from healthy control and the CVID patients in the subgroup with inflammatory complications.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 20
  publication: PMID:41991796
  notes: Identified by GEO DataSets index search for Common Variable Immunodeficiency (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE330223
  title: Convergence of cytokine dysregulation and antibody deficiency in common variable immunodeficiency with inflammatory complications
  description: 'Background: Noninfectious complications are the greatest cause of morbidity and mortality in common variable immunodeficiency (CVID), but their pathogenesis remains poorly defined. Objective: Using high-throughput approaches, we aimed to identify, correlate, and determine the significance of immunologic features of CVID with noninfectious complications (CVIDc). Methods: We simultaneously applied proteomics, RNA sequencing, and mass cytometry to a large cohort with primary antibody deficiency. Results: CVIDc is differentiated from uncomplicated CVID, other forms of primary antibody deficiency, and healthy controls by a distinct plasma proteomic profile.'
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 42
  publication: PMID:34146579
  notes: Identified by GEO DataSets index search for Common Variable Immunodeficiency (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE307095
  title: RNA-seq profiling of resting naive and CD27bright memory B cells and in vitro activated CD27bright memory B cells reveals differences in B-cell activation patterns in common variable immunodeficiency (CVID)
  description: To investigate the transcriptional differences during resting state and B-cell activation in healthy donors and patients with CVID, we sorted naive B cells and CD27bright memory B cells from the two groups and examined the resting state and TLR9 agonist (CpG)-activated CD27bright memory B cells.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 50
  publication: PMID:41124223
  notes: Identified by GEO DataSets index search for Common Variable Immunodeficiency (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
- accession: ega:EGAS50000000368
  title: COVID-19 progression and convalescence in common variable immunodeficiency patients
  description: Longitudinal analysis of single-cell RNAseq datasets of PBMCs from COVID-19 CVID patients and controls.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: SINGLE_CELL_RNA_SEQ
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Common Variable Immunodeficiency"); description-level mentions were not accepted. EGA study_type: Transcriptome Analysis. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'

📚

References & Deep Research

Deep Research

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

Falcon ▸

Disease Pathophysiology Research Template

Edison Scientific Literature 32 citations 2026-03-06T04:06:20.239384

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Pathophysiology Research Template

Target Disease

Disease Name: Common Variable Immunodeficiency
MONDO ID: (if available)
Category: Complex

Research Objectives

Please provide a comprehensive research report on the pathophysiology of Common Variable Immunodeficiency. Focus on the molecular and cellular mechanisms underlying disease progression.

Required Information

1. Core Pathophysiology

What are the primary pathophysiological mechanisms?
What molecular pathways are dysregulated?
What cellular processes are affected?

2. Key Molecular Players

Genes/Proteins: Which genes are causally involved or implicated?
Chemical Entities: What metabolites, drugs, or small molecules are relevant?
Cell Types: Which cell types are primarily affected?
Anatomical Locations: Which tissues/organs are involved?

3. Biological Processes (for GO annotation)

What biological processes (GO terms) are disrupted?
Consider: signaling pathways, metabolic processes, cellular responses, transport, etc.

4. Cellular Components

Where in the cell do key processes occur?
Consider: organelles, membrane compartments, extracellular space, etc.

5. Disease Progression

What is the sequence of events from initial trigger to clinical manifestation?
Are there distinct stages or phases?

6. Phenotypic Manifestations

What are the key clinical phenotypes?
How do they relate to the underlying mechanisms?

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic claims
Prioritize recent reviews and landmark papers
Include direct quotes where possible to support key statements

Output Format

Structure your response as a narrative that could be used to populate a disease knowledge base entry with: - Pathophysiology description - Gene/protein annotations with ontology terms (HGNC, GO) - Phenotype associations (HP terms) - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Evidence items with PMIDs

Comprehensive Research Report: Common Variable Immunodeficiency (CVID) Pathophysiology (Molecular/Cellular)

Disease identifiers and classification

Disease name: Common variable immunodeficiency (CVID)
MONDO ID: MONDO:0015517 (“common variable immunodeficiency”) as represented in Open Targets disease mapping ().
Category: Complex/heterogeneous inborn error of immunity (IEI) syndrome; increasingly partitioned into (i) polygenic/multifactorial “CVID” and (ii) monogenic “CVID-like” disorders (alhakim2024thescopeand pages 2-4).

1. Key concepts and definitions (current understanding)

Definition (clinical-immunologic)

CVID is defined by hypogammaglobulinemia (IgG ≥2 SD below age-adjusted mean, with low IgA and/or IgM), poor vaccine responses, and exclusion of secondary causes, reflecting failure to generate effective humoral immunity (sircana2023commonvariableimmunodeficiency pages 3-4). Mechanistically, it is centered on failure of B-cell terminal differentiation in germinal centers, leading to reduced plasma cells and memory B cells and inadequate antibody production (sircana2023commonvariableimmunodeficiency pages 3-4).

Epidemiology and baseline quantitative features

Estimated prevalence/incidence: commonly reported as ~1:25,000–1:50,000 (sircana2023commonvariableimmunodeficiency pages 3-4, barbati2024monogeniccommonvariable pages 1-5) and also described as ~1 in 20,000–50,000 (cunninghamrundles2024commonvariableimmunodeficiency pages 1-2).
Hypogammaglobulinemia depth: in two large cohorts, 85–94% of cases had IgG <4.5 g/L (alhakim2024thescopeand pages 2-4).
Familial aggregation: familial inheritance of CVID/IgA deficiency is reported at ~20% (alhakim2024thescopeand pages 2-4), with familial clustering estimates ~5–25% in other summaries (sircana2023commonvariableimmunodeficiency pages 3-4).

“CVID+” immune dysregulation endotype

Beyond infection susceptibility, a major conceptual advance is routine recognition of an “immune dysregulation” phenotype (often termed CVID+) with inflammatory/autoimmune complications: - >50% of patients have inflammatory and/or autoimmune complications (“CVID+”) and ~25% have autoimmunity (alhakim2024thescopeand pages 2-4). - In a cohort of 408 CVID patients, 122 (30%) had hematologic autoimmune manifestations (ITP, AIHA, Evans syndrome, neutropenia) (cunninghamrundles2024commonvariableimmunodeficiency pages 1-2).

