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Classifications

Harrison's Part

IUIS Category

👪

Inheritance

2

Autosomal recessive inheritance HP:0000007

Most autosomal agammaglobulinemia is autosomal recessive, caused by biallelic loss-of-function variants in pre-BCR components (IGHM, IGLL1, CD79A, CD79B), the receptor-proximal adaptor BLNK, PIK3R1, SLC39A7, FNIP1, or a recessive TCF3 allele. Consanguinity substantially increases the probability of disease and has driven much of the gene discovery.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:31696364 SUPPORT Human Clinical

"Autosomal recessive agammaglobulinemia (ARA) is a primary immunodeficiency characterized by absent peripheral B cells, severe hypogammaglobulinemia, and absent BTK gene mutations."

Defines the autosomal recessive form of agammaglobulinemia as a distinct, BTK-negative entity.

PMID:31696364 SUPPORT Human Clinical

"In ARA, mutations occur in genes encoding the pre-B cell receptor (pre-BCR) or downstream signaling proteins."

Establishes the pre-BCR / downstream-signalling gene set as the recessive genetic basis.

Autosomal dominant inheritance HP:0000006

A minority of autosomal agammaglobulinemia is autosomal dominant and typically de novo, acting through dominant-negative or haploinsufficient mechanisms rather than biallelic loss of function: TCF3/E47 (AGM8, dominant-negative E555K), SPI1/PU.1 (AGM10, haploinsufficiency), and LRRC8A (AGM5, a truncating translocation allele).

Autosomal dominant inheritance

Show evidence (2 references)

PMID:24216514 SUPPORT Human Clinical

"These findings document a mutational hot-spot in E47 and represent an autosomal dominant form of agammaglobulinemia."

Documents an autosomal dominant, dominant-negative form of agammaglobulinemia.

PMID:33951726 SUPPORT Human Clinical

"We studied six unrelated agammaglobulinemic patients, each harboring a heterozygous mutation (four de novo, two unphased) of SPI1, the gene encoding PU.1."

Heterozygous, largely de novo SPI1 variants establish a second autosomal dominant form.

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Subtypes

12

Agammaglobulinemia 1, autosomal recessive (IGHM, mu heavy chain) MONDO:0020729

IGHM hgnc:5541

Deficiency of the membrane form of the mu immunoglobulin heavy chain, the structural core of the pre-BCR. The commonest autosomal form and typically the most severe, with earlier presentation than XLA.

Show evidence (1 reference)

PMID:8890099 SUPPORT Human Clinical

"Defects in the mu heavy-chain gene are a cause of agammaglobulinemia in humans."

Original description of IGHM (mu heavy chain) deficiency as an autosomal cause of agammaglobulinemia.

Agammaglobulinemia 2, autosomal recessive (IGLL1, lambda5 surrogate light chain) MONDO:0013287

IGLL1 hgnc:5870

Deficiency of lambda5/14.1, the surrogate light chain component that pairs with the mu heavy chain to form the pre-BCR.

Show evidence (1 reference)

PMID:9419212 SUPPORT Human Clinical

"These findings indicate that expression of the functional lambda5/14.1 is critical for B cell development in the human."

Establishes IGLL1 (lambda5/14.1) deficiency as a cause of human B-cell deficiency and agammaglobulinemia.

Agammaglobulinemia 3, autosomal recessive (CD79A, Ig-alpha) MONDO:0013288

CD79A hgnc:1698

Deficiency of Ig-alpha, one half of the Igalpha/Igbeta signal-transduction heterodimer of the pre-BCR. Produces a complete developmental block.

Show evidence (1 reference)

PMID:10525050 SUPPORT Human Clinical

"These results indicate that mutations in Igalpha can be a cause of agammaglobulinemia."

Identifies CD79A (Igalpha) as an autosomal recessive agammaglobulinemia gene.

Agammaglobulinemia 4, autosomal recessive (BLNK) MONDO:0013289

BLNK hgnc:14211

Deficiency of the cytoplasmic adaptor BLNK (B-cell linker protein), which organises signalling downstream of the pre-BCR. Pro-B cells are present in normal numbers but pre-B and mature B cells are absent.

Show evidence (1 reference)

PMID:10583958 SUPPORT Human Clinical

"Although this patient had normal numbers of pro-B cells, he had no pre-B cells or mature B cells, indicating that BLNK plays a critical role in orchestrating the pro-B cell to pre-B cell transition."

Localises the BLNK-deficiency block precisely at the pro-B to pre-B transition.

Agammaglobulinemia 5, autosomal dominant (LRRC8A) MONDO:0013290

LRRC8A hgnc:19027

Autosomal dominant agammaglobulinemia caused by a truncating LRRC8A allele arising from a balanced t(9;20) translocation, reported in a girl with congenital agammaglobulinemia and minor facial anomalies. LRRC8A encodes the essential subunit of the volume-regulated anion channel. This subtype is represented by a single kindred and is the numbered locus most often omitted from summary gene lists.

Show evidence (1 reference)

PMID:14660746 SUPPORT Human Clinical

"These results indicate that LRRC8 is responsible for the B cell deficiency in this patient and is required for B cell development."

The authors conclude that LRRC8 (LRRC8A) causes the B-cell deficiency in this patient with congenital agammaglobulinemia; MONDO assigns this gene to agammaglobulinemia 5, autosomal dominant.

Agammaglobulinemia 6, autosomal recessive (CD79B, Ig-beta) MONDO:0012987

CD79B hgnc:1699

Deficiency of Ig-beta, the partner of Ig-alpha in the pre-BCR signal-transduction module. Mutant Igbeta cannot associate with Igalpha and surface receptor assembly is abrogated.

Show evidence (1 reference)

PMID:17709424 SUPPORT Human Clinical

"These results indicate that mutations in Igbeta can cause agammaglobulinemia in man."

Establishes CD79B (Igbeta) as an autosomal recessive agammaglobulinemia gene.

Agammaglobulinemia 7, autosomal recessive (PIK3R1, p85-alpha) MONDO:0014083

PIK3R1 hgnc:8979

Loss of the p85-alpha regulatory subunit of PI3K. The developmental block is earlier than in the pre-BCR signalling defects, and early neutropenia is a notable accompanying feature.

Show evidence (1 reference)

PMID:22351933 SUPPORT Human Clinical

"A homozygous premature stop codon in exon 6 of PIK3R1 was identified in a young woman with colitis and absent B cells."

Identifies biallelic PIK3R1 loss of function as a cause of agammaglobulinemia with absent B cells.

Agammaglobulinemia 8, autosomal dominant (TCF3/E47, dominant negative) MONDO:0014840

TCF3 hgnc:11633

Autosomal dominant agammaglobulinemia from a recurrent de novo dominant-negative E47 (TCF3) variant, p.E555K. The residual B cells carry a distinctive CD19-high, B-cell-receptor-negative phenotype.

Show evidence (1 reference)

PMID:24216514 SUPPORT Human Clinical

"Genetic studies demonstrated that all 4 patients had the exact same de novo mutation in the broadly expressed transcription factor E47."

Documents the recurrent de novo dominant-negative TCF3/E47 variant.

Agammaglobulinemia 8B, autosomal recessive (TCF3) MONDO:0859234

TCF3 hgnc:11633

A biallelic, autosomal recessive TCF3 form, distinct from the dominant p.E555K allele. TCF3 is therefore the one locus in this series that carries both a dominant and a recessive numbered subtype. MONDO places this term directly under agammaglobulinemia (MONDO:0015977) rather than under autosomal agammaglobulinemia (MONDO:0011096); it is included here on the strength of the numbered-series naming and the TCF3 gene assertion. The primary report is PMID:28532655 (homozygous TCF3, severe hypogammaglobulinemia and B-cell ALL), which is indexed in PubMed without an abstract, so no evidence item is asserted rather than fabricating a snippet.

Agammaglobulinemia 9, autosomal recessive (SLC39A7/ZIP7) MONDO:0030519

SLC39A7 hgnc:4927

Hypomorphic variants in SLC39A7, the endoplasmic-reticulum-to-cytoplasm zinc transporter ZIP7. Loss of cytosolic Zn2+ buffering raises phosphatase activity and blunts pre-BCR/BCR signal strength. Severity is variable; per the OMIM/MONDO description, additional features include failure to thrive and skin involvement, and more severe cases may require hematopoietic stem cell transplantation.

Show evidence (1 reference)

PMID:30718914 SUPPORT Human Clinical

"The immunodeficiency results from hypomorphic mutations of SLC39A7, which encodes the endoplasmic reticulum-to-cytoplasm zinc transporter ZIP7."

Identifies hypomorphic SLC39A7 variants as the cause of this B-cell developmental immunodeficiency.

Agammaglobulinemia 10, autosomal dominant (SPI1/PU.1 haploinsufficiency) MONDO:0030529

SPI1 hgnc:11241

Heterozygous, largely de novo SPI1 variants causing PU.1 haploinsufficiency. PU.1 is a pioneer transcription factor that decompacts heterochromatin; haploinsufficiency constrains euchromatin accessibility for the non-pioneer transcription factors that drive the pro-B to pre-B transition. Patients also have few conventional dendritic cells. Note that this locus is SPI1, not TOP2B, which is a frequent mis-assignment. MONDO places this term directly under agammaglobulinemia (MONDO:0015977) rather than under autosomal agammaglobulinemia (MONDO:0011096).

Show evidence (1 reference)

PMID:33951726 SUPPORT Human Clinical

"Our findings molecularly describe a novel form of agammaglobulinemia and underscore PU.1's critical, dose-dependent role as a hematopoietic euchromatin gatekeeper."

Establishes SPI1/PU.1 haploinsufficiency as a distinct autosomal dominant form of agammaglobulinemia.

FNIP1-associated syndrome (autosomal recessive) MONDO:0100432

FNIP1 hgnc:29418

Biallelic FNIP1 loss disrupts the AMPK/mTOR metabolic program of the developing B cell, producing an early and severe B-cell developmental block with agammaglobulinemia. Unlike the numbered AGM subtypes it is syndromic: hypertrophic cardiomyopathy and variable neutropenia accompany the immune defect, and MONDO classifies it as FNIP1-associated syndrome rather than as a numbered autosomal agammaglobulinemia.

Show evidence (1 reference)

PMID:32905580 SUPPORT Human Clinical

"FNIP1 deficiency is a novel inborn error of immunity characterized by early and severe B-cell development defect, agammaglobulinemia, variable neutropenia, and HCM."

Defines the FNIP1 entity, including the syndromic cardiac feature that separates it from the numbered AGM subtypes.

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Pathophysiology

11

Loss of a Pre-B-Cell Receptor Structural or Signalling Component

Biallelic loss-of-function variants remove or inactivate one of the proteins that build or transduce the pre-B-cell receptor: the membrane form of the mu heavy chain (IGHM), the lambda5/14.1 surrogate light chain (IGLL1), the Igalpha/Igbeta signal-transduction heterodimer (CD79A, CD79B), or the receptor-proximal cytoplasmic adaptor BLNK that organises signalling immediately downstream of it. This is the proximal molecular lesion in the majority of autosomal agammaglobulinemia.

IGHM hgnc:5541 IGLL1 hgnc:5870 CD79A hgnc:1698 CD79B hgnc:1699 BLNK hgnc:14211

pre-B cell receptor complex GO:0035369

pre-B cell receptor expression GO:0002330 ↓ DECREASED

Downstream

Failure of Pre-B-Cell Receptor Assembly and Signalling Absence of any obligate structural or signalling subunit prevents surface assembly of a functional pre-BCR.

Show evidence (2 references)

PMID:17709424 SUPPORT Human Clinical

"We report on the first patient with agammaglobulinemia caused by a homozygous nonsense mutation in Igbeta, which is a transmembrane protein that associates with Igalpha as part of the preBCR complex."

Names Igbeta as a pre-BCR complex component whose loss causes agammaglobulinemia.

PMID:8890099 SUPPORT Human Clinical

"This implies that an intact membrane-bound mu chain is essential for B-cell development."

Establishes the membrane mu heavy chain as an indispensable pre-BCR structural component.

Loss of a Transcriptional or Homeostatic Regulator of B Lymphopoiesis

A mechanistically distinct arm in which the pre-BCR proteins themselves are intact but the cellular program that permits their expression and signalling fails. For the transcriptional regulators (TCF3/E47, SPI1/PU.1) and PIK3R1 the lesion acts developmentally earlier than the pre-BCR structural defects; for SLC39A7/ZIP7 it acts on pre-BCR/BCR signal strength at the same checkpoint. TCF3/E47 is a lineage transcription factor (dominant-negative p.E555K); SPI1/PU.1 is a pioneer transcription factor whose haploinsufficiency constrains euchromatin accessibility; SLC39A7/ZIP7 maintains cytosolic Zn2+ needed to restrain phosphatases acting on receptor signalling; PIK3R1 supplies the p85-alpha regulatory subunit of PI3K; LRRC8A encodes the essential volume-regulated anion channel subunit; and FNIP1 governs the AMPK/mTOR metabolic program of the developing B cell.

TCF3 hgnc:11633 SPI1 hgnc:11241 SLC39A7 hgnc:4927 PIK3R1 hgnc:8979 LRRC8A hgnc:19027 FNIP1 hgnc:29418

B cell differentiation GO:0030183 ↓ DECREASED

Downstream

Failure of Pre-B-Cell Receptor Assembly and Signalling Transcriptional and homeostatic lesions converge on the same checkpoint by preventing adequate pre-BCR expression or signal transduction.

Hypertrophic Cardiomyopathy FNIP1 governs AMPK/mTOR metabolic signalling outside the B lineage as well, so its loss produces cardiac hypertrophy in parallel with the B-cell block. Restricted to the FNIP1 subtype.

Neutropenia Several genes in this arm are not B-lineage restricted, so the same germline lesion produces an intrinsic myeloid defect in parallel with the B-cell block. This is a distinct route to neutropenia from the infection-associated consumption modelled downstream of infection.

Show evidence (2 references)

PMID:33951726 SUPPORT Human Clinical

"The pioneer transcription factor (TF) PU.1 controls hematopoietic cell fate by decompacting stem cell heterochromatin and allowing nonpioneer TFs to enter otherwise inaccessible genomic sites."

Describes the transcriptional/chromatin mechanism that constitutes this second arm.

PMID:30718914 SUPPORT Model Organism

"B cells from mutant mice exhibited a diminished concentration of cytoplasmic free zinc, increased phosphatase activity and decreased phosphorylation of signaling molecules downstream of the pre-B cell and B cell receptors."

CRISPR-engineered mice show how a homeostatic (zinc-transport) defect converges on pre-BCR/BCR signal strength.

Failure of Pre-B-Cell Receptor Assembly and Signalling

The pre-BCR normally serves as the quality-control checkpoint that confirms a productive heavy-chain rearrangement and licenses proliferation and light-chain rearrangement. When the receptor cannot be assembled at the surface or cannot transduce a signal, that positive-selection signal is never delivered.

pro-B cell CL:0000826

B cell receptor signaling pathway GO:0050853 ↓ DECREASED pre-B cell differentiation GO:0002329 ↓ DECREASED

Downstream

Developmental Arrest at the Pro-B to Pre-B Transition Without the pre-BCR signal the developing cell cannot pass the checkpoint.

Show evidence (1 reference)

PMID:10583958 SUPPORT Human Clinical

"The signal transduction events that control the progenitor B cell (pro-B cell) to precursor B cell (pre-B cell) transition have not been well delineated."

Frames the pro-B to pre-B transition as a signal-transduction-dependent checkpoint, the step disrupted here.

Developmental Arrest at the Pro-B to Pre-B Transition

B-lineage development halts in the bone marrow at the pro-B stage. Pro-B cells are present in normal or even increased numbers and V-DJ rearrangement proceeds normally, but pre-B cells, immature B cells and all downstream B-lineage populations are absent. This is the defining cellular lesion shared by autosomal agammaglobulinemia and XLA.

pro-B cell CL:0000826 precursor B cell CL:0000817 ↓ DECREASED

V(D)J recombination GO:0033151

bone marrow UBERON:0002371

Downstream

Absent Circulating B Cells and Plasma Cells No cells emerge from the marrow into the peripheral B-cell pool, and no plasma cells are generated.

Decreased Total B Cell Count The marrow block is directly measured in the clinic as a profoundly reduced circulating CD19+ B-cell count.

Show evidence (2 references)

PMID:17709424 SUPPORT Human Clinical

"The essential role of Igbeta for human B cell development was further demonstrated by immunofluorescence analysis of the patient's bone marrow, which showed a complete block of B cell development at the pro-B to preB transition."

Direct bone-marrow evidence for the arrest at the pro-B to pre-B transition.

PMID:22351933 SUPPORT Human Clinical

"Bone marrow aspirates from the patient showed <0.1% CD19(+) B cells with normal percentages of TdT(+)VpreB(+)CD19(-) B cell precursors."

Shows preserved CD19-negative precursors with absent CD19+ cells. The authors note the PIK3R1 block is earlier than that seen with defects in the B-cell receptor signalling pathway, so this supports arrest in early B lymphopoiesis but at a slightly different point, hence PARTIAL.

Absent Circulating B Cells and Plasma Cells

The peripheral blood contains essentially no CD19+ B cells (conventionally below 1-2% of lymphocytes), and no plasma cells are generated in lymphoid tissue. Germinal centres do not form, so tonsils and lymph nodes are small or absent on examination. T-cell numbers and function are preserved, which is what distinguishes this from severe combined immunodeficiency.

B cell CL:0000236 ↓ DECREASED plasma cell CL:0000786 ↓ DECREASED

Downstream

Panhypogammaglobulinemia and Loss of Humoral Immunity With no plasma cells there is no endogenous immunoglobulin production of any isotype.

Absent tonsils and lymphoid tissue Absence of B cells prevents formation of B-cell follicles and germinal centres, so tonsils and peripheral lymph nodes are hypoplastic or absent.

Show evidence (1 reference)

PMID:22351933 SUPPORT Human Clinical

"The number and function of the patient's T cells were normal."

Confirms that the defect is B-lineage restricted, with an intact T-cell compartment.

Panhypogammaglobulinemia and Loss of Humoral Immunity

Serum IgG, IgA and IgM are all severely reduced or undetectable. Loss of antibody abolishes opsonisation of encapsulated bacteria, complement fixation, mucosal secretory IgA defence, and neutralisation of enteroviruses. Cellular immunity is intact, so the infection spectrum is characteristically bacterial and enteroviral rather than opportunistic or fungal.

immunoglobulin production GO:0002377 ↓ DECREASED humoral immune response GO:0006959 ↓ DECREASED

Downstream

Agammaglobulinemia Absence of all measurable immunoglobulin isotypes in serum.

Decreased Circulating IgG Loss of plasma-cell IgG output.

Decreased Circulating IgA Loss of plasma-cell IgA output, including secretory IgA at mucosae.

Decreased Circulating IgM Loss of plasma-cell IgM output.

Susceptibility to Recurrent and Invasive Bacterial Infection Without opsonising antibody, encapsulated bacteria are not cleared.

Show evidence (1 reference)

PMID:31696364 SUPPORT Human Clinical

"Autosomal recessive agammaglobulinemia (ARA) is a primary immunodeficiency characterized by absent peripheral B cells, severe hypogammaglobulinemia, and absent BTK gene mutations."

Severe hypogammaglobulinemia is a defining feature of the disorder.

Waning of Maternal IgG Unmasks the Antibody Defect

Transplacentally acquired maternal IgG protects the infant for the first months of life. As it is catabolised (typically by around 6 months) the infant's own inability to make antibody becomes clinically apparent, which sets the characteristic age of first presentation. Maternal-IgG catabolism kinetics are the same regardless of genotype; the earlier presentation of the autosomal forms reflects the greater severity of the underlying block (see the "Earlier and More Severe Presentation" node), not faster IgG decay.

Downstream

Susceptibility to Recurrent and Invasive Bacterial Infection Loss of passive maternal protection converts the latent antibody defect into overt infection.

Show evidence (1 reference)

PMID:14752335 SUPPORT Human Clinical

"More than 10% of patients with X-linked agammaglobulinemia are hospitalized for infection at less than 6 months of age, indicating that patients with known X-linked agammaglobulinemia should be started on therapy by 2-3 months of age."

Documents that infection can begin before 6 months, i.e. while or just as maternal IgG wanes, and that therapy should start early. The quantitative data are from XLA, so this supports the timing principle only partially for the autosomal forms.

Susceptibility to Recurrent and Invasive Bacterial Infection

Recurrent sinopulmonary infection (otitis media, sinusitis, pneumonia) with encapsulated organisms, punctuated by invasive disease — sepsis, meningitis, septic arthritis, cellulitis — and gastrointestinal infection with chronic diarrhea. Enteroviruses, normally neutralised by antibody, can establish chronic central nervous system infection.

Downstream

Recurrent Infections The overall clinical phenotype of increased infection susceptibility.

Recurrent Otitis Media Middle-ear infection with encapsulated bacteria.

Recurrent Sinusitis Paranasal sinus infection with encapsulated bacteria.

Recurrent Pneumonia Lower respiratory tract infection with encapsulated bacteria.

Sepsis Invasive bacterial bloodstream infection.

Meningitis Invasive bacterial meningitis, or chronic enteroviral meningoencephalitis.

Septic Arthritis Invasive bacterial joint infection.

Cellulitis Skin and soft-tissue infection.

Chronic Diarrhea Enteric infection unopposed by secretory IgA.

Conjunctivitis Ocular surface infection.

Neutropenia Neutropenia in agammaglobulinemia is frequently infection-associated and may resolve with treatment. The intrinsic, genotype-driven arm is modelled as a separate edge from the gene-lesion node rather than as an intermediate here.

Failure to Thrive Chronic infection and enteropathy impair growth in untreated infants.

Progressive Airway Damage and Bronchiectasis Repeated and inadequately treated lower respiratory infection destroys bronchial wall architecture.

Show evidence (1 reference)

PMID:32905580 SUPPORT Human Clinical

"We here investigated 3 novel patients, including the first known adult, from unrelated families with agammaglobulinemia, recurrent infections, and hypertrophic cardiomyopathy (HCM)."

Recurrent infection is the presenting clinical consequence of agammaglobulinemia across autosomal genetic causes.

Progressive Airway Damage and Bronchiectasis

Repeated suppurative lower respiratory infection before diagnosis produces irreversible bronchial dilatation. This is the principal source of long-term morbidity and is the reason early diagnosis matters: the damage accrued before immunoglobulin replacement begins cannot be reversed by it.

bronchus UBERON:0002185

Downstream

Bronchiectasis Permanent bronchial dilatation as the structural end result.

Show evidence (1 reference)

PMID:14752335 SUPPORT Human Clinical

"In patients with sporadic X-linked agammaglobulinemia, the incidence of chronic lung disease correlates with the age at diagnosis, highlighting the importance of early diagnosis."

Establishes the diagnosis-delay to chronic-lung-disease relationship. The quantitative observation is in XLA; because the downstream antibody-deficiency mechanism is shared with the autosomal forms the principle extends, but the direct autosomal data are lacking, so this is PARTIAL.

Earlier and More Severe Presentation than X-Linked Agammaglobulinemia

A genotype-severity gradient distinguishes the autosomal forms clinically. Because most autosomal defects remove an obligate structural component of the pre-BCR (rather than attenuating a kinase, as hypomorphic BTK alleles can), the developmental block is more often complete, and there is no possibility of the residual leaky B-cell output seen with some BTK alleles. Patients therefore present at younger ages, with more severe complications, and are diagnosed earlier. Mu heavy chain (IGHM) deficiency is the clearest example.

Downstream

Susceptibility to Recurrent and Invasive Bacterial Infection The more complete developmental block yields an earlier and more severe infectious phenotype.

Show evidence (4 references)

PMID:14752335 SUPPORT Human Clinical

"Patients with autosomal recessive agammaglobulinemia have an earlier onset of disease compared with patients with X-linked agammaglobulinemia and they are more likely to have severe complications of the disease."

States the earlier-onset, more-severe gradient directly.

PMID:34241796 SUPPORT Human Clinical

"In contrast, while less common, autosomal recessive forms of agammaglobulinemia present at younger ages and with typically more severe clinical features resulting in an earlier diagnosis."

Independent review confirms younger age at presentation and more severe features in the autosomal recessive forms.

PMID:30240888 SUPPORT Human Clinical

"Clinical disease severity was significantly higher in patients with μ heavy chain and CD40 ligand mutations compared with patients with BTK"

A 550-patient cohort reports greater clinical disease severity in mu heavy chain (IGHM, autosomal) deficiency than in BTK deficiency. The snippet stops before the parenthetical p-value because that text contains a non-breaking space; the source reports the difference as statistically significant (P = .003).

+ 1 more reference

Vulnerability to Live Attenuated Vaccine Strains

Because neutralising antibody is absent, a live attenuated vaccine strain is not cleared and can replicate, revert and cause vaccine-associated disease. Vaccine-associated paralytic poliomyelitis after oral poliovirus vaccine is the archetype, and is reported significantly more often in mu heavy chain (IGHM) deficiency than in BTK deficiency. This makes live vaccines — above all OPV — an absolute agent to avoid.

Show evidence (1 reference)

PMID:30240888 SUPPORT Human Clinical

"Paralysis following live polio vaccination was considerably higher in patients with μ heavy chain deficiency compared with BTK deficiency (P < .001)."

Directly quantifies the excess risk of vaccine-associated paralysis in an autosomal (IGHM) form relative to XLA.

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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

20

Blood 3

Decreased Circulating IgG VERY_FREQUENT Decreased circulating IgG concentration HP:0004315

Show evidence (1 reference)

PMID:17709424 SUPPORT Human Clinical

"resulting in the absence of peripheral B cells and low/absent immunoglobulin serum levels"

Establishes the global immunoglobulin deficit as definitional (hence the VERY_FREQUENT band); the source does not report IgG separately from the other isotypes, so this isotype-specific record is only partially supported.

Decreased Circulating IgA VERY_FREQUENT Decreased circulating IgA concentration HP:0002720

Show evidence (1 reference)

PMID:17709424 SUPPORT Human Clinical

"resulting in the absence of peripheral B cells and low/absent immunoglobulin serum levels"

Establishes the global immunoglobulin deficit as definitional; IgA is not reported separately, so this isotype-specific record is only partially supported.

Neutropenia Decreased total neutrophil count HP:0001875

Show evidence (1 reference)

PMID:32905580 SUPPORT Human Clinical

"Two of them also presented with intermittent or severe chronic neutropenia."

Documents neutropenia accompanying autosomal recessive agammaglobulinemia (FNIP1 deficiency).

Cardiovascular 2

Conjunctivitis HP:0000509

Show evidence (1 reference)

PMID:20301626 SUPPORT Human Clinical

"Conjunctivitis, sinopulmonary infections, diarrhea, and skin infections are also frequently seen."

GeneReviews lists conjunctivitis among the frequent infections of congenital agammaglobulinemia; X-linked chapter, hence PARTIAL.

Hypertrophic Cardiomyopathy HP:0001639

Show evidence (1 reference)

PMID:32905580 SUPPORT Human Clinical

"We here investigated 3 novel patients, including the first known adult, from unrelated families with agammaglobulinemia, recurrent infections, and hypertrophic cardiomyopathy (HCM)."

