Autosomal Agammaglobulinemia

Mendelian MONDO:0011096 Pathograph 83 Show in embeddings browser Primary Immunodeficiency Antibody Deficiency Disorder Congenital Agammaglobulinemia

Autosomal agammaglobulinemia comprises recessive and dominant disorders with severely reduced circulating B cells and antibody production. Defects affect pre-B-cell receptor components, intracellular signaling, transcriptional regulation, zinc transport, or metabolic homeostasis. The developmental stage, residual B-cell output, immunoglobulin concentrations, and accompanying cell defects vary by gene and allele; a single universal pro-B-to-pre-B arrest does not describe the whole group. Recurrent sinopulmonary and invasive bacterial infections are central manifestations, but onset can extend into adulthood. Inflammatory disease and syndromic features occur in selected forms. Immunoglobulin replacement and infection management are the mainstay of care; transplantation requires gene-specific assessment.

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Classifications

Harrison's Part

IUIS Category

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Inheritance

Autosomal recessive inheritance HP:0000007

Biallelic pathogenic variants underlie IGHM, IGLL1, CD79A, CD79B, BLNK, PIK3R1, PIK3CD, SLC39A7, FNIP1 and recessive TCF3 disease. Consanguineous families have contributed substantially to gene discovery, but consanguinity is not required.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:31696364 SUPPORT DIRECT BACKGROUND 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 DIRECT PRIMARY RESULT 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

Dominant TCF3/E47 disease and SPI1 haploinsufficiency can be de novo or familial; SPI1 disease has variable expressivity and incomplete penetrance. TOP2B-related Hoffman syndrome is another dominant B-cell immunodeficiency. The historical LRRC8A association rests on one truncating-translocation case and currently has Limited gene-disease validity.

Autosomal dominant inheritance

Show evidence (3 references)

PMID:24216514 SUPPORT DIRECT PRIMARY RESULT 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 DIRECT PRIMARY RESULT 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.

url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"6 were apparently unaffected, indicating a disease penetrance of 81.8% with incomplete expressivity."

Familial segregation of heterozygous loss-of-function SPI1 variants, including apparently unaffected carriers, gives an estimated 81.8% penetrance; the authors note that ascertainment bias and late onset limit this estimate.

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Subtypes

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

IGHM hgnc:5541

Biallelic IGHM defects impair the membrane immunoglobulin mu heavy chain. Some early cohorts found more severe disease than XLA; that comparison should not be generalized to all autosomal genes.

Show evidence (1 reference)

PMID:8890099 SUPPORT DIRECT PRIMARY RESULT 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 DIRECT PRIMARY RESULT 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

Biallelic CD79A deficiency affects Ig-alpha. The original splice-defect case showed profound early B-cell developmental arrest; this observation is not a universal assay of every allele.

Show evidence (1 reference)

PMID:10525050 SUPPORT DIRECT PRIMARY RESULT 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

Biallelic BLNK deficiency affects a cytoplasmic signaling adaptor rather than a structural receptor subunit. The original patient had pro-B cells but no detected pre-B or mature B cells; subsequent phenotypes vary.

Show evidence (1 reference)

PMID:10583958 SUPPORT DIRECT PRIMARY RESULT 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

Historical numbered subtype associated with a heterozygous truncating LRRC8A allele from a balanced t(9;20) in one girl. ClinGen currently classifies the LRRC8A-agammaglobulinemia relationship as Limited. Dominant interference is proposed; neither a specific channel defect nor its mediation of the human immune phenotype was demonstrated.

Show evidence (1 reference)

PMID:14660746 SUPPORT DIRECT PRIMARY RESULT 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 original authors interpreted their single human case and mutant-expression model as causal; current ClinGen validity remains Limited.

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

CD79B hgnc:1699

Biallelic CD79B deficiency affects Ig-beta. The original Q80-stop allele prevented surface receptor assembly in a heterologous mature-BCR reconstitution assay. Other alleles may be hypomorphic; the assay is not a direct measurement of every patient pre-BCR.

Show evidence (1 reference)

PMID:17709424 SUPPORT DIRECT PRIMARY RESULT 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

Biallelic loss of PIK3R1 p85-alpha is distinct from activating PI3K-pathway immunodeficiencies. The original woman had a profound early B-lineage defect, colitis and transient early neutropenia, with preserved measured T-cell function.

Show evidence (1 reference)

PMID:22351933 SUPPORT DIRECT PRIMARY RESULT 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 DIRECT PRIMARY RESULT 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

Biallelic TCF3 loss affects both E12 and E47, with B-cell deficiency, variable dysmorphic features and reported B-cell acute lymphoblastic leukemia. It is distinct from E47-selective dominant-negative disease and heterozygous TCF3 haploinsufficiency with CVID-like disease.

Show evidence (1 reference)

PMID:39073655 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Complete AR TCF3 deficiency is associated with reduced B cells, hypogammaglobulinemia, dysmorphic phenotypes, and B-cell acute lymphoblastic leukemia (B-ALL)"

The 2024 article synthesizes the recessive phenotype; the original short report was not available as a substantive cached body.

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

SLC39A7 hgnc:4927

Hypomorphic SLC39A7 variants impair the zinc transporter ZIP7. Human and mouse evidence supports a B-cell developmental defect involving zinc homeostasis and signaling; the strongest mouse block is late-pre-B to immature B cell. Severe patients can also have skin disease and failure to thrive.

Show evidence (1 reference)

PMID:30718914 SUPPORT DIRECT PRIMARY RESULT 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 SPI1 loss reduces PU.1 activity. B-cell and dendritic-cell deficiency can present in infancy or adulthood, and relatives can have mild or no antibody abnormalities. Chromatin-accessibility mechanisms were tested in edited pro-B cell lines rather than directly in every patient lineage.

Show evidence (3 references)

PMID:33951726 SUPPORT DIRECT PRIMARY RESULT 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.

url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Of the 11 relatives harboring heterozygous LOF PU.1 variants, 6 were clinically well with laboratory evaluations documenting serum antibody and circulating B-cell concentrations within age- adjusted normal ranges."

Variant-carrying relatives with normal antibody and B-cell values support the mild-or-unaffected end of the AGM10 spectrum described here.

url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"In a cluster of patients, disease onset was delayed, sometimes into adulthood."

The expanded SPI1 cohort documents diagnosis and symptom onset extending beyond infancy into adulthood.

FNIP1-associated syndrome (autosomal recessive) MONDO:0100432

FNIP1 hgnc:29418

Biallelic FNIP1 deficiency is a syndromic B-cell immunodeficiency with hypertrophic cardiomyopathy and variable neutropenia. Patient-cell metabolic and phosphosignaling abnormalities provide mechanistic clues, but do not establish the causal route to cardiomyopathy or a uniform developmental arrest.

Show evidence (1 reference)

url:https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content SUPPORT DIRECT PRIMARY RESULT 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.

TOP2B-related Hoffman syndrome

TOP2B hgnc:11990

Dominant TOP2B-related B-cell immunodeficiency with variable distal-limb, facial and urogenital anomalies. This syndromic overlap is included in the IUIS agammaglobulinemia category; it is not AGM10, which denotes SPI1 disease.

Show evidence (1 reference)

PMID:31409799 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"In three families with Hoffman syndrome 9,10, we identi ﬁed three heterozygous mutations affecting the TOPRIM, or DNA gating, domain of the type II topoisomerase TOP2B."

Three families establish the reported human syndrome; mechanistic assays use separate yeast and mouse systems.

Recessive p110-delta deficiency

PIK3CD hgnc:8977

Biallelic loss of the p110-delta catalytic subunit can cause severe antibody deficiency with reduced B cells. This is distinct from dominant activating PIK3CD variants causing activated PI3K-delta syndrome. The historical numbered AGM series does not exhaust the modern disease spectrum.

Show evidence (1 reference)

PMID:34241796 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"There are an additional 6 cases of homozygous PIK3CD gene mutation resulting in LOF of PIK3 delta enzyme complex. These patients also displayed hypogammaglobulinemia or agammaglobulinemia as well as decreased B cells [34]."

The review summarizes recessive p110-delta loss with B-cell and antibody deficiency; activating PIK3CD disease is a distinct mechanism.

Discussions and Knowledge Gaps

Does the historical LRRC8A truncation define a reproducible dominant agammaglobulinemia mechanism?

KNOWLEDGE GAP gap_autosomal_agamma_lrrc8a

Attached to

pathophysiology#Truncated LRRC8A Protein

The human claim rests on a single balanced-translocation case. ClinGen labels the relationship Limited. Forced mutant expression and global null mouse studies use different allele mechanisms; preserved null-mouse antibody function cannot establish or refute a dominant human effect. Additional unrelated families and allele-specific functional evidence are needed.

Show evidence (2 references)

url:https://thegencc.org/submissions/SGC-107391.2 SUPPORT DIRECT REVIEW SYNTHESIS Other

"Since other patients with B cell deficiency and heterozygous LRRC8A have not been identified, the curation is classified as Limited."

ClinGen explains the Limited classification by the lack of additional human cases.

PMID:24752297 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Lrrc8a(-/-) mice displayed a modest block in B cell development but intact intrinsic B cell function."

Global null mice have a different allele mechanism from the single human heterozygous truncation.

What predicts onset, expressivity and long-term risk in SPI1 carriers?

KNOWLEDGE GAP gap_autosomal_agamma_spi1_penetrance

Attached to

pathophysiology#Reduced PU.1 Dosage or Activity

The 2025 cohort has 22 agammaglobulinemic patients, 5 relatives with milder antibody abnormalities and 6 apparently unaffected relatives. Its 81.8% estimate concerns any antibody phenotype and is affected by familial ascertainment and possible later onset. No hematologic malignancy was observed over 514 patient-years, but the small cohort cannot establish zero risk. The L180F family has marked within-family variation; a simple PU.1 abundance-to-severity relationship is not established.

Show evidence (2 references)

url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

Six heterozygous relatives had normal clinical and laboratory findings at assessment, which is the variable-penetrance observation this knowledge gap asks to explain.

url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"our cohort remains too small to conclude that inborn LOF PU.1 variants convey 0 malignancy risks."

The authors explicitly limit inference from the absence of observed blood cancers.

Which genetic forms benefit from transplantation, and which compartments must be corrected?

KNOWLEDGE GAP gap_autosomal_agamma_transplant

Attached to

treatments#Allogeneic Hematopoietic Cell Transplantation

ZIP7 sibling outcomes contrast with two SPI1 attempts that did not achieve independence from replacement. Persistent tissue-resident macrophages and donor competitive advantage are proposed explanations in SPI1, not demonstrated mechanisms. Gene-specific outcome data and donor genotype matter; immunologic improvement must be distinguished from skin or other organ recovery.

Show evidence (2 references)

PMID:30718914 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"(P1 and P2, family 1) additionally showed severe blistering dermatosis (Fig. 1b), failure to thrive and thrombocytopenia, prompting hematopoietic stem cell transplantation; this resulted in cure of immunologic abnormalities and amelioration of skin disease."

Two siblings among six ZIP7-deficient patients had severe skin disease, poor growth and thrombocytopenia; transplantation outcomes are specific to them.

url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Five years after transplantation, he remains IRT dependent because of undetectable serum immunoglobulin (IgA) and IgM despite naïve B-cell reconstitution and >99% donor peripheral blood engraftment in B-cell, T-cell, and myeloid cell compart- ments."

Long-term SPI1 follow-up documents persistent antibody-production failure despite donor engraftment.

How does FNIP1 deficiency produce cardiomyopathy and variable neutropenia?

KNOWLEDGE GAP gap_autosomal_agamma_fnip_cardio

Attached to

pathophysiology#FNIP1 Protein Deficiency pathophysiology#Increased B-Cell Mitochondrial Abundance pathophysiology#Increased B-Cell Mitochondrial Activity Signal pathophysiology#Increased B-Cell AKT Phosphorylation pathophysiology#Increased B-Cell 4EBP1 Phosphorylation

The clinical syndrome is genetically associated with these features, but small B-cell metabolic assays do not establish heart or granulocyte causal pathways. The original marrow observation lacks a discrete block, and later cases differ in neutrophil number and stimulus-dependent function.