2. Core pathophysiology (molecular and cellular mechanisms)

CVID is best understood as a syndrome of convergent failures in germinal-center (GC)–dependent humoral immunity and peripheral tolerance, arising from diverse genetic and non-genetic perturbations.

2.1 B-cell developmental/GC output failure (central axis)

A core feature is defective generation of class-switched memory B cells and plasma cells, reflecting impaired GC maturation and/or post-GC survival. - Reviews emphasize impaired differentiation into class-switched memory B cells and plasma cells, with reductions in mucosal sites and bone marrow noted in CVID cohorts (alhakim2024thescopeand pages 2-4). - A foundational mechanistic framing is “failure of B-cell terminal differentiation in germinal centers” with reduced plasma cells/memory B cells (sircana2023commonvariableimmunodeficiency pages 3-4).

2.2 BAFF/APRIL–TACI axis and NF-κB signaling (B-cell survival and plasma cell differentiation)

The BAFF/APRIL system is repeatedly implicated in CVID pathophysiology, connecting survival signaling with plasma cell generation and tolerance. - BAFF/APRIL bind overlapping receptors, and TACI activation triggers NFAT, NF-κB, and AP‑1 to promote antibody production and plasma cell differentiation (peng2023commonvariableimmunodeficiency pages 7-9). - TNFRSF13B (TACI) variants are associated with CVID/sIgAD; heterozygous variants can promote autoimmunity by preserving autoreactive B cells responsive to Tfh stimulation (peng2023commonvariableimmunodeficiency pages 7-9). - Population genetics highlight incomplete penetrance: common TNFRSF13B alleles (e.g., C104R, A181E) can abrogate signaling yet have substantial asymptomatic carriage (∼25% asymptomatic carriers in some family-based observations; allele frequency ~0.5–0.7% in Europeans) (peng2023commonvariableimmunodeficiency pages 7-9). - NF-κB pathway lesions are central; both canonical and non-canonical NF-κB pathways are key to B-cell development/function (peng2023commonvariableimmunodeficiency pages 9-10). NFKB1 loss-of-function/haploinsufficiency is linked to CVID and described as “the most common monogenic cause” in Europeans (peng2023commonvariableimmunodeficiency pages 22-23).

2.3 PI3Kδ–AKT–mTOR pathway dysregulation (APDS and GC disruption)

Hyperactive PI3K signaling provides a clear mechanistic bridge between signaling gain-of-function, GC collapse, and CVID-like antibody deficiency. - In APDS1 (PIK3CD GOF), disease includes “uncontrolled lymphocyte proliferation, accelerated T cell maturation and senescence, and impaired B cell maturation” (direct quote) (peng2023commonvariableimmunodeficiency pages 9-10). - Hyperactive PI3K signaling can disrupt GC structure and interfere with CSR (class-switch recombination), yielding a hyper-IgM–like phenotype (peng2023commonvariableimmunodeficiency pages 9-10).

2.4 T-cell help and tolerance checkpoints (Tfh/Treg/CTLA-4–LRBA)

Although classified as an antibody deficiency, a substantial subset involves impaired or dysregulated T-cell help and tolerance. - T-cell defects are reported in ~one-third of CVID cases (alhakim2024thescopeand pages 2-4). - Defects in central and peripheral tolerance pathways and dysregulated Tfh responses can impair CSR/memory B-cell generation (peng2023commonvariableimmunodeficiency pages 12-13). - CTLA4 haploinsufficiency and LRBA deficiency exemplify a mechanism where defective inhibitory costimulation and altered CTLA-4 trafficking produce hypogammaglobulinemia with autoimmunity/organ infiltration (enteropathy, interstitial lung disease) (peng2023commonvariableimmunodeficiency pages 13-15, tessarin2023monogenicformsof pages 4-5). LRBA mutations (identified in ~140 patients) can cause functional CTLA-4 loss, autophagy-related abnormalities (reduced LC3 localization), and failure of B cells to form plasmablasts; marked clinical responses to CTLA-4–Ig (abatacept) are reported (peng2023commonvariableimmunodeficiency pages 13-15).

2.5 Additional mechanistic routes (DNA repair, transcriptional regulation, organelle/trafficking)

CVID encompasses many routes beyond classical BCR signaling. - CSR/SHM defects can occur via AID trafficking perturbations (e.g., CTNNBL1 effect on AID nuclear translocation) leading to impaired SHM and inefficient GC reactions, with risk of autoreactive clones and autoimmunity (peng2023commonvariableimmunodeficiency pages 12-13). - Transcriptional regulators (e.g., BACH2 haploinsufficiency) disrupt T/B specification and CSR/plasmablast differentiation (peng2023commonvariableimmunodeficiency pages 13-15). - Broader “organelle/trafficking” mechanisms (e.g., SEC61A1, SH3KBP1, DEF6, SAMD9) affect ER homeostasis, calcium flux, mitochondrial health and receptor signaling and can produce CVID-like phenotypes with autoimmunity/autoinflammation (peng2023commonvariableimmunodeficiency pages 13-15).

3. Key molecular players (genes/proteins, cells, tissues, chemicals)

3.1 Genes/Proteins (HGNC symbols)

CVID and CVID-like disorders have substantial genetic heterogeneity spanning B-cell intrinsic and immune regulatory genes.