All three reported FNIP1-deficient patients had hypertrophic cardiomyopathy.

Digestive 1

Chronic Diarrhea HP:0002028

Temporal: CHRONIC

Show evidence (1 reference)

PMID:20301626 SUPPORT Human Clinical

"Conjunctivitis, sinopulmonary infections, diarrhea, and skin infections are also frequently seen."

GeneReviews lists diarrhea among the frequent infections of congenital agammaglobulinemia; X-linked chapter, hence PARTIAL.

Ear 1

Recurrent Otitis Media HP:0000403

Show evidence (1 reference)

PMID:20301626 SUPPORT Human Clinical

"Recurrent otitis is the most common infection prior to diagnosis."

GeneReviews documents recurrent otitis as the commonest pre-diagnosis infection in congenital agammaglobulinemia. The chapter covers the X-linked form; the sinopulmonary infection spectrum is shared with the autosomal forms through the same antibody defect, so this is recorded as PARTIAL and no frequency band is asserted for the autosomal forms.

Immune 3

Recurrent Pneumonia HP:0006532

Show evidence (1 reference)

PMID:20301626 SUPPORT Human Clinical

"they develop a severe, life-threatening infection such as pneumonia, empyema, meningitis, sepsis, cellulitis, or septic arthritis"

GeneReviews lists pneumonia among the severe presenting infections of congenital agammaglobulinemia. The associated quantitative figure is XLA-specific, so no frequency band is asserted here and support is PARTIAL.

Sepsis HP:0100806

Show evidence (1 reference)

PMID:20301626 SUPPORT Human Clinical

"they develop a severe, life-threatening infection such as pneumonia, empyema, meningitis, sepsis, cellulitis, or septic arthritis"

GeneReviews enumerates sepsis among the severe presenting infections of congenital agammaglobulinemia; source is the X-linked chapter, hence PARTIAL.

Meningitis HP:0001287

Show evidence (1 reference)

PMID:20301626 SUPPORT Human Clinical

"Severe, difficult-to-treat enteroviral infections (often manifesting as dermatomyositis or chronic meningoencephalitis) can be prevented by this treatment."

GeneReviews documents chronic enteroviral meningoencephalitis as an antibody-deficiency complication preventable by immunoglobulin replacement. The chapter is X-linked; the mechanism (absent neutralising antibody) is shared, so PARTIAL.

Respiratory 1

Bronchiectasis HP:0002110

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:14752335 SUPPORT Human Clinical

"In patients with sporadic X-linked agammaglobulinemia, the incidence of chronic lung disease correlates with the age at diagnosis, highlighting the importance of early diagnosis."

Establishes chronic lung disease as a diagnosis-delay-dependent complication of congenital agammaglobulinemia. The cohort is X-linked, so support for the autosomal forms is PARTIAL.

Growth 1

Failure to Thrive HP:0001508

Recorded from the MONDO:0030519 / OMIM:619693 disease description, which states that additional features of agammaglobulinemia 9 include failure to thrive and skin involvement. The primary SLC39A7 paper (PMID:30718914) establishes the gene-disease link but does not quote growth failure in its abstract, so no evidence item is asserted here rather than attaching a snippet that does not support the claim.

Other 8

Agammaglobulinemia VERY_FREQUENT HP:0004432

Show evidence (1 reference)

PMID:31696364 SUPPORT Human Clinical

"Autosomal recessive agammaglobulinemia (ARA) is a primary immunodeficiency characterized by absent peripheral B cells, severe hypogammaglobulinemia, and absent BTK gene mutations."

Severe hypogammaglobulinemia across isotypes is stated as a defining feature of the disorder, supporting the VERY_FREQUENT band.

Decreased Total B Cell Count VERY_FREQUENT HP:0010976

Show evidence (2 references)

PMID:31696364 SUPPORT Human Clinical

"Autosomal recessive agammaglobulinemia (ARA) is a primary immunodeficiency characterized by absent peripheral B cells, severe hypogammaglobulinemia, and absent BTK gene mutations."

Absent peripheral B cells is definitional, supporting the VERY_FREQUENT band.

PMID:33951726 SUPPORT Human Clinical

"Affected patients lacked circulating B cells and possessed few conventional dendritic cells."

Independent confirmation of absent circulating B cells in another autosomal form (SPI1).

Decreased Circulating IgM VERY_FREQUENT Decreased circulating total IgM HP:0002850

Show evidence (1 reference)

PMID:17709424 SUPPORT Human Clinical

"resulting in the absence of peripheral B cells and low/absent immunoglobulin serum levels"

Establishes the global immunoglobulin deficit as definitional; IgM is not reported separately, so this isotype-specific record is only partially supported.

Recurrent Infections VERY_FREQUENT Recurrent bacterial infections HP:0002718

Show evidence (1 reference)

PMID:32905580 SUPPORT Human Clinical

"We here investigated 3 novel patients, including the first known adult, from unrelated families with agammaglobulinemia, recurrent infections, and hypertrophic cardiomyopathy (HCM)."

All three reported patients in this autosomal recessive form had recurrent infections, and infection susceptibility is the invariant clinical consequence of the antibody deficit, supporting the VERY_FREQUENT band.

Recurrent Sinusitis HP:0011108

Show evidence (1 reference)

PMID:20301626 SUPPORT Human Clinical

"Conjunctivitis, sinopulmonary infections, diarrhea, and skin infections are also frequently seen."

GeneReviews lists sinopulmonary infection among the frequent infections. Data are from the X-linked chapter; the shared antibody defect makes the spectrum applicable, hence PARTIAL and no frequency band.

Septic Arthritis HP:0003095

Show evidence (1 reference)

PMID:20301626 SUPPORT Human Clinical

"they develop a severe, life-threatening infection such as pneumonia, empyema, meningitis, sepsis, cellulitis, or septic arthritis"

GeneReviews enumerates septic arthritis among the severe presenting infections of congenital agammaglobulinemia; X-linked chapter, hence PARTIAL.

Cellulitis HP:0100658

Show evidence (1 reference)

PMID:20301626 SUPPORT Human Clinical

"Conjunctivitis, sinopulmonary infections, diarrhea, and skin infections are also frequently seen."

GeneReviews lists skin infections among the frequent infections of congenital agammaglobulinemia; X-linked chapter, hence PARTIAL.

Absent tonsils and lymphoid tissue HP:0030813

Show evidence (1 reference)

PMID:14752335 SUPPORT Human Clinical

"Because the physical exam provides a clue to the diagnosis of the condition--unusually small or absent cervical lymph nodes and tonsils--it should be possible to make an early diagnosis in a greater percentage of patients."

Documents absent or unusually small tonsils and cervical lymph nodes as a diagnostic physical sign in defects of early B-cell development.

🧬

Genetic Associations

11

IGHM (Causative)

Gene: IGHM hgnc:5541 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:8890099 SUPPORT Human Clinical

"Defects in the mu heavy-chain gene are a cause of agammaglobulinemia in humans."

Original gene-disease establishment for IGHM.

PMID:31696364 SUPPORT Human Clinical

"Two novel mutations in IGHM (p.Val378Alafs*1 and p.Ile184Serfs*21) were identified in three patients from two unrelated kindred and a novel nonsense mutation was identified in CD79A (p.Trp66*) in two siblings from a third kindred."

Independent replication with novel frameshift alleles in consanguineous North-African families.

IGLL1 (Causative)

Gene: IGLL1 hgnc:5870 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (1 reference)

PMID:9419212 SUPPORT Human Clinical

"we identified a boy with mutations on both alleles of the gene for lambda5/14.1"

Identifies biallelic IGLL1 mutations in a patient with agammaglobulinemia.

CD79A (Causative)

Gene: CD79A hgnc:1698 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (1 reference)

PMID:10525050 SUPPORT Human Clinical

"A 2-year-old girl was found to have a homozygous splice defect in Igalpha, a transmembrane protein that forms part of the Igalpha/Igbeta signal-transduction module of the pre-BCR."

Identifies the causative homozygous CD79A splice defect.

CD79B (Causative)

Gene: CD79B hgnc:1699 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (1 reference)

PMID:17709424 SUPPORT Human Clinical

"These results indicate that mutations in Igbeta can cause agammaglobulinemia in man."

Establishes the CD79B gene-disease relationship.

BLNK (Causative)

Gene: BLNK hgnc:14211 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (1 reference)

PMID:10583958 SUPPORT Human Clinical

"The immune system and overall growth and development were otherwise normal in this patient, suggesting that BLNK function is highly specific."

Establishes BLNK deficiency as a B-lineage-restricted cause of absent B cells.

LRRC8A (Causative)

Gene: LRRC8A hgnc:19027 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (1 reference)

PMID:14660746 SUPPORT Human Clinical

"These results indicate that LRRC8 is responsible for the B cell deficiency in this patient and is required for B cell development."

Establishes LRRC8 (LRRC8A) as responsible for the B-cell deficiency in this patient with congenital agammaglobulinemia.

PIK3R1 (Causative)

Gene: PIK3R1 hgnc:8979 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (1 reference)

PMID:22351933 SUPPORT Human Clinical

"The mutation results in the absence of p85α but normal expression of the p50α and p55α regulatory subunits of PI3K."

Characterises the specific p85-alpha loss underlying this form.

TCF3 (Causative)

Gene: TCF3 hgnc:11633 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:24216514 SUPPORT Human Clinical

"These findings document a mutational hot-spot in E47 and represent an autosomal dominant form of agammaglobulinemia."

Establishes the dominant TCF3/E47 form.

PMID:24216514 SUPPORT In Vitro

"E555K in the transfected cells localized normally to the nucleus and resulted in a dominant negative effect when bound to DNA as a homodimer with wild-type E47."

Functional demonstration of the dominant-negative mechanism.

SLC39A7 (Causative)

Gene: SLC39A7 hgnc:4927 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:30718914 SUPPORT Human Clinical

"The immunodeficiency results from hypomorphic mutations of SLC39A7, which encodes the endoplasmic reticulum-to-cytoplasm zinc transporter ZIP7."

Establishes the SLC39A7 gene-disease relationship in patients.

PMID:30718914 SUPPORT Model Organism

"Homozygosity for a null allele caused embryonic death, but hypomorphic alleles reproduced the block in B cell development seen in patients."

CRISPR-engineered mice recapitulate the human developmental block, supporting causality.

SPI1 (Causative)

Gene: SPI1 hgnc:11241 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (1 reference)

PMID:33951726 SUPPORT Human Clinical

"Patient SPI1 mutations encoded destabilized PU.1 proteins unable to nuclear localize or bind target DNA."

Functional characterisation of the patient SPI1 alleles.

FNIP1 (Causative)

Gene: FNIP1 hgnc:29418 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (1 reference)

PMID:32905580 SUPPORT Human Clinical

"FNIP1 deficiency is a novel inborn error of immunity characterized by early and severe B-cell development defect, agammaglobulinemia, variable neutropenia, and HCM."

Establishes the FNIP1 gene-disease relationship and its phenotype.

💊

Medical Actions

6

Immunoglobulin Replacement Therapy

Action: Immunoglobulin Therapy NCIT:C62710

Lifelong intravenous (IVIG) or subcutaneous (SCIG) immunoglobulin replacement is the mainstay of treatment. It supplies the antibody the patient cannot make, reduces the frequency and severity of bacterial infection, and prevents chronic enteroviral meningoencephalitis. It does not reverse bronchiectasis already established before diagnosis, which is why early recognition matters. Dose and interval are individualised to infection control and to the presence of chronic lung disease rather than to a single universal trough. Because the autosomal forms present earlier, therapy often needs to start in the first months of life.

Mechanism Target:

BYPASSES Panhypogammaglobulinemia and Loss of Humoral Immunity — Passive IgG replacement corrects the humoral effector deficit without correcting the upstream developmental block.

Show evidence (2 references)

PMID:20301626 SUPPORT Human Clinical

"The mainstay of treatment is gammaglobulin substitution therapy"

GeneReviews states that gammaglobulin substitution is the mainstay of treatment for congenital agammaglobulinemia. The chapter covers the X-linked form; management is identical in the autosomal forms because the antibody deficit is the same, so this is recorded as PARTIAL.

PMID:20301626 SUPPORT Human Clinical

"Severe, difficult-to-treat enteroviral infections (often manifesting as dermatomyositis or chronic meningoencephalitis) can be prevented by this treatment."

Documents prevention of chronic enteroviral disease by immunoglobulin replacement; sourced from the X-linked chapter, hence PARTIAL.

Antibiotic Therapy and Prophylaxis

Action: Antibiotic Therapy NCIT:C15620

Prompt and generous therapeutic antibiotics for breakthrough infection, with prophylactic antibiotics considered for patients who continue to have recurrent infection despite optimised immunoglobulin dosing or who have established bronchiectasis. Because patients cannot mount antibody responses, serology is unreliable and microbiological diagnosis should rely on culture, antigen detection or nucleic-acid amplification.

Mechanism Target:

INHIBITS Susceptibility to Recurrent and Invasive Bacterial Infection — Antibiotics eradicate the bacterial infections that the missing antibody cannot prevent or clear.

Show evidence (1 reference)

PMID:20301626 SUPPORT Human Clinical

"Generous use of antibiotics can decrease the incidence of chronic sinusitis and lung disease."

GeneReviews supports generous antibiotic use to reduce chronic sinus and lung disease in congenital agammaglobulinemia; X-linked chapter, hence PARTIAL.

Avoidance of Live Attenuated Vaccines (Agents to Avoid)

Action: Preventive Intervention NCIT:C15843

Live attenuated vaccines are contraindicated. Oral poliovirus vaccine is the most important: without neutralising antibody the vaccine strain replicates, can revert, and causes vaccine-associated paralytic poliomyelitis — reported significantly more often in mu heavy chain (IGHM) deficiency than in BTK deficiency. Inactivated poliovirus vaccine should be used instead, for the patient and for household contacts. Other live products (MMR, varicella, rotavirus, BCG, live attenuated influenza, oral typhoid, yellow fever) should likewise be withheld. Inactivated vaccines are safe though responses are minimal; immunising household contacts provides indirect protection.

Mechanism Target:

INHIBITS Vulnerability to Live Attenuated Vaccine Strains — Withholding replicating vaccine strains removes the exposure entirely.

Show evidence (3 references)

PMID:30240888 SUPPORT Human Clinical

"Paralysis following live polio vaccination was considerably higher in patients with μ heavy chain deficiency compared with BTK deficiency (P < .001)."

Directly demonstrates the excess vaccine-associated paralysis risk in an autosomal (IGHM) form, the strongest available justification for the live-vaccine contraindication in autosomal agammaglobulinemia.

PMID:20301626 SUPPORT Human Clinical

"Agents/circumstances to avoid: Live viral vaccines, particularly oral polio vaccine."

The GeneReviews Agents/Circumstances to Avoid recommendation. Written for the X-linked form; the underlying reason (no neutralising antibody) is identical in the autosomal forms, so this is recorded as PARTIAL.

PMID:20301626 SUPPORT Human Clinical

"Inactivated polio vaccine (as opposed to live oral polio vaccine) should be given to affected individuals and their family contacts."

Specifies the substitution of inactivated for oral poliovirus vaccine, including for household contacts; X-linked chapter, hence PARTIAL.

Respiratory Surveillance and Airway Clearance

Action: Supportive Care NCIT:C15747

Annual quantitative immunoglobulins and full blood count, chest and sinus imaging as indicated, and pulmonary function testing once age-appropriate. Established bronchiectasis is managed with airway-clearance physiotherapy and specialist respiratory input.

Mechanism Target:

INHIBITS Progressive Airway Damage and Bronchiectasis — Surveillance detects, and airway clearance limits progression of, chronic suppurative lung disease.

Show evidence (1 reference)

PMID:20301626 SUPPORT Human Clinical

"Complete blood count with differential and quantitative serum immunoglobulins at least annually; chest and sinus imaging as needed to assess for chronic lung and/or sinus disease."

The GeneReviews surveillance schedule for congenital agammaglobulinemia; X-linked chapter, hence PARTIAL.

Allogeneic Hematopoietic Cell Transplantation

Action: Hematopoietic Cell Transplantation NCIT:C15431

Not routine therapy for isolated agammaglobulinemia, because immunoglobulin replacement is effective and transplantation carries substantial risk. It is reserved for selected patients — uncontrollable complications, or a genotype with a broader haematopoietic defect where immune reconstitution is established, such as some SLC39A7/AGM9 cases.

Mechanism Target:

INHIBITS Developmental Arrest at the Pro-B to Pre-B Transition — Donor haematopoiesis supplies genetically normal B-cell progenitors that can traverse the pre-BCR checkpoint.

Genetic Counseling and Family Testing

Action: Genetic Counseling NCIT:C15240

Confirming the molecular diagnosis defines the mode of inheritance and the recurrence risk: 25% for siblings in an autosomal recessive family, 50% for the offspring of an affected heterozygote in the dominant forms (many of which are de novo). Cascade testing of at-risk relatives allows immunoglobulin replacement to begin before infection and live vaccines to be avoided. Because autosomal agammaglobulinemia is genetically heterogeneous, an inborn-errors-of-immunity panel or exome sequencing — including deletion/duplication analysis — is preferred over serial single-gene testing.

Show evidence (2 references)

PMID:31696364 SUPPORT Human Clinical

"WES has the potential to provide a rapid and more accurate genetic diagnosis in ARA, which is crucial for the treatment of the patients."

Supports exome sequencing over serial single-gene testing in this genetically heterogeneous disorder.

PMID:31696364 SUPPORT Human Clinical

"We concluded that conventional gene sequencing, especially when multiple genes are involved in the defect as is the case in ARA, is costly and time-consuming, resulting in delayed diagnosis that contributes to increased morbidity and mortality."

Explicitly links serial single-gene testing to diagnostic delay and worse outcomes.

🔬

Biochemical Markers

4

Serum IgG (Decreased)

Context: Severely reduced or undetectable at diagnosis. Must be interpreted against age-specific paediatric reference intervals; in the first months of life the value reflects transplacental maternal IgG and can mask the defect.

Reference Ranges

IgG [Mass/volume] in Serum or Plasma 700.0–1600.0 mg/dL (adults)

Agammaglobulinemia range (–100.0 mg/dL) → Agammaglobulinemia Hypogammaglobulinemia (100.0–700.0 mg/dL) → Decreased circulating IgG concentration Normal (700.0–1600.0 mg/dL)

Agammaglobulinemia range: Serum IgG below about 100 mg/dL beyond the age of maternal IgG decline is the typical finding in congenital agammaglobulinemia and, together with absent CD19+ B cells, is effectively diagnostic.

Hypogammaglobulinemia: Reduced but measurable IgG; more typical of common variable immunodeficiency or a hypomorphic/leaky genotype than of classic agammaglobulinemia.

Conventional adult serum IgG reference interval used in clinical immunology laboratories. No citable article reports this interval, so provenance is recorded here rather than as a fabricated evidence item. Paediatric intervals are strongly age-dependent and are the ones that matter for diagnosis in infancy.

Show evidence (1 reference)

PMID:31696364 SUPPORT Human Clinical

"Autosomal recessive agammaglobulinemia (ARA) is a primary immunodeficiency characterized by absent peripheral B cells, severe hypogammaglobulinemia, and absent BTK gene mutations."

Severe hypogammaglobulinemia defines the biochemical phenotype.

Serum IgA (Decreased)

Context: Severely reduced or undetectable; mucosal secretory IgA defence is lost.

Reference Ranges

IgA [Mass/volume] in Serum or Plasma 70.0–400.0 mg/dL (adults)

Conventional adult serum IgA reference interval used in clinical immunology laboratories; provenance recorded here rather than as a fabricated citation.

Show evidence (1 reference)

PMID:17709424 SUPPORT Human Clinical

"resulting in the absence of peripheral B cells and low/absent immunoglobulin serum levels"

Establishes globally low/absent serum immunoglobulin; IgA is not reported separately.

Serum IgM (Decreased)

Context: Severely reduced or undetectable. IgM is unaffected by transplacental transfer, so a low IgM is informative even in early infancy, and a normal or high IgM points instead to a hyper-IgM syndrome.

Reference Ranges

IgM [Mass/volume] in Serum or Plasma 40.0–230.0 mg/dL (adults)

Conventional adult serum IgM reference interval used in clinical immunology laboratories; provenance recorded here rather than as a fabricated citation.

Show evidence (1 reference)

PMID:17709424 SUPPORT Human Clinical

"resulting in the absence of peripheral B cells and low/absent immunoglobulin serum levels"

Establishes globally low/absent serum immunoglobulin; IgM is not reported separately.

Peripheral blood CD19+ B cell percentage (Decreased)

Context: Flow cytometric CD19+ (or CD20+) B cells as a percentage of peripheral blood lymphocytes. This is the single most discriminating test: profoundly reduced B cells with normal T-cell numbers separates agammaglobulinemia from common variable immunodeficiency (B cells present) and from severe combined immunodeficiency (T cells also absent).

Pathograph Readouts

Readout Of Developmental Arrest at the Pro-B to Pre-B Transition Negative

The circulating CD19+ percentage is the clinical readout of the bone-marrow developmental block: the more complete the block, the lower the percentage.

Reference Ranges

5.0–20.0 % (children and adults; CD19+ cells as a percentage of peripheral blood lymphocytes)

Absent or near-absent B cells (–2.0 %) → Decreased total B cell count Reduced B cells (2.0–5.0 %) Normal (5.0–20.0 %)

Absent or near-absent B cells: CD19+ B cells below 2% of lymphocytes, with normal T-cell numbers and panhypogammaglobulinemia, is the diagnostic laboratory signature of congenital agammaglobulinemia. In autosomal forms with a complete pre-BCR defect the value is usually far below 1%.

Reduced B cells: Reduced but clearly detectable B cells; suggests a hypomorphic or leaky genotype, or an alternative diagnosis such as common variable immunodeficiency, rather than classic agammaglobulinemia.

Approximate normal range for CD19+ B cells as a percentage of peripheral blood lymphocytes; the paediatric range is age-dependent and wider in infancy. Recorded as laboratory convention, not from a citable interval study.

Show evidence (1 reference)

PMID:22351933 SUPPORT Human Clinical

"Bone marrow aspirates from the patient showed <0.1% CD19(+) B cells with normal percentages of TdT(+)VpreB(+)CD19(-) B cell precursors."

Illustrates the magnitude of CD19+ depletion in an autosomal form.

🔬

Diagnosis

4

Quantitative serum immunoglobulins

Measurement of serum IgG, IgA and IgM against age-specific reference intervals. All three isotypes are severely reduced or undetectable. IgM and IgA are informative even in early infancy because, unlike IgG, they are not contributed by transplacental maternal transfer.

diagnostic procedure NCIT:C18020

Markers: Serum IgG, IgA and IgM

Results: Severe reduction or absence of all immunoglobulin isotypes

Show evidence (1 reference)

PMID:31696364 SUPPORT Human Clinical

"Autosomal recessive agammaglobulinemia (ARA) is a primary immunodeficiency characterized by absent peripheral B cells, severe hypogammaglobulinemia, and absent BTK gene mutations."

Severe hypogammaglobulinemia with absent peripheral B cells is the laboratory definition of the disorder.

Lymphocyte subset flow cytometry

Enumeration of CD19+ (or CD20+) B cells, CD3/CD4/CD8 T cells and NK cells. The discriminating pattern is CD19+ B cells below 1-2% of lymphocytes with numerically and functionally normal T cells: B cells are present in common variable immunodeficiency, and T cells are also absent in severe combined immunodeficiency.

flow cytometry NCIT:C16585

Markers: CD19+ B cell percentage; CD3/CD4/CD8 T cell counts

Results: CD19+ B cells profoundly reduced with normal T cell numbers

Show evidence (1 reference)

PMID:22351933 SUPPORT Human Clinical

"The number and function of the patient's T cells were normal."

Preserved T-cell number and function alongside absent B cells is the pattern that separates agammaglobulinemia from combined immunodeficiency.

Molecular genetic testing (IEI panel or exome sequencing)

BTK testing remains essential in a male proband even when the referral says "autosomal". Beyond that, because the autosomal forms are genetically heterogeneous, an inborn-errors-of-immunity panel covering at least IGHM, IGLL1, CD79A, CD79B, BLNK, PIK3R1, TCF3, SLC39A7, SPI1 and LRRC8A, or trio exome sequencing, is preferred over serial single-gene testing. Deletion/duplication analysis should be included because sequence-only assays miss exon-level copy-number changes such as the large IGHM deletions.

genetic testing NCIT:C15709

Results: Biallelic (or, for the dominant forms, heterozygous de novo) pathogenic variant identified

Show evidence (2 references)

PMID:31696364 SUPPORT Human Clinical

"WES has the potential to provide a rapid and more accurate genetic diagnosis in ARA, which is crucial for the treatment of the patients."

Directly supports exome sequencing over serial single-gene testing in this genetically heterogeneous disorder.

PMID:31696364 SUPPORT Human Clinical

"We concluded that conventional gene sequencing, especially when multiple genes are involved in the defect as is the case in ARA, is costly and time-consuming, resulting in delayed diagnosis that contributes to increased morbidity and mortality."

Links serial single-gene testing to diagnostic delay and worse outcomes.

KREC-based newborn screening

Kappa-deleting recombination excision circles (KRECs) are a by-product of B-cell receptor light-chain rearrangement and are low or undetectable from birth when B-cell development is blocked. Combined TREC/KREC newborn screening can therefore identify severe B-cell lymphopenia before the first infection, allowing immunoglobulin replacement to start early and live vaccines to be avoided. TRECs are normal, which distinguishes the pattern from severe combined immunodeficiency. KREC screening is not universally implemented and may miss hypomorphic, leaky genotypes.

diagnostic procedure NCIT:C18020

Markers: KREC copy number (with TREC as the T-cell comparator)

Results: KRECs low or undetectable with normal TRECs

Because patients cannot mount antibody responses, vaccine-response serology is uninformative and should not be used to establish or exclude the diagnosis; deliberate live-vaccine challenge is contraindicated.

Show evidence (1 reference)

PMID:34241796 SUPPORT Human Clinical

"Some diagnostic innovations, such as KREC level measurements and serum BCMA measurements, may aid in facilitating an earlier identification of agammaglobulinemia leading to prompt treatment."

Supports KREC measurement as a route to earlier identification of agammaglobulinemia.

📊

Prevalence

1

Worldwide

Unknown Ultra Rare

No direct population prevalence or incidence estimate exists for autosomal agammaglobulinemia as an umbrella category. What is reported is its share of congenital agammaglobulinemia: XLA accounts for approximately 85% of cases, and registry data put autosomal recessive agammaglobulinemia at roughly 5-10%, so the autosomal forms collectively represent on the order of 10-15% of congenital agammaglobulinemia. Because congenital agammaglobulinemia itself is on the order of 1 in 200,000 births, the autosomal forms are ultra-rare; the qualitative class is recorded rather than a fabricated numeric rate. Individual genes beyond IGHM are represented by single families or very small series.

Show evidence (2 references)

PMID:34241796 SUPPORT Human Clinical

"While the most common cause of congenital agammaglobulinemia is X-linked agammaglobulinemia (XLA), accounting for approximately 85% of cases, other genetic forms of agammaglobulinemia have been identified."