Show evidence (3 references)

url:https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content SUPPORT DIRECT PRIMARY RESULT In Vitro

"Specifically, p4EBP1 and pAkt473 were significantly activated ( 12.46±1.86 vs 4.00±0.53, p = 0.00 02; 3.82±1.78 vs 0.97±0. 09, p = 0.029). As opposite, no difference could be found in S6 phosphorylation (1.46±0.14 vs 2.70±0.51, p = 0.14)."

One patient marrow comparison showed increased p4EBP1 and pAKT473 but not pS6; small repeated assays do not expand the donor count.

url:https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content SUPPORT DIRECT PRIMARY RESULT Human Clinical

"B -cell precursors did not show evidence of a maturation block, unlike classical agammaglobulinemia14, although a relative increase of earlier maturation stages (pro-B and pre-B1) and a significant reduction of immature B-cells was observed (Figure 1E and supplemental Figure 8)."

One patient had altered precursor proportions without a discrete maturation block, limiting a universal pro-B arrest model.

url:https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content SUPPORT DIRECT PRIMARY RESULT In Vitro

"Indeed, circulating P1 B-cells exhibited increased numbers of mitochondria and mitochondrial activity relative to healthy control (HC) B-cells (Figure 1F and supplemental Figure 9 )."

Mitochondrial dye readouts were measured in rare circulating B cells from one patient compared with a healthy control; they do not establish a general ATP-production flux.

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Pathophysiology

Impaired Membrane Mu Heavy-Chain Expression

Biallelic IGHM variants disrupt the membrane heavy-chain component required for early B-cell receptor function. Allele-specific residual expression varies.

IGHM hgnc:5541

Downstream

Impaired Pre-B-Cell Receptor Assembly Membrane mu deficiency impairs receptor formation; the human developmental phenotype and receptor biology support this bridge.

Show evidence (1 reference)

PMID:8890099 SUPPORT DIRECT PRIMARY RESULT Human Clinical

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

Original gene-disease establishment for IGHM.

Defective Lambda5 Surrogate Light Chain

IGLL1 disease disrupts functional lambda5. In the original compound-heterozygous patient, one allele lacked detectable transcript and the tested P142L-containing protein folded and secreted abnormally in COS cells.

IGLL1 hgnc:5870

Experimental models

IGLL1 folding and secretion in COS cells CELL LINE Mutant lambda5 has abnormal folding and secretion.

Downstream

Impaired Pre-B-Cell Receptor Assembly A defective surrogate light-chain component is expected to limit receptor assembly; this is not a direct assembly assay in the patient marrow.

Show evidence (2 references)

PMID:9419212 SUPPORT DIRECT PRIMARY RESULT 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.

PMID:9419212 SUPPORT DIRECT PRIMARY RESULT In Vitro

"the allele carrying the pseudogene sequence resulted in defective folding and secretion of mutant lambda5/14.1."

COS-cell expression showed defective folding/secretion of the P142L-containing allele; this is not a direct patient pre-BCR surface assay.

Ig-Alpha Deficiency

Biallelic CD79A defects impair the Ig-alpha component. The original splice mutation produced abnormal transcripts and profound early B-cell depletion.

CD79A hgnc:1698

Downstream

Impaired Pre-B-Cell Receptor Assembly Ig-alpha provides a required receptor component; downstream assembly is inferred from structural function and the clinical developmental defect.

Show evidence (1 reference)

PMID:10525050 SUPPORT DIRECT PRIMARY RESULT 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.

Ig-Beta Deficiency

Biallelic CD79B defects impair Ig-beta. The original Q80-stop allele prevents association with Ig-alpha and surface BCR reconstitution; later hypomorphic alleles need not have identical residual function.

CD79B hgnc:1699

Downstream

Impaired Pre-B-Cell Receptor Assembly The measured mature-BCR assembly defect supports the pre-BCR route, with a different receptor and cellular context.

Show evidence (2 references)

PMID:17709424 SUPPORT DIRECT PRIMARY RESULT Human Clinical

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

Establishes the CD79B gene-disease relationship.

PMID:17709424 SUPPORT DIRECT PRIMARY RESULT In Vitro

"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."

Mixed-species mature-BCR reconstitution in cultured S2 cells establishes an assembly defect for the tested Q80-stop allele; extension to human pre-BCR development is indirect.

Impaired Pre-B-Cell Receptor Assembly

Structural-component defects compromise receptor formation. Direct heterologous evidence here concerns the mature BCR containing the CD79B Q80-stop allele, rather than all patient pre-BCR genotypes.

pre-B cell receptor complex GO:0035369

Experimental models

CD79B mature-BCR reconstitution in S2 cells CELL LINE The tested Ig-beta mutation prevents mature BCR surface assembly, supporting a receptor-component defect.

Downstream

Reduced Receptor-Proximal B-Cell Signaling Insufficient receptor assembly limits developmental signals; the molecular signaling intermediates were not all assayed in each patient.

Show evidence (1 reference)

PMID:17709424 SUPPORT DIRECT PRIMARY RESULT In Vitro

Mixed-species mature-BCR reconstitution in cultured S2 cells establishes an assembly defect for the tested Q80-stop allele; extension to human pre-BCR development is indirect.

BLNK Adaptor Deficiency

BLNK is a cytoplasmic signaling adaptor. Its loss is a signaling defect and does not by itself establish absence of receptor assembly.

BLNK hgnc:14211

Downstream

Reduced Receptor-Proximal B-Cell Signaling The adaptor organizes receptor-proximal signals needed for B-cell development; exact stage and residual output vary.

Show evidence (1 reference)

PMID:10583958 SUPPORT DIRECT PRIMARY RESULT Human Clinical

The original BLNK patient had a defined early B-lineage developmental block; this is not an estimate of all alleles or a receptor-assembly assay.

Reduced Receptor-Proximal B-Cell Signaling

Insufficient signaling through the B-cell developmental checkpoint can follow receptor-component or adaptor defects. This is a shared functional consequence, not proof that all listed genotypes have identical signaling lesions.

B cell receptor signaling pathway GO:0050853 ↓ DECREASED

Downstream

Impaired B-Cell Development Receptor/adaptor defects reduce developmental progression; the original BLNK patient had pro-B cells without detected pre-B or mature B cells.

Show evidence (1 reference)

PMID:10583958 SUPPORT DIRECT PRIMARY RESULT Human Clinical

The original BLNK patient had a defined early B-lineage developmental block; this is not an estimate of all alleles or a receptor-assembly assay.

Loss of PI3K p85-Alpha

The original recessive PIK3R1 stop variant eliminated p85-alpha. Reduced p110-delta abundance accompanied its absence in T cells, neutrophils and dendritic cells. These observations do not measure signaling in the missing B-cell population.

PIK3R1 hgnc:8979

Downstream

Impaired B-Cell Development The homozygous patient had very few early B-lineage cells. The precise lineage-specific pathway from p85-alpha loss remains incompletely resolved.

Colitis Colitis co-occurs in the original patient; the inflammatory route is not resolved by the B-cell assay.

Show evidence (2 references)

PMID:22351933 SUPPORT DIRECT PRIMARY RESULT In Vitro

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

Patient-cell protein assays distinguish loss of p85-alpha from preserved shorter regulatory isoforms; the assay was not performed in the missing B cells.

PMID:22351933 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Western blot showed markedly decreased p110δ, as well as absent p85α, in patient T cells, neutrophils, and dendritic cells."

Protein abundance was measured in accessible patient lineages, not in the missing B-cell population.

Reduced PI3K p110-Delta Function

PIK3CD hgnc:8977

Downstream

Impaired B-Cell Development Recessive catalytic-subunit deficiency is associated with reduced B-cell output; the cited synthesis does not isolate one universal developmental stage or each downstream signal.

Show evidence (1 reference)

PMID:34241796 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

The review summarizes recessive p110-delta loss with B-cell and antibody deficiency; activating PIK3CD disease is a distinct mechanism.

Defective TCF3 Transcription-Factor Activity

Dominant E47 E555K impairs tested E-box binding/transactivation and interferes with wild-type E47. Recessive loss affects both E12 and E47; heterozygous haploinsufficiency can instead produce CVID-like disease. These allele mechanisms are not interchangeable.

TCF3 hgnc:11633

Experimental models

TCF3 E47 binding and reporter assays CELL LINE E555K fails the tested homodimer DNA-binding assay while supporting MyoD heterodimer binding.

Downstream

Impaired B-Cell Development Reduced or interfering transcription-factor activity impairs B-lineage output. The particular transcriptional targets that mediate each human phenotype are unresolved.

B Acute Lymphoblastic Leukemia Biallelic TCF3 disease has reported leukemia risk, without a uniform oncogenic mechanism established across all TCF3 allele classes.

Show evidence (4 references)

PMID:24216514 SUPPORT DIRECT PRIMARY RESULT 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 DIRECT PRIMARY RESULT In Vitro

"Although E555K E47 did not bind to the μE5 or creatinine kinase probes as a homodimer, it did allow MyoD to bind to the creatinine kinase probe (Figure 3D)."

E555K disrupts measured homodimer DNA binding while preserving the tested MyoD heterodimer interaction; it is not loss of all E-protein partnerships.

PMID:24216514 SUPPORT DIRECT PRIMARY RESULT 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."

Transfection assays show that E555K interferes with wild-type E47 when bound to DNA as a homodimer.

+ 1 more reference

Reduced PU.1 Dosage or Activity

SPI1 haploinsufficiency can arise through protein instability, localization defects or impaired DNA binding, depending on the allele. Reporter coexpression did not demonstrate dominant interference. The human phenotype ranges from unaffected carriers to progressive B-cell aplasia.

SPI1 hgnc:11241

Experimental models

Expanded PU.1 variant reporter panel CELL LINE Tested loss-of-function alleles reduce effective PU.1 activity without demonstrated dominant-negative action.

Downstream

Restricted B-Lineage Chromatin Accessibility Engineered PU.1 dosage reduction in a pro-B leukemia cell line constrains accessible chromatin; extension to every patient precursor remains indirect.

Decreased Dendritic Cell Abundance Human cohort immunophenotyping also finds conventional and plasmacytoid dendritic-cell depletion, without a uniform monocyte or T-cell deficit.

Inflammatory Arthritis The selected SPI1 cohort documents this associated inflammatory manifestation; cell-specific causal intermediates are unresolved.

Autoimmune Thrombocytopenia The selected SPI1 cohort documents this associated inflammatory manifestation; cell-specific causal intermediates are unresolved.

Type I Diabetes Mellitus The selected SPI1 cohort documents this associated inflammatory manifestation; cell-specific causal intermediates are unresolved.

Show evidence (3 references)

PMID:33951726 SUPPORT DIRECT PRIMARY RESULT 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."

The original SPI1 cohort establishes the human genetic association; later families show inherited variants and milder phenotypes.

PMID:33951726 SUPPORT DIRECT PRIMARY RESULT In Vitro

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

Functional assays identify allele-dependent protein instability, localization or DNA-binding defects; no single defect applies to every variant.

url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf SUPPORT DIRECT PRIMARY RESULT In Vitro

"either by destabilizing PU.1, impeding nuclear localization, or directly interfering with transcription."

Functional testing of the loss-of-function variants identifies allele-dependent instability, nuclear-localization or transcriptional defects, all acting through reduced PU.1 dosage.

Restricted B-Lineage Chromatin Accessibility

ATAC-seq in edited RS4;11 pro-B leukemia cells links reduced PU.1 dose to a less accessible B-lineage regulatory landscape. Cell-line gene-network effects support a developmental model but are not direct chromatin measurements in all patients.