High-confidence/commonly implicated (examples): - NF-κB signaling: NFKB1, NFKB2 (peng2023commonvariableimmunodeficiency pages 22-23, peng2023commonvariableimmunodeficiency pages 9-10). - BAFF/APRIL/TACI axis: TNFRSF13B (TACI), TNFRSF13C (BAFF-R) (peng2023commonvariableimmunodeficiency pages 7-9, sircana2023commonvariableimmunodeficiency pages 3-4, sircana2023commonvariableimmunodeficiency pages 4-6). - BCR co-receptors: CD19, CD81, MS4A1 (CD20), CR2 (CD21) (alhakim2024thescopeand pages 2-4, sircana2023commonvariableimmunodeficiency pages 3-4). - PI3K pathway: PIK3CD, PIK3R1, PTEN (peng2023commonvariableimmunodeficiency pages 9-10, tessarin2023monogenicformsof pages 1-2). - Immune regulation: CTLA4, LRBA (peng2023commonvariableimmunodeficiency pages 13-15, tessarin2023monogenicformsof pages 4-5). - Transcription/regulatory: IKZF1, BACH2, STAT3, STAT1, SOCS1 (peng2023commonvariableimmunodeficiency pages 12-13, peng2023commonvariableimmunodeficiency pages 9-10).

Recent (2024) pediatric cohort genetic yield and gene list: In a pediatric CVID cohort (n=32), variants were identified in 17 (53%), including SLC39A7, PRKCD, STAT3, NFKB1, PIK3R1, PLCG2, RFXANK, PRKDC, TNFRSF13B, and novel SPI1 and NFKB1 variants (barbati2024monogeniccommonvariable pages 1-5).

Open Targets disease–gene associations: Open Targets lists top CVID-associated targets including TNFRSF13B, LRBA, IKZF1, NFKB2, ICOS, and CD19 (). (Note: Open Targets is an evidence integration resource; mechanistic interpretation still relies on primary/review literature.)

3.2 Chemical entities / therapeutics (CHEBI-relevant entities)

While CVID is not typically “metabolic,” small molecules and biologics are directly relevant via pathway-targeted therapy: - Abatacept (CTLA-4–Ig fusion protein): used as targeted immunomodulation in CTLA-4 haploinsufficiency / LRBA deficiency, with reported high efficacy for chronic enteropathy and lymphoproliferation and variable results for cytopenias/neurologic features; for GLILD, full/partial resolution reported in up to ~70% (tessarin2023monogenicformsof pages 4-5). A case report in a CVID patient with CTLA4/LRBA variants described rapid regression of clinical/lab findings and weight gain after abatacept initiation (). - PI3K inhibitors (APDS): direct PI3K inhibitor approval and clinical improvement in APDS is highlighted in recent reviews (tessarin2023monogenicformsof pages 1-2, tessarin2023monogenicformsof pages 4-5). - Sirolimus (mTOR inhibitor): reported benefit in some immune dysregulation settings to enhance Treg responses (tessarin2023monogenicformsof pages 4-5). - Immunoglobulin replacement therapy (IgRT; IVIG/SCIG): mainstay therapy that reduces infectious episode rate/severity (tessarin2023monogenicformsof pages 1-2, cunninghamrundles2024commonvariableimmunodeficiency pages 1-2).

3.3 Cell types (Cell Ontology; CL terms suggested)

Key affected or mechanistically implicated immune cell types include: - B cell (CL:0000236) and differentiation states: naïve B cell, memory B cell, class-switched memory B cell, plasmablast, plasma cell (central in terminal differentiation failure) (sircana2023commonvariableimmunodeficiency pages 3-4, alhakim2024thescopeand pages 2-4). - T follicular helper (Tfh) cell (CL:0002057) and regulatory T cell (Treg; CL:0000815): dysregulated help/tolerance links to failed CSR and autoimmunity (peng2023commonvariableimmunodeficiency pages 12-13, peng2023commonvariableimmunodeficiency pages 13-15, alhakim2024thescopeand pages 2-4). - Natural killer cell (CL:0000623): NK defects are discussed in CVID-like phenotypes such as NFKB2-mutated disease (peng2023commonvariableimmunodeficiency pages 22-23) and broader CVID heterogeneity includes NK involvement (alhakim2024thescopeand pages 2-4).

3.4 Anatomical locations (UBERON suggested)

Key sites where the pathophysiology manifests: - Secondary lymphoid organs (UBERON:0002106): lymph nodes (UBERON:0000029), spleen (UBERON:0002106) as germinal center sites supporting CSR and GC output (sircana2023commonvariableimmunodeficiency pages 3-4). - Bone marrow (UBERON:0002371): plasma cell survival/maintenance; reductions in plasma cells noted (alhakim2024thescopeand pages 2-4). - Gastrointestinal tract (e.g., small intestine UBERON:0002108; colon UBERON:0001155; stomach UBERON:0000945): CVID enteropathy is associated with plasma-cell paucity across much of the GI tract (except esophagus) (marsden2024paucityofgastrointestinal pages 1-2). - Lung (UBERON:0002048): granulomatous-lymphocytic interstitial lung disease (GLILD) is part of immune dysregulation phenotypes responsive in some cases to abatacept (tessarin2023monogenicformsof pages 4-5).

4. Biological processes and pathways (GO-oriented annotation candidates)

Below are GO-aligned biological processes strongly supported by the cited literature as disrupted in CVID/CVID-like disease: - B cell differentiation / plasma cell differentiation (GO:0030183; GO:0002314) (sircana2023commonvariableimmunodeficiency pages 3-4, alhakim2024thescopeand pages 2-4). - Immunoglobulin production (GO:0002377) and humoral immune response (GO:0006959) (sircana2023commonvariableimmunodeficiency pages 3-4, alhakim2024thescopeand pages 2-4). - Immunoglobulin class switch recombination (GO:0042167) and somatic hypermutation of immunoglobulin genes (GO:0016446) (peng2023commonvariableimmunodeficiency pages 12-13, peng2023commonvariableimmunodeficiency pages 9-10). - NF-κB signaling (GO:0043122) (peng2023commonvariableimmunodeficiency pages 22-23, peng2023commonvariableimmunodeficiency pages 9-10). - Phosphatidylinositol 3-kinase signaling / AKT-mTOR signaling (GO:0014065; GO:0032008) (peng2023commonvariableimmunodeficiency pages 9-10, tessarin2023monogenicformsof pages 1-2). - T cell co-stimulation / negative regulation of T cell activation (GO:0050863; GO:0050868) (CTLA-4/LRBA axis) (peng2023commonvariableimmunodeficiency pages 13-15, tessarin2023monogenicformsof pages 4-5). - Immune tolerance / regulation of autoimmunity (broadly supported conceptually by tolerance gene involvement and autoimmune enrichment) (peng2023commonvariableimmunodeficiency pages 12-13, alhakim2024thescopeand pages 2-4, cunninghamrundles2024commonvariableimmunodeficiency pages 1-2).