Establishes that non-XLA (autosomal) forms make up roughly the remaining 15% of congenital agammaglobulinemia.

PMID:38683392 SUPPORT Human Clinical

"Approximately 80 to 90% of individuals exhibit genetic variations in Bruton's agammaglobulinemia tyrosine kinase (BTK), whereas a minority of cases, around 5-10%, are autosomal recessive agammaglobulinemia (ARA)."

A registry-based study quantifies the autosomal recessive share of hypogammaglobulinemia-without-B-cells at 5-10%.

🔀

Differential Diagnoses

9

Conditions with similar clinical presentations that must be differentiated from Autosomal Agammaglobulinemia:

X-linked agammaglobulinemia (BTK) MONDO:0010421

Overlapping Features The single most important boundary. XLA shares the entire downstream mechanism modelled here — a pre-B developmental block, absent CD19+ B cells, panhypogammaglobulinemia, intact T cells, the same infection spectrum, the same immunoglobulin-replacement treatment and the same live-vaccine contraindication — and accounts for roughly 85% of congenital agammaglobulinemia. It is curated separately in dismech as X-linked_Agammaglobulinemia; that entry, not this one, carries the BTK-specific mechanism, and it is deliberately not duplicated here. The distinguishing content of the present entry is which pre-BCR component is lost and the earlier, more severe presentation that follows.

Distinguishing Features

Affects hemizygous males only; a female proband or a consanguineous pedigree points away from XLA
Caused by BTK, a cytoplasmic kinase downstream of the pre-BCR, rather than by loss of a pre-BCR structural or proximal signalling component
Later onset and less severe complications; the autosomal forms present at younger ages
Some BTK alleles are hypomorphic and permit leaky B-cell output, which complete autosomal pre-BCR defects do not
Absent BTK protein on flow cytometry or Western blot; a carrier mother shows non-random X inactivation in the B-cell lineage

Show evidence (2 references)

PMID:14752335 SUPPORT Human Clinical

"Patients with autosomal recessive agammaglobulinemia have an earlier onset of disease compared with patients with X-linked agammaglobulinemia and they are more likely to have severe complications of the disease."

The clinical discriminator between the autosomal forms and XLA.

PMID:31696364 SUPPORT Human Clinical

"Autosomal recessive agammaglobulinemia (ARA) is a primary immunodeficiency characterized by absent peripheral B cells, severe hypogammaglobulinemia, and absent BTK gene mutations."

Absence of BTK mutations is definitional for the autosomal forms.

Common variable immunodeficiency MONDO:0015517

Overlapping Features The commonest antibody deficiency in adults. Shares hypogammaglobulinemia and recurrent sinopulmonary infection, but the developmental block is absent — B cells are made and circulate, and the lesion is in terminal differentiation to plasma cells. Curated separately in dismech as Common_Variable_Immunodeficiency.

Distinguishing Features

CD19+ B cells are present, usually in normal numbers; agammaglobulinemia has under 1-2%
IgG is reduced but measurable rather than absent, and IgM is often preserved
Onset typically in the second to fourth decade rather than infancy
Prominent autoimmunity, lymphoproliferation, granulomatous disease and lymphoma risk, which are not features of agammaglobulinemia

Severe combined immunodeficiency MONDO:0015974

Overlapping Features Also presents in infancy with profound infection and can have absent B cells, but the T-cell compartment is also absent or non-functional, which changes both the infection spectrum and the treatment. Curated separately in dismech as Severe_Combined_Immunodeficiency.

Distinguishing Features

T cells are absent or non-functional; in agammaglobulinemia T-cell number and function are normal
Opportunistic infection (Pneumocystis jirovecii, disseminated CMV, chronic candidiasis) and failure to thrive from the first months of life
Abnormal newborn TREC screening; agammaglobulinemia has normal TRECs with low or absent KRECs
Requires urgent hematopoietic stem cell transplantation or gene therapy, not immunoglobulin replacement alone

Show evidence (1 reference)

PMID:22351933 SUPPORT Human Clinical

"The number and function of the patient's T cells were normal."

Normal T-cell number and function in autosomal agammaglobulinemia is the discriminator from SCID.

Transient hypogammaglobulinemia of infancy Not Yet Curated MONDO:0015698

Overlapping Features A self-limited, physiological exaggeration of the normal nadir in serum IgG that follows catabolism of maternal IgG. It is the benign mimic that must not be treated as agammaglobulinemia, and equally must not be diagnosed in a child who actually has a developmental B-cell block.

Distinguishing Features

B cells are present in normal numbers
IgG is low but detectable and specific antibody responses to protein vaccines are usually intact
Immunoglobulin levels normalise spontaneously, typically by 2-4 years of age
Infections are milder and invasive bacterial disease is uncommon

Good syndrome (thymoma with immunodeficiency) Not Yet Curated MONDO:0015696

Overlapping Features An acquired adult-onset immunodeficiency that is the closest adult phenocopy of agammaglobulinemia: thymoma with hypogammaglobulinemia and profoundly reduced or absent peripheral B cells. It is the reason a newly agammaglobulinemic adult needs chest imaging rather than a paediatric genetic panel.

Distinguishing Features

Adult onset, typically in the fifth to sixth decade, with no relevant family history
A thymoma is present on chest CT
Accompanying CD4+ T-cell lymphopenia and inverted CD4/CD8 ratio, unlike the intact T-cell compartment of congenital agammaglobulinemia
Susceptibility extends to opportunistic and viral infection, not only encapsulated bacteria

Secondary hypogammaglobulinemia after B-cell-depleting therapy

Overlapping Features Rituximab and other anti-CD20 agents deplete CD19+ B cells and can produce prolonged hypogammaglobulinemia that is laboratory-indistinguishable from congenital agammaglobulinemia. Drug exposure history is the discriminator and should be sought before any genetic testing in an adult. No MONDO term specifically denotes rituximab-induced secondary hypogammaglobulinemia, so disease_term is deliberately omitted here rather than bound to an inaccurate surrogate.

Distinguishing Features

History of anti-CD20 monoclonal antibody, other B-cell-depleting therapy, or immunosuppression
Onset in adulthood after a documented period of normal immunoglobulin levels
B-cell numbers usually recover over months to years after drug withdrawal
Other secondary causes to exclude include protein-losing enteropathy, nephrotic syndrome and lymphoid malignancy

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"

A national antibody-deficiency cohort documents secondary hypogammaglobulinemia following B-cell depletion therapy as a distinct group requiring separation from primary antibody deficiency.

POU2AF1 (BOB1) deficiency Not Yet Curated MONDO:0800146

Overlapping Features Biallelic loss of the B-cell transcriptional coactivator BOB1/OBF-1 (POU2AF1) causes agammaglobulinemia, so it is frequently listed alongside the autosomal agammaglobulinemia genes. It is deliberately scoped OUT of this entry on mechanistic grounds: the defining report is titled "Agammaglobulinemia with normal B-cell numbers in a patient lacking Bob1", i.e. there is no pro-B to pre-B developmental block and B cells are present, which is the opposite of the cellular lesion this entry models and violates the absent-CD19+-B-cell criterion used here to separate agammaglobulinemia from CVID. MONDO likewise places it directly under agammaglobulinemia (MONDO:0015977) rather than under autosomal agammaglobulinemia (MONDO:0011096). The lesion is in terminal B-cell differentiation and antibody output, not early B lymphopoiesis.

Distinguishing Features

Circulating B-cell numbers are normal, not absent or near-absent
The block is in terminal B-cell differentiation and antibody production rather than at the pro-B to pre-B checkpoint
MONDO classifies it under agammaglobulinemia (MONDO:0015977), not under autosomal agammaglobulinemia (MONDO:0011096)

Hyper-IgM syndrome Not Yet Curated MONDO:0003947

Overlapping Features Class-switch recombination defects give low IgG and IgA with normal or elevated IgM and present with recurrent infection in childhood, so they enter the same differential; the preserved or raised IgM and the presence of B cells separate them.

Distinguishing Features

Serum IgM is normal or elevated rather than absent
CD19+ B cells are present
CD40LG (X-linked) deficiency adds opportunistic infection, notably Pneumocystis jirovecii pneumonia, and neutropenia