Experimental models

SPI1 dosage-edited RS4;11 pro-B cells CELL LINE Reduced PU.1 dosage accompanies lower accessibility at PU.1-associated regulatory regions.

Downstream

Impaired B-Cell Development Chromatin restriction is proposed to constrain the transcriptional program needed for B-cell progression. Patient phenotype and edited HSPC experiments support the model without proving every intervening regulatory target.

Show evidence (2 references)

PMID:33951726 SUPPORT DIRECT PRIMARY RESULT In Vitro

"PU.1 OCRs were significantly more accessible in SPI1+/+ than SPI1+/− or SPI1−/− cell lines"

ATAC-seq in edited RS4;11 pro-B leukemia cells shows a PU.1-dose-associated accessibility difference.

PMID:33951726 SUPPORT DIRECT PRIMARY RESULT In Vitro

"we employed assay for transposase-accessible chromatin using sequencing (ATAC-seq) to generate genome-wide chromatin accessibility maps of human RS4;11 pro–B cell lines either unedited (SPI1+/+) or CRISPR/Cas9 edited with monoallelic (SPI1+/−) or biallelic (SPI1−/−) SPI1 exon one indels that..."

ATAC-seq compared transformed RS4;11 pro-B cell lines with monoallelic or biallelic engineered disruption; these are not patient-cell chromatin maps.

Decreased Dendritic Cell Abundance

SPI1-related disease can reduce both conventional and plasmacytoid dendritic cells. B-cell and dendritic-cell sample denominators differ; the cohort did not show a consistent monocyte, T-cell or NK-cell reduction.

Show evidence (1 reference)

url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"circulating plasmacytoid DC (pDC) concentrations were also signi ﬁcantly lower in patients than healthy donors (9.2 vs 3.4 cells per μL; P < .001), an immunophenotypic feature not previously appreciated."

Flow cytometry supports reduced circulating pDCs in 16 patients compared with 17 controls.

FNIP1 Protein Deficiency

Biallelic FNIP1 variants can eliminate the protein and produce syndromic antibody deficiency. Cardiomyopathy and variable neutropenia co-occur, but their tissue mechanisms are not established by B-cell assays. Complete protein absence was measured in stimulated cultured patient T cells.

FNIP1 hgnc:29418

Downstream

Hypertrophic Cardiomyopathy HCM is a recurrent clinical component of the FNIP1 syndrome; the bridge is genetically associated and has unresolved cardiac intermediates.

Neutropenia Variable neutropenia occurs in the syndrome, without a universal intrinsic granulopoiesis defect demonstrated.

Impaired B-Cell Development Human deficiency is associated with impaired B-lineage output, without a discrete universal arrest or an experimentally isolated metabolic mediator.

Increased B-Cell Mitochondrial Abundance This measured cellular abnormality accompanies FNIP1 deficiency. Its intervening molecular mechanism and necessity for the human developmental phenotype remain unresolved.

Increased B-Cell Mitochondrial Activity Signal This measured cellular abnormality accompanies FNIP1 deficiency. Its intervening molecular mechanism and necessity for the human developmental phenotype remain unresolved.

Increased B-Cell AKT Phosphorylation This measured cellular abnormality accompanies FNIP1 deficiency. Its intervening molecular mechanism and necessity for the human developmental phenotype remain unresolved.

Increased B-Cell 4EBP1 Phosphorylation This measured cellular abnormality accompanies FNIP1 deficiency. Its intervening molecular mechanism and necessity for the human developmental phenotype remain unresolved.

Show evidence (2 references)

url:https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content SUPPORT DIRECT PRIMARY RESULT 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.

url:https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content SUPPORT DIRECT PRIMARY RESULT In Vitro

"Immunoblotting demonstrated the complete absence of FNIP1 in all the patients (Figure 1D)."

Protein absence was assayed in stimulated cultured T cells from the three patients, not every affected tissue.

Truncated LRRC8A Protein

One human balanced translocation generated a truncated LRRC8A protein alongside wild-type protein. The gene-disease relationship remains Limited. Dominant interference is a hypothesis supported by a forced-expression mouse experiment, not an established universal channel mechanism.

LRRC8A hgnc:19027

Downstream

Impaired B-Cell Development The single human association and experimental mutant expression support a provisional link; the relevant molecular intermediates and replication in additional families remain unresolved.

Show evidence (2 references)

PMID:14660746 SUPPORT DIRECT PRIMARY RESULT 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 original authors interpreted their single human case and mutant-expression model as causal; current ClinGen validity remains Limited.

url:https://thegencc.org/submissions/SGC-107391.2 SUPPORT DIRECT REVIEW SYNTHESIS Other

"Since other patients with B cell deficiency and heterozygous LRRC8A have not been identified, the curation is classified as Limited."

ClinGen explains the Limited classification by the lack of additional human cases.

Impaired TOP2B Activity

Heterozygous TOPRIM-domain TOP2B variants cause Hoffman syndrome. Yeast growth and decatenation experiments support loss of activity with partial dominant interference. Human B-cell enzyme activity and marrow arrest stage were not directly measured.

TOP2B hgnc:11990

Experimental models

TOP2B yeast complementation and decatenation OTHER Mutant-plus-wild-type yeast fractions decatenate less effectively than the single-wild-type-copy comparator.

Downstream

Impaired B-Cell Development Mouse conditional and disease-allele models impair multiple B-cell stages. DNA topology, damage and transcriptional programs are candidate mediators rather than a single proven human pathway.

Show evidence (2 references)

PMID:31409799 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"In three families with Hoffman syndrome 9,10, we identi ﬁed three heterozygous mutations affecting the TOPRIM, or DNA gating, domain of the type II topoisomerase TOP2B."

Identifies the heterozygous TOPRIM-domain TOP2B variants in three Hoffman syndrome families; the loss of enzyme activity itself is shown by the separate yeast assays below.

PMID:31409799 SUPPORT DIRECT PRIMARY RESULT In Vitro

"fractions from the strain with only one copy of wild-type TOP2 decatenated kine- toplast DNA more effectively than fractions from strains with one wild-type and one mutant copy of TOP2 (Fig. 2d, Supplementary Fig. 4c)."

Yeast nuclear-fraction decatenation supports partial dominant interference for tested substitutions; this is not a direct patient B-cell enzyme assay.

Impaired B-Cell Development

Different autosomal defects reduce B-lineage progression at different stages. A pro-B-to-pre-B block fits several structural/adaptor disorders, but ZIP7, PIK3R1, FNIP1 and progressive SPI1 disease show distinct patterns. The umbrella does not imply a universal complete arrest.

B cell CL:0000236

B cell differentiation GO:0030183 ↓ DECREASED

bone marrow UBERON:0002371

Experimental models

SPI1-edited human hematopoietic progenitor differentiation PRIMARY CELL CULTURE SPI1 editing impairs early B-cell and myeloid differentiation in culture.

Animal models

Global Lrrc8a-null and Lrrc8a-null marrow into Rag2-null recipients Mouse Mouse partially recapitulates The null model reproduces only a modest B-development phenotype.

B-lineage conditional Top2b deletion and a heterozygous disease-associated EE587E allele Mouse Mouse partially recapitulates The conditional model alters B-cell differentiation and the expression of selected B-lineage regulators.

Downstream

Reduced Circulating B-Cell Output Impaired differentiation and survival reduce mature B-cell output, with residual cells and evolving depletion in some alleles.

Show evidence (3 references)

PMID:31696364 SUPPORT DIRECT BACKGROUND Human Clinical

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

The cited source describes the B-cell and antibody-deficiency phenotype. No frequency band or universal complete absence is inferred.

PMID:10583958 SUPPORT DIRECT PRIMARY RESULT Human Clinical

The original BLNK patient had a defined early B-lineage developmental block; this is not an estimate of all alleles or a receptor-assembly assay.

url:https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content SUPPORT DIRECT PRIMARY RESULT Human Clinical

One patient had altered precursor proportions without a discrete maturation block, limiting a universal pro-B arrest model.

Reduced Circulating B-Cell Output

Circulating B cells are severely depleted in established agammaglobulinemia, but are not invariably absent. Plasma-cell absence cannot be assumed without tissue evidence.

Downstream

Reduced Immunoglobulin Production Low B-lineage output limits antibody production, while residual immunoglobulins, maternally acquired IgG and replacement therapy modify measured concentrations.

Decreased Total B Cell Count Peripheral flow cytometry detects this cellular deficit.

Show evidence (1 reference)

PMID:31696364 SUPPORT DIRECT BACKGROUND Human Clinical

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

The cited source describes the B-cell and antibody-deficiency phenotype. No frequency band or universal complete absence is inferred.

Reduced Immunoglobulin Production

Severely reduced endogenous antibody production compromises humoral defense. The extent differs among isotypes, ages and alleles; replacement IgG does not reconstitute the developmental program.

immunoglobulin production GO:0002377 ↓ DECREASED

Downstream

Deficient Antibody-Mediated Host Defense Antibody deficiency reduces protective humoral responses and contributes to infection susceptibility.

Agammaglobulinemia The laboratory phenotype reflects reduced endogenous antibody production, interpreted with age and treatment context.

Decreased Circulating IgG The laboratory phenotype reflects reduced endogenous antibody production, interpreted with age and treatment context.

Decreased Circulating IgA The laboratory phenotype reflects reduced endogenous antibody production, interpreted with age and treatment context.

Decreased Circulating IgM The laboratory phenotype reflects reduced endogenous antibody production, interpreted with age and treatment context.

Show evidence (1 reference)

PMID:31696364 SUPPORT DIRECT BACKGROUND Human Clinical

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

The cited source describes the B-cell and antibody-deficiency phenotype. No frequency band or universal complete absence is inferred.

Deficient Antibody-Mediated Host Defense

Loss of effective antibody defense contributes to recurrent bacterial and selected viral infections. Dendritic-cell depletion in SPI1 disease is not independently assigned as the cause of this entire infection spectrum.

humoral immune response GO:0006959 ↓ DECREASED

Downstream

Recurrent Infections The infection phenotype is associated with deficient antibody protection; organism and anatomical susceptibility depend on exposure and host context.

Recurrent Otitis Media The infection phenotype is associated with deficient antibody protection; organism and anatomical susceptibility depend on exposure and host context.

Recurrent Sinusitis The infection phenotype is associated with deficient antibody protection; organism and anatomical susceptibility depend on exposure and host context.

Recurrent Pneumonia The infection phenotype is associated with deficient antibody protection; organism and anatomical susceptibility depend on exposure and host context.

Sepsis Invasive or skin infection is a documented complication of the antibody-deficiency phenotype.

Meningitis Invasive or skin infection is a documented complication of the antibody-deficiency phenotype.

Septic Arthritis Invasive or skin infection is a documented complication of the antibody-deficiency phenotype.

Cellulitis Invasive or skin infection is a documented complication of the antibody-deficiency phenotype.

Infection-Associated Airway Injury Recurrent lower respiratory infections can contribute to chronic airway injury; timing, treatment and other host factors modify progression.

Unusual Enteroviral Infection Deficient antibody protection can contribute to severe or prolonged enteroviral disease, with exposure and host factors modifying the outcome.

Show evidence (2 references)

url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"recurrent bacterial sinopulmonary infections including otitis, sinusitis, and/or pneumonia, which were universally experienced by patients before initiation of IRT ( Table 1 )."

The expanded SPI1 agammaglobulinemia cohort experienced respiratory infections before replacement; no umbrella frequency is inferred.

url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Hematogenous spread of streptococcal, Haemophilus, and staphylococcal septicemia and osteomyelitis, arthritis, and meningitis were each reported."

Invasive infection manifestations were observed in the SPI1 cohort.

Infection-Associated Airway Injury

Repeated respiratory infections can accompany chronic bronchial injury and bronchiectasis. The selected SPI1 cohort documents their association, without proving every episode or a uniform rate of structural progression.

bronchus UBERON:0002185

Downstream

Bronchiectasis Chronic airway injury contributes to bronchial dilatation, with variable clinical course.