5. Cellular components (GO-CC candidates)

Literature-supported cellular compartments where key pathogenic processes occur include: - Germinal center microenvironment (anatomical/functional compartment; mechanistically central to CSR/SHM and selection) (sircana2023commonvariableimmunodeficiency pages 3-4, peng2023commonvariableimmunodeficiency pages 12-13). - Plasma cell niches in bone marrow and mucosa (alhakim2024thescopeand pages 2-4). - Cell surface receptor complexes (BCR co-receptors CD19/CD81; costimulatory CTLA-4) (alhakim2024thescopeand pages 2-4, peng2023commonvariableimmunodeficiency pages 13-15). - Endomembrane trafficking compartments relevant to CTLA-4/LRBA trafficking and organelle/ER homeostasis in some monogenic forms (peng2023commonvariableimmunodeficiency pages 13-15).

6. Disease progression: mechanistic sequence (model)

A practical progression model consistent with current reviews is: 1. Predisposition/initiating defects: inherited or de novo variants affecting B-cell activation/survival (NF-κB; BAFF/APRIL/TACI), GC help and regulation (ICOS, Tfh/Treg axis; CTLA4/LRBA), or signaling/metabolic checkpoints (PI3Kδ/AKT/mTOR) (peng2023commonvariableimmunodeficiency pages 7-9, peng2023commonvariableimmunodeficiency pages 9-10, peng2023commonvariableimmunodeficiency pages 13-15). 2. Germinal center failure or mis-selection: impaired CSR/SHM, altered selection thresholds, and reduced generation of long-lived plasma cells/switched memory B cells (peng2023commonvariableimmunodeficiency pages 12-13, sircana2023commonvariableimmunodeficiency pages 3-4, peng2023commonvariableimmunodeficiency pages 9-10). 3. Hypogammaglobulinemia and impaired vaccine responses: reduced effective antibody titers, recurrent infections, and persistent antigenic stimulation (alhakim2024thescopeand pages 2-4, sircana2023commonvariableimmunodeficiency pages 3-4). 4. Immune dysregulation amplification (“CVID+”): chronic inflammation, breakdown of tolerance, autoimmunity, lymphoproliferation, organ infiltration (enteropathy, lung disease), and increased morbidity/mortality in severe subsets (alhakim2024thescopeand pages 2-4, cunninghamrundles2024commonvariableimmunodeficiency pages 1-2, tessarin2023monogenicformsof pages 4-5).

7. Phenotypic manifestations and mechanism links (HP-oriented)

Selected phenotype associations (HP terms suggested) grounded in the evidence: - Hypogammaglobulinemia (HP:0004313) and recurrent infections (HP:0002719) arise from impaired plasma cell/memory B-cell output and reduced Ig levels (alhakim2024thescopeand pages 2-4, sircana2023commonvariableimmunodeficiency pages 3-4). - Autoimmune cytopenias (e.g., immune thrombocytopenia HP:0001891; autoimmune hemolytic anemia HP:0001890): observed in 30% (122/408) in one cohort, reflecting immune dysregulation/tolerance loss (cunninghamrundles2024commonvariableimmunodeficiency pages 1-2). - Enteropathy / chronic diarrhea (HP:0002028): immune-mediated enteropathy is a hallmark of CTLA4/LRBA dysregulation subsets and broader CVID-E; GI biopsies frequently show plasma-cell paucity (tessarin2023monogenicformsof pages 4-5, marsden2024paucityofgastrointestinal pages 1-2). - Interstitial lung disease / GLILD (HP:0006530): part of immune dysregulation; abatacept responses reported in some cohorts (tessarin2023monogenicformsof pages 4-5).

8. Recent developments (prioritizing 2023–2024)

8.1 Genetics: increasing recognition of monogenic drivers and stratification tools

Recent summaries emphasize that while earlier estimates suggested 2–10% monogenic causes, newer genomic analyses identify monogenic causes in ~20–50% of CVID/CVID-like cases, and monogenic CVID-like entities are increasingly separated from “true CVID” (alhakim2024thescopeand pages 2-4).
In hematology-focused CVID cohorts, monogenic etiologies are now estimated at ~25–30%, with 43% of patients with hematologic autoimmunity (53/122) having one or more genetic mutations considered related to the immune defect (cunninghamrundles2024commonvariableimmunodeficiency pages 1-2).
A 2024 pediatric cohort (n=32) achieved 53% gene-variant identification and proposed a clinical/immunologic scoring system (Mo-CVID score) to prioritize genetic work-up, highlighting higher yield in early onset, positive family history, autoimmunity, lymphoproliferation, and specific immunologic alterations (barbati2024monogeniccommonvariable pages 1-5).

8.2 Diagnostic yield of sequencing in PID (generalizable implementation evidence)

A 2024 meta-analysis in suspected PIDs (not CVID-specific) provides implementable expectations for NGS: - Across 29 studies and 5,847 patients, pooled NGS diagnostic detection rate was 42% (95% CI 0.29–0.54) (chen2024diagnosticyieldof pages 1-3). - Yield was higher with a family history (58%) vs none (33%) (chen2024diagnosticyieldof pages 1-3). This supports real-world adoption of NGS/WES/WGS in antibody deficiency evaluation pathways, especially in familial/early-onset/complex phenotypes (chen2024diagnosticyieldof pages 1-3, barbati2024monogeniccommonvariable pages 1-5).