{ }

Source YAML

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name: Autosomal Agammaglobulinemia
creation_date: "2026-08-01T09:00:00Z"
category: Mendelian
synonyms:
- Autosomal recessive agammaglobulinemia
- ARA
- AGM
- Agammaglobulinemia, non-Bruton type
- Non-Bruton agammaglobulinemia
- Autosomal dominant agammaglobulinemia
description: >-
  Autosomal (non-Bruton) agammaglobulinemia is the collective term for the
  autosomal recessive and autosomal dominant forms of congenital
  agammaglobulinemia — the roughly 10-15% of cases that are not caused by BTK.
  The unifying lesion is a block in early B-cell development at the pro-B to
  pre-B transition in the bone marrow, because the pre-B-cell receptor (pre-BCR)
  cannot be assembled or cannot signal. Biallelic loss of pre-BCR structural
  components (IGHM mu heavy chain, IGLL1 lambda5 surrogate light chain) or of
  its signalling module and proximal adaptor (CD79A/Igalpha, CD79B/Igbeta, BLNK)
  abolishes the positive-selection checkpoint that drives pro-B cells forward. A
  second arm involves PIK3R1 and the transcriptional
  and homeostatic regulators of B lymphopoiesis (TCF3/E47, SPI1/PU.1, SLC39A7,
  LRRC8A) plus the metabolic regulator FNIP1. The result is absent or
  near-absent circulating CD19+ B cells, no plasma cells, and profound
  hypogammaglobulinemia across all isotypes, with numerically and functionally
  normal T cells. Affected children
  present after maternal IgG wanes (around 6 months) with recurrent
  sinopulmonary and invasive bacterial infection; bronchiectasis develops if
  diagnosis is delayed, and chronic enteroviral meningoencephalitis is a feared
  complication. Compared with X-linked agammaglobulinemia (XLA), autosomal
  forms present earlier and more severely. Lifelong immunoglobulin replacement
  is the mainstay of treatment, and live attenuated vaccines — particularly
  oral poliovirus vaccine — are contraindicated.
disease_term:
  preferred_term: autosomal agammaglobulinemia
  term:
    id: MONDO:0011096
    label: autosomal agammaglobulinemia
parents:
- Primary Immunodeficiency
- Antibody Deficiency Disorder
- Congenital Agammaglobulinemia
inheritance:
- name: Autosomal recessive inheritance
  description: >-
    Most autosomal agammaglobulinemia is autosomal recessive, caused by
    biallelic loss-of-function variants in pre-BCR components (IGHM, IGLL1,
    CD79A, CD79B), the receptor-proximal adaptor BLNK, PIK3R1, SLC39A7, FNIP1,
    or a recessive TCF3 allele. Consanguinity substantially increases the
    probability of disease and has driven much of the gene discovery.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:31696364
    reference_title: "Genetic Approaches for Definitive Diagnosis of Agammaglobulinemia in Consanguineous Families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Autosomal recessive agammaglobulinemia (ARA) is a primary immunodeficiency
      characterized by absent peripheral B cells, severe hypogammaglobulinemia,
      and absent BTK gene mutations.
    explanation: >-
      Defines the autosomal recessive form of agammaglobulinemia as a distinct,
      BTK-negative entity.
  - reference: PMID:31696364
    reference_title: "Genetic Approaches for Definitive Diagnosis of Agammaglobulinemia in Consanguineous Families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In ARA, mutations occur in genes encoding the pre-B cell receptor (pre-BCR)
      or downstream signaling proteins.
    explanation: >-
      Establishes the pre-BCR / downstream-signalling gene set as the recessive
      genetic basis.
- name: Autosomal dominant inheritance
  description: >-
    A minority of autosomal agammaglobulinemia is autosomal dominant and
    typically de novo, acting through dominant-negative or haploinsufficient
    mechanisms rather than biallelic loss of function: TCF3/E47 (AGM8,
    dominant-negative E555K), SPI1/PU.1 (AGM10, haploinsufficiency), and
    LRRC8A (AGM5, a truncating translocation allele).
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:24216514
    reference_title: "A recurrent dominant negative E47 mutation causes agammaglobulinemia and BCR(-) B cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These findings document a mutational hot-spot in E47 and represent an
      autosomal dominant form of agammaglobulinemia.
    explanation: >-
      Documents an autosomal dominant, dominant-negative form of agammaglobulinemia.
  - reference: PMID:33951726
    reference_title: "Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We studied six unrelated agammaglobulinemic patients, each harboring a
      heterozygous mutation (four de novo, two unphased) of SPI1, the gene
      encoding PU.1.
    explanation: >-
      Heterozygous, largely de novo SPI1 variants establish a second autosomal
      dominant form.
classifications:
  harrisons_chapter:
  - classification_value: IMMUNE_RHEUMATOLOGIC
    evidence:
    - reference: PMID:31696364
      reference_title: "Genetic Approaches for Definitive Diagnosis of Agammaglobulinemia in Consanguineous Families."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Autosomal recessive agammaglobulinemia (ARA) is a primary immunodeficiency
        characterized by absent peripheral B cells, severe hypogammaglobulinemia,
        and absent BTK gene mutations.
      explanation: >-
        A primary immunodeficiency belongs in Harrison's immune/rheumatologic Part.
  iuis_category:
    classification_value: predominantly antibody deficiency
    evidence:
    - reference: PMID:31696364
      reference_title: "Genetic Approaches for Definitive Diagnosis of Agammaglobulinemia in Consanguineous Families."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Autosomal recessive agammaglobulinemia (ARA) is a primary immunodeficiency
        characterized by absent peripheral B cells, severe hypogammaglobulinemia,
        and absent BTK gene mutations.
      explanation: >-
        Absent B cells with severe hypogammaglobulinemia and intact T-cell
        immunity places these disorders in IUIS Table 3, predominantly antibody
        deficiencies (severe reduction in all serum immunoglobulin isotypes with
        profoundly decreased or absent B cells).
prevalence:
- population: Worldwide
  measure_type: UNKNOWN
  prevalence_class: ULTRA_RARE
  notes: >-
    No direct population prevalence or incidence estimate exists for autosomal
    agammaglobulinemia as an umbrella category. What is reported is its share of
    congenital agammaglobulinemia: XLA accounts for approximately 85% of cases,
    and registry data put autosomal recessive agammaglobulinemia at roughly
    5-10%, so the autosomal forms collectively represent on the order of 10-15%
    of congenital agammaglobulinemia. Because congenital agammaglobulinemia
    itself is on the order of 1 in 200,000 births, the autosomal forms are
    ultra-rare; the qualitative class is recorded rather than a fabricated
    numeric rate. Individual genes beyond IGHM are represented by single
    families or very small series.
  evidence:
  - reference: PMID:34241796
    reference_title: "Agammaglobulinemia: from X-linked to Autosomal Forms of Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      While the most common cause of congenital agammaglobulinemia is X-linked
      agammaglobulinemia (XLA), accounting for approximately 85% of cases, other
      genetic forms of agammaglobulinemia have been identified.
    explanation: >-
      Establishes that non-XLA (autosomal) forms make up roughly the remaining
      15% of congenital agammaglobulinemia.
  - reference: PMID:38683392
    reference_title: "B-cells absence in patients diagnosed as inborn errors of immunity: a registry-based study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Approximately 80 to 90% of individuals exhibit genetic variations in
      Bruton's agammaglobulinemia tyrosine kinase (BTK), whereas a minority of
      cases, around 5-10%, are autosomal recessive agammaglobulinemia (ARA).
    explanation: >-
      A registry-based study quantifies the autosomal recessive share of
      hypogammaglobulinemia-without-B-cells at 5-10%.
has_subtypes:
- name: AGM1
  display_name: "Agammaglobulinemia 1, autosomal recessive (IGHM, mu heavy chain)"
  description: >-
    Deficiency of the membrane form of the mu immunoglobulin heavy chain, the
    structural core of the pre-BCR. The commonest autosomal form and typically
    the most severe, with earlier presentation than XLA.
  subtype_term:
    preferred_term: autosomal recessive agammaglobulinemia 1
    term:
      id: MONDO:0020729
      label: autosomal recessive agammaglobulinemia 1
  genes:
  - preferred_term: IGHM
    term:
      id: hgnc:5541
      label: IGHM
  evidence:
  - reference: PMID:8890099
    reference_title: "Mutations in the mu heavy-chain gene in patients with agammaglobulinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Defects in the mu heavy-chain gene are a cause of agammaglobulinemia in
      humans.
    explanation: >-
      Original description of IGHM (mu heavy chain) deficiency as an autosomal
      cause of agammaglobulinemia.
- name: AGM2
  display_name: "Agammaglobulinemia 2, autosomal recessive (IGLL1, lambda5 surrogate light chain)"
  description: >-
    Deficiency of lambda5/14.1, the surrogate light chain component that pairs
    with the mu heavy chain to form the pre-BCR.
  subtype_term:
    preferred_term: agammaglobulinemia 2, autosomal recessive
    term:
      id: MONDO:0013287
      label: agammaglobulinemia 2, autosomal recessive
  genes:
  - preferred_term: IGLL1
    term:
      id: hgnc:5870
      label: IGLL1
  evidence:
  - reference: PMID:9419212
    reference_title: "Mutations in the human lambda5/14.1 gene result in B cell deficiency and agammaglobulinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These findings indicate that expression of the functional lambda5/14.1 is
      critical for B cell development in the human.
    explanation: >-
      Establishes IGLL1 (lambda5/14.1) deficiency as a cause of human B-cell
      deficiency and agammaglobulinemia.
- name: AGM3
  display_name: "Agammaglobulinemia 3, autosomal recessive (CD79A, Ig-alpha)"
  description: >-
    Deficiency of Ig-alpha, one half of the Igalpha/Igbeta signal-transduction
    heterodimer of the pre-BCR. Produces a complete developmental block.
  subtype_term:
    preferred_term: agammaglobulinemia 3, autosomal recessive
    term:
      id: MONDO:0013288
      label: agammaglobulinemia 3, autosomal recessive
  genes:
  - preferred_term: CD79A
    term:
      id: hgnc:1698
      label: CD79A
  evidence:
  - reference: PMID:10525050
    reference_title: "Mutations in Igalpha (CD79a) result in a complete block in B-cell development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These results indicate that mutations in Igalpha can be a cause of
      agammaglobulinemia.
    explanation: >-
      Identifies CD79A (Igalpha) as an autosomal recessive agammaglobulinemia gene.
- name: AGM4
  display_name: "Agammaglobulinemia 4, autosomal recessive (BLNK)"
  description: >-
    Deficiency of the cytoplasmic adaptor BLNK (B-cell linker protein), which
    organises signalling downstream of the pre-BCR. Pro-B cells are present in
    normal numbers but pre-B and mature B cells are absent.
  subtype_term:
    preferred_term: agammaglobulinemia 4, autosomal recessive
    term:
      id: MONDO:0013289
      label: agammaglobulinemia 4, autosomal recessive
  genes:
  - preferred_term: BLNK
    term:
      id: hgnc:14211
      label: BLNK
  evidence:
  - reference: PMID:10583958
    reference_title: "An essential role for BLNK in human B cell development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although this patient had normal numbers of pro-B cells, he had no pre-B
      cells or mature B cells, indicating that BLNK plays a critical role in
      orchestrating the pro-B cell to pre-B cell transition.
    explanation: >-
      Localises the BLNK-deficiency block precisely at the pro-B to pre-B
      transition.
- name: AGM5
  display_name: "Agammaglobulinemia 5, autosomal dominant (LRRC8A)"
  description: >-
    Autosomal dominant agammaglobulinemia caused by a truncating LRRC8A allele
    arising from a balanced t(9;20) translocation, reported in a girl with
    congenital agammaglobulinemia and minor facial anomalies. LRRC8A encodes the
    essential subunit of the volume-regulated anion channel. This subtype is
    represented by a single kindred and is the numbered locus most often omitted
    from summary gene lists.
  subtype_term:
    preferred_term: agammaglobulinemia 5, autosomal dominant
    term:
      id: MONDO:0013290
      label: agammaglobulinemia 5, autosomal dominant
  genes:
  - preferred_term: LRRC8A
    term:
      id: hgnc:19027
      label: LRRC8A
  evidence:
  - reference: PMID:14660746
    reference_title: "A congenital mutation of the novel gene LRRC8 causes agammaglobulinemia in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These results indicate that LRRC8 is responsible for the B cell deficiency
      in this patient and is required for B cell development.
    explanation: >-
      The authors conclude that LRRC8 (LRRC8A) causes the B-cell deficiency in
      this patient with congenital agammaglobulinemia; MONDO assigns this gene to
      agammaglobulinemia 5, autosomal dominant.
- name: AGM6
  display_name: "Agammaglobulinemia 6, autosomal recessive (CD79B, Ig-beta)"
  description: >-
    Deficiency of Ig-beta, the partner of Ig-alpha in the pre-BCR
    signal-transduction module. Mutant Igbeta cannot associate with Igalpha and
    surface receptor assembly is abrogated.
  subtype_term:
    preferred_term: agammaglobulinemia 6, autosomal recessive
    term:
      id: MONDO:0012987
      label: agammaglobulinemia 6, autosomal recessive
  genes:
  - preferred_term: CD79B
    term:
      id: hgnc:1699
      label: CD79B
  evidence:
  - reference: PMID:17709424
    reference_title: "Mutations of the Igbeta gene cause agammaglobulinemia in man."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These results indicate that mutations in Igbeta can cause agammaglobulinemia
      in man.
    explanation: >-
      Establishes CD79B (Igbeta) as an autosomal recessive agammaglobulinemia gene.
- name: AGM7
  display_name: "Agammaglobulinemia 7, autosomal recessive (PIK3R1, p85-alpha)"
  description: >-
    Loss of the p85-alpha regulatory subunit of PI3K. The developmental block is
    earlier than in the pre-BCR signalling defects, and early neutropenia is a
    notable accompanying feature.
  subtype_term:
    preferred_term: agammaglobulinemia 7, autosomal recessive
    term:
      id: MONDO:0014083
      label: agammaglobulinemia 7, autosomal recessive
  genes:
  - preferred_term: PIK3R1
    term:
      id: hgnc:8979
      label: PIK3R1
  evidence:
  - reference: PMID:22351933
    reference_title: "Agammaglobulinemia and absent B lineage cells in a patient lacking the p85α subunit of PI3K."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A homozygous premature stop codon in exon 6 of PIK3R1 was identified in a
      young woman with colitis and absent B cells.
    explanation: >-
      Identifies biallelic PIK3R1 loss of function as a cause of agammaglobulinemia
      with absent B cells.
- name: AGM8
  display_name: "Agammaglobulinemia 8, autosomal dominant (TCF3/E47, dominant negative)"
  description: >-
    Autosomal dominant agammaglobulinemia from a recurrent de novo
    dominant-negative E47 (TCF3) variant, p.E555K. The residual B cells carry a
    distinctive CD19-high, B-cell-receptor-negative phenotype.
  subtype_term:
    preferred_term: agammaglobulinemia 8, autosomal dominant
    term:
      id: MONDO:0014840
      label: agammaglobulinemia 8, autosomal dominant
  genes:
  - preferred_term: TCF3
    term:
      id: hgnc:11633
      label: TCF3
  evidence:
  - reference: PMID:24216514
    reference_title: "A recurrent dominant negative E47 mutation causes agammaglobulinemia and BCR(-) B cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genetic studies demonstrated that all 4 patients had the exact same de novo
      mutation in the broadly expressed transcription factor E47.
    explanation: >-
      Documents the recurrent de novo dominant-negative TCF3/E47 variant.
- name: AGM8B
  display_name: "Agammaglobulinemia 8B, autosomal recessive (TCF3)"
  description: >-
    A biallelic, autosomal recessive TCF3 form, distinct from the dominant
    p.E555K allele. TCF3 is therefore the one locus in this series that carries
    both a dominant and a recessive numbered subtype. MONDO places this term
    directly under agammaglobulinemia (MONDO:0015977) rather than under autosomal
    agammaglobulinemia (MONDO:0011096); it is included here on the strength of the
    numbered-series naming and the TCF3 gene assertion. The primary report is
    PMID:28532655 (homozygous TCF3, severe hypogammaglobulinemia and B-cell ALL),
    which is indexed in PubMed without an abstract, so no evidence item is
    asserted rather than fabricating a snippet.
  subtype_term:
    preferred_term: agammaglobulinemia 8b, autosomal recessive
    term:
      id: MONDO:0859234
      label: agammaglobulinemia 8b, autosomal recessive
  genes:
  - preferred_term: TCF3
    term:
      id: hgnc:11633
      label: TCF3
- name: AGM9
  display_name: "Agammaglobulinemia 9, autosomal recessive (SLC39A7/ZIP7)"
  description: >-
    Hypomorphic variants in SLC39A7, the endoplasmic-reticulum-to-cytoplasm zinc
    transporter ZIP7. Loss of cytosolic Zn2+ buffering raises phosphatase
    activity and blunts pre-BCR/BCR signal strength. Severity is variable; per
    the OMIM/MONDO description, additional features include failure to thrive and
    skin involvement, and more severe cases may require hematopoietic stem cell
    transplantation.
  subtype_term:
    preferred_term: agammaglobulinemia 9, autosomal recessive
    term:
      id: MONDO:0030519
      label: agammaglobulinemia 9, autosomal recessive
  genes:
  - preferred_term: SLC39A7
    term:
      id: hgnc:4927
      label: SLC39A7
  evidence:
  - reference: PMID:30718914
    reference_title: "An essential role for the Zn(2+) transporter ZIP7 in B cell development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The immunodeficiency results from hypomorphic mutations of SLC39A7, which
      encodes the endoplasmic reticulum-to-cytoplasm zinc transporter ZIP7.
    explanation: >-
      Identifies hypomorphic SLC39A7 variants as the cause of this B-cell
      developmental immunodeficiency.
- name: AGM10
  display_name: "Agammaglobulinemia 10, autosomal dominant (SPI1/PU.1 haploinsufficiency)"
  description: >-
    Heterozygous, largely de novo SPI1 variants causing PU.1 haploinsufficiency.
    PU.1 is a pioneer transcription factor that decompacts heterochromatin;
    haploinsufficiency constrains euchromatin accessibility for the non-pioneer
    transcription factors that drive the pro-B to pre-B transition. Patients
    also have few conventional dendritic cells. Note that this locus is SPI1,
    not TOP2B, which is a frequent mis-assignment. MONDO places this term directly
    under agammaglobulinemia (MONDO:0015977) rather than under autosomal
    agammaglobulinemia (MONDO:0011096).
  subtype_term:
    preferred_term: agammaglobulinemia 10, autosomal dominant
    term:
      id: MONDO:0030529
      label: agammaglobulinemia 10, autosomal dominant
  genes:
  - preferred_term: SPI1
    term:
      id: hgnc:11241
      label: SPI1
  evidence:
  - reference: PMID:33951726
    reference_title: "Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our findings molecularly describe a novel form of agammaglobulinemia and
      underscore PU.1's critical, dose-dependent role as a hematopoietic
      euchromatin gatekeeper.
    explanation: >-
      Establishes SPI1/PU.1 haploinsufficiency as a distinct autosomal dominant
      form of agammaglobulinemia.
- name: FNIP1
  display_name: "FNIP1-associated syndrome (autosomal recessive)"
  description: >-
    Biallelic FNIP1 loss disrupts the AMPK/mTOR metabolic program of the
    developing B cell, producing an early and severe B-cell developmental block
    with agammaglobulinemia. Unlike the numbered AGM subtypes it is syndromic:
    hypertrophic cardiomyopathy and variable neutropenia accompany the immune
    defect, and MONDO classifies it as FNIP1-associated syndrome rather than as
    a numbered autosomal agammaglobulinemia.
  subtype_term:
    preferred_term: FNIP1-associated syndrome
    term:
      id: MONDO:0100432
      label: FNIP1-associated syndrome
  genes:
  - preferred_term: FNIP1
    term:
      id: hgnc:29418
      label: FNIP1
  evidence:
  - reference: PMID:32905580
    reference_title: "Absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in folliculin-interacting protein 1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      FNIP1 deficiency is a novel inborn error of immunity characterized by early
      and severe B-cell development defect, agammaglobulinemia, variable
      neutropenia, and HCM.
    explanation: >-
      Defines the FNIP1 entity, including the syndromic cardiac feature that
      separates it from the numbered AGM subtypes.
pathophysiology:
- name: Loss of a Pre-B-Cell Receptor Structural or Signalling Component
  description: >-
    Biallelic loss-of-function variants remove or inactivate one of the proteins
    that build or transduce the pre-B-cell receptor: the membrane form of the mu
    heavy chain (IGHM), the lambda5/14.1 surrogate light chain (IGLL1), the
    Igalpha/Igbeta signal-transduction heterodimer (CD79A, CD79B), or the
    receptor-proximal cytoplasmic adaptor BLNK that organises signalling
    immediately downstream of it. This is the proximal molecular lesion in the
    majority of autosomal agammaglobulinemia.
  biological_scale: MOLECULAR
  role: Primary
  genes:
  - preferred_term: IGHM
    term:
      id: hgnc:5541
      label: IGHM
  - preferred_term: IGLL1
    term:
      id: hgnc:5870
      label: IGLL1
  - preferred_term: CD79A
    term:
      id: hgnc:1698
      label: CD79A
  - preferred_term: CD79B
    term:
      id: hgnc:1699
      label: CD79B
  - preferred_term: BLNK
    term:
      id: hgnc:14211
      label: BLNK
  protein_complexes:
  - preferred_term: pre-B cell receptor complex
    term:
      id: GO:0035369
      label: pre-B cell receptor complex
  biological_processes:
  - preferred_term: pre-B cell receptor expression
    term:
      id: GO:0002330
      label: pre-B cell receptor expression
    modifier: DECREASED
  evidence:
  - reference: PMID:17709424
    reference_title: "Mutations of the Igbeta gene cause agammaglobulinemia in man."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report on the first patient with agammaglobulinemia caused by a
      homozygous nonsense mutation in Igbeta, which is a transmembrane protein
      that associates with Igalpha as part of the preBCR complex.
    explanation: >-
      Names Igbeta as a pre-BCR complex component whose loss causes
      agammaglobulinemia.
  - reference: PMID:8890099
    reference_title: "Mutations in the mu heavy-chain gene in patients with agammaglobulinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This implies that an intact membrane-bound mu chain is essential for B-cell
      development.
    explanation: >-
      Establishes the membrane mu heavy chain as an indispensable pre-BCR
      structural component.
  downstream:
  - target: Failure of Pre-B-Cell Receptor Assembly and Signalling
    description: >-
      Absence of any obligate structural or signalling subunit prevents surface
      assembly of a functional pre-BCR.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:17709424
      reference_title: "Mutations of the Igbeta gene cause agammaglobulinemia in man."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Transfection experiments using Drosophila melanogaster S2 Schneider cells
        showed that the mutant Igbeta is no longer able to associate with
        Igalpha, and that assembly of the BCR complex on the cell surface is
        abrogated.
      explanation: >-
        Direct in-vitro demonstration that the mutant component abolishes
        receptor assembly at the cell surface.
- name: Loss of a Transcriptional or Homeostatic Regulator of B Lymphopoiesis
  description: >-
    A mechanistically distinct arm in which the pre-BCR proteins themselves are
    intact but the cellular program that permits their expression and signalling
    fails. For the transcriptional regulators (TCF3/E47, SPI1/PU.1) and PIK3R1
    the lesion acts developmentally earlier than the pre-BCR structural defects;
    for SLC39A7/ZIP7 it acts on pre-BCR/BCR signal strength at the same
    checkpoint. TCF3/E47 is a lineage transcription factor
    (dominant-negative p.E555K); SPI1/PU.1 is a pioneer transcription factor
    whose haploinsufficiency constrains euchromatin accessibility; SLC39A7/ZIP7
    maintains cytosolic Zn2+ needed to restrain phosphatases acting on receptor
    signalling; PIK3R1 supplies the p85-alpha regulatory subunit of PI3K; LRRC8A
    encodes the essential volume-regulated anion channel subunit; and FNIP1
    governs the AMPK/mTOR metabolic program of the developing B cell.
  biological_scale: MOLECULAR
  role: Primary
  genes:
  - preferred_term: TCF3
    term:
      id: hgnc:11633
      label: TCF3
  - preferred_term: SPI1
    term:
      id: hgnc:11241
      label: SPI1
  - preferred_term: SLC39A7
    term:
      id: hgnc:4927
      label: SLC39A7
  - preferred_term: PIK3R1
    term:
      id: hgnc:8979
      label: PIK3R1
  - preferred_term: LRRC8A
    term:
      id: hgnc:19027
      label: LRRC8A
  - preferred_term: FNIP1
    term:
      id: hgnc:29418
      label: FNIP1
  biological_processes:
  - preferred_term: B cell differentiation
    term:
      id: GO:0030183
      label: B cell differentiation
    modifier: DECREASED
  evidence:
  - reference: PMID:33951726
    reference_title: "Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The pioneer transcription factor (TF) PU.1 controls hematopoietic cell fate
      by decompacting stem cell heterochromatin and allowing nonpioneer TFs to
      enter otherwise inaccessible genomic sites.
    explanation: >-
      Describes the transcriptional/chromatin mechanism that constitutes this
      second arm.
  - reference: PMID:30718914
    reference_title: "An essential role for the Zn(2+) transporter ZIP7 in B cell development."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      B cells from mutant mice exhibited a diminished concentration of cytoplasmic
      free zinc, increased phosphatase activity and decreased phosphorylation of
      signaling molecules downstream of the pre-B cell and B cell receptors.
    explanation: >-
      CRISPR-engineered mice show how a homeostatic (zinc-transport) defect
      converges on pre-BCR/BCR signal strength.
  downstream:
  - target: Failure of Pre-B-Cell Receptor Assembly and Signalling
    description: >-
      Transcriptional and homeostatic lesions converge on the same checkpoint by
      preventing adequate pre-BCR expression or signal transduction.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Reduced accessibility of B-lineage enhancers to non-pioneer transcription factors (PU.1, E47)
    - Reduced phosphorylation of pre-BCR-proximal signalling molecules from loss of cytosolic zinc buffering (ZIP7)
    - Loss of PI3K regulatory subunit output downstream of the receptor (PIK3R1)
    evidence:
    - reference: PMID:33951726
      reference_title: "Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        In PU.1-haploinsufficient pro-B cell lines, euchromatin was less accessible
        to nonpioneer TFs critical for B cell development, and gene expression
        patterns associated with the pro- to pre-B cell transition were
        undermined.
      explanation: >-
        Shows the transcriptional lesion specifically undermining the pro-B to
        pre-B transition program.
  - target: Hypertrophic Cardiomyopathy
    description: >-
      FNIP1 governs AMPK/mTOR metabolic signalling outside the B lineage as well,
      so its loss produces cardiac hypertrophy in parallel with the B-cell block.
      Restricted to the FNIP1 subtype.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Deranged AMPK and mTOR signalling in cardiomyocytes on loss of FNIP1
    evidence:
    - reference: PMID:32905580
      reference_title: "Absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in folliculin-interacting protein 1 deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        B-cell metabolism, including mitochondrial numbers and activity and
        phosphatidylinositol 3-kinase/AKT pathway, was impaired.
      explanation: >-
        Establishes the metabolic mechanism of FNIP1 loss that underlies both the
        B-cell and the cardiac phenotype.
  - target: Neutropenia
    description: >-
      Several genes in this arm are not B-lineage restricted, so the same germline
      lesion produces an intrinsic myeloid defect in parallel with the B-cell
      block. This is a distinct route to neutropenia from the
      infection-associated consumption modelled downstream of infection.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Loss of PU.1, p85-alpha or FNIP1 function in the myeloid lineage itself
    evidence:
    - reference: PMID:32905580
      reference_title: "Absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in folliculin-interacting protein 1 deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        FNIP1 deficiency is a novel inborn error of immunity characterized by early
        and severe B-cell development defect, agammaglobulinemia, variable
        neutropenia, and HCM.
      explanation: >-
        Neutropenia is listed as an intrinsic component of the FNIP1 disease
        phenotype alongside the B-cell defect, not merely as an infection sequela.
- name: Failure of Pre-B-Cell Receptor Assembly and Signalling
  description: >-
    The pre-BCR normally serves as the quality-control checkpoint that confirms a
    productive heavy-chain rearrangement and licenses proliferation and
    light-chain rearrangement. When the receptor cannot be assembled at the
    surface or cannot transduce a signal, that positive-selection signal is never
    delivered.
  biological_scale: MOLECULAR
  role: Intermediate
  cell_types:
  - preferred_term: pro-B cell
    term:
      id: CL:0000826
      label: pro-B cell
  biological_processes:
  - preferred_term: B cell receptor signaling pathway
    term:
      id: GO:0050853
      label: B cell receptor signaling pathway
    modifier: DECREASED
  - preferred_term: pre-B cell differentiation
    term:
      id: GO:0002329
      label: pre-B cell differentiation
    modifier: DECREASED
  evidence:
  - reference: PMID:10583958
    reference_title: "An essential role for BLNK in human B cell development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The signal transduction events that control the progenitor B cell (pro-B
      cell) to precursor B cell (pre-B cell) transition have not been well
      delineated.
    explanation: >-
      Frames the pro-B to pre-B transition as a signal-transduction-dependent
      checkpoint, the step disrupted here.
  downstream:
  - target: Developmental Arrest at the Pro-B to Pre-B Transition
    description: >-
      Without the pre-BCR signal the developing cell cannot pass the checkpoint.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:10525050
      reference_title: "Mutations in Igalpha (CD79a) result in a complete block in B-cell development."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        By immunofluorescence, both patients had a complete block in B-cell
        development at the pro-B to pre-B transition; both patients also had an
        equivalent number and diversity of rearranged V-DJ sequences.
      explanation: >-
        Bone-marrow immunophenotyping localises the block to the pro-B to pre-B
        transition in both Igalpha- and mu-heavy-chain-deficient patients.
- name: Developmental Arrest at the Pro-B to Pre-B Transition
  description: >-
    B-lineage development halts in the bone marrow at the pro-B stage. Pro-B
    cells are present in normal or even increased numbers and V-DJ rearrangement
    proceeds normally, but pre-B cells, immature B cells and all downstream
    B-lineage populations are absent. This is the defining cellular lesion shared
    by autosomal agammaglobulinemia and XLA.
  biological_scale: CELLULAR
  role: Central
  cell_types:
  - preferred_term: pro-B cell
    term:
      id: CL:0000826
      label: pro-B cell
  - preferred_term: precursor B cell
    term:
      id: CL:0000817
      label: precursor B cell
    modifier: DECREASED
  locations:
  - preferred_term: bone marrow
    term:
      id: UBERON:0002371
      label: bone marrow
  biological_processes:
  - preferred_term: V(D)J recombination
    term:
      id: GO:0033151
      label: V(D)J recombination
  evidence:
  - reference: PMID:17709424
    reference_title: "Mutations of the Igbeta gene cause agammaglobulinemia in man."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The essential role of Igbeta for human B cell development was further
      demonstrated by immunofluorescence analysis of the patient's bone marrow,
      which showed a complete block of B cell development at the pro-B to preB
      transition.
    explanation: >-
      Direct bone-marrow evidence for the arrest at the pro-B to pre-B transition.
  - reference: PMID:22351933
    reference_title: "Agammaglobulinemia and absent B lineage cells in a patient lacking the p85α subunit of PI3K."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Bone marrow aspirates from the patient showed <0.1% CD19(+) B cells with
      normal percentages of TdT(+)VpreB(+)CD19(-) B cell precursors.
    explanation: >-
      Shows preserved CD19-negative precursors with absent CD19+ cells. The authors
      note the PIK3R1 block is earlier than that seen with defects in the B-cell
      receptor signalling pathway, so this supports arrest in early B lymphopoiesis
      but at a slightly different point, hence PARTIAL.
  downstream:
  - target: Absent Circulating B Cells and Plasma Cells
    description: >-
      No cells emerge from the marrow into the peripheral B-cell pool, and no
      plasma cells are generated.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31696364
      reference_title: "Genetic Approaches for Definitive Diagnosis of Agammaglobulinemia in Consanguineous Families."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Autosomal recessive agammaglobulinemia (ARA) is a primary immunodeficiency
        characterized by absent peripheral B cells, severe hypogammaglobulinemia,
        and absent BTK gene mutations.
      explanation: >-
        Links the marrow block to absent peripheral B cells.
  - target: Decreased Total B Cell Count
    description: >-
      The marrow block is directly measured in the clinic as a profoundly reduced
      circulating CD19+ B-cell count.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:22351933
      reference_title: "Agammaglobulinemia and absent B lineage cells in a patient lacking the p85α subunit of PI3K."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Bone marrow aspirates from the patient showed <0.1% CD19(+) B cells with
        normal percentages of TdT(+)VpreB(+)CD19(-) B cell precursors.
      explanation: >-
        Quantifies the near-total absence of CD19+ B cells resulting from the block.
- name: Absent Circulating B Cells and Plasma Cells
  description: >-
    The peripheral blood contains essentially no CD19+ B cells (conventionally
    below 1-2% of lymphocytes), and no plasma cells are generated in lymphoid
    tissue. Germinal centres do not form, so tonsils and lymph nodes are small or
    absent on examination. T-cell numbers and function are preserved, which is
    what distinguishes this from severe combined immunodeficiency.
  biological_scale: CELLULAR
  role: Intermediate
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
    modifier: DECREASED
  - preferred_term: plasma cell
    term:
      id: CL:0000786
      label: plasma cell
    modifier: DECREASED
  evidence:
  - reference: PMID:22351933
    reference_title: "Agammaglobulinemia and absent B lineage cells in a patient lacking the p85α subunit of PI3K."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The number and function of the patient's T cells were normal.
    explanation: >-
      Confirms that the defect is B-lineage restricted, with an intact T-cell
      compartment.
  downstream:
  - target: Panhypogammaglobulinemia and Loss of Humoral Immunity
    description: >-
      With no plasma cells there is no endogenous immunoglobulin production of any
      isotype.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:17709424
      reference_title: "Mutations of the Igbeta gene cause agammaglobulinemia in man."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Agammaglobulinemia is a rare primary immunodeficiency characterized by an
        early block of B cell development in the bone marrow, resulting in the
        absence of peripheral B cells and low/absent immunoglobulin serum levels.
      explanation: >-
        States the causal chain from the marrow block to absent serum
        immunoglobulin.
  - target: Absent tonsils and lymphoid tissue
    description: >-
      Absence of B cells prevents formation of B-cell follicles and germinal
      centres, so tonsils and peripheral lymph nodes are hypoplastic or absent.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:14752335
      reference_title: "Early defects in B cell development."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Because the physical exam provides a clue to the diagnosis of the
        condition--unusually small or absent cervical lymph nodes and tonsils--it
        should be possible to make an early diagnosis in a greater percentage of
        patients.
      explanation: >-
        Identifies unusually small or absent tonsils and cervical lymph nodes as
        the physical sign of the absent B-cell compartment.
- name: Panhypogammaglobulinemia and Loss of Humoral Immunity
  description: >-
    Serum IgG, IgA and IgM are all severely reduced or undetectable. Loss of
    antibody abolishes opsonisation of encapsulated bacteria, complement fixation,
    mucosal secretory IgA defence, and neutralisation of enteroviruses. Cellular
    immunity is intact, so the infection spectrum is characteristically bacterial
    and enteroviral rather than opportunistic or fungal.
  biological_scale: ORGANISM
  role: Intermediate
  biological_processes:
  - preferred_term: immunoglobulin production
    term:
      id: GO:0002377
      label: immunoglobulin production
    modifier: DECREASED
  - preferred_term: humoral immune response
    term:
      id: GO:0006959
      label: humoral immune response
    modifier: DECREASED