Show evidence (1 reference)

url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Radiographic evidence of bronchiectasis from recurrent respiratory infections was com- mon."

Bronchiectasis was observed in a selected SPI1 cohort in association with recurrent respiratory infections.

Biallelic SLC39A7 Variants

Biallelic hypomorphic or truncating SLC39A7 variants define this genetic subtype. The reported viable patients should not be described as proven complete ZIP7 knockouts.

SLC39A7 hgnc:4927

Downstream

Reduced ZIP7 Zinc Transport Tested human alleles impair transporter function.

Abnormal Skin Blistering Severe ZIP7 disease is associated with this clinical feature; organ-specific intermediates are unresolved.

Thrombocytopenia Severe ZIP7 disease is associated with this clinical feature; organ-specific intermediates are unresolved.

Failure to Thrive Severe ZIP7 disease is associated with this clinical feature; organ-specific intermediates are unresolved.

Show evidence (1 reference)

PMID:30718914 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Six individuals from 5 kindreds of white European, South Asian or Hispanic ancestry, were found to harbor compound heterozygous (4 families) or homozygous (1 family) rare variants in SLC39A7"

Six affected people from five kindreds carry biallelic variants.

Reduced ZIP7 Zinc Transport

Reduced zinc transport was measured for human P190A and E363K. Residual expression and ER localization distinguish transport impairment from universal protein absence.

Downstream

Reduced B-Cell Cytosolic Free Zinc Reduced transport is associated with deficient cytosolic zinc in the mouse cellular model; compartmental buffering and compensation were not fully resolved.

Show evidence (1 reference)

PMID:30718914 SUPPORT DIRECT PRIMARY RESULT In Vitro

"In keeping with hypomorphic behavior, the Zn2+ signal generated by either mutant ZIP7 was significantly reduced compared with WT (Fig. 2h), despite similar amounts of protein expression"

The P190A and E363K transport assays show reduced reporter signal at comparable protein expression.

Reduced B-Cell Cytosolic Free Zinc

Mutant mouse B-cell cultures have lower free cytosolic zinc. This is not evidence of systemic zinc deficiency, excess free ER zinc or a measured local zinc pulse.

Experimental models

ZIP7-mutant mouse B-cell signaling and zinc assays PRIMARY CELL CULTURE Measures reduced free cytosolic zinc.

Downstream

Increased B-Cell Phosphatase Activity Loss of zinc-mediated phosphatase inhibition is a proposed partial mediator. No selective zinc restoration experiment proves necessity.

Show evidence (1 reference)

PMID:30718914 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Cytoplasmic Zn2+ concentrations were indeed lower in mutant compared to WT cells, whereas ER Zn2+ amounts were equivalent"

FRET-FLIM in IL7-expanded mutant mouse marrow B-cell cultures measures lower free cytosolic zinc with unchanged free ER zinc.

Increased B-Cell Phosphatase Activity

Developing mutant B cells show increased constitutive activity on a broad phosphatase substrate. Specific PTEN hyperactivity is not isolated by this assay.

Experimental models

ZIP7-mutant mouse B-cell signaling and zinc assays PRIMARY CELL CULTURE Measures increased broad substrate activity.

Downstream

Reduced B-Cell Receptor Signaling Elevated phosphatase activity may contribute to reduced signaling, but multiple pathways remain involved and the PTEN-only rescue experiment was negative.

Show evidence (1 reference)

PMID:30718914 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Constitutive phosphatase activity was indeed higher in ZIP7P198A/P198A compared to WT pre-B and immature B cells, as measured by flow cytometry using a cell-permeable alkaline phosphatase substrate"

The broad live phosphatase-substrate assay does not isolate PTEN activity.

Reduced B-Cell Receptor Signaling

Antigen-stimulated immature mutant B cells have reduced phosphorylation of SYK, PLCγ2 and ERK despite equivalent surface receptor expression. These are parallel signaling readouts rather than demonstrated intrinsic kinase defects.

Experimental models

ZIP7-mutant mouse B-cell signaling and zinc assays PRIMARY CELL CULTURE Measures reduced antigen-induced phosphorylation.

Downstream

Impaired ZIP7-Dependent B-Cell Maturation Deficient nascent-BCR signaling is proposed to impair positive selection. This is not a fully isolated necessary sequence.

Show evidence (1 reference)

PMID:30718914 SUPPORT DIRECT PRIMARY RESULT In Vitro

"immature ZIP7P198A/P198A SWHel B cells showed impaired antigen-induced signalling as judged by reduced amounts of multiple phosphorylated intermediates, including SYK, PLCγ2 and ERK"

Ex-vivo antigen stimulation demonstrates reduced phosphorylation despite comparable surface BCR.

Impaired ZIP7-Dependent B-Cell Maturation

ZIP7 hypofunction blocks B-cell development, most clearly at late pre-B to immature transition in mixed marrow chimeras; an earlier contribution cannot be excluded.

Animal models

Slc39a7 hypomorphic mice and mixed marrow chimeras Mouse recapitulates Recapitulates B-cell intrinsic maturation failure.

Downstream

Reduced Circulating B-Cell Output Mouse late-pre-B/immature maturation failure and human B-cell depletion support reduced output, without imposing one stage on all autosomal forms.

Show evidence (1 reference)

PMID:30718914 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Eight weeks after BM transfer, our analysis confirmed a B cell intrinsic block in development, which was most evident in a failure to progress from the late pre-B (FrD) to immature B (FrE) cell stage, with no residual mutant cells in the recirculating FrF population"

Mixed marrow chimeras show cell-intrinsic developmental failure strongest at late-pre-B to immature transition.

Increased B-Cell Mitochondrial Abundance

Mitochondrial abundance was increased in rare circulating B cells from one FNIP1-deficient patient. This is not a measure in marrow progenitors or cardiac tissue.

Experimental models

FNIP1 patient-cell metabolic assays PRIMARY CELL CULTURE Mitochondrial abundance was increased in rare circulating B cells from one FNIP1-deficient patient. This is not a measure in marrow progenitors or cardiac tissue.

Show evidence (1 reference)

url:https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content SUPPORT DIRECT PRIMARY RESULT In Vitro

"Indeed, circulating P1 B-cells exhibited increased numbers of mitochondria and mitochondrial activity relative to healthy control (HC) B-cells (Figure 1F and supplemental Figure 9 )."

Mitochondrial dye readouts were measured in rare circulating B cells from one patient compared with a healthy control; they do not establish a general ATP-production flux.

Increased B-Cell Mitochondrial Activity Signal

A mitochondrial activity-associated dye readout was increased in circulating B cells from one FNIP1-deficient patient. It is distinct from mitochondrial abundance and does not establish increased ATP synthesis or respiratory flux.

Experimental models

FNIP1 patient-cell metabolic assays PRIMARY CELL CULTURE A mitochondrial activity-associated dye readout was increased in circulating B cells from one FNIP1-deficient patient. It is distinct from mitochondrial abundance and does not establish increased ATP synthesis or respiratory flux.

Show evidence (1 reference)

url:https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content SUPPORT DIRECT PRIMARY RESULT In Vitro

"Indeed, circulating P1 B-cells exhibited increased numbers of mitochondria and mitochondrial activity relative to healthy control (HC) B-cells (Figure 1F and supplemental Figure 9 )."

Mitochondrial dye readouts were measured in rare circulating B cells from one patient compared with a healthy control; they do not establish a general ATP-production flux.

Increased B-Cell AKT Phosphorylation

Marrow B-cell progenitors from one FNIP1-deficient patient had increased AKT Ser473 phosphorylation relative to a healthy control. This is an observed signaling state, not a direct assay of a unique kinase mechanism.

Experimental models

FNIP1 patient-cell metabolic assays PRIMARY CELL CULTURE Marrow B-cell progenitors from one FNIP1-deficient patient had increased AKT Ser473 phosphorylation relative to a healthy control. This is an observed signaling state, not a direct assay of a unique kinase mechanism.

Show evidence (1 reference)

url:https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content SUPPORT DIRECT PRIMARY RESULT In Vitro

One patient marrow comparison showed increased p4EBP1 and pAKT473 but not pS6; small repeated assays do not expand the donor count.

Increased B-Cell 4EBP1 Phosphorylation

Marrow B-cell progenitors from one FNIP1-deficient patient had increased 4EBP1 phosphorylation; pS6 was not significantly altered. BEZ235 lowered the 4EBP1 readout without demonstrating restored B-cell development or clinical benefit.

Experimental models

FNIP1 patient-cell metabolic assays PRIMARY CELL CULTURE Marrow B-cell progenitors from one FNIP1-deficient patient had increased 4EBP1 phosphorylation; pS6 was not significantly altered. BEZ235 lowered the 4EBP1 readout without demonstrating restored B-cell development or clinical benefit.

Show evidence (1 reference)

url:https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content SUPPORT DIRECT PRIMARY RESULT In Vitro

One patient marrow comparison showed increased p4EBP1 and pAKT473 but not pS6; small repeated assays do not expand the donor count.

⬡

Pathograph

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Phenotypes

Blood 9

Agammaglobulinemia HP:0004432

Show evidence (1 reference)

PMID:31696364 SUPPORT DIRECT BACKGROUND Human Clinical

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

The cited source describes the B-cell and antibody-deficiency phenotype. No frequency band or universal complete absence is inferred.

Decreased Total B Cell Count HP:0010976

Show evidence (2 references)

PMID:31696364 SUPPORT DIRECT BACKGROUND Human Clinical

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

The cited source describes the B-cell and antibody-deficiency phenotype. No frequency band or universal complete absence is inferred.

PMID:33951726 SUPPORT DIRECT PRIMARY RESULT 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 IgG Decreased circulating IgG concentration HP:0004315

Show evidence (1 reference)

PMID:17709424 SUPPORT DIRECT PRIMARY RESULT Human Clinical

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

The cited source describes the B-cell and antibody-deficiency phenotype. No frequency band or universal complete absence is inferred.

Decreased Circulating IgA Decreased circulating IgA concentration HP:0002720

Show evidence (1 reference)

PMID:17709424 SUPPORT DIRECT PRIMARY RESULT 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.

Decreased Circulating IgM Decreased circulating total IgM HP:0002850

Show evidence (1 reference)

PMID:17709424 SUPPORT DIRECT PRIMARY RESULT 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.

Neutropenia Decreased total neutrophil count HP:0001875

Show evidence (1 reference)

url:https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content SUPPORT DIRECT PRIMARY RESULT Human Clinical

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

Documents neutropenia accompanying autosomal recessive agammaglobulinemia (FNIP1 deficiency).

Autoimmune Thrombocytopenia HP:0001973

Show evidence (1 reference)

url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"juvenile idiopathic arthritis (n = 2); type 1 diabetes mellitus (n = 2); and single cases of immune thrombocytopenia, psoriasis, hidrade- nitis suppurativa, and autoimmune lipodystrophy."

These are gene-specific observations in 22 selected SPI1 agammaglobulinemia patients, without disease-wide frequency inference.

Thrombocytopenia HP:0001873

Show evidence (1 reference)

PMID:30718914 SUPPORT DIRECT PRIMARY RESULT Human Clinical

Two siblings among six ZIP7-deficient patients had severe skin disease, poor growth and thrombocytopenia; transplantation outcomes are specific to them.

B Acute Lymphoblastic Leukemia HP:0004812

Show evidence (1 reference)

PMID:39073655 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Complete AR TCF3 deficiency is associated with reduced B cells, hypogammaglobulinemia, dysmorphic phenotypes, and B-cell acute lymphoblastic leukemia (B-ALL)"

The 2024 article synthesizes the recessive phenotype; the original short report was not available as a substantive cached body.

Cardiovascular 3

Conjunctivitis HP:0000509

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1453/ SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

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

Shared XLA clinical synthesis is extrapolated to this related antibody-deficiency spectrum.