8.3 Targeted therapies: pathway-directed treatment for CVID-like immune dysregulation

2023–2024 reviews highlight increasing implementation of abatacept for CTLA4/LRBA-associated immune dysregulation and PI3K inhibitors for APDS (tessarin2023monogenicformsof pages 1-2, tessarin2023monogenicformsof pages 4-5).
A 2023 case report describes abatacept benefit in a patient with severe immune-mediated enteropathy and CTLA4/LRBA variants after a prior CVID diagnosis ().

8.4 GI pathophysiology: standardizing plasma-cell paucity metrics in CVID enteropathy

A 2024 systematic review of GI plasma cells proposes standardized quantification: - Plasma cell paucity is reported across studies in ~50–90% of CVID enteropathy biopsies (marsden2024paucityofgastrointestinal pages 1-2). - Proposed conservative definitions: <10 plasma cells/HPF at 40×, or 1–5% of mononuclear cells, recorded across ≥3 sections and ≥2 biopsies (marsden2024paucityofgastrointestinal pages 1-2, marsden2024paucityofgastrointestinal pages 5-7). - Colon biopsies show paucity/absence in ~60–85% in most studies; IgA+ plasma cells are frequently most reduced (marsden2024paucityofgastrointestinal pages 3-5).

9. Current applications and real-world implementations

9.1 Standard of care

Immunoglobulin replacement therapy (IgRT) (IVIG/SCIG) is the “mainstay,” with evidence that it reduces infectious episode rates and severity (tessarin2023monogenicformsof pages 1-2) and is described as standard management when antibody production is insufficient (cunninghamrundles2024commonvariableimmunodeficiency pages 1-2).

9.2 Precision medicine in monogenic CVID-like disease

Abatacept (CTLA-4–Ig) is “widely implemented” as bridge therapy in CTLA-4/LRBA defects with good results in key inflammatory manifestations (tessarin2023monogenicformsof pages 1-2, tessarin2023monogenicformsof pages 4-5).
Direct PI3K inhibitors have been approved for APDS and show encouraging clinical/immunological control in that defined subgroup (tessarin2023monogenicformsof pages 1-2, tessarin2023monogenicformsof pages 4-5).
Sirolimus is described as beneficial in some settings to enhance T-reg responses (tessarin2023monogenicformsof pages 4-5).

9.3 Diagnostic implementation: integrating immunophenotype + genomics

The 2024 pediatric Mo-CVID work and 2024 PID sequencing meta-analysis both support structured criteria (clinical and immunologic) to prioritize and interpret NGS/WES in clinical practice (barbati2024monogeniccommonvariable pages 1-5, chen2024diagnosticyieldof pages 1-3).

10. Expert opinions / authoritative synthesis (review-derived analysis)

A central interpretive position is that “CVID” is an umbrella phenotype with “incredible diversity of pathophysiological mechanisms,” where genotyping is increasingly necessary to resolve distinct disease entities and guide targeted therapy (peng2023commonvariableimmunodeficiency pages 12-13, alhakim2024thescopeand pages 2-4).
Mechanistically, authoritative reviews emphasize convergent failure of GC outputs via disrupted NF-κB, PI3K/AKT/mTOR, and BAFF/APRIL/TACI signaling, plus immune regulatory lesions (CTLA4/LRBA) that produce combined antibody deficiency and organ-specific inflammation (peng2023commonvariableimmunodeficiency pages 7-9, peng2023commonvariableimmunodeficiency pages 9-10, peng2023commonvariableimmunodeficiency pages 13-15, tessarin2023monogenicformsof pages 4-5).

Structured knowledge-base elements

Pathophysiology description (knowledge-base ready)

CVID is a heterogeneous IEI syndrome characterized by hypogammaglobulinemia and impaired vaccine responses due to failure of germinal center–dependent B-cell terminal differentiation and reduced production/maintenance of class-switched memory B cells and plasma cells. Pathogenic mechanisms converge on (i) B-cell survival/differentiation signaling (BAFF/APRIL/TACI and NF-κB), (ii) GC organization and CSR/SHM (including PI3Kδ hyperactivation and AID-related mechanisms), and (iii) immune tolerance/checkpoint regulation (CTLA-4/LRBA and related Tfh/Treg dysregulation), leading not only to infections but frequently to immune dysregulation (autoimmunity, lymphoproliferation, enteropathy, and interstitial lung disease) in a substantial fraction of patients (peng2023commonvariableimmunodeficiency pages 7-9, sircana2023commonvariableimmunodeficiency pages 3-4, peng2023commonvariableimmunodeficiency pages 9-10, peng2023commonvariableimmunodeficiency pages 13-15, alhakim2024thescopeand pages 2-4, cunninghamrundles2024commonvariableimmunodeficiency pages 1-2, marsden2024paucityofgastrointestinal pages 1-2).

Gene/protein annotations (HGNC; representative set)

NFKB1, NFKB2 — NF-κB signaling; monogenic CVID-like disease; NFKB1 described as a common monogenic cause (peng2023commonvariableimmunodeficiency pages 22-23, peng2023commonvariableimmunodeficiency pages 9-10).
TNFRSF13B (TACI), TNFRSF13C (BAFF-R) — BAFF/APRIL signaling; association with CVID/sIgAD and autoimmunity risk in some carriers (peng2023commonvariableimmunodeficiency pages 7-9, sircana2023commonvariableimmunodeficiency pages 4-6).
PIK3CD, PIK3R1 — PI3Kδ pathway; APDS with CSR/GC disruption and CVID-like phenotype; PI3K inhibitors approved for APDS (peng2023commonvariableimmunodeficiency pages 9-10, tessarin2023monogenicformsof pages 1-2, tessarin2023monogenicformsof pages 4-5).
CTLA4, LRBA — immune checkpoint/trafficking; immune dysregulation with antibody deficiency; abatacept widely used (peng2023commonvariableimmunodeficiency pages 13-15, tessarin2023monogenicformsof pages 4-5).
ICOS — T-cell costimulation and GC Tfh help; included among key CVID genes (alhakim2024thescopeand pages 2-4).