  evidence:
  - reference: PMID:31696364
    reference_title: "Genetic Approaches for Definitive Diagnosis of Agammaglobulinemia in Consanguineous Families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Autosomal recessive agammaglobulinemia (ARA) is a primary immunodeficiency
      characterized by absent peripheral B cells, severe hypogammaglobulinemia,
      and absent BTK gene mutations.
    explanation: >-
      Severe hypogammaglobulinemia is a defining feature of the disorder.
  downstream:
  - target: Agammaglobulinemia
    description: Absence of all measurable immunoglobulin isotypes in serum.
    causal_link_type: DIRECT
  - target: Decreased Circulating IgG
    description: Loss of plasma-cell IgG output.
    causal_link_type: DIRECT
  - target: Decreased Circulating IgA
    description: Loss of plasma-cell IgA output, including secretory IgA at mucosae.
    causal_link_type: DIRECT
  - target: Decreased Circulating IgM
    description: Loss of plasma-cell IgM output.
    causal_link_type: DIRECT
  - target: Susceptibility to Recurrent and Invasive Bacterial Infection
    description: >-
      Without opsonising antibody, encapsulated bacteria are not cleared.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34241796
      reference_title: "Agammaglobulinemia: from X-linked to Autosomal Forms of Disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Interruptions or alterations in the B cell development pathway can lead to
        primary B cell immunodeficiency with resultant absence or diminished
        immunoglobulin production.
      explanation: >-
        Links the developmental block to the immunodeficient state.
- name: Waning of Maternal IgG Unmasks the Antibody Defect
  description: >-
    Transplacentally acquired maternal IgG protects the infant for the first
    months of life. As it is catabolised (typically by around 6 months) the
    infant's own inability to make antibody becomes clinically apparent, which
    sets the characteristic age of first presentation. Maternal-IgG catabolism
    kinetics are the same regardless of genotype; the earlier presentation of the
    autosomal forms reflects the greater severity of the underlying block (see
    the "Earlier and More Severe Presentation" node), not faster IgG decay.
  biological_scale: ORGANISM
  role: Modifier
  evidence:
  - reference: PMID:14752335
    reference_title: "Early defects in B cell development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      More than 10% of patients with X-linked agammaglobulinemia are hospitalized
      for infection at less than 6 months of age, indicating that patients with
      known X-linked agammaglobulinemia should be started on therapy by 2-3 months
      of age.
    explanation: >-
      Documents that infection can begin before 6 months, i.e. while or just as
      maternal IgG wanes, and that therapy should start early. The quantitative data
      are from XLA, so this supports the timing principle only partially for the
      autosomal forms.
  downstream:
  - target: Susceptibility to Recurrent and Invasive Bacterial Infection
    description: >-
      Loss of passive maternal protection converts the latent antibody defect into
      overt infection.
    causal_link_type: DIRECT
- name: Susceptibility to Recurrent and Invasive Bacterial Infection
  description: >-
    Recurrent sinopulmonary infection (otitis media, sinusitis, pneumonia) with
    encapsulated organisms, punctuated by invasive disease — sepsis, meningitis,
    septic arthritis, cellulitis — and gastrointestinal infection with chronic
    diarrhea. Enteroviruses, normally neutralised by antibody, can establish
    chronic central nervous system infection.
  biological_scale: ORGANISM
  role: Consequence
  evidence:
  - reference: PMID:32905580
    reference_title: "Absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in folliculin-interacting protein 1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We here investigated 3 novel patients, including the first known adult, from
      unrelated families with agammaglobulinemia, recurrent infections, and
      hypertrophic cardiomyopathy (HCM).
    explanation: >-
      Recurrent infection is the presenting clinical consequence of
      agammaglobulinemia across autosomal genetic causes.
  downstream:
  - target: Recurrent Infections
    causal_link_type: DIRECT
    description: The overall clinical phenotype of increased infection susceptibility.
  - target: Recurrent Otitis Media
    causal_link_type: DIRECT
    description: Middle-ear infection with encapsulated bacteria.
  - target: Recurrent Sinusitis
    causal_link_type: DIRECT
    description: Paranasal sinus infection with encapsulated bacteria.
  - target: Recurrent Pneumonia
    causal_link_type: DIRECT
    description: Lower respiratory tract infection with encapsulated bacteria.
  - target: Sepsis
    causal_link_type: DIRECT
    description: Invasive bacterial bloodstream infection.
  - target: Meningitis
    causal_link_type: DIRECT
    description: >-
      Invasive bacterial meningitis, or chronic enteroviral meningoencephalitis.
  - target: Septic Arthritis
    causal_link_type: DIRECT
    description: Invasive bacterial joint infection.
  - target: Cellulitis
    causal_link_type: DIRECT
    description: Skin and soft-tissue infection.
  - target: Chronic Diarrhea
    causal_link_type: DIRECT
    description: Enteric infection unopposed by secretory IgA.
  - target: Conjunctivitis
    causal_link_type: DIRECT
    description: Ocular surface infection.
  - target: Neutropenia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Neutropenia in agammaglobulinemia is frequently infection-associated and may
      resolve with treatment. The intrinsic, genotype-driven arm is modelled as a
      separate edge from the gene-lesion node rather than as an intermediate here.
    intermediate_mechanisms:
    - Neutrophil consumption and marrow suppression during severe bacterial infection
  - target: Failure to Thrive
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Chronic infection and enteropathy impair growth in untreated infants.
    intermediate_mechanisms:
    - Chronic infectious and inflammatory catabolic burden
    - Enteric protein and nutrient loss from persistent enteropathy
  - target: Progressive Airway Damage and Bronchiectasis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Repeated and inadequately treated lower respiratory infection destroys
      bronchial wall architecture.
    intermediate_mechanisms:
    - Recurrent suppurative pneumonia with neutrophil protease-mediated airway wall injury
    - Impaired mucociliary clearance perpetuating bacterial colonisation
- name: Progressive Airway Damage and Bronchiectasis
  description: >-
    Repeated suppurative lower respiratory infection before diagnosis produces
    irreversible bronchial dilatation. This is the principal source of long-term
    morbidity and is the reason early diagnosis matters: the damage accrued before
    immunoglobulin replacement begins cannot be reversed by it.
  biological_scale: TISSUE
  role: Consequence
  locations:
  - preferred_term: bronchus
    term:
      id: UBERON:0002185
      label: bronchus
  evidence:
  - reference: PMID:14752335
    reference_title: "Early defects in B cell development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In patients with sporadic X-linked agammaglobulinemia, the incidence of
      chronic lung disease correlates with the age at diagnosis, highlighting the
      importance of early diagnosis.
    explanation: >-
      Establishes the diagnosis-delay to chronic-lung-disease relationship. The
      quantitative observation is in XLA; because the downstream antibody-deficiency
      mechanism is shared with the autosomal forms the principle extends, but the
      direct autosomal data are lacking, so this is PARTIAL.
  downstream:
  - target: Bronchiectasis
    causal_link_type: DIRECT
    description: Permanent bronchial dilatation as the structural end result.
- name: Earlier and More Severe Presentation than X-Linked Agammaglobulinemia
  description: >-
    A genotype-severity gradient distinguishes the autosomal forms clinically.
    Because most autosomal defects remove an obligate structural component of the
    pre-BCR (rather than attenuating a kinase, as hypomorphic BTK alleles can),
    the developmental block is more often complete, and there is no possibility of
    the residual leaky B-cell output seen with some BTK alleles. Patients
    therefore present at younger ages, with more severe complications, and are
    diagnosed earlier. Mu heavy chain (IGHM) deficiency is the clearest example.
  biological_scale: ORGANISM
  role: Modifier
  evidence:
  - reference: PMID:14752335
    reference_title: "Early defects in B cell development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with autosomal recessive agammaglobulinemia have an earlier onset of
      disease compared with patients with X-linked agammaglobulinemia and they are
      more likely to have severe complications of the disease.
    explanation: >-
      States the earlier-onset, more-severe gradient directly.
  - reference: PMID:34241796
    reference_title: "Agammaglobulinemia: from X-linked to Autosomal Forms of Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In contrast, while less common, autosomal recessive forms of
      agammaglobulinemia present at younger ages and with typically more severe
      clinical features resulting in an earlier diagnosis.
    explanation: >-
      Independent review confirms younger age at presentation and more severe
      features in the autosomal recessive forms.
  - reference: PMID:30240888
    reference_title: "Comparison of Common Monogenic Defects in a Large Predominantly Antibody Deficiency Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical disease severity was significantly higher in patients
      with μ heavy chain and CD40 ligand mutations compared with patients with BTK
    explanation: >-
      A 550-patient cohort reports greater clinical disease severity in mu heavy
      chain (IGHM, autosomal) deficiency than in BTK deficiency. The snippet stops
      before the parenthetical p-value because that text contains a non-breaking
      space; the source reports the difference as statistically significant
      (P = .003).
  - reference: PMID:26910880
    reference_title: "Cohort of Iranian Patients with Congenital Agammaglobulinemia: Mutation Analysis and Novel Gene Defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      our data suggest that BTK-deficient and autosomal recessive agammaglobulinemia
      patients differ significantly regarding clinical/immunologic characteristics.
    explanation: >-
      A second national cohort finds significant clinical and immunological
      differences between BTK-deficient and autosomal recessive patients.
  downstream:
  - target: Susceptibility to Recurrent and Invasive Bacterial Infection
    description: >-
      The more complete developmental block yields an earlier and more severe
      infectious phenotype.
    causal_link_type: DIRECT
- name: Vulnerability to Live Attenuated Vaccine Strains
  description: >-
    Because neutralising antibody is absent, a live attenuated vaccine strain is
    not cleared and can replicate, revert and cause vaccine-associated disease.
    Vaccine-associated paralytic poliomyelitis after oral poliovirus vaccine is
    the archetype, and is reported significantly more often in mu heavy chain
    (IGHM) deficiency than in BTK deficiency. This makes live vaccines — above all
    OPV — an absolute agent to avoid.
  biological_scale: ORGANISM
  role: Consequence
  evidence:
  - reference: PMID:30240888
    reference_title: "Comparison of Common Monogenic Defects in a Large Predominantly Antibody Deficiency Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Paralysis following live polio vaccination was considerably higher in patients
      with μ heavy chain deficiency compared with BTK deficiency (P < .001).
    explanation: >-
      Directly quantifies the excess risk of vaccine-associated paralysis in an
      autosomal (IGHM) form relative to XLA.
phenotypes:
- name: Agammaglobulinemia
  category: Immunologic
  frequency: VERY_FREQUENT
  description: >-
    Severe reduction or complete absence of all serum immunoglobulin isotypes,
    the defining laboratory abnormality of the disorder.
  diagnostic: true
  phenotype_term:
    preferred_term: Agammaglobulinemia
    term:
      id: HP:0004432
      label: Agammaglobulinemia
  evidence:
  - reference: PMID:31696364
    reference_title: "Genetic Approaches for Definitive Diagnosis of Agammaglobulinemia in Consanguineous Families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Autosomal recessive agammaglobulinemia (ARA) is a primary immunodeficiency
      characterized by absent peripheral B cells, severe hypogammaglobulinemia,
      and absent BTK gene mutations.
    explanation: >-
      Severe hypogammaglobulinemia across isotypes is stated as a defining feature
      of the disorder, supporting the VERY_FREQUENT band.
- name: Decreased Total B Cell Count
  category: Immunologic
  frequency: VERY_FREQUENT
  description: >-
    Absent or near-absent circulating CD19+ B cells, conventionally below 1-2% of
    peripheral blood lymphocytes. This is the key discriminator from common
    variable immunodeficiency, in which B cells are present.
  diagnostic: true
  phenotype_term:
    preferred_term: Decreased total B cell count
    term:
      id: HP:0010976
      label: Decreased total B cell count
  evidence:
  - reference: PMID:31696364
    reference_title: "Genetic Approaches for Definitive Diagnosis of Agammaglobulinemia in Consanguineous Families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Autosomal recessive agammaglobulinemia (ARA) is a primary immunodeficiency
      characterized by absent peripheral B cells, severe hypogammaglobulinemia,
      and absent BTK gene mutations.
    explanation: >-
      Absent peripheral B cells is definitional, supporting the VERY_FREQUENT band.
  - reference: PMID:33951726
    reference_title: "Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected patients lacked circulating B cells and possessed few conventional
      dendritic cells.
    explanation: >-
      Independent confirmation of absent circulating B cells in another autosomal
      form (SPI1).
- name: Decreased Circulating IgG
  category: Immunologic
  frequency: VERY_FREQUENT
  description: Severely reduced or undetectable serum IgG.
  phenotype_term:
    preferred_term: Decreased circulating IgG concentration
    term:
      id: HP:0004315
      label: Decreased circulating IgG concentration
  evidence:
  - reference: PMID:17709424
    reference_title: "Mutations of the Igbeta gene cause agammaglobulinemia in man."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      resulting in the absence of peripheral B cells and low/absent immunoglobulin
      serum levels
    explanation: >-
      Establishes the global immunoglobulin deficit as definitional (hence the
      VERY_FREQUENT band); the source does not report IgG separately from the other
      isotypes, so this isotype-specific record is only partially supported.
- name: Decreased Circulating IgA
  category: Immunologic
  frequency: VERY_FREQUENT
  description: Severely reduced or undetectable serum IgA.
  phenotype_term:
    preferred_term: Decreased circulating IgA concentration
    term:
      id: HP:0002720
      label: Decreased circulating IgA concentration
  evidence:
  - reference: PMID:17709424
    reference_title: "Mutations of the Igbeta gene cause agammaglobulinemia in man."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      resulting in the absence of peripheral B cells and low/absent immunoglobulin
      serum levels
    explanation: >-
      Establishes the global immunoglobulin deficit as definitional; IgA is not
      reported separately, so this isotype-specific record is only partially
      supported.
- name: Decreased Circulating IgM
  category: Immunologic
  frequency: VERY_FREQUENT
  description: >-
    Severely reduced or undetectable serum IgM. The absence of IgM is what
    distinguishes agammaglobulinemia from the hyper-IgM syndromes, in which IgM is
    normal or elevated.
  phenotype_term:
    preferred_term: Decreased circulating total IgM
    term:
      id: HP:0002850
      label: Decreased circulating total IgM
  evidence:
  - reference: PMID:17709424
    reference_title: "Mutations of the Igbeta gene cause agammaglobulinemia in man."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      resulting in the absence of peripheral B cells and low/absent immunoglobulin
      serum levels
    explanation: >-
      Establishes the global immunoglobulin deficit as definitional; IgM is not
      reported separately, so this isotype-specific record is only partially
      supported.
- name: Recurrent Infections
  category: Immunologic
  frequency: VERY_FREQUENT
  description: >-
    Recurrent bacterial infection beginning in infancy, typically after maternal
    IgG wanes, and earlier in the autosomal than in the X-linked forms.
  phenotype_term:
    preferred_term: Recurrent bacterial infections
    term:
      id: HP:0002718
      label: Recurrent bacterial infections
  evidence:
  - reference: PMID:32905580
    reference_title: "Absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in folliculin-interacting protein 1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We here investigated 3 novel patients, including the first known adult, from
      unrelated families with agammaglobulinemia, recurrent infections, and
      hypertrophic cardiomyopathy (HCM).
    explanation: >-
      All three reported patients in this autosomal recessive form had recurrent
      infections, and infection susceptibility is the invariant clinical consequence
      of the antibody deficit, supporting the VERY_FREQUENT band.
- name: Recurrent Otitis Media
  category: Otolaryngologic
  description: >-
    Recurrent middle-ear infection, typically with Streptococcus pneumoniae and
    Haemophilus influenzae, and often the earliest recognised infection.
  phenotype_term:
    preferred_term: Recurrent otitis media
    term:
      id: HP:0000403
      label: Recurrent otitis media
  evidence:
  - reference: PMID:20301626
    reference_title: "X-Linked Agammaglobulinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recurrent otitis is the most common infection prior to diagnosis.
    explanation: >-
      GeneReviews documents recurrent otitis as the commonest pre-diagnosis
      infection in congenital agammaglobulinemia. The chapter covers the X-linked
      form; the sinopulmonary infection spectrum is shared with the autosomal forms
      through the same antibody defect, so this is recorded as PARTIAL and no
      frequency band is asserted for the autosomal forms.
- name: Recurrent Sinusitis
  category: Otolaryngologic
  description: Recurrent paranasal sinus infection, often becoming chronic.
  phenotype_term:
    preferred_term: Recurrent sinusitis
    term:
      id: HP:0011108
      label: Recurrent sinusitis
  evidence:
  - reference: PMID:20301626
    reference_title: "X-Linked Agammaglobulinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Conjunctivitis, sinopulmonary infections, diarrhea, and skin infections are
      also frequently seen.
    explanation: >-
      GeneReviews lists sinopulmonary infection among the frequent infections. Data
      are from the X-linked chapter; the shared antibody defect makes the spectrum
      applicable, hence PARTIAL and no frequency band.
- name: Recurrent Pneumonia
  category: Respiratory
  description: >-
    Recurrent lower respiratory tract infection; if inadequately treated it is the
    proximate cause of bronchiectasis.
  phenotype_term:
    preferred_term: Recurrent pneumonia
    term:
      id: HP:0006532
      label: Recurrent pneumonia
  evidence:
  - reference: PMID:20301626
    reference_title: "X-Linked Agammaglobulinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      they develop a severe, life-threatening infection such as pneumonia, empyema,
      meningitis, sepsis, cellulitis, or septic arthritis
    explanation: >-
      GeneReviews lists pneumonia among the severe presenting infections of
      congenital agammaglobulinemia. The associated quantitative figure is
      XLA-specific, so no frequency band is asserted here and support is PARTIAL.
- name: Bronchiectasis
  category: Respiratory
  description: >-
    Irreversible bronchial dilatation from repeated suppurative infection before
    diagnosis; the dominant long-term morbidity and the reason early diagnosis and
    adequate immunoglobulin dosing matter.
  phenotype_term:
    preferred_term: Bronchiectasis
    term:
      id: HP:0002110
      label: Bronchiectasis
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:14752335
    reference_title: "Early defects in B cell development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In patients with sporadic X-linked agammaglobulinemia, the incidence of
      chronic lung disease correlates with the age at diagnosis, highlighting the
      importance of early diagnosis.
    explanation: >-
      Establishes chronic lung disease as a diagnosis-delay-dependent complication of
      congenital agammaglobulinemia. The cohort is X-linked, so support for the
      autosomal forms is PARTIAL.
- name: Sepsis
  category: Immunologic
  description: >-
    Invasive bloodstream infection, a common mode of presentation in undiagnosed
    infants.
  phenotype_term:
    preferred_term: Sepsis
    term:
      id: HP:0100806
      label: Sepsis
  evidence:
  - reference: PMID:20301626
    reference_title: "X-Linked Agammaglobulinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      they develop a severe, life-threatening infection such as pneumonia, empyema,
      meningitis, sepsis, cellulitis, or septic arthritis
    explanation: >-
      GeneReviews enumerates sepsis among the severe presenting infections of
      congenital agammaglobulinemia; source is the X-linked chapter, hence PARTIAL.
- name: Meningitis
  category: Neurologic
  description: >-
    Invasive bacterial meningitis, and — distinctively for antibody deficiency —
    chronic enteroviral meningoencephalitis, which antibody normally prevents and
    which immunoglobulin replacement largely averts.
  phenotype_term:
    preferred_term: Meningitis
    term:
      id: HP:0001287
      label: Meningitis
  evidence:
  - reference: PMID:20301626
    reference_title: "X-Linked Agammaglobulinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Severe, difficult-to-treat enteroviral infections (often manifesting as
      dermatomyositis or chronic meningoencephalitis) can be prevented by this
      treatment.
    explanation: >-
      GeneReviews documents chronic enteroviral meningoencephalitis as an
      antibody-deficiency complication preventable by immunoglobulin replacement.
      The chapter is X-linked; the mechanism (absent neutralising antibody) is
      shared, so PARTIAL.
- name: Septic Arthritis
  category: Musculoskeletal
  description: Invasive bacterial joint infection.
  phenotype_term:
    preferred_term: Septic arthritis
    term:
      id: HP:0003095
      label: Septic arthritis
  evidence:
  - reference: PMID:20301626
    reference_title: "X-Linked Agammaglobulinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      they develop a severe, life-threatening infection such as pneumonia, empyema,
      meningitis, sepsis, cellulitis, or septic arthritis
    explanation: >-
      GeneReviews enumerates septic arthritis among the severe presenting infections
      of congenital agammaglobulinemia; X-linked chapter, hence PARTIAL.
- name: Cellulitis
  category: Dermatologic
  description: Skin and soft-tissue bacterial infection.
  phenotype_term:
    preferred_term: Cellulitis
    term:
      id: HP:0100658
      label: Cellulitis
  evidence:
  - reference: PMID:20301626
    reference_title: "X-Linked Agammaglobulinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Conjunctivitis, sinopulmonary infections, diarrhea, and skin infections are
      also frequently seen.
    explanation: >-
      GeneReviews lists skin infections among the frequent infections of congenital
      agammaglobulinemia; X-linked chapter, hence PARTIAL.
- name: Chronic Diarrhea
  category: Gastrointestinal
  description: >-
    Chronic or recurrent diarrhea from enteric infection unopposed by secretory
    IgA; part of the presenting picture in the Orphanet definition adopted by
    MONDO for this disorder.
  phenotype_term:
    preferred_term: Chronic diarrhea
    term:
      id: HP:0002028
      label: Chronic diarrhea
    temporality: CHRONIC
  evidence:
  - reference: PMID:20301626
    reference_title: "X-Linked Agammaglobulinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Conjunctivitis, sinopulmonary infections, diarrhea, and skin infections are
      also frequently seen.
    explanation: >-
      GeneReviews lists diarrhea among the frequent infections of congenital
      agammaglobulinemia; X-linked chapter, hence PARTIAL.
- name: Conjunctivitis
  category: Ophthalmologic
  description: Recurrent bacterial conjunctivitis.
  phenotype_term:
    preferred_term: Conjunctivitis
    term:
      id: HP:0000509
      label: Conjunctivitis
  evidence:
  - reference: PMID:20301626
    reference_title: "X-Linked Agammaglobulinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Conjunctivitis, sinopulmonary infections, diarrhea, and skin infections are
      also frequently seen.
    explanation: >-
      GeneReviews lists conjunctivitis among the frequent infections of congenital
      agammaglobulinemia; X-linked chapter, hence PARTIAL.
- name: Absent tonsils and lymphoid tissue
  category: Immunologic
  description: >-
    Unusually small or absent tonsils and cervical lymph nodes, reflecting the
    absence of B-cell follicles. An easily missed bedside sign that should prompt
    immunological evaluation.
  diagnostic: true
  phenotype_term:
    preferred_term: Absent tonsils
    term:
      id: HP:0030813
      label: Absent tonsils
  evidence:
  - reference: PMID:14752335
    reference_title: "Early defects in B cell development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Because the physical exam provides a clue to the diagnosis of the
      condition--unusually small or absent cervical lymph nodes and tonsils--it
      should be possible to make an early diagnosis in a greater percentage of
      patients.
    explanation: >-
      Documents absent or unusually small tonsils and cervical lymph nodes as a
      diagnostic physical sign in defects of early B-cell development.
- name: Neutropenia
  category: Hematologic
  description: >-
    Neutropenia is a recognised accompaniment and sometimes an early presenting
    feature; it is particularly noted in PIK3R1 and FNIP1 deficiency and may
    improve with treatment.
  phenotype_term:
    preferred_term: Decreased total neutrophil count
    term:
      id: HP:0001875
      label: Decreased total neutrophil count
  evidence:
  - reference: PMID:32905580
    reference_title: "Absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in folliculin-interacting protein 1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two of them also presented with intermittent or severe chronic neutropenia.
    explanation: >-
      Documents neutropenia accompanying autosomal recessive agammaglobulinemia
      (FNIP1 deficiency).
- name: Hypertrophic Cardiomyopathy
  category: Cardiovascular
  subtype: FNIP1
  description: >-
    Hypertrophic cardiomyopathy is a cardinal, non-immune feature of FNIP1
    deficiency and is what makes that entity syndromic rather than an isolated
    agammaglobulinemia. It is not a feature of the numbered AGM subtypes.
  phenotype_term:
    preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  evidence:
  - reference: PMID:32905580
    reference_title: "Absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in folliculin-interacting protein 1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We here investigated 3 novel patients, including the first known adult, from
      unrelated families with agammaglobulinemia, recurrent infections, and
      hypertrophic cardiomyopathy (HCM).
    explanation: >-
      All three reported FNIP1-deficient patients had hypertrophic cardiomyopathy.
- name: Failure to Thrive
  category: Growth
  subtype: AGM9
  description: >-
    Poor growth in untreated infants from chronic infection and enteropathy;
    explicitly part of the OMIM/MONDO description of the SLC39A7 (AGM9) subtype.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  notes: >-
    Recorded from the MONDO:0030519 / OMIM:619693 disease description, which states
    that additional features of agammaglobulinemia 9 include failure to thrive and
    skin involvement. The primary SLC39A7 paper (PMID:30718914) establishes the
    gene-disease link but does not quote growth failure in its abstract, so no
    evidence item is asserted here rather than attaching a snippet that does not
    support the claim.
biochemical:
- name: Serum IgG
  presence: Decreased
  context: >-
    Severely reduced or undetectable at diagnosis. Must be interpreted against
    age-specific paediatric reference intervals; in the first months of life the
    value reflects transplacental maternal IgG and can mask the defect.
  biomarker_term:
    preferred_term: Immunoglobulin G Measurement
    term:
      id: NCIT:C81971
      label: Immunoglobulin G Measurement
  evidence:
  - reference: PMID:31696364
    reference_title: "Genetic Approaches for Definitive Diagnosis of Agammaglobulinemia in Consanguineous Families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Autosomal recessive agammaglobulinemia (ARA) is a primary immunodeficiency
      characterized by absent peripheral B cells, severe hypogammaglobulinemia,
      and absent BTK gene mutations.
    explanation: Severe hypogammaglobulinemia defines the biochemical phenotype.
  reference_ranges:
  - loinc_term:
      id: LOINC:2465-3
      label: IgG [Mass/volume] in Serum or Plasma
    lower_bound: 700.0
    upper_bound: 1600.0
    unit: mg/dL
    population: adults
    notes: >-
      Conventional adult serum IgG reference interval used in clinical
      immunology laboratories. No citable article reports this interval, so
      provenance is recorded here rather than as a fabricated evidence item.
      Paediatric intervals are strongly age-dependent and are the ones that
      matter for diagnosis in infancy.
    interpretation_bands:
    - name: Agammaglobulinemia range
      upper_bound: 100.0
      unit: mg/dL
      abnormal_flag: CRITICAL_LOW
      severity: SEVERE
      phenotype_term:
        preferred_term: Agammaglobulinemia
        term:
          id: HP:0004432
          label: Agammaglobulinemia
      interpretation: >-
        Serum IgG below about 100 mg/dL beyond the age of maternal IgG decline is
        the typical finding in congenital agammaglobulinemia and, together with
        absent CD19+ B cells, is effectively diagnostic.
    - name: Hypogammaglobulinemia
      lower_bound: 100.0
      upper_bound: 700.0
      unit: mg/dL
      abnormal_flag: LOW
      severity: MODERATE
      phenotype_term:
        preferred_term: Decreased circulating IgG concentration
        term:
          id: HP:0004315
          label: Decreased circulating IgG concentration
      interpretation: >-
        Reduced but measurable IgG; more typical of common variable
        immunodeficiency or a hypomorphic/leaky genotype than of classic
        agammaglobulinemia.
    - name: Normal
      lower_bound: 700.0
      upper_bound: 1600.0
      unit: mg/dL
      abnormal_flag: NORMAL
- name: Serum IgA
  presence: Decreased
  context: Severely reduced or undetectable; mucosal secretory IgA defence is lost.
  biomarker_term:
    preferred_term: Immunoglobulin A Measurement
    term:
      id: NCIT:C81969
      label: Immunoglobulin A Measurement
  evidence:
  - reference: PMID:17709424
    reference_title: "Mutations of the Igbeta gene cause agammaglobulinemia in man."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      resulting in the absence of peripheral B cells and low/absent immunoglobulin
      serum levels
    explanation: >-
      Establishes globally low/absent serum immunoglobulin; IgA is not reported
      separately.
  reference_ranges:
  - loinc_term:
      id: LOINC:2458-8
      label: IgA [Mass/volume] in Serum or Plasma
    lower_bound: 70.0
    upper_bound: 400.0
    unit: mg/dL
    population: adults
    notes: >-
      Conventional adult serum IgA reference interval used in clinical immunology
      laboratories; provenance recorded here rather than as a fabricated citation.
- name: Serum IgM
  presence: Decreased
  context: >-
    Severely reduced or undetectable. IgM is unaffected by transplacental transfer,
    so a low IgM is informative even in early infancy, and a normal or high IgM
    points instead to a hyper-IgM syndrome.
  biomarker_term:
    preferred_term: Immunoglobulin M Measurement
    term:
      id: NCIT:C81972
      label: Immunoglobulin M Measurement
  evidence:
  - reference: PMID:17709424
    reference_title: "Mutations of the Igbeta gene cause agammaglobulinemia in man."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      resulting in the absence of peripheral B cells and low/absent immunoglobulin
      serum levels
    explanation: >-
      Establishes globally low/absent serum immunoglobulin; IgM is not reported
      separately.
  reference_ranges:
  - loinc_term:
      id: LOINC:2472-9
      label: IgM [Mass/volume] in Serum or Plasma
    lower_bound: 40.0
    upper_bound: 230.0
    unit: mg/dL
    population: adults
    notes: >-
      Conventional adult serum IgM reference interval used in clinical immunology
      laboratories; provenance recorded here rather than as a fabricated citation.
- name: Peripheral blood CD19+ B cell percentage
  presence: Decreased
  context: >-
    Flow cytometric CD19+ (or CD20+) B cells as a percentage of peripheral blood
    lymphocytes. This is the single most discriminating test: profoundly reduced
    B cells with normal T-cell numbers separates agammaglobulinemia from common
    variable immunodeficiency (B cells present) and from severe combined
    immunodeficiency (T cells also absent).
  biomarker_term:
    preferred_term: B-Lymphocyte Count
    term:
      id: NCIT:C174314
      label: B-Lymphocyte Count
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  readouts:
  - target: Developmental Arrest at the Pro-B to Pre-B Transition
    relationship: READOUT_OF
    direction: NEGATIVE
    description: >-
      The circulating CD19+ percentage is the clinical readout of the bone-marrow
      developmental block: the more complete the block, the lower the percentage.
  evidence:
  - reference: PMID:22351933
    reference_title: "Agammaglobulinemia and absent B lineage cells in a patient lacking the p85α subunit of PI3K."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Bone marrow aspirates from the patient showed <0.1% CD19(+) B cells with
      normal percentages of TdT(+)VpreB(+)CD19(-) B cell precursors.
    explanation: >-
      Illustrates the magnitude of CD19+ depletion in an autosomal form.
  notes: >-
    The diagnostic threshold conventionally applied is CD19+ B cells below 2% of
    peripheral blood lymphocytes (many laboratories and case series use below 1%),
    derived from the PAGID/ESID diagnostic criteria for primary immunodeficiencies
    (Conley, Notarangelo and Etzioni, PMID:10600329). That reference is indexed in
    PubMed without an abstract, so the threshold is recorded here as provenance
    rather than as an evidence item with a fabricated snippet. No non-deprecated
    LOINC code exists for CD19+ cells per 100 lymphocytes in blood, so loinc_term
    is omitted from the range below.
  reference_ranges:
  - lower_bound: 5.0
    upper_bound: 20.0
    unit: '%'
    population: >-
      children and adults; CD19+ cells as a percentage of peripheral blood
      lymphocytes
    notes: >-
      Approximate normal range for CD19+ B cells as a percentage of peripheral
      blood lymphocytes; the paediatric range is age-dependent and wider in
      infancy. Recorded as laboratory convention, not from a citable interval
      study.
    interpretation_bands:
    - name: Absent or near-absent B cells
      upper_bound: 2.0
      unit: '%'
      abnormal_flag: CRITICAL_LOW
      severity: SEVERE
      phenotype_term:
        preferred_term: Decreased total B cell count
        term:
          id: HP:0010976
          label: Decreased total B cell count
      interpretation: >-
        CD19+ B cells below 2% of lymphocytes, with normal T-cell numbers and
        panhypogammaglobulinemia, is the diagnostic laboratory signature of
        congenital agammaglobulinemia. In autosomal forms with a complete
        pre-BCR defect the value is usually far below 1%.
    - name: Reduced B cells
      lower_bound: 2.0
      upper_bound: 5.0
      unit: '%'
      abnormal_flag: LOW
      severity: MILD
      interpretation: >-
        Reduced but clearly detectable B cells; suggests a hypomorphic or leaky
        genotype, or an alternative diagnosis such as common variable
        immunodeficiency, rather than classic agammaglobulinemia.
    - name: Normal
      lower_bound: 5.0
      upper_bound: 20.0
      unit: '%'
      abnormal_flag: NORMAL
genetic:
- name: IGHM
  gene_term:
    preferred_term: IGHM
    term:
      id: hgnc:5541
      label: IGHM
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: AGM1
  notes: >-
    Encodes the immunoglobulin mu heavy chain. Biallelic loss of the membrane form
    abolishes pre-BCR assembly. The commonest and most severe autosomal form.
  evidence:
  - reference: PMID:8890099
    reference_title: "Mutations in the mu heavy-chain gene in patients with agammaglobulinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Defects in the mu heavy-chain gene are a cause of agammaglobulinemia in
      humans.
    explanation: Original gene-disease establishment for IGHM.
  - reference: PMID:31696364
    reference_title: "Genetic Approaches for Definitive Diagnosis of Agammaglobulinemia in Consanguineous Families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two novel mutations in IGHM (p.Val378Alafs*1 and p.Ile184Serfs*21) were
      identified in three patients from two unrelated kindred and a novel nonsense
      mutation was identified in CD79A (p.Trp66*) in two siblings from a third
      kindred.
    explanation: >-
      Independent replication with novel frameshift alleles in consanguineous
      North-African families.
- name: IGLL1
  gene_term:
    preferred_term: IGLL1
    term:
      id: hgnc:5870
      label: IGLL1
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: AGM2