Absent tonsils HP:0030813

Show evidence (1 reference)

PMID:14752335 SUPPORT INDIRECT REVIEW SYNTHESIS 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."

In context the physical-examination clue refers to X-linked agammaglobulinemia; it is applied to the autosomal forms by extrapolation from the shared early B-cell defect.

Hypertrophic Cardiomyopathy HP:0001639

Show evidence (2 references)

url:https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content SUPPORT DIRECT PRIMARY RESULT Human Clinical

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

All three original unrelated FNIP1 patients had HCM; no umbrella frequency is inferred.

PMID:39537849 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"hypertrophic cardiomyopathy, recurrent infections, and chronic diarrhea during infancy. Immune workup revealed agammaglobulinemia and a lack of B lymphocytes."

An additional genotyped FNIP1 girl had cardiomyopathy; her deceased brother was not genetically confirmed.

Digestive 2

Chronic Diarrhea HP:0002028

Temporal: CHRONIC

Show evidence (1 reference)

PMID:39537849 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"hypertrophic cardiomyopathy, recurrent infections, and chronic diarrhea during infancy. Immune workup revealed agammaglobulinemia and a lack of B lymphocytes."

One additional genotyped FNIP1 case had chronic diarrhea during infancy; no general frequency is inferred.

Colitis Inflammation of the large intestine HP:0002037

Show evidence (1 reference)

PMID:22351933 SUPPORT DIRECT PRIMARY RESULT Human Clinical

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

One original patient links the recessive PIK3R1 defect with colitis and B-cell deficiency.

Ear 1

Recurrent Otitis Media HP:0000403

Show evidence (1 reference)

url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"recurrent bacterial sinopulmonary infections including otitis, sinusitis, and/or pneumonia, which were universally experienced by patients before initiation of IRT ( Table 1 )."

The expanded SPI1 agammaglobulinemia cohort experienced respiratory infections before replacement; no umbrella frequency is inferred.

Endocrine 1

Type I Diabetes Mellitus HP:0100651

Show evidence (1 reference)

url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"juvenile idiopathic arthritis (n = 2); type 1 diabetes mellitus (n = 2); and single cases of immune thrombocytopenia, psoriasis, hidrade- nitis suppurativa, and autoimmune lipodystrophy."

These are gene-specific observations in 22 selected SPI1 agammaglobulinemia patients, without disease-wide frequency inference.

Head and Neck 2

Recurrent Sinusitis HP:0011108

Show evidence (1 reference)

url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"recurrent bacterial sinopulmonary infections including otitis, sinusitis, and/or pneumonia, which were universally experienced by patients before initiation of IRT ( Table 1 )."

The expanded SPI1 agammaglobulinemia cohort experienced respiratory infections before replacement; no umbrella frequency is inferred.

Abnormal Facial Shape HP:0001999

Show evidence (1 reference)

PMID:34241796 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Autosomal dominant mutations in TOP2B, a gene coding for a type II topoisomerase, has been reported in patients with recurrent infections with encapsulated organisms, absent B cells, and agammaglobulinemia, in addition to facial dysmorphism and limb abnormalities"

Review summarizes TOP2B-associated syndromic findings; this broad term preserves the unspecific facial description and is limited to the TOP2B subtype.

Immune 6

Recurrent Infections Recurrent bacterial infections HP:0002718

Show evidence (1 reference)

url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"recurrent bacterial sinopulmonary infections including otitis, sinusitis, and/or pneumonia, which were universally experienced by patients before initiation of IRT ( Table 1 )."

The expanded SPI1 agammaglobulinemia cohort experienced respiratory infections before replacement; no umbrella frequency is inferred.

Recurrent Pneumonia HP:0006532

Show evidence (1 reference)

url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"recurrent bacterial sinopulmonary infections including otitis, sinusitis, and/or pneumonia, which were universally experienced by patients before initiation of IRT ( Table 1 )."

The expanded SPI1 agammaglobulinemia cohort experienced respiratory infections before replacement; no umbrella frequency is inferred.

Sepsis HP:0100806

Show evidence (1 reference)

url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Hematogenous spread of streptococcal, Haemophilus, and staphylococcal septicemia and osteomyelitis, arthritis, and meningitis were each reported."

Invasive infection manifestations were observed in the SPI1 cohort.

Meningitis HP:0001287

Show evidence (1 reference)

url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Hematogenous spread of streptococcal, Haemophilus, and staphylococcal septicemia and osteomyelitis, arthritis, and meningitis were each reported."

Invasive infection manifestations were observed in the SPI1 cohort.

Osteomyelitis HP:0002754

Show evidence (1 reference)

url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Hematogenous spread of streptococcal, Haemophilus, and staphylococcal septicemia and osteomyelitis, arthritis, and meningitis were each reported."

Invasive infection manifestations were observed in the SPI1 cohort.

Unusual Enteroviral Infection Unusual enterovirus infection HP:5210314

Show evidence (2 references)

url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Viral infections, most notably enteroviruses, affected multiple patients."

Direct SPI1 cohort observation; prolonged echoviremia and vaccine-associated poliomyelitis illustrate severity without defining an umbrella frequency.

url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Patient A.II.2 experienced reactive arthritis during a prolonged period of echoviremia."

Prolonged enteroviral infection in one SPI1 patient supports the unusual-infection scope, without assuming recurrent episodes in every patient.

Integument 1

Abnormal Skin Blistering Abnormal blistering of the skin HP:0008066

Show evidence (1 reference)

PMID:30718914 SUPPORT DIRECT PRIMARY RESULT Human Clinical

Two siblings among six ZIP7-deficient patients had severe skin disease, poor growth and thrombocytopenia; transplantation outcomes are specific to them.

Musculoskeletal 3

Septic Arthritis HP:0003095

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url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Hematogenous spread of streptococcal, Haemophilus, and staphylococcal septicemia and osteomyelitis, arthritis, and meningitis were each reported."

Invasive infection manifestations were observed in the SPI1 cohort.

Cellulitis HP:0100658

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url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Staphylococcal skin infec- tions and periorbital cellulitis also occurred."

Direct autosomal clinical observation.

Inflammatory Arthritis HP:0001369

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url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"juvenile idiopathic arthritis (n = 2); type 1 diabetes mellitus (n = 2); and single cases of immune thrombocytopenia, psoriasis, hidrade- nitis suppurativa, and autoimmune lipodystrophy."

These are gene-specific observations in 22 selected SPI1 agammaglobulinemia patients, without disease-wide frequency inference.

Nervous System 1

Neurodevelopmental Delay HP:0012758

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url:https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content SUPPORT DIRECT PRIMARY RESULT Human Clinical

"neurologica l examination showed developmental delay associated with MRI abnormalities (supplemental Figure 3)."

One patient observation; no global-domain assessment is inferred.

Respiratory 1

Bronchiectasis HP:0002110

Course: PROGRESSIVE

Show evidence (1 reference)

url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Radiographic evidence of bronchiectasis from recurrent respiratory infections was com- mon."

Bronchiectasis was observed in a selected SPI1 cohort in association with recurrent respiratory infections.

Growth 1

Failure to Thrive HP:0001508

Show evidence (1 reference)

PMID:30718914 SUPPORT DIRECT PRIMARY RESULT Human Clinical

Two siblings among six ZIP7-deficient patients had severe skin disease, poor growth and thrombocytopenia; transplantation outcomes are specific to them.

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Genetic Associations

IGHM (Causative)

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

Show evidence (2 references)

PMID:8890099 SUPPORT DIRECT PRIMARY RESULT 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 DIRECT PRIMARY RESULT 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 DIRECT PRIMARY RESULT 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 DIRECT PRIMARY RESULT 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 gene page relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (1 reference)

PMID:17709424 SUPPORT DIRECT PRIMARY RESULT 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 DIRECT PRIMARY RESULT Human Clinical

The original BLNK patient had a defined early B-lineage developmental block; this is not an estimate of all alleles or a receptor-assembly assay.

LRRC8A (Limited gene-disease evidence)

Gene: LRRC8A hgnc:19027 variant_origin: GERMLINE

Show evidence (2 references)

PMID:14660746 SUPPORT DIRECT PRIMARY RESULT 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 original authors interpreted their single human case and mutant-expression model as causal; current ClinGen validity remains Limited.

url:https://thegencc.org/submissions/SGC-107391.2 SUPPORT DIRECT REVIEW SYNTHESIS Other

"Since other patients with B cell deficiency and heterozygous LRRC8A have not been identified, the curation is classified as Limited."

ClinGen explains the Limited classification by the lack of additional human cases.

PIK3R1 (Causative)

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

Show evidence (2 references)

PMID:22351933 SUPPORT DIRECT PRIMARY RESULT Human Clinical

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

One original patient links the recessive PIK3R1 defect with colitis and B-cell deficiency.

PMID:22351933 SUPPORT DIRECT PRIMARY RESULT In Vitro

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

Patient-cell protein assays distinguish loss of p85-alpha from preserved shorter regulatory isoforms; the assay was not performed in the missing B cells.

TCF3 (Causative)

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

Show evidence (3 references)

PMID:24216514 SUPPORT DIRECT PRIMARY RESULT 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 DIRECT PRIMARY RESULT 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.

PMID:39073655 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Complete AR TCF3 deficiency is associated with reduced B cells, hypogammaglobulinemia, dysmorphic phenotypes, and B-cell acute lymphoblastic leukemia (B-ALL)"

The 2024 article synthesizes the recessive phenotype; the original short report was not available as a substantive cached body.

SLC39A7 (Causative)

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

Show evidence (2 references)

PMID:30718914 SUPPORT DIRECT PRIMARY RESULT 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 DIRECT PRIMARY RESULT 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 gene page relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (4 references)

PMID:33951726 SUPPORT DIRECT PRIMARY RESULT 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."

The original SPI1 cohort establishes the human genetic association; later families show inherited variants and milder phenotypes.

PMID:33951726 SUPPORT DIRECT PRIMARY RESULT In Vitro

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

Functional assays identify allele-dependent protein instability, localization or DNA-binding defects; no single defect applies to every variant.

url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

Variant-carrying relatives with normal antibody and B-cell values support the statement that relatives can have no antibody abnormality.

+ 1 more reference

FNIP1 (Causative)

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

Show evidence (1 reference)

url:https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content SUPPORT DIRECT PRIMARY RESULT 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.

TOP2B (Causative)

Gene: TOP2B hgnc:11990 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (1 reference)

PMID:31409799 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"In three families with Hoffman syndrome 9,10, we identi ﬁed three heterozygous mutations affecting the TOPRIM, or DNA gating, domain of the type II topoisomerase TOP2B."

Three families establish the reported human syndrome; mechanistic assays use separate yeast and mouse systems.

PIK3CD (Causative)

Gene: PIK3CD hgnc:8977 gene page relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (1 reference)

PMID:34241796 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

The review summarizes recessive p110-delta loss with B-cell and antibody deficiency; activating PIK3CD disease is a distinct mechanism.

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Medical Actions

Immunoglobulin Replacement Therapy

Action: Immunoglobulin Therapy NCIT:C62710

Platform: Protein replacement

IVIG or SCIG is standard supportive treatment for clinically significant antibody deficiency. Dose and interval are individualized to infections, trough concentrations and lung disease. It supplies passive IgG without restoring the underlying B-cell program; infections and noninfectious complications may persist. The route schedule is extrapolated from XLA guidance, with direct autosomal cohort evidence of continuing replacement dependence.

Mechanism Target:

BYPASSES Reduced Immunoglobulin Production — Passive antibody supplies an effector product without correcting endogenous production or B-cell development.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1453/ SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"The mainstay of treatment is gammaglobulin substitution therapy (by weekly subcutaneous injection or intravenous infusion every two to four weeks) to prevent bacterial infections."