GO biological process candidates (selected)

Immunoglobulin class switch recombination; somatic hypermutation; B-cell differentiation; plasma cell differentiation; NF-κB signaling; PI3K/AKT/mTOR signaling; regulation of T-cell activation/co-stimulation (peng2023commonvariableimmunodeficiency pages 12-13, peng2023commonvariableimmunodeficiency pages 7-9, peng2023commonvariableimmunodeficiency pages 9-10, peng2023commonvariableimmunodeficiency pages 13-15).

Cell types (CL candidates)

B cell, plasma cell, T follicular helper cell, regulatory T cell, natural killer cell (alhakim2024thescopeand pages 2-4, peng2023commonvariableimmunodeficiency pages 13-15).

Anatomical locations (UBERON candidates)

Lymph node/spleen (germinal centers), bone marrow, small intestine/colon/stomach, lung (alhakim2024thescopeand pages 2-4, sircana2023commonvariableimmunodeficiency pages 3-4, marsden2024paucityofgastrointestinal pages 3-5, marsden2024paucityofgastrointestinal pages 1-2).

Chemical entities (selected)

Abatacept; PI3K inhibitors (APDS); sirolimus; immunoglobulin replacement products (tessarin2023monogenicformsof pages 1-2, tessarin2023monogenicformsof pages 4-5).

Evidence tables

Mechanistic Theme	Key Cells / Tissues	Key Pathways / Molecules	Representative Genes	Key Evidence / Statistics
B-cell Maturation & Survival Defects	B cells (Bone marrow, Lymph nodes), Plasma cells	BAFF/APRIL/TACI signaling; NF-κB signaling (canonical/non-canonical)	TNFRSF13B (TACI), TNFRSF13C (BAFF-R), NFKB1, NFKB2, CD19, CD20, CD21, CD81	• 85–94% of cases show IgG <4.5 g/L (alhakim2024thescopeand pages 2-4). • TACI/BAFF-R defects found in 20–30% of patients (sircana2023commonvariableimmunodeficiency pages 4-6). • NFKB1 LOF variants are a common monogenic cause (peng2023commonvariableimmunodeficiency pages 22-23).
Class-Switch & Plasma Cell Differentiation	Germinal Center B cells, Plasma cells	CD40/CD40L; ICOS/ICOS-L; Cytokine signaling (IL-21, IL-10); Transcription factors	ICOS, CD40LG, AICDA, STAT3, BACH2, PRKCD, IKZF1	• Failure of terminal differentiation into memory B cells and plasma cells is central (alhakim2024thescopeand pages 2-4, sircana2023commonvariableimmunodeficiency pages 3-4). • Gastrointestinal plasma cell paucity observed in 50–90% of CVID enteropathy biopsies (marsden2024paucityofgastrointestinal pages 2-3, marsden2024paucityofgastrointestinal pages 1-2).
Immune Dysregulation & Tolerance Loss	Regulatory T cells (Tregs), Tfh cells, Autoreactive B cells	CTLA-4 checkpoint; Transendocytosis; Autophagy	CTLA4, LRBA, FOXP3, AIRE	• CTLA4 mutations (1.7–20.8%) and LRBA deficiency (0.9–7.2%) are major causes of immune dysregulation (tessarin2023monogenicformsof pages 4-5). • Over 50% of patients have inflammatory/autoimmune complications (alhakim2024thescopeand pages 2-4).
PI3K/AKT/mTOR Signaling	B cells, T cells	PI3Kδ hyperactivation (APDS); AKT/mTOR signaling	PIK3CD, PIK3R1, PTEN, TTC7A	• PIK3CD GOF causes APDS with lymphoproliferation and exhausted T cells (peng2023commonvariableimmunodeficiency pages 9-10, tessarin2023monogenicformsof pages 1-2). • Direct PI3K inhibitors approved for APDS (tessarin2023monogenicformsof pages 1-2, tessarin2023monogenicformsof pages 4-5).
T-cell Dysfunction & Help	CD4+ T cells, Tfh cells	T-cell activation; Cytokine production; Cytoskeletal dynamics	ICOS, MAGT1, PLCG2, RAC2, DOCK8	• T-cell defects documented in ~1/3 of CVID cases (alhakim2024thescopeand pages 2-4). • MAGT1 defects link magnesium transport to T-cell activation and EBV control (peng2023commonvariableimmunodeficiency pages 22-23).
Diagnostic Yield & Genetics	Systemic	NGS (WES/Targeted Panels)	N/A	• Monogenic causes identified in 20–50% of cases (alhakim2024thescopeand pages 2-4, cunninghamrundles2024commonvariableimmunodeficiency pages 1-2). • Diagnostic yield of NGS in PIDs is ~42%, higher with family history (~58%) (chen2024diagnosticyieldof pages 1-3).

Table: Summary of core pathophysiological mechanisms in Common Variable Immunodeficiency, including affected cells, pathways, representative genes, and key statistical evidence from recent literature.

Key references (with URLs and publication timing)