  notes: >-
    Encodes lambda5/14.1, one of the two surrogate light chain proteins of the
    pre-BCR.
  evidence:
  - reference: PMID:9419212
    reference_title: "Mutations in the human lambda5/14.1 gene result in B cell deficiency and agammaglobulinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we identified a boy with mutations on both alleles of the gene for
      lambda5/14.1
    explanation: Identifies biallelic IGLL1 mutations in a patient with agammaglobulinemia.
- name: CD79A
  gene_term:
    preferred_term: CD79A
    term:
      id: hgnc:1698
      label: CD79A
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: AGM3
  notes: >-
    Encodes Ig-alpha, one half of the pre-BCR signal-transduction heterodimer.
    Produces a complete developmental block.
  evidence:
  - reference: PMID:10525050
    reference_title: "Mutations in Igalpha (CD79a) result in a complete block in B-cell development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A 2-year-old girl was found to have a homozygous splice defect in Igalpha, a
      transmembrane protein that forms part of the Igalpha/Igbeta
      signal-transduction module of the pre-BCR.
    explanation: Identifies the causative homozygous CD79A splice defect.
- name: CD79B
  gene_term:
    preferred_term: CD79B
    term:
      id: hgnc:1699
      label: CD79B
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: AGM6
  notes: >-
    Encodes Ig-beta, the partner of Ig-alpha. Some alleles are hypomorphic and
    produce a leakier block than CD79A.
  evidence:
  - reference: PMID:17709424
    reference_title: "Mutations of the Igbeta gene cause agammaglobulinemia in man."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These results indicate that mutations in Igbeta can cause agammaglobulinemia
      in man.
    explanation: Establishes the CD79B gene-disease relationship.
- name: BLNK
  gene_term:
    preferred_term: BLNK
    term:
      id: hgnc:14211
      label: BLNK
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: AGM4
  notes: >-
    Encodes the B-cell linker adaptor protein that organises pre-BCR-proximal
    signalling. The defect is highly B-lineage specific.
  evidence:
  - reference: PMID:10583958
    reference_title: "An essential role for BLNK in human B cell development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The immune system and overall growth and development were otherwise normal in
      this patient, suggesting that BLNK function is highly specific.
    explanation: >-
      Establishes BLNK deficiency as a B-lineage-restricted cause of absent B cells.
- name: LRRC8A
  gene_term:
    preferred_term: LRRC8A
    term:
      id: hgnc:19027
      label: LRRC8A
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: AGM5
  notes: >-
    Encodes the essential subunit of the volume-regulated anion channel. A
    truncating allele arising from a balanced t(9;20)(q33.2;q12) translocation
    caused autosomal dominant agammaglobulinemia in a single reported kindred.
    MONDO assigns LRRC8A to agammaglobulinemia 5, autosomal dominant (OMIM
    613506). This locus is frequently omitted from summary gene lists of autosomal
    agammaglobulinemia, including the deep-research report used for this entry;
    the assignment was verified against MONDO:0013290 / OMIM:613506 with OAK.
  evidence:
  - reference: PMID:14660746
    reference_title: "A congenital mutation of the novel gene LRRC8 causes agammaglobulinemia in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These results indicate that LRRC8 is responsible for the B cell deficiency
      in this patient and is required for B cell development.
    explanation: >-
      Establishes LRRC8 (LRRC8A) as responsible for the B-cell deficiency in this
      patient with congenital agammaglobulinemia.
- name: PIK3R1
  gene_term:
    preferred_term: PIK3R1
    term:
      id: hgnc:8979
      label: PIK3R1
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: AGM7
  notes: >-
    Encodes the p85-alpha regulatory subunit of PI3K. Biallelic loss produces an
    earlier developmental block than the pre-BCR signalling defects. Distinct from
    the activating PIK3R1 splice-site variants that cause APDS2, which is curated
    separately in dismech as Activated PI3K-delta Syndrome.
  evidence:
  - reference: PMID:22351933
    reference_title: "Agammaglobulinemia and absent B lineage cells in a patient lacking the p85α subunit of PI3K."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The mutation results in the absence of p85α but normal expression of the p50α
      and p55α regulatory subunits of PI3K.
    explanation: >-
      Characterises the specific p85-alpha loss underlying this form.
- name: TCF3
  gene_term:
    preferred_term: TCF3
    term:
      id: hgnc:11633
      label: TCF3
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: AGM8
  notes: >-
    Encodes the E2A transcription factor (E47 isoform). Carries both a dominant
    (AGM8, recurrent de novo dominant-negative p.E555K) and a recessive (AGM8B)
    numbered subtype — the only locus in the series with both. The subtype foreign
    key here points at the dominant form; see has_subtypes AGM8B for the recessive
    one.
  evidence:
  - reference: PMID:24216514
    reference_title: "A recurrent dominant negative E47 mutation causes agammaglobulinemia and BCR(-) B cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These findings document a mutational hot-spot in E47 and represent an
      autosomal dominant form of agammaglobulinemia.
    explanation: Establishes the dominant TCF3/E47 form.
  - reference: PMID:24216514
    reference_title: "A recurrent dominant negative E47 mutation causes agammaglobulinemia and BCR(-) B cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      E555K in the transfected cells localized normally to the nucleus and resulted
      in a dominant negative effect when bound to DNA as a homodimer with wild-type
      E47.
    explanation: Functional demonstration of the dominant-negative mechanism.
- name: SLC39A7
  gene_term:
    preferred_term: SLC39A7
    term:
      id: hgnc:4927
      label: SLC39A7
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: AGM9
  notes: >-
    Encodes the zinc transporter ZIP7. Hypomorphic alleles reduce cytosolic free
    zinc, raise phosphatase activity and blunt pre-BCR/BCR signalling.
  evidence:
  - reference: PMID:30718914
    reference_title: "An essential role for the Zn(2+) transporter ZIP7 in B cell development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The immunodeficiency results from hypomorphic mutations of SLC39A7, which
      encodes the endoplasmic reticulum-to-cytoplasm zinc transporter ZIP7.
    explanation: Establishes the SLC39A7 gene-disease relationship in patients.
  - reference: PMID:30718914
    reference_title: "An essential role for the Zn(2+) transporter ZIP7 in B cell development."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Homozygosity for a null allele caused embryonic death, but hypomorphic alleles
      reproduced the block in B cell development seen in patients.
    explanation: >-
      CRISPR-engineered mice recapitulate the human developmental block, supporting
      causality.
- name: SPI1
  gene_term:
    preferred_term: SPI1
    term:
      id: hgnc:11241
      label: SPI1
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: AGM10
  notes: >-
    Encodes the pioneer transcription factor PU.1. Heterozygous, largely de novo
    variants cause haploinsufficiency, constraining chromatin accessibility for
    the non-pioneer transcription factors that drive the pro-B to pre-B
    transition. Patients also have few conventional dendritic cells.
    Agammaglobulinemia 10, autosomal dominant (MONDO:0030529, OMIM 619707) is
    caused by SPI1, not TOP2B. TOP2B causes a mechanistically and clinically
    distinct syndromic entity (MONDO:0012243, OMIM 609296; see
    differential_diagnoses). Verified with OAK against MONDO.
  evidence:
  - reference: PMID:33951726
    reference_title: "Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patient SPI1 mutations encoded destabilized PU.1 proteins unable to nuclear
      localize or bind target DNA.
    explanation: Functional characterisation of the patient SPI1 alleles.
- name: FNIP1
  gene_term:
    preferred_term: FNIP1
    term:
      id: hgnc:29418
      label: FNIP1
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: FNIP1
  notes: >-
    Encodes folliculin-interacting protein 1. Biallelic loss causes a metabolic
    (AMPK/mTOR) form of agammaglobulinemia with an early B-cell developmental
    block, variable neutropenia and hypertrophic cardiomyopathy. Not part of the
    numbered AGM series; MONDO classifies it as FNIP1-associated syndrome
    (MONDO:0100432) and the cardiomyopathy makes it syndromic, but the B-cell
    mechanism is the same final common pathway, so it is retained here with its
    syndromic features scoped to the FNIP1 subtype.
  evidence:
  - reference: PMID:32905580
    reference_title: "Absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in folliculin-interacting protein 1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      FNIP1 deficiency is a novel inborn error of immunity characterized by early
      and severe B-cell development defect, agammaglobulinemia, variable
      neutropenia, and HCM.
    explanation: Establishes the FNIP1 gene-disease relationship and its phenotype.
differential_diagnoses:
- name: X-linked agammaglobulinemia (BTK)
  description: >-
    The single most important boundary. XLA shares the entire downstream
    mechanism modelled here — a pre-B developmental block, absent CD19+ B cells,
    panhypogammaglobulinemia, intact T cells, the same infection spectrum, the
    same immunoglobulin-replacement treatment and the same live-vaccine
    contraindication — and accounts for roughly 85% of congenital
    agammaglobulinemia. It is curated separately in dismech as
    X-linked_Agammaglobulinemia; that entry, not this one, carries the
    BTK-specific mechanism, and it is deliberately not duplicated here. The
    distinguishing content of the present entry is which pre-BCR component is
    lost and the earlier, more severe presentation that follows.
  disease_term:
    preferred_term: Bruton-type agammaglobulinemia
    term:
      id: MONDO:0010421
      label: Bruton-type agammaglobulinemia
  distinguishing_features:
  - Affects hemizygous males only; a female proband or a consanguineous pedigree points away from XLA
  - Caused by BTK, a cytoplasmic kinase downstream of the pre-BCR, rather than by loss of a pre-BCR structural or proximal signalling component
  - Later onset and less severe complications; the autosomal forms present at younger ages
  - Some BTK alleles are hypomorphic and permit leaky B-cell output, which complete autosomal pre-BCR defects do not
  - Absent BTK protein on flow cytometry or Western blot; a carrier mother shows non-random X inactivation in the B-cell lineage
  evidence:
  - reference: PMID:14752335
    reference_title: "Early defects in B cell development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with autosomal recessive agammaglobulinemia have an earlier onset of
      disease compared with patients with X-linked agammaglobulinemia and they are
      more likely to have severe complications of the disease.
    explanation: >-
      The clinical discriminator between the autosomal forms and XLA.
  - reference: PMID:31696364
    reference_title: "Genetic Approaches for Definitive Diagnosis of Agammaglobulinemia in Consanguineous Families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Autosomal recessive agammaglobulinemia (ARA) is a primary immunodeficiency
      characterized by absent peripheral B cells, severe hypogammaglobulinemia,
      and absent BTK gene mutations.
    explanation: >-
      Absence of BTK mutations is definitional for the autosomal forms.
  notes: >-
    In a classic male phenotype, BTK testing remains essential even when the
    referring label says "autosomal", because BTK is by far the most likely gene.
- name: Common variable immunodeficiency
  description: >-
    The commonest antibody deficiency in adults. Shares hypogammaglobulinemia and
    recurrent sinopulmonary infection, but the developmental block is absent — B
    cells are made and circulate, and the lesion is in terminal differentiation to
    plasma cells. Curated separately in dismech as Common_Variable_Immunodeficiency.
  disease_term:
    preferred_term: common variable immunodeficiency
    term:
      id: MONDO:0015517
      label: common variable immunodeficiency
  distinguishing_features:
  - CD19+ B cells are present, usually in normal numbers; agammaglobulinemia has under 1-2%
  - IgG is reduced but measurable rather than absent, and IgM is often preserved
  - Onset typically in the second to fourth decade rather than infancy
  - Prominent autoimmunity, lymphoproliferation, granulomatous disease and lymphoma risk, which are not features of agammaglobulinemia
- name: Severe combined immunodeficiency
  description: >-
    Also presents in infancy with profound infection and can have absent B cells,
    but the T-cell compartment is also absent or non-functional, which changes both
    the infection spectrum and the treatment. Curated separately in dismech as
    Severe_Combined_Immunodeficiency.
  disease_term:
    preferred_term: severe combined immunodeficiency
    term:
      id: MONDO:0015974
      label: severe combined immunodeficiency
  distinguishing_features:
  - T cells are absent or non-functional; in agammaglobulinemia T-cell number and function are normal
  - Opportunistic infection (Pneumocystis jirovecii, disseminated CMV, chronic candidiasis) and failure to thrive from the first months of life
  - Abnormal newborn TREC screening; agammaglobulinemia has normal TRECs with low or absent KRECs
  - Requires urgent hematopoietic stem cell transplantation or gene therapy, not immunoglobulin replacement alone
  evidence:
  - reference: PMID:22351933
    reference_title: "Agammaglobulinemia and absent B lineage cells in a patient lacking the p85α subunit of PI3K."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The number and function of the patient's T cells were normal.
    explanation: >-
      Normal T-cell number and function in autosomal agammaglobulinemia is the
      discriminator from SCID.
- name: Transient hypogammaglobulinemia of infancy
  description: >-
    A self-limited, physiological exaggeration of the normal nadir in serum IgG
    that follows catabolism of maternal IgG. It is the benign mimic that must not
    be treated as agammaglobulinemia, and equally must not be diagnosed in a child
    who actually has a developmental B-cell block.
  disease_term:
    preferred_term: transient hypogammaglobulinemia of infancy
    term:
      id: MONDO:0015698
      label: transient hypogammaglobulinemia of infancy
  distinguishing_features:
  - B cells are present in normal numbers
  - IgG is low but detectable and specific antibody responses to protein vaccines are usually intact
  - Immunoglobulin levels normalise spontaneously, typically by 2-4 years of age
  - Infections are milder and invasive bacterial disease is uncommon
- name: Good syndrome (thymoma with immunodeficiency)
  description: >-
    An acquired adult-onset immunodeficiency that is the closest adult phenocopy of
    agammaglobulinemia: thymoma with hypogammaglobulinemia and profoundly reduced or
    absent peripheral B cells. It is the reason a newly agammaglobulinemic adult
    needs chest imaging rather than a paediatric genetic panel.
  disease_term:
    preferred_term: Good syndrome
    term:
      id: MONDO:0015696
      label: Good syndrome
  distinguishing_features:
  - Adult onset, typically in the fifth to sixth decade, with no relevant family history
  - A thymoma is present on chest CT
  - Accompanying CD4+ T-cell lymphopenia and inverted CD4/CD8 ratio, unlike the intact T-cell compartment of congenital agammaglobulinemia
  - Susceptibility extends to opportunistic and viral infection, not only encapsulated bacteria
- name: Secondary hypogammaglobulinemia after B-cell-depleting therapy
  description: >-
    Rituximab and other anti-CD20 agents deplete CD19+ B cells and can produce
    prolonged hypogammaglobulinemia that is laboratory-indistinguishable from
    congenital agammaglobulinemia. Drug exposure history is the discriminator and
    should be sought before any genetic testing in an adult. No MONDO term
    specifically denotes rituximab-induced secondary hypogammaglobulinemia, so
    disease_term is deliberately omitted here rather than bound to an inaccurate
    surrogate.
  distinguishing_features:
  - History of anti-CD20 monoclonal antibody, other B-cell-depleting therapy, or immunosuppression
  - Onset in adulthood after a documented period of normal immunoglobulin levels
  - B-cell numbers usually recover over months to years after drug withdrawal
  - Other secondary causes to exclude include protein-losing enteropathy, nephrotic syndrome and lymphoid malignancy
  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: >-
      A national antibody-deficiency cohort documents secondary hypogammaglobulinemia
      following B-cell depletion therapy as a distinct group requiring separation
      from primary antibody deficiency.
- name: POU2AF1 (BOB1) deficiency
  description: >-
    Biallelic loss of the B-cell transcriptional coactivator BOB1/OBF-1
    (POU2AF1) causes agammaglobulinemia, so it is frequently listed alongside the
    autosomal agammaglobulinemia genes. It is deliberately scoped OUT of this
    entry on mechanistic grounds: the defining report is titled
    "Agammaglobulinemia with normal B-cell numbers in a patient lacking Bob1",
    i.e. there is no pro-B to pre-B developmental block and B cells are present,
    which is the opposite of the cellular lesion this entry models and violates
    the absent-CD19+-B-cell criterion used here to separate agammaglobulinemia
    from CVID. MONDO likewise places it directly under agammaglobulinemia
    (MONDO:0015977) rather than under autosomal agammaglobulinemia
    (MONDO:0011096). The lesion is in terminal B-cell differentiation and
    antibody output, not early B lymphopoiesis.
  disease_term:
    preferred_term: agammaglobulinemia, autosomal recessive, due to BOB1 deficiency
    term:
      id: MONDO:0800146
      label: agammaglobulinemia, autosomal recessive, due to BOB1 deficiency
  distinguishing_features:
  - Circulating B-cell numbers are normal, not absent or near-absent
  - The block is in terminal B-cell differentiation and antibody production rather than at the pro-B to pre-B checkpoint
  - MONDO classifies it under agammaglobulinemia (MONDO:0015977), not under autosomal agammaglobulinemia (MONDO:0011096)
  notes: >-
    Primary report PMID:33571536 (Kury et al., J Allergy Clin Immunol 2021). Its
    PubMed record carries no abstract body, so no snippet-backed evidence item is
    asserted here; the exclusion rests on the article title and the MONDO
    placement, both verified directly.
- name: Hyper-IgM syndrome
  description: >-
    Class-switch recombination defects give low IgG and IgA with normal or elevated
    IgM and present with recurrent infection in childhood, so they enter the same
    differential; the preserved or raised IgM and the presence of B cells separate
    them.
  disease_term:
    preferred_term: hyper-IgM syndrome
    term:
      id: MONDO:0003947
      label: hyper-IgM syndrome
  distinguishing_features:
  - Serum IgM is normal or elevated rather than absent
  - CD19+ B cells are present
  - CD40LG (X-linked) deficiency adds opportunistic infection, notably Pneumocystis jirovecii pneumonia, and neutropenia
- name: TOP2B-related B-cell immunodeficiency with distal limb and urogenital anomalies
  description: >-
    Dominant-negative TOP2B variants cause a syndromic B-cell immunodeficiency
    (also called Hoffman syndrome) with facial dysmorphism, distal limb anomalies
    and urogenital malformations alongside the B-cell defect. It is listed here
    explicitly because TOP2B is frequently and incorrectly listed as one of the
    numbered autosomal agammaglobulinemia loci; MONDO assigns it to a separate
    disease (MONDO:0012243, OMIM 609296), not to the AGM series.
  disease_term:
    preferred_term: "B-cell immunodeficiency, distal limb anomalies, and urogenital malformations"
    term:
      id: MONDO:0012243
      label: "B-cell immunodeficiency, distal limb anomalies, and urogenital malformations"
  distinguishing_features:
  - Extra-immune congenital malformations (facial, distal limb, urogenital) that isolated agammaglobulinemia lacks
  - Autosomal dominant, dominant-negative TOP2B variants
  - Classified by MONDO as a distinct disease rather than a numbered autosomal agammaglobulinemia subtype
  evidence:
  - reference: PMID:31409799
    reference_title: "Mutations in topoisomerase IIβ result in a B cell immunodeficiency."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      dominant negative effect on enzyme function, resulting in defective
      proliferation, survival of B-2 cells, causing a block in B cell development,
      and impair humoral function in response to immunization
    explanation: >-
      Yeast and knock-in/knockout mouse work establishes the dominant-negative TOP2B
      mechanism for this separate syndromic entity.
treatments:
- name: Immunoglobulin Replacement Therapy
  description: >-
    Lifelong intravenous (IVIG) or subcutaneous (SCIG) immunoglobulin replacement
    is the mainstay of treatment. It supplies the antibody the patient cannot make,
    reduces the frequency and severity of bacterial infection, and prevents chronic
    enteroviral meningoencephalitis. It does not reverse bronchiectasis already
    established before diagnosis, which is why early recognition matters. Dose and
    interval are individualised to infection control and to the presence of chronic
    lung disease rather than to a single universal trough. Because the autosomal
    forms present earlier, therapy often needs to start in the first months of life.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: Immunoglobulin Therapy
    term:
      id: NCIT:C62710
      label: Immunoglobulin Therapy
  target_mechanisms:
  - target: Panhypogammaglobulinemia and Loss of Humoral Immunity
    treatment_effect: BYPASSES
    description: >-
      Passive IgG replacement corrects the humoral effector deficit without
      correcting the upstream developmental block.
  evidence:
  - reference: PMID:20301626
    reference_title: "X-Linked Agammaglobulinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The mainstay of treatment is gammaglobulin substitution therapy
    explanation: >-
      GeneReviews states that gammaglobulin substitution is the mainstay of treatment
      for congenital agammaglobulinemia. The chapter covers the X-linked form;
      management is identical in the autosomal forms because the antibody deficit is
      the same, so this is recorded as PARTIAL.
  - reference: PMID:20301626
    reference_title: "X-Linked Agammaglobulinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Severe, difficult-to-treat enteroviral infections (often manifesting as
      dermatomyositis or chronic meningoencephalitis) can be prevented by this
      treatment.
    explanation: >-
      Documents prevention of chronic enteroviral disease by immunoglobulin
      replacement; sourced from the X-linked chapter, hence PARTIAL.
- name: Antibiotic Therapy and Prophylaxis
  description: >-
    Prompt and generous therapeutic antibiotics for breakthrough infection, with
    prophylactic antibiotics considered for patients who continue to have recurrent
    infection despite optimised immunoglobulin dosing or who have established
    bronchiectasis. Because patients cannot mount antibody responses, serology is
    unreliable and microbiological diagnosis should rely on culture, antigen
    detection or nucleic-acid amplification.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Antibiotic Therapy
    term:
      id: NCIT:C15620
      label: Antibiotic Therapy
  target_mechanisms:
  - target: Susceptibility to Recurrent and Invasive Bacterial Infection
    treatment_effect: INHIBITS
    description: >-
      Antibiotics eradicate the bacterial infections that the missing antibody
      cannot prevent or clear.
  evidence:
  - reference: PMID:20301626
    reference_title: "X-Linked Agammaglobulinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Generous use of antibiotics can decrease the incidence of chronic sinusitis
      and lung disease.
    explanation: >-
      GeneReviews supports generous antibiotic use to reduce chronic sinus and lung
      disease in congenital agammaglobulinemia; X-linked chapter, hence PARTIAL.
- name: Avoidance of Live Attenuated Vaccines (Agents to Avoid)
  description: >-
    Live attenuated vaccines are contraindicated. Oral poliovirus vaccine is the
    most important: without neutralising antibody the vaccine strain replicates,
    can revert, and causes vaccine-associated paralytic poliomyelitis — reported
    significantly more often in mu heavy chain (IGHM) deficiency than in BTK
    deficiency. Inactivated poliovirus vaccine should be used instead, for the
    patient and for household contacts. Other live products (MMR, varicella,
    rotavirus, BCG, live attenuated influenza, oral typhoid, yellow fever) should
    likewise be withheld. Inactivated vaccines are safe though responses are
    minimal; immunising household contacts provides indirect protection.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Preventive Intervention
    term:
      id: NCIT:C15843
      label: Preventive Intervention
  target_mechanisms:
  - target: Vulnerability to Live Attenuated Vaccine Strains
    treatment_effect: INHIBITS
    description: >-
      Withholding replicating vaccine strains removes the exposure entirely.
  evidence:
  - reference: PMID:30240888
    reference_title: "Comparison of Common Monogenic Defects in a Large Predominantly Antibody Deficiency Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Paralysis following live polio vaccination was considerably higher in patients
      with μ heavy chain deficiency compared with BTK deficiency (P < .001).
    explanation: >-
      Directly demonstrates the excess vaccine-associated paralysis risk in an
      autosomal (IGHM) form, the strongest available justification for the
      live-vaccine contraindication in autosomal agammaglobulinemia.
  - reference: PMID:20301626
    reference_title: "X-Linked Agammaglobulinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Agents/circumstances to avoid: Live viral
      vaccines, particularly oral polio vaccine.
    explanation: >-
      The GeneReviews Agents/Circumstances to Avoid recommendation. Written for the
      X-linked form; the underlying reason (no neutralising antibody) is identical in
      the autosomal forms, so this is recorded as PARTIAL.
  - reference: PMID:20301626
    reference_title: "X-Linked Agammaglobulinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Inactivated polio vaccine (as opposed to live oral polio vaccine) should be
      given to affected individuals and their family contacts.
    explanation: >-
      Specifies the substitution of inactivated for oral poliovirus vaccine,
      including for household contacts; X-linked chapter, hence PARTIAL.
- name: Respiratory Surveillance and Airway Clearance
  description: >-
    Annual quantitative immunoglobulins and full blood count, chest and sinus
    imaging as indicated, and pulmonary function testing once age-appropriate.
    Established bronchiectasis is managed with airway-clearance physiotherapy and
    specialist respiratory input.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Progressive Airway Damage and Bronchiectasis
    treatment_effect: INHIBITS
    description: >-
      Surveillance detects, and airway clearance limits progression of, chronic
      suppurative lung disease.
  evidence:
  - reference: PMID:20301626
    reference_title: "X-Linked Agammaglobulinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Complete blood count with differential and quantitative serum
      immunoglobulins at least annually; chest and sinus imaging as needed to assess
      for chronic lung and/or sinus disease.
    explanation: >-
      The GeneReviews surveillance schedule for congenital agammaglobulinemia;
      X-linked chapter, hence PARTIAL.
- name: Allogeneic Hematopoietic Cell Transplantation
  description: >-
    Not routine therapy for isolated agammaglobulinemia, because immunoglobulin
    replacement is effective and transplantation carries substantial risk. It is
    reserved for selected patients — uncontrollable complications, or a genotype
    with a broader haematopoietic defect where immune reconstitution is
    established, such as some SLC39A7/AGM9 cases.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: Hematopoietic Cell Transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  target_mechanisms:
  - target: Developmental Arrest at the Pro-B to Pre-B Transition
    treatment_effect: INHIBITS
    description: >-
      Donor haematopoiesis supplies genetically normal B-cell progenitors that can
      traverse the pre-BCR checkpoint.
  notes: >-
    The OMIM/MONDO description of agammaglobulinemia 9 (SLC39A7, MONDO:0030519)
    states that more severe cases may require hematopoietic stem cell
    transplantation whereas others are treated effectively with immunoglobulin
    replacement. No transplant-outcome series specific to autosomal
    agammaglobulinemia was identified with a quotable abstract, so no evidence item
    is asserted.
- name: Genetic Counseling and Family Testing
  description: >-
    Confirming the molecular diagnosis defines the mode of inheritance and the
    recurrence risk: 25% for siblings in an autosomal recessive family, 50% for the
    offspring of an affected heterozygote in the dominant forms (many of which are
    de novo). Cascade testing of at-risk relatives allows immunoglobulin
    replacement to begin before infection and live vaccines to be avoided. Because
    autosomal agammaglobulinemia is genetically heterogeneous, an
    inborn-errors-of-immunity panel or exome sequencing — including
    deletion/duplication analysis — is preferred over serial single-gene testing.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:31696364
    reference_title: "Genetic Approaches for Definitive Diagnosis of Agammaglobulinemia in Consanguineous Families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      WES has the potential to provide a rapid and more accurate genetic diagnosis
      in ARA, which is crucial for the treatment of the patients.
    explanation: >-
      Supports exome sequencing over serial single-gene testing in this genetically
      heterogeneous disorder.
  - reference: PMID:31696364
    reference_title: "Genetic Approaches for Definitive Diagnosis of Agammaglobulinemia in Consanguineous Families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We concluded that conventional gene sequencing, especially when multiple genes
      are involved in the defect as is the case in ARA, is costly and time-consuming,
      resulting in delayed diagnosis that contributes to increased morbidity and
      mortality.
    explanation: >-
      Explicitly links serial single-gene testing to diagnostic delay and worse
      outcomes.
diagnosis:
- name: Quantitative serum immunoglobulins
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  description: >-
    Measurement of serum IgG, IgA and IgM against age-specific reference
    intervals. All three isotypes are severely reduced or undetectable. IgM and
    IgA are informative even in early infancy because, unlike IgG, they are not
    contributed by transplacental maternal transfer.
  markers: Serum IgG, IgA and IgM
  results: Severe reduction or absence of all immunoglobulin isotypes
  evidence:
  - reference: PMID:31696364
    reference_title: "Genetic Approaches for Definitive Diagnosis of Agammaglobulinemia in Consanguineous Families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Autosomal recessive agammaglobulinemia (ARA) is a primary immunodeficiency
      characterized by absent peripheral B cells, severe hypogammaglobulinemia,
      and absent BTK gene mutations.
    explanation: >-
      Severe hypogammaglobulinemia with absent peripheral B cells is the
      laboratory definition of the disorder.
- name: Lymphocyte subset flow cytometry
  diagnosis_term:
    preferred_term: flow cytometry
    term:
      id: NCIT:C16585
      label: Flow Cytometry
  description: >-
    Enumeration of CD19+ (or CD20+) B cells, CD3/CD4/CD8 T cells and NK cells.
    The discriminating pattern is CD19+ B cells below 1-2% of lymphocytes with
    numerically and functionally normal T cells: B cells are present in common
    variable immunodeficiency, and T cells are also absent in severe combined
    immunodeficiency.
  markers: CD19+ B cell percentage; CD3/CD4/CD8 T cell counts
  results: CD19+ B cells profoundly reduced with normal T cell numbers
  evidence:
  - reference: PMID:22351933
    reference_title: "Agammaglobulinemia and absent B lineage cells in a patient lacking the p85α subunit of PI3K."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The number and function of the patient's T cells were normal.
    explanation: >-
      Preserved T-cell number and function alongside absent B cells is the
      pattern that separates agammaglobulinemia from combined immunodeficiency.
- name: Molecular genetic testing (IEI panel or exome sequencing)
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: >-
    BTK testing remains essential in a male proband even when the referral says
    "autosomal". Beyond that, because the autosomal forms are genetically
    heterogeneous, an inborn-errors-of-immunity panel covering at least IGHM,
    IGLL1, CD79A, CD79B, BLNK, PIK3R1, TCF3, SLC39A7, SPI1 and LRRC8A, or
    trio exome sequencing, is preferred over serial single-gene testing.
    Deletion/duplication analysis should be included because sequence-only
    assays miss exon-level copy-number changes such as the large IGHM deletions.
  results: Biallelic (or, for the dominant forms, heterozygous de novo) pathogenic variant identified
  evidence:
  - reference: PMID:31696364
    reference_title: "Genetic Approaches for Definitive Diagnosis of Agammaglobulinemia in Consanguineous Families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      WES has the potential to provide a rapid and more accurate genetic diagnosis
      in ARA, which is crucial for the treatment of the patients.
    explanation: >-
      Directly supports exome sequencing over serial single-gene testing in this
      genetically heterogeneous disorder.
  - reference: PMID:31696364
    reference_title: "Genetic Approaches for Definitive Diagnosis of Agammaglobulinemia in Consanguineous Families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We concluded that conventional gene sequencing, especially when multiple genes
      are involved in the defect as is the case in ARA, is costly and time-consuming,
      resulting in delayed diagnosis that contributes to increased morbidity and
      mortality.
    explanation: >-
      Links serial single-gene testing to diagnostic delay and worse outcomes.
- name: KREC-based newborn screening
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  description: >-
    Kappa-deleting recombination excision circles (KRECs) are a by-product of
    B-cell receptor light-chain rearrangement and are low or undetectable from
    birth when B-cell development is blocked. Combined TREC/KREC newborn
    screening can therefore identify severe B-cell lymphopenia before the first
    infection, allowing immunoglobulin replacement to start early and live
    vaccines to be avoided. TRECs are normal, which distinguishes the pattern
    from severe combined immunodeficiency. KREC screening is not universally
    implemented and may miss hypomorphic, leaky genotypes.
  markers: KREC copy number (with TREC as the T-cell comparator)
  results: KRECs low or undetectable with normal TRECs
  evidence:
  - reference: PMID:34241796
    reference_title: "Agammaglobulinemia: from X-linked to Autosomal Forms of Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Some diagnostic innovations, such as KREC level measurements and serum BCMA
      measurements, may aid in facilitating an earlier identification of
      agammaglobulinemia leading to prompt treatment.
    explanation: >-
      Supports KREC measurement as a route to earlier identification of
      agammaglobulinemia.
  notes: >-
    Because patients cannot mount antibody responses, vaccine-response serology
    is uninformative and should not be used to establish or exclude the
    diagnosis; deliberate live-vaccine challenge is contraindicated.
notes: >-
  Gene-to-numbered-subtype mapping was re-derived independently from MONDO and
  OMIM using OAK (RO:0004003 "has material basis in germline mutation in"
  relationships plus OMIM xrefs) rather than taken from the curation brief or the
  deep-research report. The verified series is: AGM1 / MONDO:0020729 /
  OMIM:601495 = IGHM (AR); AGM2 / MONDO:0013287 / OMIM:613500 = IGLL1 (AR); AGM3 /
  MONDO:0013288 / OMIM:613501 = CD79A (AR); AGM4 / MONDO:0013289 / OMIM:613502 =
  BLNK (AR); AGM5 / MONDO:0013290 / OMIM:613506 = LRRC8A (AD); AGM6 /
  MONDO:0012987 / OMIM:612692 = CD79B (AR); AGM7 / MONDO:0014083 / OMIM:615214 =
  PIK3R1 (AR); AGM8 / MONDO:0014840 / OMIM:616941 = TCF3 (AD); AGM8B /
  MONDO:0859234 / OMIM:619824 = TCF3 (AR); AGM9 / MONDO:0030519 / OMIM:619693 =
  SLC39A7 (AR); and AGM10 / MONDO:0030529 / OMIM:619707 = SPI1 (AD). Two
  corrections resulted: LRRC8A (AGM5) is a numbered locus that is routinely
  omitted from gene lists, and AGM10 is SPI1, not TOP2B — TOP2B causes a separate
  syndromic disease (MONDO:0012243, OMIM:609296) recorded under
  differential_diagnoses. Note that MONDO places AGM1-AGM9 under
  MONDO:0011096 (their definitions read "Any autosomal agammaglobulinemia in
  which..."), whereas AGM8B (MONDO:0859234) and AGM10 (MONDO:0030529) sit
  directly under agammaglobulinemia (MONDO:0015977); both are nonetheless
  retained here on the strength of the numbered-series naming and their gene
  assertions. FNIP1 (MONDO:0100432, FNIP1-associated syndrome) is a further
  autosomal cause outside the numbered series and is retained as a syndromic
  subtype, with its hypertrophic cardiomyopathy scoped to that subtype.
  POU2AF1/BOB1 (MONDO:0800146) was deliberately scoped OUT and moved to
  differential_diagnoses: its defining report (PMID:33571536) is titled
  "Agammaglobulinemia with normal B-cell numbers in a patient lacking Bob1", so
  it has no pro-B to pre-B block and does not satisfy the absent-B-cell criterion
  this entry is built on.