GeneReviews expert guidance is for XLA; shared antibody-replacement principles are extrapolated to autosomal disease.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1453/ SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"The mainstay of treatment is gammaglobulin substitution therapy (by weekly subcutaneous injection or intravenous infusion every two to four weeks) to prevent bacterial infections."

GeneReviews expert guidance is for XLA; shared antibody-replacement principles are extrapolated to autosomal disease.

url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"All patients with PU.MA were IRT dependent"

All 22 affected patients in the expanded SPI1 cohort used replacement.

Antibiotic Therapy and Prophylaxis

Action: Antibiotic Therapy NCIT:C15620

Platform: Small molecule

Treat suspected or proven bacterial infection promptly. Selected patients with recurrent infections despite replacement may receive specialist-directed prophylaxis; it is not mandatory for every genotype or patient.

Mechanism Target:

INHIBITS Recurrent Infections — Antimicrobial treatment addresses infection and selected prophylaxis reduces recurrence.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1453/ SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"Generous use of antibiotics can decrease the incidence of chronic sinusitis and lung disease. Prophylactic antibiotics can be considered to prevent infections."

XLA management synthesis supports prompt treatment and selected prophylaxis; autosomal treatment is individualized.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1453/ SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"Generous use of antibiotics can decrease the incidence of chronic sinusitis and lung disease. Prophylactic antibiotics can be considered to prevent infections."

XLA management synthesis supports prompt treatment and selected prophylaxis; autosomal treatment is individualized.

Avoidance of Live Attenuated Vaccines (Agents to Avoid)

Action: Preventive Intervention NCIT:C15843

Platform: Behavioral / lifestyle

Avoid live viral vaccines, especially oral polio vaccine, in severe antibody deficiency under immunology guidance. Inactivated polio vaccine is used for affected people and family contacts. The SPI1 cohort directly documents vaccine-associated paralytic poliomyelitis; this does not quantify all vaccines or all genotypes.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1453/ SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"Live viral vaccines, particularly oral polio vaccine."

GeneReviews lists these among agents to avoid in XLA; severe autosomal antibody deficiency shares the relevant concern.

url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"One (D.II.1) of 5 patients receiving live-attenuated oral polio vaccine developed iatrogenic paralytic poliomyelitis."

Direct SPI1 cohort evidence of a live oral polio vaccine complication; the small exposed denominator is not a general vaccine-risk estimate.

Clinical and Respiratory Surveillance

Action: Supportive Care NCIT:C15747

Platform: Behavioral / lifestyle

Monitor infections, blood counts and immunoglobulins; assess chronic lung or sinus disease when clinically indicated. Follow genotype-specific skin, cardiac, gastrointestinal and inflammatory complications. Surveillance detects complications; it does not itself inhibit the molecular defect.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1453/ SUPPORT INDIRECT REVIEW SYNTHESIS 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."

XLA surveillance schedule provides a clinical framework, adapted for genotype, age, complications and treatment.

Allogeneic Hematopoietic Cell Transplantation

Action: Hematopoietic Cell Transplantation NCIT:C15431

Platform: Cell therapy

Consider HSCT only through individualized specialist assessment of the genetic disorder, morbidity, donor genotype and transplant risk. Two severely affected ZIP7 siblings had correction of immunologic abnormalities and improvement of skin disease. In SPI1 disease, one recipient remained replacement-dependent five years after full trilineage donor engraftment; another failed engraftment after receiving cells from an unknowingly variant-carrying sister. These contrasting small series do not establish a uniform curative strategy.

Show evidence (3 references)

PMID:30718914 SUPPORT DIRECT PRIMARY RESULT Human Clinical

Two siblings among six ZIP7-deficient patients had severe skin disease, poor growth and thrombocytopenia; transplantation outcomes are specific to them.

url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

Long-term SPI1 follow-up documents persistent antibody-production failure despite donor engraftment.

url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The second patient (L.II.1) who received HSCT received stem cells from her healthy sister (L.II.2) at the age of 16 but failed to engraft. 18 Unbeknown at the time of HSCT, the donor harbored the same PU.1 variant as the recipient."

The second SPI1 attempt failed; donor variant status was recognized retrospectively.

Genetic Counseling and Family Testing

Action: Genetic Counseling NCIT:C15240

Platform: Behavioral / lifestyle

Explain gene- and allele-specific inheritance, test at-risk relatives after a molecular diagnosis, and reassess initially mild SPI1 carriers over time. A clinically healthy related donor can carry the familial variant; donor assessment should include this possibility.

Show evidence (2 references)

url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"PU.1 variant carriers now counted as unaffected could later develop antibody de ﬁciency or frank agammaglobulinemia."

The authors caution that apparently unaffected carriers may develop disease later, which supports reassessing initially mild or unaffected carriers over time.

url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"Unbeknown at the time of HSCT, the donor harbored the same PU.1 variant as the recipient."

Retrospective donor genotyping illustrates the relevance of variable expressivity to family and donor assessment.

Individualized Management of Inflammatory Complications

Action: Pharmacotherapy NCIT:C15986

Platform: Small molecule

Treat inflammatory complications according to the affected organ and infection risk. In the SPI1 cohort, mesalamine, mycophenolate and adalimumab were reported for bowel inflammation, whereas multiple agents had limited success in one refractory arthritis case. These are uncontrolled treatment experiences, not comparative efficacy evidence or a disease-wide regimen.

Show evidence (1 reference)

url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Immune modulating treatments successfully used for inﬂammatory bowel disorder included mesalamine, mycophenolate, and tumor necrosis factor inhibition (adalimumab). A series of therapies (methotrexate, hydroxychloroquine, etanercept, tocilizumab, abatacept, and canakinumab) were trialed with..."

Retrospective case-level treatment experience; no controlled efficacy estimate.

🔬

Biochemical Markers

Serum IgG (Decreased)

Context: Interpret serum IgG against age-specific laboratory intervals, maternal IgG in infancy, infection status and immunoglobulin replacement. Residual or previously normal IgG occurs in later-onset and hypomorphic disease; no single unsupported threshold is imposed here.

Show evidence (1 reference)

PMID:31696364 SUPPORT DIRECT BACKGROUND 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: Often very low or undetectable, but residual and age-dependent values occur. Serum concentration does not directly measure mucosal secretory IgA.

Show evidence (1 reference)

PMID:17709424 SUPPORT DIRECT PRIMARY RESULT 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: Often severely reduced or undetectable; residual IgM does not exclude a hypomorphic or evolving autosomal form.

Show evidence (1 reference)

PMID:17709424 SUPPORT DIRECT PRIMARY RESULT 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: Quantify absolute B-cell counts and percentage together with age-aware T/NK subsets. Profound depletion supports the phenotype but is not unique to autosomal agammaglobulinemia; counts may decline over time. Marrow precursor percentages cannot be substituted for peripheral-blood thresholds.

Show evidence (1 reference)

PMID:22351933 SUPPORT DIRECT PRIMARY RESULT 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.

Circulating dendritic-cell counts in SPI1 disease (Decreased)

Context: The expanded SPI1 cohort found reduced conventional and plasmacytoid dendritic-cell counts in 16 patients compared with 17 controls; no consistent monocyte/T/NK reduction was found. This is not an umbrella diagnostic threshold.

Show evidence (1 reference)

url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

Gene-specific flow-cytometric observation.

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Diagnosis

Quantitative serum immunoglobulins

Measure IgG, IgA and IgM with age-specific laboratory interpretation. Maternal IgG, replacement therapy and residual or evolving antibody production affect results.

diagnostic procedure NCIT:C18020

Markers: Serum IgG, IgA and IgM

Results: Severely reduced endogenous antibody concentrations support the phenotype, with variable residual values.

Show evidence (1 reference)

PMID:31696364 SUPPORT DIRECT BACKGROUND 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

Assess absolute and proportional B cells plus T/NK subsets; add lineage-specific studies when indicated. Normal T cells are common but not universal. Repeat testing may reveal progressive B-cell depletion.

flow cytometry NCIT:C16585

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

Results: Profoundly low B cells, with genotype-dependent accompanying abnormalities.

Show evidence (2 references)

PMID:31696364 SUPPORT DIRECT BACKGROUND Human Clinical

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

The cited source describes the B-cell and antibody-deficiency phenotype. No frequency band or universal complete absence is inferred.

url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The delayed and progressive B-cell loss seen in some patients with PU.MA"

Delayed and progressive B-cell loss in some SPI1 patients supports repeat lymphocyte-subset testing when initial B-cell counts are not diagnostic.

Molecular genetic testing (IEI panel or exome sequencing)

Use phenotype-informed gene testing, multigene panels or exome/genome approaches as appropriate. Evaluate inheritance, copy-number/splice variants and functional evidence; a VUS or a historical gene label alone does not establish causality.

genetic testing NCIT:C15709

Results: Pathogenic or likely pathogenic variants consistent with the clinical phenotype and inheritance; both inherited and de novo dominant disease occur.

Show evidence (2 references)

PMID:31696364 SUPPORT DIRECT PRIMARY RESULT 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 DIRECT PRIMARY RESULT 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

KREC testing can detect deficient B-cell output before symptoms in some screening settings. It is a screening adjunct requiring immunophenotypic and molecular confirmation; later-onset forms may not be recognized at birth.

diagnostic procedure NCIT:C18020

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

Results: Low KRECs suggest impaired new B-cell output, without identifying a specific gene.

Residual vaccine titers can persist in evolving SPI1 disease and do not exclude it. Serology is also affected by maternal or replacement antibodies. Do not use live-vaccine challenge to investigate severe antibody deficiency.

Show evidence (1 reference)

PMID:34241796 SUPPORT DIRECT REVIEW SYNTHESIS 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.

Respiratory complication assessment

Assess chest and sinus disease using imaging when indicated, and obtain baseline pulmonary function testing when the patient can cooperate. This evaluates complications rather than establishing the molecular diagnosis. The XLA GeneReviews framework is extrapolated to autosomal antibody deficiency and individualized to age and clinical course.

diagnostic procedure NCIT:C18020

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1453/ SUPPORT INDIRECT REVIEW SYNTHESIS 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."

XLA guidance supports chest and sinus imaging for suspected chronic disease; application to autosomal antibody deficiency is extrapolated.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1453/ SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"Baseline chest & sinus radiographs ... Baseline pulmonary function tests ... If able to cooperate w/testing"

XLA guidance recommends pulmonary function testing in those able to cooperate; its application here is extrapolated.

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Progression

Variable onset and evolving B-cell deficiency

Age: Infancy through adulthood

Many structural pre-BCR defects present early. SPI1 and some TCF3 cases can retain B cells or antibody responses for years before progressing. Diagnostic delay and genuinely later biological onset are distinct.

Show evidence (1 reference)

url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The 7 remaining late diagnoses developed infectious symptoms later in life, sometimes well into adulthood (range, aged 4-33 years)."

Seven late-diagnosed SPI1 patients developed infectious symptoms later in life; this is a selected gene-specific cohort.

Long-term treated disease

Immunoglobulin replacement often improves infection control, while bronchiectasis, inflammatory complications and gene-specific syndromic findings can persist. The long-term course cannot be summarized as uniformly more severe than XLA.

Show evidence (1 reference)

url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"All patients with PU.MA were IRT dependent"

All 22 agammaglobulinemic patients in this expanded SPI1 cohort required replacement; this is not a trial estimate of all autosomal forms.

📊

Prevalence

Worldwide

Unknown

No reliable population rate for this heterogeneous umbrella is established by the cited sources. Historical reviews estimate that XLA accounts for approximately 85% of congenital agammaglobulinemia; the remaining proportion is not a directly measured autosomal population prevalence. Gene discovery, referral patterns, ancestry and later-onset cases affect case composition.

Show evidence (1 reference)

PMID:34241796 SUPPORT DIRECT REVIEW SYNTHESIS 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."

A review gives an approximate diagnostic share, not an autosomal population prevalence.