Peng XP, Caballero-Oteyza A, Grimbacher B. Common Variable Immunodeficiency: More Pathways than Roads to Rome. Annual Review of Pathology. Jan 2023. https://doi.org/10.1146/annurev-pathmechdis-031521-024229 (peng2023commonvariableimmunodeficiency pages 12-13)
Sircana MC et al. Common Variable Immunodeficiency and Selective IgA Deficiency: Focus on Autoimmune Manifestations and Their Pathogenesis. Int J Transl Med. Oct 2023. https://doi.org/10.3390/ijtm3040031 (sircana2023commonvariableimmunodeficiency pages 3-4)
Tessarin G et al. Monogenic forms of common variable immunodeficiency and implications on target therapeutic approaches. Curr Opin Allergy Clin Immunol. Sep 2023. https://doi.org/10.1097/aci.0000000000000947 (tessarin2023monogenicformsof pages 1-2)
Al‑Hakim A et al. The Scope and Impact of Viral Infections in CVID and CVID-like Disorders: A Literature Review. J Clin Med. Mar 2024. https://doi.org/10.3390/jcm13061717 (alhakim2024thescopeand pages 2-4)
Chen Y et al. Diagnostic yield of next-generation sequencing in suspect primary immunodeficiencies diseases: a systematic review and meta-analysis. Clin Exp Med. Jun 2024. https://doi.org/10.1007/s10238-024-01392-2 (chen2024diagnosticyieldof pages 1-3)
Cunningham‑Rundles C et al. Common variable immunodeficiency: autoimmune cytopenias and advances in molecular diagnosis. Hematology (ASH Education). Dec 2024. https://doi.org/10.1182/hematology.2024000538 (cunninghamrundles2024commonvariableimmunodeficiency pages 1-2)
Marsden JWN et al. Paucity of gastrointestinal plasma cells in common variable immunodeficiency. Curr Opin Allergy Clin Immunol. Oct 2024. https://doi.org/10.1097/aci.0000000000001040 (marsden2024paucityofgastrointestinal pages 1-2)

Notes on limitations of this synthesis

This report is constrained to mechanisms and quantitative statistics present in the retrieved full-text excerpts; some CVID-specific sequencing yield estimates and mechanistic details for particular pathways may require additional primary studies not yet retrieved in this run.
Some evidence items above (e.g., abatacept response rates) are derived from authoritative reviews summarizing multiple cohorts; interpretation should consider underlying study heterogeneity (tessarin2023monogenicformsof pages 4-5).

References

(alhakim2024thescopeand pages 2-4): Adam Al-Hakim, Mark Kacar, and Sinisa Savic. The scope and impact of viral infections in common variable immunodeficiency (cvid) and cvid-like disorders: a literature review. Journal of Clinical Medicine, 13:1717, Mar 2024. URL: https://doi.org/10.3390/jcm13061717, doi:10.3390/jcm13061717. This article has 8 citations.
(sircana2023commonvariableimmunodeficiency pages 3-4): Marta Chiara Sircana, Gianpaolo Vidili, Antonio Gidaro, Alessandro Palmerio Delitala, Fabiana Filigheddu, Roberto Castelli, and Roberto Manetti. Common variable immunodeficiency and selective iga deficiency: focus on autoimmune manifestations and their pathogenesis. International Journal of Translational Medicine, 3:432-460, Oct 2023. URL: https://doi.org/10.3390/ijtm3040031, doi:10.3390/ijtm3040031. This article has 7 citations.
(barbati2024monogeniccommonvariable pages 1-5): Federica Barbati, Lorenzo Lodi, Silvia Boscia, Martina Cortimiglia, Elisa Calistri, Francesca Quaranta, Laura Maggi, Alessio Mazzoni, Boaz Palterer, Francesco Annunziato, Chiara Azzari, and Silvia Ricci. Monogenic common variable immunodeficiency (mo-cvid) score for optimizing the diagnostic metamorphosis in pediatric cvid cohort. Unknown journal, Jun 2024. URL: https://doi.org/10.21203/rs.3.rs-4438029/v1, doi:10.21203/rs.3.rs-4438029/v1.
(cunninghamrundles2024commonvariableimmunodeficiency pages 1-2): Charlotte Cunningham-Rundles, Jean-Laurent Casanova, and Bertrand Boisson. Common variable immunodeficiency: autoimmune cytopenias and advances in molecular diagnosis. Hematology, 2024:137-142, Dec 2024. URL: https://doi.org/10.1182/hematology.2024000538, doi:10.1182/hematology.2024000538. This article has 10 citations and is from a peer-reviewed journal.
(peng2023commonvariableimmunodeficiency pages 7-9): Xiao P. Peng, Andrés Caballero-Oteyza, and Bodo Grimbacher. Common variable immunodeficiency: more pathways than roads to rome. Jan 2023. URL: https://doi.org/10.1146/annurev-pathmechdis-031521-024229, doi:10.1146/annurev-pathmechdis-031521-024229. This article has 65 citations and is from a domain leading peer-reviewed journal.
(peng2023commonvariableimmunodeficiency pages 9-10): Xiao P. Peng, Andrés Caballero-Oteyza, and Bodo Grimbacher. Common variable immunodeficiency: more pathways than roads to rome. Jan 2023. URL: https://doi.org/10.1146/annurev-pathmechdis-031521-024229, doi:10.1146/annurev-pathmechdis-031521-024229. This article has 65 citations and is from a domain leading peer-reviewed journal.
(peng2023commonvariableimmunodeficiency pages 22-23): Xiao P. Peng, Andrés Caballero-Oteyza, and Bodo Grimbacher. Common variable immunodeficiency: more pathways than roads to rome. Jan 2023. URL: https://doi.org/10.1146/annurev-pathmechdis-031521-024229, doi:10.1146/annurev-pathmechdis-031521-024229. This article has 65 citations and is from a domain leading peer-reviewed journal.
(peng2023commonvariableimmunodeficiency pages 12-13): Xiao P. Peng, Andrés Caballero-Oteyza, and Bodo Grimbacher. Common variable immunodeficiency: more pathways than roads to rome. Jan 2023. URL: https://doi.org/10.1146/annurev-pathmechdis-031521-024229, doi:10.1146/annurev-pathmechdis-031521-024229. This article has 65 citations and is from a domain leading peer-reviewed journal.
(peng2023commonvariableimmunodeficiency pages 13-15): Xiao P. Peng, Andrés Caballero-Oteyza, and Bodo Grimbacher. Common variable immunodeficiency: more pathways than roads to rome. Jan 2023. URL: https://doi.org/10.1146/annurev-pathmechdis-031521-024229, doi:10.1146/annurev-pathmechdis-031521-024229. This article has 65 citations and is from a domain leading peer-reviewed journal.
(tessarin2023monogenicformsof pages 4-5): Giulio Tessarin, Manuela Baronio, and Vassilios Lougaris. Monogenic forms of common variable immunodeficiency and implications on target therapeutic approaches. Current Opinion in Allergy and Clinical Immunology, 23:461-466, Sep 2023. URL: https://doi.org/10.1097/aci.0000000000000947, doi:10.1097/aci.0000000000000947. This article has 7 citations and is from a peer-reviewed journal.
(sircana2023commonvariableimmunodeficiency pages 4-6): Marta Chiara Sircana, Gianpaolo Vidili, Antonio Gidaro, Alessandro Palmerio Delitala, Fabiana Filigheddu, Roberto Castelli, and Roberto Manetti. Common variable immunodeficiency and selective iga deficiency: focus on autoimmune manifestations and their pathogenesis. International Journal of Translational Medicine, 3:432-460, Oct 2023. URL: https://doi.org/10.3390/ijtm3040031, doi:10.3390/ijtm3040031. This article has 7 citations.
(tessarin2023monogenicformsof pages 1-2): Giulio Tessarin, Manuela Baronio, and Vassilios Lougaris. Monogenic forms of common variable immunodeficiency and implications on target therapeutic approaches. Current Opinion in Allergy and Clinical Immunology, 23:461-466, Sep 2023. URL: https://doi.org/10.1097/aci.0000000000000947, doi:10.1097/aci.0000000000000947. This article has 7 citations and is from a peer-reviewed journal.
(marsden2024paucityofgastrointestinal pages 1-2): Jan Willem N. Marsden, Miangela M. Laclé, Mirjam Severs, and Helen Louisa Leavis. Paucity of gastrointestinal plasma cells in common variable immunodeficiency. Oct 2024. URL: https://doi.org/10.1097/aci.0000000000001040, doi:10.1097/aci.0000000000001040. This article has 8 citations and is from a peer-reviewed journal.
(chen2024diagnosticyieldof pages 1-3): Yingying Chen, Dongrui Li, Jiawen Yin, Jinglin Xiong, Min Xu, Qing Qi, and Wenlin Yang. Diagnostic yield of next-generation sequencing in suspect primary immunodeficiencies diseases: a systematic review and meta-analysis. Clinical and Experimental Medicine, Jun 2024. URL: https://doi.org/10.1007/s10238-024-01392-2, doi:10.1007/s10238-024-01392-2. This article has 8 citations and is from a peer-reviewed journal.
(marsden2024paucityofgastrointestinal pages 5-7): Jan Willem N. Marsden, Miangela M. Laclé, Mirjam Severs, and Helen Louisa Leavis. Paucity of gastrointestinal plasma cells in common variable immunodeficiency. Oct 2024. URL: https://doi.org/10.1097/aci.0000000000001040, doi:10.1097/aci.0000000000001040. This article has 8 citations and is from a peer-reviewed journal.
(marsden2024paucityofgastrointestinal pages 3-5): Jan Willem N. Marsden, Miangela M. Laclé, Mirjam Severs, and Helen Louisa Leavis. Paucity of gastrointestinal plasma cells in common variable immunodeficiency. Oct 2024. URL: https://doi.org/10.1097/aci.0000000000001040, doi:10.1097/aci.0000000000001040. This article has 8 citations and is from a peer-reviewed journal.
(marsden2024paucityofgastrointestinal pages 2-3): Jan Willem N. Marsden, Miangela M. Laclé, Mirjam Severs, and Helen Louisa Leavis. Paucity of gastrointestinal plasma cells in common variable immunodeficiency. Oct 2024. URL: https://doi.org/10.1097/aci.0000000000001040, doi:10.1097/aci.0000000000001040. This article has 8 citations and is from a peer-reviewed journal.