  GeneReviews has no chapter for the autosomal forms; the only agammaglobulinemia
  chapter is "X-Linked Agammaglobulinemia" (PMID:20301626). Its cached content is
  fully minable (Clinical Characteristics, Management and Agents/Circumstances to
  Avoid are all present), and it is used here for the shared antibody-deficiency
  clinical and management content, always marked supports: PARTIAL with an
  explanation that the source cohort is X-linked. Claims specific to the autosomal
  forms use autosomal-specific primary sources instead, and no XLA-specific
  frequency figures are carried over as frequency bands.

  Deep research: Edison/Falcon, 553 s. Its 17 citations resolved to only four
  distinct works (Ben-Ali 2020, Della Mina 2021, Cardenas-Morales 2022, Tangye
  2023), so the entry was built primarily from an independent PubMed E-utilities
  sweep of the primary gene-discovery literature. The Falcon report proposed two
  ontology identifiers that OAK showed to be semantically wrong — HP:0030245 was
  offered for "Tonsillar hypoplasia" but is actually Intrapartum fever, and
  HP:0031693 was offered for "Recurrent viral infections" but is actually Severe
  Epstein Barr virus infection. Neither was used. The report also omitted LRRC8A
  and SPI1 while presenting TOP2B as a numbered AGM locus.
references:
- reference: PMID:20301626
  title: "X-Linked Agammaglobulinemia."
  tags:
  - GeneReviews
  findings:
  - statement: >-
      Recurrent otitis is the commonest infection prior to diagnosis in congenital
      agammaglobulinemia, with conjunctivitis, sinopulmonary infection, diarrhea
      and skin infection also frequent.
    supporting_text: >-
      Recurrent otitis is the most common infection prior to diagnosis.
  - statement: >-
      A majority of affected individuals are recognised only when they develop a
      severe, life-threatening infection.
    supporting_text: >-
      they develop a severe, life-threatening infection such as pneumonia, empyema,
      meningitis, sepsis, cellulitis, or septic arthritis
  - statement: >-
      Gammaglobulin substitution therapy is the mainstay of treatment.
    supporting_text: >-
      The mainstay of treatment is gammaglobulin substitution therapy
  - statement: >-
      Agents and circumstances to avoid are live viral vaccines, particularly oral
      polio vaccine; inactivated poliovirus vaccine should be substituted, for
      affected individuals and their family contacts.
    supporting_text: >-
      Inactivated polio vaccine (as opposed to live oral polio vaccine) should be
      given to affected individuals and their family contacts.
  - statement: >-
      This chapter covers the X-linked form only; no GeneReviews chapter exists
      for the autosomal forms. It is therefore used in the present entry solely
      for the shared antibody-deficiency clinical and management content, always
      with supports PARTIAL.
- reference: PMID:34241796
  title: "Agammaglobulinemia: from X-linked to Autosomal Forms of Disease."
  findings:
  - statement: >-
      XLA accounts for approximately 85% of congenital agammaglobulinemia; the
      autosomal recessive forms present at younger ages and with more severe
      clinical features.
    supporting_text: >-
      In contrast, while less common, autosomal recessive forms of
      agammaglobulinemia present at younger ages and with typically more severe
      clinical features resulting in an earlier diagnosis.
- reference: PMID:37273190
  title: "Inborn errors of human B cell development, differentiation, and function."
  findings:
  - statement: >-
      Contemporary framework review integrating pre-BCR, PI3K, transcriptional,
      ionic and metabolic defects of human B-cell development, using monogenic
      patients as natural experiments defining essential pathways.
    supporting_text: >-
      analysis of individuals with monogenic defects that disrupt immune cell
      function are unprecedented models to link genotypes to clinical phenotypes,
      establish mechanisms of disease pathogenesis, and elucidate critical pathways
      for immune cell development and differentiation

📚

References & Deep Research

References

3

PMID:20301626

X-Linked Agammaglobulinemia.

5 findings

Recurrent otitis is the commonest infection prior to diagnosis in congenital agammaglobulinemia, with conjunctivitis, sinopulmonary infection, diarrhea and skin infection also frequent.

"Recurrent otitis is the most common infection prior to diagnosis."

A majority of affected individuals are recognised only when they develop a severe, life-threatening infection.

"they develop a severe, life-threatening infection such as pneumonia, empyema, meningitis, sepsis, cellulitis, or septic arthritis"

Gammaglobulin substitution therapy is the mainstay of treatment.

"The mainstay of treatment is gammaglobulin substitution therapy"

Agents and circumstances to avoid are live viral vaccines, particularly oral polio vaccine; inactivated poliovirus vaccine should be substituted, for affected individuals and their family contacts.

"Inactivated polio vaccine (as opposed to live oral polio vaccine) should be given to affected individuals and their family contacts."

This chapter covers the X-linked form only; no GeneReviews chapter exists for the autosomal forms. It is therefore used in the present entry solely for the shared antibody-deficiency clinical and management content, always with supports PARTIAL.

PMID:34241796

Agammaglobulinemia: from X-linked to Autosomal Forms of Disease.

1 finding

XLA accounts for approximately 85% of congenital agammaglobulinemia; the autosomal recessive forms present at younger ages and with more severe clinical features.

"In contrast, while less common, autosomal recessive forms of agammaglobulinemia present at younger ages and with typically more severe clinical features resulting in an earlier diagnosis."

PMID:37273190

Inborn errors of human B cell development, differentiation, and function.

1 finding

Contemporary framework review integrating pre-BCR, PI3K, transcriptional, ionic and metabolic defects of human B-cell development, using monogenic patients as natural experiments defining essential pathways.

"analysis of individuals with monogenic defects that disrupt immune cell function are unprecedented models to link genotypes to clinical phenotypes, establish mechanisms of disease pathogenesis, and elucidate critical pathways for immune cell development and differentiation"

Deep Research

1

Falcon ▸

Autosomal Agammaglobulinemia: Disease-Characteristics Research Report

Edison Scientific Literature 17 citations 2026-08-01T08:42:59.285558

Autosomal Agammaglobulinemia: Disease-Characteristics Research Report

Executive summary and scope

Autosomal agammaglobulinemia is not one monogenic disease but a heterogeneous group of inherited disorders in which early B-cell development fails because of an autosomal defect. The defining laboratory pattern is profound reduction or absence of circulating B cells, markedly reduced immunoglobulins, and preserved T-cell numbers/function in the classic forms. It phenocopies X-linked agammaglobulinemia (XLA) but lacks a causal BTK variant. Autosomal recessive (AR) disease predominates; uncommon autosomal dominant (AD) syndromes involve genes such as TCF3 and TOP2B. XLA accounts for approximately 85% of congenital agammaglobulinemia, leaving autosomal and genetically unresolved forms as a small minority. AR forms generally present younger and more severely than XLA. (benali2020geneticapproachesfor pages 1-2, mina2021molecularrequirementsfor pages 4-5, cardenasmorales2022agammaglobulinemiafromxlinked pages 4-5)

The strongest recent synthesis is Tangye et al., Journal of Experimental Medicine, published June 2023, DOI 10.1084/jem.20221105. Its abstract states: “The fundamental importance of the role of human B cells in host defense against infectious diseases has been established by the discovery of inborn errors of immunity that disrupt B cell development, differentiation, or function.” (tangye2023inbornerrorsof pages 3-3, tangye2023inbornerrorsof pages 2-3)

Evidence boundary. Autosomal disease is exceptionally rare, and most treatment, outcome, quality-of-life, and infection-management evidence is extrapolated from combined agammaglobulinemia or primary-antibody-deficiency cohorts dominated by XLA. Subtype-specific claims below are identified where possible. PMID values were not exposed in the retrieved full-text metadata; DOI URLs are therefore supplied rather than inventing PMID identifiers.

1. Disease information

Definition and classification

Autosomal agammaglobulinemia is an inborn error of immunity/predominantly antibody deficiency caused by germline variants that interrupt B-cell lineage development, usually at the pro-B–to–pre-B transition. The operational phenotype is:

severe hypogammaglobulinemia or agammaglobulinemia;
absent or profoundly reduced peripheral CD19+/CD20+ B cells, commonly below 0.5–2% of lymphocytes;
recurrent, severe, or unusual bacterial infections, usually beginning in infancy after maternally transferred IgG wanes;
no pathogenic BTK variant;
usually normal T-cell counts in isolated pre-BCR-pathway defects. (benali2020geneticapproachesfor pages 1-2, benali2020geneticapproachesfor pages 4-6)

Identifiers and synonyms

Preferred label: autosomal agammaglobulinemia.
Common synonyms: autosomal recessive agammaglobulinemia; non-X-linked agammaglobulinemia; congenital autosomal agammaglobulinemia; agammaglobulinemia due to a specified gene defect; autosomal B-cell deficiency.
ICD-10-CM: D80.0, hereditary hypogammaglobulinemia, is the closest umbrella code; coding should preserve the molecular subtype in accompanying text.
ICD-11: classified under predominantly antibody deficiencies/inborn errors of immunity; a subtype-specific code should be verified in the local release.
MeSH: Agammaglobulinemia.
MONDO/OMIM/Orphanet: individual molecular forms have separate entries; the retrieved evidence did not verify a single authoritative MONDO or Orphanet identifier covering every autosomal form. A knowledge base should therefore model “autosomal agammaglobulinemia” as an umbrella concept linked to gene-defined child diseases, rather than assign an unverified single identifier.

The evidence is primarily aggregated disease-level literature, reviews, and small molecular cohorts—not individual EHR records. The most informative primary cohort comprised six affected people from four consanguineous North-African families. (benali2020geneticapproachesfor pages 1-2)

2. Etiology, risks, protective factors, and gene–environment relationships

Causal factors

The primary cause is a germline genetic defect affecting one of four functional modules:

Pre-B-cell receptor assembly: IGHM, IGLL1, CD79A, CD79B.
Pre-BCR/BCR signal transduction: BLNK, PIK3R1, and in some classifications PIK3CD.
Transcription, DNA topology, or ionic homeostasis: TCF3, TOP2B, SLC39A7.
Cellular metabolic control: FNIP1, involving AMPK–mTOR homeostasis. (mina2021molecularrequirementsfor pages 4-5, tangye2023inbornerrorsof pages 3-3, tangye2023inbornerrorsof pages 2-3, tangye2023inbornerrorsof pages 6-7)

A 2020 human study found homozygous IGHM frameshifts p.Val378Alafs1 and p.Ile184Serfs21 in three patients and homozygous CD79A p.Trp66 in two sisters. All had undetectable or very low immunoglobulins, B cells below 0.5%, and normal T-cell counts. A sixth agammaglobulinemic patient had homozygous RAG2 p.Glu407, illustrating that a broader combined-immunodeficiency differential may mimic the phenotype. (benali2020geneticapproachesfor pages 1-2, benali2020geneticapproachesfor pages 4-6)

Risk factors

Family history and consanguinity: the major ascertainable risks for AR disease. The North-African cohort explicitly arose from consanguineous families. (benali2020geneticapproachesfor pages 1-2)
Sex: unlike XLA, autosomal disease affects all sexes. A female infant or child with absent B cells particularly warrants evaluation for an autosomal defect.
De novo dominant variation: relevant to AD TCF3 or TOP2B disease.
Age: age does not cause disease, but clinical infection susceptibility rises as maternal IgG falls during infancy.

Protective factors

No validated protective allele, diet, lifestyle, or environmental exposure prevents the underlying developmental defect. Clinically protective measures include early diagnosis, immunoglobulin replacement, rapid antimicrobial treatment, selected prophylactic antibiotics, respiratory surveillance, and avoidance of live vaccines. (benali2020geneticapproachesfor pages 1-2, cardenasmorales2022agammaglobulinemiafromxlinked pages 8-10)

Gene–environment interaction

The genotype establishes profound humoral immune failure; environmental exposure determines which infections occur and how much secondary organ damage accumulates. Repeated airway infections cause a feed-forward cycle of epithelial injury, impaired mucociliary clearance, bronchiectasis, and further infection. There is no evidence that toxins, smoking, diet, pollution, or occupational exposure initiates the Mendelian disease, although smoke and respiratory pollutants plausibly worsen acquired lung damage. Infectious agents are complications, not causes.

3. Phenotypes

Phenotype	Type and characteristics	Suggested HPO term
Profoundly reduced/absent B cells	Laboratory abnormality; congenital, persistent; B cells often <0.5–2% of lymphocytes	HP:0005363, Abnormality of B-cell physiology; use the current HPO child term for decreased circulating B cells
Agammaglobulinemia/hypogammaglobulinemia	Laboratory abnormality; severe and lifelong without immune reconstitution	HP:0004432, Agammaglobulinemia; HP:0004313, Hypogammaglobulinemia
Recurrent respiratory infection	Symptom/sign; usually begins in infancy or early childhood; episodic but recurrent	HP:0002205, Recurrent respiratory infections
Recurrent bacterial infection	Clinical manifestation; often encapsulated organisms; severity variable to life-threatening sepsis	HP:0002718, Recurrent bacterial infections
Otitis media/sinusitis/pneumonia	Clinical signs; recurrent; downstream bronchiectasis risk	HP:0000403, Recurrent otitis media; HP:0011108, Recurrent sinusitis; HP:0006532, Recurrent pneumonia
Gastrointestinal infection/diarrhea	Episodic or chronic, especially with enteric pathogens	HP:0002028, Chronic diarrhea; HP:0004387, Enteric infection
Enteroviral infection	Potentially severe or chronic; neurologic disease is a feared complication of agammaglobulinemia	HP:0031693, Recurrent viral infections; add organism-specific annotation
Sepsis	Acute, potentially fatal; Pseudomonas sepsis particularly reported in μ-heavy-chain deficiency	HP:0100806, Sepsis
Neutropenia	Laboratory abnormality; sometimes an early presenting feature; approximately 30% in reported IGHM deficiency and notable in PIK3R1 disease; may improve with treatment/time	HP:0001875, Neutropenia
Small/absent tonsils and lymph nodes	Physical sign reflecting absent mature B-cell follicles; not universally documented in autosomal-only cohorts	HP:0030245, Tonsillar hypoplasia, if confirmed
Bronchiectasis/chronic lung disease	Acquired complication; progressive if infections are not controlled	HP:0002110, Bronchiectasis
Syndromic malformations	TOP2B/Hoffman syndrome: facial dysmorphism, limb and urogenital anomalies; variable	HP:0001999, Abnormal facial shape; phenotype-specific limb/urogenital terms

Children with IGHM deficiency presented at a reported mean of 11 months, compared with 35 months in BTK-related XLA, and had severe infections including enteroviral disease and Pseudomonas sepsis. Approximately 30% developed neutropenia. (cardenasmorales2022agammaglobulinemiafromxlinked pages 4-5)

Quality of life is impaired by infection burden, chronic airway disease, school/work disruption, repeated infusions, venous access, and anxiety about infection. However, no validated EQ-5D, SF-36, or PROMIS estimates specific to autosomal agammaglobulinemia were identified.

4. Genetic and molecular information

The principal molecular subtypes are summarized below.

Gene/pathway	Inheritance	Developmental block / mechanism	Human phenotype or quantitative evidence	Representative variant / evidence
Autosomal agammaglobulinemia (umbrella term)	Mostly autosomal recessive; rarer autosomal dominant forms reported	Heterogeneous early B-cell developmental disorders; often a phenocopy of X-linked agammaglobulinemia, usually involving pre-BCR/BCR components or downstream signaling	Review evidence indicates XLA accounts for ~85% of congenital agammaglobulinemia, with non-BTK autosomal forms comprising the remainder; AR forms typically present younger and more severely than XLA (cardenasmorales2022agammaglobulinemiafromxlinked pages 4-5, cardenasmorales2022agammaglobulinemiafromxlinked pages 8-10, tangye2023inbornerrorsof pages 2-3)	Classification caveat: this is an umbrella category rather than a single monogenic disease entity (benali2020geneticapproachesfor pages 1-2, cardenasmorales2022agammaglobulinemiafromxlinked pages 4-5)
IGHM (μ heavy chain / pre-BCR)	Autosomal recessive	Early block at the pro-B to pre-B transition due to absent/defective μ heavy chain in the pre-BCR (mina2021molecularrequirementsfor pages 4-5, tangye2023inbornerrorsof pages 2-3)	Mean age at presentation reported as 11 months versus 35 months for BTK/XLA; μ heavy-chain deficiency accounts for about 5% of agammaglobulinemia cases; ~30% of affected patients develop neutropenia; severe infections including enteroviral infection and Pseudomonas sepsis emphasized (cardenasmorales2022agammaglobulinemiafromxlinked pages 4-5)	Human cohort: novel homozygous frameshifts *p.Val378Alafs1 and p.Ile184Serfs21* in 3 patients; absent/severely reduced B cells <0.5% with very low/undetectable immunoglobulins (benali2020geneticapproachesfor pages 1-2, benali2020geneticapproachesfor pages 4-6)
IGLL1 (λ5 surrogate light chain / pre-BCR)	Autosomal recessive	Pre-BCR assembly defect causing block at the pro-B to pre-B transition (mina2021molecularrequirementsfor pages 4-5, tangye2023inbornerrorsof pages 2-3)	Patients with CD79A, CD79B, IGLL1, or BLNK defects are described as clinically indistinguishable from BTK deficiency in major features (mina2021molecularrequirementsfor pages 4-5)	Identified by review evidence as a recurrent AR cause of agammaglobulinemia/B-cell deficiency; no quantitative patient numbers in available context (cardenasmorales2022agammaglobulinemiafromxlinked pages 4-5, cardenasmorales2022agammaglobulinemiafromxlinked pages 12-13)
CD79A (Igα / pre-BCR signaling)	Autosomal recessive	Complete block in B-cell development from defective Igα-mediated pre-BCR signaling (cardenasmorales2022agammaglobulinemiafromxlinked pages 12-13)	In a human cohort, 2 sisters had undetectable/very low immunoglobulins, absent or severely reduced B cells <0.5%, and normal T-cell counts (benali2020geneticapproachesfor pages 4-6)	Novel homozygous nonsense variant p.Trp66* (c.197G>A) in extracellular domain; review literature characterizes CD79A defects as causing a complete developmental block (benali2020geneticapproachesfor pages 4-6, cardenasmorales2022agammaglobulinemiafromxlinked pages 12-13)
CD79B (Igβ / pre-BCR signaling)	Autosomal recessive	Defective Igβ signaling in the pre-BCR/BCR pathway; described as a more hypomorphic/leaky developmental defect than CD79A (cardenasmorales2022agammaglobulinemiafromxlinked pages 12-13)	Clinically grouped with CD79A/IGLL1/BLNK deficiencies as resembling BTK-related agammaglobulinemia (mina2021molecularrequirementsfor pages 4-5)	Human case evidence is referenced in reviews, including hypomorphic/leaky defects; no exact variant details available in cited context (cardenasmorales2022agammaglobulinemiafromxlinked pages 12-13)
BLNK (B-cell linker protein)	Autosomal recessive	Downstream pre-BCR/BCR signal transduction defect; integrated with BTK and PI3K signaling during B-cell development (tangye2023inbornerrorsof pages 3-3)	Review evidence states BLNK-deficient patients are phenotypically similar to BTK/XLA; no quantitative cohort details in available context (mina2021molecularrequirementsfor pages 4-5)	Listed in recent reviews among genes causing AR agammaglobulinemia; heterozygous carriers reported healthy, supporting biallelic disease mechanism (tangye2023inbornerrorsof pages 3-3, tangye2023inbornerrorsof pages 2-3)
PIK3R1 / PIK3CD (PI3K pathway)	PIK3R1: autosomal recessive and dominant disease forms reported in agammaglobulinemia literature; PIK3CD mentioned as a B-cell deficiency/agammaglobulinemia gene in review context	PI3K regulatory/catalytic subunits activated after BCR ligation to generate PIP3; disruption impairs BCR signaling and B-cell development (tangye2023inbornerrorsof pages 3-3, tangye2023inbornerrorsof pages 2-3)	Review evidence highlights early neutropenia as notable in PIK3R1-related agammaglobulinemia, often improving over time (cardenasmorales2022agammaglobulinemiafromxlinked pages 8-10)	Included in 2022-2023 reviews as established pathway genes for autosomal agammaglobulinemia/B-cell deficiency; no exact patient-level variants in available context (cardenasmorales2022agammaglobulinemiafromxlinked pages 8-10, tangye2023inbornerrorsof pages 3-3, tangye2023inbornerrorsof pages 2-3)
SLC39A7 (zinc transporter / signaling homeostasis)	Autosomal recessive	Perturbs divalent-cation–dependent signaling required for early B-cell development; developmental block grouped with pre-B to immature B-cell deficiency (mina2021molecularrequirementsfor pages 4-5)	Review notes 6 individuals from 5 kindreds with peripheral B-cell deficiency and preserved T-cell function (mina2021molecularrequirementsfor pages 4-5)	Identified in recent reviews as a novel AR cause of agammaglobulinemia/B-cell lymphopenia; no specific variant listed in available context (mina2021molecularrequirementsfor pages 4-5)
TCF3 (E2A/E47 transcription factor)	Autosomal recessive and autosomal dominant	Earlier developmental defect than classic pre-BCR genes, with block around the common lymphoid progenitor to pro-B stage; dominant-negative E47 effect can yield BCR-negative B cells (mina2021molecularrequirementsfor pages 4-5, cardenasmorales2022agammaglobulinemiafromxlinked pages 12-13)	Review evidence describes autosomal dominant and recessive agammaglobulinemia, including cases from Pakistan; clinical severity can include agammaglobulinemia and neutropenia-spectrum presentations (cardenasmorales2022agammaglobulinemiafromxlinked pages 12-13)	Recent reviews note dominant-negative mechanism and BCR-negative B cells; exact variant not provided in available context (cardenasmorales2022agammaglobulinemiafromxlinked pages 12-13)
TOP2B (topoisomerase IIβ)	Autosomal dominant	Earlier block in B-cell development; patient mutations have a dominant negative effect, impairing proliferation/survival of B-2 cells and humoral responses (mina2021molecularrequirementsfor pages 4-5)	Primary paper identified 10 individuals from 5 kindreds with syndromic B-cell immunodeficiency/Hoffman syndrome features including facial dysmorphism, limb anomalies, and urogenital malformations (mina2021molecularrequirementsfor pages 4-5)	Abstract-supported model evidence: patient mutations in TOP2B had a dominant-negative effect; yeast plus knock-in/knockout mouse models showed defective B-cell development and impaired humoral function (mina2021molecularrequirementsfor pages 4-5)
FNIP1 (metabolic/mTOR-AMPK pathway)	Autosomal recessive	Early B-cell developmental defect with altered cellular energy homeostasis; increased mTOR and AMPK activity compromises B-cell development/survival (tangye2023inbornerrorsof pages 6-7)	6 patients from 5 families had frank B-cell deficiency, agammaglobulinemia, and recurrent respiratory infections; bone marrow showed increased pro-B and pre-B1 cells with reduced pre-BII and immature B cells (tangye2023inbornerrorsof pages 6-7)	Recent 2023 review highlights FNIP1 as an AR agammaglobulinemia cause with marrow-stage quantitative abnormalities, representing a newer metabolic subtype (tangye2023inbornerrorsof pages 6-7)

Table: This table summarizes the autosomal genetic subtypes of agammaglobulinemia supported by the retrieved evidence, highlighting inheritance, developmental mechanisms, and representative human findings. It is useful for distinguishing the umbrella diagnosis from its heterogeneous molecular causes.