⚖️

Clinical Burden

High

Severe infection risk, repeated immunoglobulin infusions and ongoing monitoring impose substantial burden. Chronic lung disease and selected inflammatory or syndromic complications add morbidity. Age at onset, severity and transplant suitability differ by genotype; the umbrella is not uniformly more severe than XLA.

🔀

Differential Diagnoses

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

X-linked agammaglobulinemia (BTK) MONDO:0010421

Overlapping Features BTK-related XLA shares severe B-cell and antibody deficiency and is usually male, but rare heterozygous females are affected. Sex, consanguinity and age alone do not distinguish it from all autosomal forms; molecular testing determines the cause.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1453/ SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"Females with a heterozygous pathogenic variant in <i>BTK</i> extremely rarely have clinical and laboratory findings of XLA."

The chapter explicitly recognizes rare affected females, correcting an absolute male-only boundary.

Common variable immunodeficiency MONDO:0015517

Overlapping Features CVID generally retains B cells with impaired antibody function, but some autosomal transcription-factor disorders can begin with a CVID-like phenotype and later lose B cells. This is a molecular and longitudinal distinction, not a single universal count threshold.

Show evidence (1 reference)

PMID:39073655 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"TCF3 haploinsufficiency (HI) also impacts both TCF3 isoforms, resulting in common variable immunodeficiency (CVID) with low B cells and hypogammaglobulinemia"

TCF3 allele mechanism can yield an overlapping phenotype.

Severe combined immunodeficiency MONDO:0015974

Overlapping Features Major T-cell deficiency or dysfunction suggests combined immunodeficiency rather than an isolated antibody defect. Some syndromic autosomal forms have additional immune abnormalities, so comprehensive phenotyping and molecular diagnosis remain necessary.

Show evidence (1 reference)

PMID:37273190 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"variants in RAG1 or RAG2 cause severe combined immunodeficiency (SCID) because recombination of TCR chains during thymic development is also compromised."

RAG-related T- and B-cell developmental failure distinguishes an important combined-immunodeficiency mechanism.

Transient hypogammaglobulinemia of infancy Not Yet Curated MONDO:0015698

Overlapping Features Transient hypogammaglobulinemia of infancy typically retains B cells and is confirmed by subsequent recovery. Severe infections or profound B-cell depletion require evaluation for persistent genetic disease rather than assuming a transient state.

Good syndrome (thymoma with immunodeficiency) MONDO:0015696

Overlapping Features Adult-onset antibody and B-cell deficiency associated with thymoma is an acquired syndromic differential. Adult onset alone does not exclude inherited SPI1 disease.

Secondary hypogammaglobulinemia after B-cell-depleting therapy

Overlapping Features Prior B-cell-depleting therapy can cause prolonged secondary antibody deficiency. Drug exposure, pre-treatment immune history and longitudinal recovery help distinguish it from inherited disease. The cited Greek cohort is broader PAD, not an autosomal agammaglobulinemia prevalence study.

Show evidence (1 reference)

PMID:38792965 SUPPORT DIRECT PRIMARY RESULT 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 BOB1 deficiency can cause agammaglobulinemia despite preserved peripheral B-cell numbers, reflecting a later functional differentiation defect rather than the B-cell-poor pattern emphasized here.

Show evidence (1 reference)

PMID:37273190 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Despite normal numbers of peripheral B cells, the OBF-1–deficient patient presented with recurrent respiratory infection, agammaglobulinemia, and an absence of class switched memory B cells (Kury et al., 2021)."

A review summarizes the reported BOB1 patient; the original brief report had no substantive retrievable cached text.

Hyper-IgM syndrome Not Yet Curated MONDO:0003947

Overlapping Features Class-switch defects usually preserve B-cell numbers and IgM relative to IgG/IgA. Residual IgM alone does not exclude evolving autosomal agammaglobulinemia; use the full immunophenotype and genotype.

🧫

Experimental Models

IGLL1 folding and secretion in COS cells CELL_LINE

Heterologous expression compares mutant folding and secretion. The mutant retains VpreB association but is not normally secreted; the patient also carried a separate premature-stop allele with no detected transcript.

Cell source

COS cells expressing wild-type or patient P142L-containing lambda5 with VpreB

Publication

PMID:9419212

Pathograph links

Defective Lambda5 Surrogate Light Chain measures Mutant lambda5 has abnormal folding and secretion.

Limitations: COS expression is not a patient marrow receptor-assembly assay; protein degradation is inferred.

Readouts

Secreted lambda5

Direction: DECREASED

Interpretation: Mutant lambda5 has abnormal folding and secretion.

Show evidence (1 reference)

PMID:9419212 SUPPORT DIRECT PRIMARY RESULT In Vitro

"the allele carrying the pseudogene sequence resulted in defective folding and secretion of mutant lambda5/14.1."

COS-cell expression showed defective folding/secretion of the P142L-containing allele; this is not a direct patient pre-BCR surface assay.

Show evidence (1 reference)

PMID:9419212 SUPPORT DIRECT PRIMARY RESULT In Vitro

"the allele carrying the pseudogene sequence resulted in defective folding and secretion of mutant lambda5/14.1."

COS-cell expression showed defective folding/secretion of the P142L-containing allele; this is not a direct patient pre-BCR surface assay.

CD79B mature-BCR reconstitution in S2 cells CELL_LINE

Reconstitution uses a mature BCR containing mu heavy chain, conventional light chain, Ig-alpha and wild-type or mutant Ig-beta. The Q80-stop allele prevents surface complex assembly. These cultured cells are not an in-vivo fly immune model.

Cell source

Cultured Drosophila S2 Schneider cells with mixed mouse and human BCR components

Publication

PMID:17709424

Pathograph links

Impaired Pre-B-Cell Receptor Assembly measures The tested Ig-beta mutation prevents mature BCR surface assembly, supporting a receptor-component defect.

Limitations: Mature BCR rather than pre-BCR, heterologous species mixture, and one tested allele; extension to the human pre-B checkpoint is indirect.

Readouts

Surface BCR expression

Direction: DECREASED

Interpretation: The tested Ig-beta mutation prevents mature BCR surface assembly, supporting a receptor-component defect.

Show evidence (1 reference)

PMID:17709424 SUPPORT INDIRECT PRIMARY RESULT In Vitro

Mixed-species mature-BCR reconstitution in cultured S2 cells establishes an assembly defect for the tested Q80-stop allele; extension to human pre-BCR development is indirect.

Show evidence (1 reference)

PMID:17709424 SUPPORT INDIRECT PRIMARY RESULT In Vitro

Mixed-species mature-BCR reconstitution in cultured S2 cells establishes an assembly defect for the tested Q80-stop allele; extension to human pre-BCR development is indirect.

TCF3 E47 binding and reporter assays CELL_LINE

Nuclear extracts and reporter coexpression compare E555K with wild-type E47. The mutant impairs tested E-box binding and interferes with wild-type activity, while localization and the tested MyoD heterodimer interaction are preserved.

Cell source

Patient EBV-transformed lines and transfected HEK293 cells

Publication

PMID:24216514

Pathograph links

Defective TCF3 Transcription-Factor Activity measures E555K fails the tested homodimer DNA-binding assay while supporting MyoD heterodimer binding.

Limitations: Transformed-cell and overexpression assays; not loss of every partner interaction or a complete explanation of all TCF3 allele classes.

Readouts

E47 homodimer DNA binding

Direction: DECREASED

Interpretation: E555K fails the tested homodimer DNA-binding assay while supporting MyoD heterodimer binding.

Show evidence (1 reference)

PMID:24216514 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Although E555K E47 did not bind to the μE5 or creatinine kinase probes as a homodimer, it did allow MyoD to bind to the creatinine kinase probe (Figure 3D)."

E555K disrupts measured homodimer DNA binding while preserving the tested MyoD heterodimer interaction; it is not loss of all E-protein partnerships.

Show evidence (1 reference)

PMID:24216514 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Although E555K E47 did not bind to the μE5 or creatinine kinase probes as a homodimer, it did allow MyoD to bind to the creatinine kinase probe (Figure 3D)."

E555K disrupts measured homodimer DNA binding while preserving the tested MyoD heterodimer interaction; it is not loss of all E-protein partnerships.

SPI1 dosage-edited RS4;11 pro-B cells CELL_LINE

ATAC-seq and transcriptomics compare engineered PU.1 dosage states with unedited cells. This model supplies chromatin evidence; the patient marrow transcriptomic comparison is a separate experiment involving one affected child and one control.

Cell source

Human RS4;11 pro-B leukemia cell lines with monoallelic or biallelic CRISPR SPI1 disruption

Publication

PMID:33951726

Pathograph links

Restricted B-Lineage Chromatin Accessibility measures Reduced PU.1 dosage accompanies lower accessibility at PU.1-associated regulatory regions.

Limitations: Transformed cells with engineered indels are not exact patient alleles. Accessibility and expression changes do not isolate every necessary mediator of differentiation.

Readouts

PU.1-associated chromatin accessibility

Direction: DECREASED

Interpretation: Reduced PU.1 dosage accompanies lower accessibility at PU.1-associated regulatory regions.

Show evidence (1 reference)

PMID:33951726 SUPPORT DIRECT PRIMARY RESULT In Vitro

"PU.1 OCRs were significantly more accessible in SPI1+/+ than SPI1+/− or SPI1−/− cell lines"

ATAC-seq in edited RS4;11 pro-B leukemia cells shows a PU.1-dose-associated accessibility difference.

Show evidence (1 reference)

PMID:33951726 SUPPORT DIRECT PRIMARY RESULT In Vitro

"PU.1 OCRs were significantly more accessible in SPI1+/+ than SPI1+/− or SPI1−/− cell lines"

ATAC-seq in edited RS4;11 pro-B leukemia cells shows a PU.1-dose-associated accessibility difference.

Expanded PU.1 variant reporter panel CELL_LINE

The 2025 study tested 134 rare or novel PU.1 variants, rather than 134 patients. Instability, localization and transcriptional impairment differ by allele; some low monoclonal-antibody signals reflected epitope changes. Coexpression did not show dominant interference for tested loss-of-function variants.

Cell source

HEK-based expression, localization and PU.1-responsive reporter systems

Publication

url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf

Pathograph links

Reduced PU.1 Dosage or Activity measures Tested loss-of-function alleles reduce effective PU.1 activity without demonstrated dominant-negative action.

Limitations: An empirically calibrated reporter threshold and a low gnomAD-tail value alone do not establish clinical pathogenicity. The clinical cohort contains 22 agammaglobulinemic patients plus 11 relatives.

Readouts

PU.1 reporter activity

Direction: DECREASED

Interpretation: Tested loss-of-function alleles reduce effective PU.1 activity without demonstrated dominant-negative action.

Show evidence (1 reference)

url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf SUPPORT DIRECT PRIMARY RESULT In Vitro

"Regardless of location, all tested LOF variants conveyed effects via haploinsuf ﬁciency."

HEK-based expression/reporters and coexpression assays support haploinsufficiency for the tested loss-of-function variants, with assay-calibrated pathogenicity limits.

Show evidence (1 reference)

url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf SUPPORT DIRECT PRIMARY RESULT In Vitro

"Regardless of location, all tested LOF variants conveyed effects via haploinsuf ﬁciency."

HEK-based expression/reporters and coexpression assays support haploinsufficiency for the tested loss-of-function variants, with assay-calibrated pathogenicity limits.

FNIP1 patient-cell metabolic assays PRIMARY_CELL_CULTURE

Separate assays measured protein absence in cultured T cells, increased mitochondrial abundance/activity signals in rare circulating B cells, and altered phosphorylation in marrow progenitors. The metabolic experiments center on patient 1; repeated assays do not expand the donor count. No serial mitochondrial-to-phosphosignaling mechanism or developmental rescue was demonstrated.

Cell source

Stimulated T cells from three patients; rare peripheral B cells and marrow B-cell progenitors from patient 1, with healthy-control comparisons

Publication

url:https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content

Pathograph links

Increased B-Cell Mitochondrial Abundance measures Mitochondrial abundance was increased in rare circulating B cells from one FNIP1-deficient patient. This is not a measure in marrow progenitors or cardiac tissue.