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1. Core Pathophysiology

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Comprehensive Research Report: Common Variable Immunodeficiency (CVID) Pathophysiology (Molecular/Cellular)

Disease identifiers and classification

1. Key concepts and definitions (current understanding)

Definition (clinical-immunologic)

Epidemiology and baseline quantitative features

“CVID+” immune dysregulation endotype

2. Core pathophysiology (molecular and cellular mechanisms)

2.1 B-cell developmental/GC output failure (central axis)

2.2 BAFF/APRIL–TACI axis and NF-κB signaling (B-cell survival and plasma cell differentiation)

2.3 PI3Kδ–AKT–mTOR pathway dysregulation (APDS and GC disruption)

2.4 T-cell help and tolerance checkpoints (Tfh/Treg/CTLA-4–LRBA)

2.5 Additional mechanistic routes (DNA repair, transcriptional regulation, organelle/trafficking)

3. Key molecular players (genes/proteins, cells, tissues, chemicals)

3.1 Genes/Proteins (HGNC symbols)

3.2 Chemical entities / therapeutics (CHEBI-relevant entities)

3.3 Cell types (Cell Ontology; CL terms suggested)

3.4 Anatomical locations (UBERON suggested)

4. Biological processes and pathways (GO-oriented annotation candidates)

5. Cellular components (GO-CC candidates)

6. Disease progression: mechanistic sequence (model)

7. Phenotypic manifestations and mechanism links (HP-oriented)

8. Recent developments (prioritizing 2023–2024)

8.1 Genetics: increasing recognition of monogenic drivers and stratification tools

8.2 Diagnostic yield of sequencing in PID (generalizable implementation evidence)

8.3 Targeted therapies: pathway-directed treatment for CVID-like immune dysregulation

8.4 GI pathophysiology: standardizing plasma-cell paucity metrics in CVID enteropathy

9. Current applications and real-world implementations

9.1 Standard of care

9.2 Precision medicine in monogenic CVID-like disease

9.3 Diagnostic implementation: integrating immunophenotype + genomics

10. Expert opinions / authoritative synthesis (review-derived analysis)

Structured knowledge-base elements

Pathophysiology description (knowledge-base ready)

Gene/protein annotations (HGNC; representative set)

GO biological process candidates (selected)

Cell types (CL candidates)

Anatomical locations (UBERON candidates)

Chemical entities (selected)

Evidence tables

Key references (with URLs and publication timing)

Notes on limitations of this synthesis