Variant interpretation

Origin: causal variants are germline; somatic disease is not the recognized mechanism.
Common classes: nonsense, frameshift, splice-disrupting, missense/hypomorphic, and occasionally larger deletions.
Functional effects: most AR variants are loss-of-function; dominant TOP2B and some TCF3/E47 variants act through dominant-negative effects. (cardenasmorales2022agammaglobulinemiafromxlinked pages 12-13, benali2020geneticapproachesfor pages 4-6)
Population frequency: pathogenic alleles are expected to be rare; no defensible gene-wide carrier frequency or exact gnomAD frequency can be assigned without variant-specific database queries.
ACMG classification: each variant requires case-level ACMG/AMP evaluation incorporating segregation, population frequency, predicted loss of function, functional evidence, and phenotype. “Gene associated with disease” does not make every rare variant pathogenic.
Penetrance/expressivity: severe biallelic null pre-BCR defects are generally highly penetrant, but hypomorphic variants can be leaky. Expressivity is variable, as illustrated by complete CD79A versus hypomorphic CD79B developmental blocks and syndromic TOP2B disease. (cardenasmorales2022agammaglobulinemiafromxlinked pages 12-13)

No consistently validated modifier genes, disease-specific methylation signature, histone abnormality, recurrent aneuploidy, or characteristic chromosomal rearrangement was identified. Copy-number variants remain diagnostically relevant when sequencing is negative.

5. Environmental, lifestyle, and infectious information

No non-genetic exposure is known to cause autosomal agammaglobulinemia. Environmental and lifestyle factors primarily modify complications:

respiratory smoke and pollution should be minimized because chronic airway damage can compound infection risk;
safe food and water practices reduce gastrointestinal pathogen exposure;
prompt evaluation of fever and respiratory symptoms is important;
household infection control is relevant during outbreaks.

Typical infectious susceptibility includes recurrent bacterial respiratory infections, enteric infections, and severe or chronic enterovirus infection. IGHM deficiency has been associated with enteroviral infection and Pseudomonas sepsis. Serology is unreliable because patients cannot produce normal antibody responses; pathogen diagnosis should preferentially use culture, antigen detection, or nucleic-acid amplification. (cardenasmorales2022agammaglobulinemiafromxlinked pages 4-5)

6. Mechanism and pathophysiology

Core causal chain

Pathogenic germline variant → defective pre-BCR assembly/signaling or B-lineage transcription/metabolism → developmental arrest in bone marrow → profound loss of immature and mature B cells → absent plasma-cell and antibody output → impaired neutralization, opsonization, complement recruitment, and mucosal defense → recurrent infection → cumulative tissue injury, especially bronchiectasis and gastrointestinal disease. (mina2021molecularrequirementsfor pages 4-5, tangye2023inbornerrorsof pages 3-3, tangye2023inbornerrorsof pages 2-3)

Upstream mechanisms

Pre-BCR assembly: productive μ-heavy-chain expression (IGHM) must combine with surrogate light-chain components, including λ5 (IGLL1), and signal through Igα/Igβ (CD79A/CD79B). Disruption prevents the proliferative and survival checkpoint from pro-B to pre-B cell. (mina2021molecularrequirementsfor pages 4-5, tangye2023inbornerrorsof pages 2-3)
Signal transduction: BLNK coordinates signaling involving BTK and PI3K. PIK3R1/PIK3CD encode regulatory/catalytic PI3K subunits that produce PIP3 after receptor ligation. Failure suppresses developmental survival and expansion. (tangye2023inbornerrorsof pages 3-3, tangye2023inbornerrorsof pages 2-3)
Transcription/development: TCF3/E47 acts earlier, around common lymphoid progenitor–to–pro-B commitment; dominant-negative variants may produce BCR-negative B cells. (mina2021molecularrequirementsfor pages 4-5, cardenasmorales2022agammaglobulinemiafromxlinked pages 12-13)
DNA topology: dominant-negative TOP2B variants impair proliferation and survival of conventional B-2 cells, blocking development and humoral responses. (mina2021molecularrequirementsfor pages 4-5)
Ion/metabolic homeostasis: SLC39A7 demonstrates a requirement for divalent-cation homeostasis in lymphocyte signaling. FNIP1 deficiency perturbs energy homeostasis, increasing mTOR and AMPK activity; marrow shows excess pro-B/pre-BI cells and reduced pre-BII/immature B cells. Six patients from five families had B-cell deficiency, agammaglobulinemia, and recurrent respiratory infection. (mina2021molecularrequirementsfor pages 4-5, tangye2023inbornerrorsof pages 6-7)

Downstream mechanisms

The downstream injury is predominantly infection-mediated rather than autoimmune or intrinsically degenerative. Deficient antibody production impairs opsonophagocytosis of encapsulated bacteria and viral neutralization. Repeated pulmonary infections damage airway epithelium, producing chronic suppuration and bronchiectasis. Enteroviral persistence can produce severe neurologic or systemic disease.

Ontology suggestions

GO biological process: B-cell differentiation (GO:0030183); B-cell activation (GO:0042113); B-cell receptor signaling pathway (GO:0050853); immune response (GO:0006955); immunoglobulin production (GO:0002377); phosphatidylinositol 3-kinase signaling; regulation of mTOR signaling.
Cell Ontology: hematopoietic stem cell; common lymphoid progenitor; pro-B cell; pre-B cell; immature B cell; mature B cell; plasma cell. Exact CL identifiers should be resolved against the current Cell Ontology release.
GO cellular component: pre-B-cell receptor complex; B-cell receptor complex; plasma membrane; cytosol; nucleus for TCF3/TOP2B.

No clinically validated autosomal-specific transcriptomic, proteomic, metabolomic, lipidomic, spatial-transcriptomic, or multi-omics diagnostic signature was found. Marrow flow cytometry and functional genetic studies remain more directly informative.

7. Anatomical structures affected

Primary site

The primary anatomical lesion is in bone marrow B-cell development.

Suggested UBERON: bone marrow (UBERON:0002371).
Affected cells: pro-B, pre-B, immature B, and consequently circulating mature B cells and plasma cells.
Primary compartments: pre-BCR/BCR at the plasma membrane; cytosolic signaling complexes; nucleus for TCF3 and TOP2B.

Secondary sites

Respiratory system: middle ear, paranasal sinuses, bronchi, and lungs; recurrent infection may lead to bronchiectasis.
Gastrointestinal tract: recurrent infection and chronic diarrhea.
Central nervous system: secondary involvement in severe or chronic enteroviral infection.
Lymphoid organs: small or poorly developed tonsils/lymph nodes may reflect absent B-cell follicles.
TOP2B-related disease: craniofacial, limb, and urogenital structures may be congenitally abnormal. Ten affected people from five kindreds were summarized in the retrieved review. (mina2021molecularrequirementsfor pages 4-5)

Lateralization is not characteristic.

8. Temporal development

The molecular defect is congenital, but symptoms usually emerge when maternally transferred IgG declines during the first year of life. AR forms tend to present earlier and more severely than XLA; IGHM deficiency had a mean reported presentation age of 11 months. (cardenasmorales2022agammaglobulinemiafromxlinked pages 4-5)

The untreated course is chronic and punctuated by acute infections. There are no formal disease stages, but a useful clinical model is:

Pre-symptomatic congenital phase: absent/low B-cell output; KREC may already be undetectable.
Early infectious phase: recurrent otitis, sinusitis, pneumonia, diarrhea, sepsis, or neutropenia.
Established chronic disease: recurrent infection despite care, chronic sinus or lung disease.
Complicated disease: bronchiectasis, chronic enteroviral infection, organ damage, or severe sepsis.

There is no spontaneous remission of a true null developmental defect. Apparent improvement may reflect immunoglobulin replacement, resolution of infection-associated neutropenia, or a hypomorphic/leaky genotype. The critical intervention window is before recurrent infections produce irreversible lung damage.

9. Inheritance and population

Epidemiology

Reliable prevalence or incidence per 100,000 is unavailable for autosomal agammaglobulinemia as an umbrella category. XLA represents about 85% of congenital agammaglobulinemia; IGHM deficiency alone has been estimated at approximately 5% of all cases. Other subtypes are generally represented by individual families or very small series. (benali2020geneticapproachesfor pages 1-2, cardenasmorales2022agammaglobulinemiafromxlinked pages 4-5)

Inheritance

AR: IGHM, IGLL1, CD79A, CD79B, BLNK, SLC39A7, FNIP1, and some PIK3R1/TCF3 presentations.
AD: selected TCF3 and TOP2B disorders; dominant disease may be de novo.
Recurrence risk: for a confirmed AR disorder, each full sibling has a 25% affected, 50% carrier, and 25% non-carrier probability. For an affected heterozygous AD parent, transmission risk is 50%, subject to penetrance.
Consanguinity: materially increases AR disease probability and has facilitated discovery in North-African and other consanguineous families. (benali2020geneticapproachesfor pages 1-2)
Sex ratio: expected to be approximately equal for nonsyndromic autosomal disease, although tiny cohorts preclude a stable estimate.
Anticipation: not expected.
Germline mosaicism: theoretically possible, particularly after an apparently de novo variant, but no subtype-specific rate is established.
Founder effects/carrier frequency: may exist for individual variants, but no generalizable frequency was found.

10. Diagnostics

Clinical and laboratory evaluation

Suspect the disorder in any child—especially a girl, a child of consanguineous parents, or a patient without a BTK defect—with recurrent severe infection, extremely low immunoglobulins, and absent B cells.

Recommended evaluation:

Quantitative serum IgG, IgA, and IgM, interpreted using age-specific ranges.
CBC and differential, particularly for neutropenia.
Flow cytometry for CD3, CD4, CD8, CD19/CD20, and NK cells. In classic agammaglobulinemia, B cells are commonly below 2%; the molecular cohort reported below 0.5% with normal T-cell numbers. (benali2020geneticapproachesfor pages 1-2, benali2020geneticapproachesfor pages 4-6)
Vaccine-specific antibody titers are generally absent, but intentional live-vaccine challenge is contraindicated and additional vaccination solely to prove failure is usually unnecessary in profound agammaglobulinemia.
Culture/PCR rather than antibody serology for suspected infection.
Pulmonary assessment—oxygen saturation, chest imaging, and pulmonary function when age-appropriate—if recurrent pneumonia, chronic cough, or suspected bronchiectasis is present.
Bone-marrow immunophenotyping is not routinely required but can localize the developmental block in unresolved cases.

Genetic testing strategy

Begin with an inborn-errors-of-immunity/agammaglobulinemia panel containing at least BTK, IGHM, IGLL1, CD79A, CD79B, BLNK, PIK3R1, PIK3CD, SLC39A7, TCF3, TOP2B, FNIP1, and relevant phenocopy genes such as RAG1/RAG2.
In a classic male phenotype, BTK testing remains essential even if the referral label says “autosomal.”
Use deletion/duplication analysis because sequence-only assays can miss exon or multiexon copy-number changes.
If the panel is negative or the phenotype is syndromic, proceed to trio WES or WGS. The 2020 cohort concluded that sequential testing was expensive and slow, whereas WES produced a more efficient definitive diagnosis in genetically heterogeneous families. (benali2020geneticapproachesfor pages 1-2)
Confirm candidate variants by orthogonal sequencing, segregation, population-frequency review, and functional studies when classification remains uncertain.
CMA is reasonable for syndromic disease or suspected copy-number change; routine karyotype, FISH, mitochondrial sequencing, and repeat-expansion testing are not first-line.

Newborn screening

Kappa-deleting recombination excision circles (KREC) may be low or undetectable from birth and remain low in autosomal agammaglobulinemia. Combined TREC/KREC screening can identify severe B-cell lymphopenia before infection, but KREC screening is not universally implemented and may miss leaky defects. Its potential value is earlier immunology referral, avoidance of live vaccines, and timely Ig replacement. (cardenasmorales2022agammaglobulinemiafromxlinked pages 8-10)

Differential diagnosis

XLA due to BTK variants.
Severe combined immunodeficiency or leaky SCID, including RAG1/RAG2 disease.
Transient hypogammaglobulinemia of infancy—B cells are generally present.
Common variable immunodeficiency—usually later onset with B cells present.
Hyper-IgM syndromes—IgM is normal/high rather than universally absent.
Secondary hypogammaglobulinemia from anti-CD20 therapy, nephrotic/protein-losing disease, malignancy, or immunosuppressive therapy.
Thymoma-associated immunodeficiency in adults.

11. Outcome and prognosis

Without treatment, severe bacterial infection, sepsis, chronic enteroviral disease, and progressive lung injury confer substantial morbidity and mortality. Immunoglobulin replacement prevents many infections and improves survival, but it does not reverse established bronchiectasis or congenital syndromic abnormalities. (benali2020geneticapproachesfor pages 1-2)

Major morbidity includes recurrent hospitalization, chronic sinus and lung disease, bronchiectasis, gastrointestinal infection, neurologic enterovirus complications, and treatment burden. Prognosis is best with diagnosis before irreversible organ damage, adequate Ig exposure, adherence, rapid treatment of breakthrough infections, and specialist respiratory care.

No robust autosomal-only 5-year survival, life-expectancy, mortality, disability, or quality-of-life statistic was identified. Genotype may influence prognosis: IGHM disease is often early and severe; hypomorphic CD79B/IGLL1 defects may be milder; TOP2B prognosis includes nonimmune congenital anomalies. These genotype–phenotype relationships remain based on small cohorts and should not be used deterministically. (mina2021molecularrequirementsfor pages 4-5, cardenasmorales2022agammaglobulinemiafromxlinked pages 4-5, cardenasmorales2022agammaglobulinemiafromxlinked pages 12-13)

12. Treatment

Standard therapy

Lifelong immunoglobulin replacement is the treatment of choice for non-transplanted patients. IVIG and SCIG provide passive IgG, reduce serious bacterial infection, and improve survival. The dose and interval should be individualized to infection control, pharmacokinetics, weight, bronchiectasis, and adverse effects rather than a universal trough alone. (benali2020geneticapproachesfor pages 1-2, cardenasmorales2022agammaglobulinemiafromxlinked pages 8-10)

Suggested NCIt concepts include Immunoglobulin Replacement Therapy, Intravenous Immunoglobulin, Subcutaneous Immunoglobulin, Antibiotic Therapy, and Hematopoietic Stem Cell Transplantation; exact NCIt codes should be resolved against the current NCIt release.

Antimicrobial and supportive care

Treat suspected bacterial infection promptly; obtain cultures where feasible.
Consider prophylactic antibiotics for recurrent infection despite optimized Ig replacement or established bronchiectasis.
Use airway-clearance therapy and respiratory specialist management for bronchiectasis.
Monitor CBC, immunoglobulin exposure, infection frequency, pulmonary function, and liver/renal status as clinically indicated.
Adverse effects of Ig therapy include infusion reactions, headache/aseptic meningitis, thrombosis, hemolysis, and renal injury; SCIG generally reduces systemic reactions but causes local-site reactions.

Advanced and experimental therapy

Hematopoietic stem-cell transplantation is not routine first-line therapy for isolated agammaglobulinemia because lifelong Ig replacement is effective and transplantation has substantial risk. It may be considered for selected severe syndromic/combined defects, uncontrollable complications, or a genotype for which immune reconstitution is established. No approved gene therapy, CRISPR therapy, RNA therapy, or genotype-specific small molecule exists for the autosomal agammaglobulinemia umbrella.

A ClinicalTrials.gov search retrieved IVIG/SCIG studies enrolling broad primary hypo-/agammaglobulinemia populations, including NCT00138697, NCT00161993, and NCT00520494, but no clearly autosomal-subtype-specific interventional trial. Consequently, product studies support Ig replacement generally but cannot establish gene-specific response rates.

Pharmacogenomics

No validated CPIC/PharmGKB genotype-guided dosing rule specific to these genes and immunoglobulin replacement was identified.

13. Prevention

Primary prevention

The disease cannot be prevented after conception through lifestyle change. Reproductive options after identifying the familial variant include genetic counseling, carrier testing, prenatal diagnosis, and preimplantation genetic testing. Cascade testing is appropriate for at-risk relatives.

Secondary prevention

Identify affected newborns through family-based testing or TREC/KREC programs where available.
Begin immunology follow-up and Ig replacement before severe infection when diagnostic criteria are met.
Avoid delays caused by repeated treatment of infections without immune evaluation.

Tertiary prevention

Maintain adequate Ig replacement and adherence.
Use antimicrobial prophylaxis selectively.
Perform respiratory surveillance and airway clearance.
Ensure dental, nutritional, and gastrointestinal care.
Prefer inactivated vaccines when vaccination is indicated; responses may be minimal but household immunization provides indirect protection.
Avoid live attenuated vaccines in the affected person, particularly oral poliovirus and other live viral products, unless a specialist has documented sufficient immunity in an atypical leaky phenotype.
Vaccinate close contacts according to public-health guidance while considering precautions around transmissible live vaccines.

No diet, supplement, exercise program, or environmental intervention substitutes for Ig replacement.

14. Other species and natural disease

No well-established naturally occurring veterinary disorder exactly equivalent to the full human autosomal-agammaglobulinemia umbrella was identified in the retrieved evidence. Therefore, no defensible breed, VBO identifier, animal incidence, or zoonotic implication can be assigned.

Orthologs of the implicated genes are evolutionarily conserved across vertebrates, and the pre-BCR checkpoint is conserved in mammals. The disorder is inherited and not transmissible or zoonotic. Any veterinary annotation should be made at the individual gene/ortholog level through OMIA and NCBI Gene rather than inferred from the human umbrella label.

15. Model organisms and experimental systems

The best retrieved primary model evidence concerns TOP2B. Broderick et al., Nature Communications, published August 2019, DOI 10.1038/s41467-019-11570-6, used Saccharomyces cerevisiae and knock-in/knockout mice. The abstract reports that patient variants “have a dominant negative effect on enzyme function, resulting in defective proliferation, survival of B-2 cells, causing a block in B cell development, and impair humoral function in response to immunization.” This provides cross-system functional evidence connecting variant, enzyme dysfunction, cellular phenotype, and impaired antibody response. (mina2021molecularrequirementsfor pages 4-5)

Model categories and uses

Mouse knockout/conditional knockout: localizes B-lineage developmental checkpoints and measures marrow subsets, peripheral B cells, serum immunoglobulins, and immunization responses.
Knock-in/humanized alleles: tests dominant-negative or hypomorphic patient variants.
Yeast: useful for TOP2B enzyme-function studies but cannot model adaptive immunity.
Patient-derived cells: flow cytometry, immunoblotting, signaling assays, and rescue experiments can validate candidate variants.
iPSC/organoid systems: potentially useful but no clinically mature autosomal-agammaglobulinemia platform was identified.

Limitations

Murine B-cell development is informative but not identical to human development; redundancy and lineage distribution differ. Complete knockout models may overstate the severity of human hypomorphic alleles. Yeast models assess conserved enzymatic function but not B-cell-specific physiology.

Recent developments and expert interpretation

2023 mechanistic consolidation: Tangye et al. integrated pre-BCR, PI3K, transcriptional, ionic, and metabolic defects into a human B-cell-development framework, emphasizing that rare patients function as natural experiments defining essential pathways. (tangye2023inbornerrorsof pages 3-3, tangye2023inbornerrorsof pages 2-3, tangye2023inbornerrorsof pages 6-7)
FNIP1 as a metabolic B-cell-development disorder: six patients from five families showed agammaglobulinemia with a marrow shift from later pre-B/immature cells toward earlier pro-B/pre-BI stages and abnormal AMPK–mTOR activity. (tangye2023inbornerrorsof pages 6-7)
Broadening phenotype recognition: recent work increasingly recognizes leaky B-cell lymphopenia and hypogammaglobulinemia rather than only complete absence of B cells. This supports early genomic testing and argues against requiring a textbook phenotype before sequencing.
Screening innovation: KREC measurement can detect severe B-cell lymphopenia at birth, although implementation and sensitivity for partial defects remain unresolved. (cardenasmorales2022agammaglobulinemiafromxlinked pages 8-10)
Expert consensus: early molecular diagnosis matters because it confirms inheritance, directs family counseling, distinguishes isolated antibody deficiency from combined immunodeficiency, and may alter consideration of transplantation. The 2020 cohort demonstrates the practical superiority of WES over serial single-gene testing in consanguineous, genetically heterogeneous families. (benali2020geneticapproachesfor pages 1-2)

Knowledge-base conclusions

Autosomal agammaglobulinemia should be represented as a Mendelian disease family, not as a single gene–disease pair. Its invariant biological axis is failure of early B-cell development and antibody production, but inheritance, developmental checkpoint, syndromic involvement, and severity depend on the causal gene and allele. The most robust annotations are absent/reduced B cells, severe hypogammaglobulinemia, recurrent respiratory infection, early childhood onset, pre-BCR/BCR-pathway dysfunction, and benefit from lifelong immunoglobulin replacement. Autosomal-specific prevalence, survival, quality-of-life, environmental interaction, omics biomarkers, and treatment-response statistics remain major evidence gaps.

References

(benali2020geneticapproachesfor pages 1-2): Meriem Ben-Ali, Nadia Kechout, Najla Mekki, Jing Yang, Koon Wing Chan, Abdelhamid Barakat, Zahra Aadam, Jouda Gamara, Lamia Gargouri, Beya Largueche, Nabil BelHadj-Hmida, Amel Nedri, Houcine Ben Ameur, Fethi Mellouli, Rachida Boukari, Mohamed Bejaoui, Aziz Bousfiha, Imen Ben-Mustapha, Yu-Lung Lau, and Mohamed-Ridha Barbouche. Genetic approaches for definitive diagnosis of agammaglobulinemia in consanguineous families. Journal of Clinical Immunology, 40:96-104, Nov 2020. URL: https://doi.org/10.1007/s10875-019-00706-4, doi:10.1007/s10875-019-00706-4. This article has 13 citations and is from a domain leading peer-reviewed journal.
(mina2021molecularrequirementsfor pages 4-5): Erika Della Mina, Antoine Guérin, and Stuart G. Tangye. Molecular requirements for human lymphopoiesis as defined by inborn errors of immunity. Stem Cells, 39:389-402, Jan 2021. URL: https://doi.org/10.1002/stem.3327, doi:10.1002/stem.3327. This article has 4 citations and is from a highest quality peer-reviewed journal.
(cardenasmorales2022agammaglobulinemiafromxlinked pages 4-5): Melissa Cardenas-Morales and Vivian P. Hernandez-Trujillo. Agammaglobulinemia: from x-linked to autosomal forms of disease. Clinical Reviews in Allergy & Immunology, 63:22-35, Jul 2022. URL: https://doi.org/10.1007/s12016-021-08870-5, doi:10.1007/s12016-021-08870-5. This article has 86 citations and is from a peer-reviewed journal.
(tangye2023inbornerrorsof pages 3-3): Stuart G. Tangye, Tina Nguyen, Elissa K. Deenick, Vanessa L. Bryant, and Cindy S. Ma. Inborn errors of human b cell development, differentiation, and function. The Journal of Experimental Medicine, Jun 2023. URL: https://doi.org/10.1084/jem.20221105, doi:10.1084/jem.20221105. This article has 72 citations.
(tangye2023inbornerrorsof pages 2-3): Stuart G. Tangye, Tina Nguyen, Elissa K. Deenick, Vanessa L. Bryant, and Cindy S. Ma. Inborn errors of human b cell development, differentiation, and function. The Journal of Experimental Medicine, Jun 2023. URL: https://doi.org/10.1084/jem.20221105, doi:10.1084/jem.20221105. This article has 72 citations.
(benali2020geneticapproachesfor pages 4-6): Meriem Ben-Ali, Nadia Kechout, Najla Mekki, Jing Yang, Koon Wing Chan, Abdelhamid Barakat, Zahra Aadam, Jouda Gamara, Lamia Gargouri, Beya Largueche, Nabil BelHadj-Hmida, Amel Nedri, Houcine Ben Ameur, Fethi Mellouli, Rachida Boukari, Mohamed Bejaoui, Aziz Bousfiha, Imen Ben-Mustapha, Yu-Lung Lau, and Mohamed-Ridha Barbouche. Genetic approaches for definitive diagnosis of agammaglobulinemia in consanguineous families. Journal of Clinical Immunology, 40:96-104, Nov 2020. URL: https://doi.org/10.1007/s10875-019-00706-4, doi:10.1007/s10875-019-00706-4. This article has 13 citations and is from a domain leading peer-reviewed journal.
(tangye2023inbornerrorsof pages 6-7): Stuart G. Tangye, Tina Nguyen, Elissa K. Deenick, Vanessa L. Bryant, and Cindy S. Ma. Inborn errors of human b cell development, differentiation, and function. The Journal of Experimental Medicine, Jun 2023. URL: https://doi.org/10.1084/jem.20221105, doi:10.1084/jem.20221105. This article has 72 citations.
(cardenasmorales2022agammaglobulinemiafromxlinked pages 8-10): Melissa Cardenas-Morales and Vivian P. Hernandez-Trujillo. Agammaglobulinemia: from x-linked to autosomal forms of disease. Clinical Reviews in Allergy & Immunology, 63:22-35, Jul 2022. URL: https://doi.org/10.1007/s12016-021-08870-5, doi:10.1007/s12016-021-08870-5. This article has 86 citations and is from a peer-reviewed journal.
(cardenasmorales2022agammaglobulinemiafromxlinked pages 12-13): Melissa Cardenas-Morales and Vivian P. Hernandez-Trujillo. Agammaglobulinemia: from x-linked to autosomal forms of disease. Clinical Reviews in Allergy & Immunology, 63:22-35, Jul 2022. URL: https://doi.org/10.1007/s12016-021-08870-5, doi:10.1007/s12016-021-08870-5. This article has 86 citations and is from a peer-reviewed journal.

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Autosomal Agammaglobulinemia: Disease-Characteristics Research Report

Executive summary and scope

1. Disease information

Definition and classification

Identifiers and synonyms

2. Etiology, risks, protective factors, and gene–environment relationships

Causal factors

Risk factors

Protective factors

Gene–environment interaction

3. Phenotypes

4. Genetic and molecular information

Variant interpretation

5. Environmental, lifestyle, and infectious information

6. Mechanism and pathophysiology

Core causal chain

Upstream mechanisms

Downstream mechanisms

Ontology suggestions

7. Anatomical structures affected

Primary site

Secondary sites

8. Temporal development

9. Inheritance and population

Epidemiology

Inheritance

10. Diagnostics

Clinical and laboratory evaluation

Genetic testing strategy

Newborn screening

Differential diagnosis

11. Outcome and prognosis

12. Treatment

Standard therapy

Antimicrobial and supportive care

Advanced and experimental therapy

Pharmacogenomics

13. Prevention

Primary prevention

Secondary prevention

Tertiary prevention

14. Other species and natural disease

15. Model organisms and experimental systems

Model categories and uses

Limitations

Recent developments and expert interpretation

Knowledge-base conclusions

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