Limitations: Small patient/control comparisons in distinct cell populations; no selective developmental rescue, cardiac mediation or human treatment efficacy demonstrated.

Readouts

Mitochondrial abundance signal

Direction: INCREASED

Interpretation: Mitochondrial abundance was increased in rare circulating B cells from one FNIP1-deficient patient. This is not a measure in marrow progenitors or cardiac tissue.

Show evidence (1 reference)

url:https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content SUPPORT DIRECT PRIMARY RESULT In Vitro

"Indeed, circulating P1 B-cells exhibited increased numbers of mitochondria and mitochondrial activity relative to healthy control (HC) B-cells (Figure 1F and supplemental Figure 9 )."

Mitochondrial dye readouts were measured in rare circulating B cells from one patient compared with a healthy control; they do not establish a general ATP-production flux.

Show evidence (1 reference)

url:https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content SUPPORT DIRECT PRIMARY RESULT In Vitro

"Indeed, circulating P1 B-cells exhibited increased numbers of mitochondria and mitochondrial activity relative to healthy control (HC) B-cells (Figure 1F and supplemental Figure 9 )."

Mitochondrial dye readouts were measured in rare circulating B cells from one patient compared with a healthy control; they do not establish a general ATP-production flux.

Increased B-Cell Mitochondrial Activity Signal measures A mitochondrial activity-associated dye readout was increased in circulating B cells from one FNIP1-deficient patient. It is distinct from mitochondrial abundance and does not establish increased ATP synthesis or respiratory flux.

Limitations: Small patient/control comparisons in distinct cell populations; no selective developmental rescue, cardiac mediation or human treatment efficacy demonstrated.

Readouts

Mitochondrial activity-associated dye signal

Direction: INCREASED

Interpretation: A mitochondrial activity-associated dye readout was increased in circulating B cells from one FNIP1-deficient patient. It is distinct from mitochondrial abundance and does not establish increased ATP synthesis or respiratory flux.

Show evidence (1 reference)

url:https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content SUPPORT DIRECT PRIMARY RESULT In Vitro

"Indeed, circulating P1 B-cells exhibited increased numbers of mitochondria and mitochondrial activity relative to healthy control (HC) B-cells (Figure 1F and supplemental Figure 9 )."

Mitochondrial dye readouts were measured in rare circulating B cells from one patient compared with a healthy control; they do not establish a general ATP-production flux.

Show evidence (1 reference)

url:https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content SUPPORT DIRECT PRIMARY RESULT In Vitro

"Indeed, circulating P1 B-cells exhibited increased numbers of mitochondria and mitochondrial activity relative to healthy control (HC) B-cells (Figure 1F and supplemental Figure 9 )."

Mitochondrial dye readouts were measured in rare circulating B cells from one patient compared with a healthy control; they do not establish a general ATP-production flux.

Increased B-Cell AKT Phosphorylation measures Marrow B-cell progenitors from one FNIP1-deficient patient had increased AKT Ser473 phosphorylation relative to a healthy control. This is an observed signaling state, not a direct assay of a unique kinase mechanism.

Limitations: Small patient/control comparisons in distinct cell populations; no selective developmental rescue, cardiac mediation or human treatment efficacy demonstrated.

Readouts

AKT Ser473 phosphorylation

Direction: INCREASED

Interpretation: Marrow B-cell progenitors from one FNIP1-deficient patient had increased AKT Ser473 phosphorylation relative to a healthy control. This is an observed signaling state, not a direct assay of a unique kinase mechanism.

Show evidence (1 reference)

url:https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content SUPPORT DIRECT PRIMARY RESULT In Vitro

One patient marrow comparison showed increased p4EBP1 and pAKT473 but not pS6; small repeated assays do not expand the donor count.

Show evidence (1 reference)

url:https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content SUPPORT DIRECT PRIMARY RESULT In Vitro

One patient marrow comparison showed increased p4EBP1 and pAKT473 but not pS6; small repeated assays do not expand the donor count.

Increased B-Cell 4EBP1 Phosphorylation measures Marrow B-cell progenitors from one FNIP1-deficient patient had increased 4EBP1 phosphorylation; pS6 was not significantly altered. BEZ235 lowered the 4EBP1 readout without demonstrating restored B-cell development or clinical benefit.

Limitations: Small patient/control comparisons in distinct cell populations; no selective developmental rescue, cardiac mediation or human treatment efficacy demonstrated.

Readouts

4EBP1 phosphorylation

Direction: INCREASED

Interpretation: Marrow B-cell progenitors from one FNIP1-deficient patient had increased 4EBP1 phosphorylation; pS6 was not significantly altered. BEZ235 lowered the 4EBP1 readout without demonstrating restored B-cell development or clinical benefit.

Show evidence (1 reference)

url:https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content SUPPORT DIRECT PRIMARY RESULT In Vitro

One patient marrow comparison showed increased p4EBP1 and pAKT473 but not pS6; small repeated assays do not expand the donor count.

Show evidence (1 reference)

url:https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content SUPPORT DIRECT PRIMARY RESULT In Vitro

One patient marrow comparison showed increased p4EBP1 and pAKT473 but not pS6; small repeated assays do not expand the donor count.

The patient marrow showed a relative shift toward earlier precursors and fewer immature cells, without a discrete maturation block in the reported analysis.

TOP2B yeast complementation and decatenation OTHER

Human/mouse chimeric constructs and corresponding yeast substitutions are used in complementation and biochemical assays. Growth and nuclear-fraction decatenation support loss of function and partial dominant interference.

Cell source

Saccharomyces cerevisiae strains and extracted nuclear fractions

Publication

PMID:31409799

Pathograph links

Impaired TOP2B Activity measures Mutant-plus-wild-type yeast fractions decatenate less effectively than the single-wild-type-copy comparator.

Limitations: Yeast ortholog/context and extracted fractions do not directly measure human B-cell topoisomerase function or establish a specific downstream transcriptional mediator.

Readouts

DNA decatenation activity

Direction: DECREASED

Interpretation: Mutant-plus-wild-type yeast fractions decatenate less effectively than the single-wild-type-copy comparator.

Show evidence (1 reference)

PMID:31409799 SUPPORT DIRECT PRIMARY RESULT In Vitro

Yeast nuclear-fraction decatenation supports partial dominant interference for tested substitutions; this is not a direct patient B-cell enzyme assay.

Show evidence (1 reference)

PMID:31409799 SUPPORT DIRECT PRIMARY RESULT In Vitro

Yeast nuclear-fraction decatenation supports partial dominant interference for tested substitutions; this is not a direct patient B-cell enzyme assay.

ZIP7-mutant mouse B-cell signaling and zinc assays PRIMARY_CELL_CULTURE

Compartment-targeted FRET-FLIM measures free zinc in expanded cultures. Separate ex-vivo assays measure broad phosphatase activity and antigen-induced phosphorylation with equivalent surface BCR expression. These assays support several linked abnormalities without proving one necessary PTEN-mediated sequence.

Cell source

IL7-expanded P198A homozygous and wild-type mouse marrow B cells; ex-vivo SWHEL immature B cells

Publication

PMID:30718914

Pathograph links

Reduced B-Cell Cytosolic Free Zinc measures Measures reduced free cytosolic zinc.

Limitations: ER free zinc was unchanged; local or dynamic pulses exceed the measurement resolution.

Readouts

Free cytosolic zinc

Direction: DECREASED

Interpretation: Measures reduced free cytosolic zinc.

Show evidence (1 reference)

PMID:30718914 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Cytoplasmic Zn2+ concentrations were indeed lower in mutant compared to WT cells, whereas ER Zn2+ amounts were equivalent"

FRET-FLIM in IL7-expanded mutant mouse marrow B-cell cultures measures lower free cytosolic zinc with unchanged free ER zinc.

Show evidence (1 reference)

PMID:30718914 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Cytoplasmic Zn2+ concentrations were indeed lower in mutant compared to WT cells, whereas ER Zn2+ amounts were equivalent"

FRET-FLIM in IL7-expanded mutant mouse marrow B-cell cultures measures lower free cytosolic zinc with unchanged free ER zinc.

Increased B-Cell Phosphatase Activity measures Measures increased broad substrate activity.

Limitations: No PTEN-specific catalytic assay.

Readouts

Phosphatase-substrate activity

Direction: INCREASED

Interpretation: Measures increased broad substrate activity.

Show evidence (1 reference)

PMID:30718914 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Constitutive phosphatase activity was indeed higher in ZIP7P198A/P198A compared to WT pre-B and immature B cells, as measured by flow cytometry using a cell-permeable alkaline phosphatase substrate"

The broad live phosphatase-substrate assay does not isolate PTEN activity.

Show evidence (1 reference)

PMID:30718914 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Constitutive phosphatase activity was indeed higher in ZIP7P198A/P198A compared to WT pre-B and immature B cells, as measured by flow cytometry using a cell-permeable alkaline phosphatase substrate"

The broad live phosphatase-substrate assay does not isolate PTEN activity.

Reduced B-Cell Receptor Signaling measures Measures reduced antigen-induced phosphorylation.

Limitations: Does not establish a serial SYK-to-PLCγ2-to-ERK necessity chain or generalized T-cell signaling defect.

Readouts

Antigen-induced phosphoprotein signal

Direction: DECREASED

Interpretation: Measures reduced antigen-induced phosphorylation.

Show evidence (1 reference)

PMID:30718914 SUPPORT DIRECT PRIMARY RESULT In Vitro

"immature ZIP7P198A/P198A SWHel B cells showed impaired antigen-induced signalling as judged by reduced amounts of multiple phosphorylated intermediates, including SYK, PLCγ2 and ERK"

Ex-vivo antigen stimulation demonstrates reduced phosphorylation despite comparable surface BCR.

Show evidence (1 reference)

PMID:30718914 SUPPORT DIRECT PRIMARY RESULT In Vitro

"immature ZIP7P198A/P198A SWHel B cells showed impaired antigen-induced signalling as judged by reduced amounts of multiple phosphorylated intermediates, including SYK, PLCγ2 and ERK"

Ex-vivo antigen stimulation demonstrates reduced phosphorylation despite comparable surface BCR.

The cultured zinc assay and ex-vivo signaling assays use different preparations. No UPR transcriptional signature or altered Xbp1 splicing was observed; there was no measured ER free-zinc overload. PTEN haploinsufficiency failed to rescue maturation. Findings do not establish human zinc treatment efficacy.

Show evidence (3 references)

PMID:30718914 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Cytoplasmic Zn2+ concentrations were indeed lower in mutant compared to WT cells, whereas ER Zn2+ amounts were equivalent"

FRET-FLIM in IL7-expanded mutant mouse marrow B-cell cultures measures lower free cytosolic zinc with unchanged free ER zinc.

PMID:30718914 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Constitutive phosphatase activity was indeed higher in ZIP7P198A/P198A compared to WT pre-B and immature B cells, as measured by flow cytometry using a cell-permeable alkaline phosphatase substrate"

The broad live phosphatase-substrate assay does not isolate PTEN activity.

PMID:30718914 SUPPORT DIRECT PRIMARY RESULT In Vitro

"immature ZIP7P198A/P198A SWHel B cells showed impaired antigen-induced signalling as judged by reduced amounts of multiple phosphorylated intermediates, including SYK, PLCγ2 and ERK"

Ex-vivo antigen stimulation demonstrates reduced phosphorylation despite comparable surface BCR.

SPI1-edited human hematopoietic progenitor differentiation PRIMARY_CELL_CULTURE

In-vitro B-cell, myeloid and T-cell differentiation compares edited and control progenitors. Editing introduces mixtures of monoallelic and biallelic indels rather than precise patient variants; allele enrichment among surviving differentiated cells is distinct from a universal lineage arrest.

Cell source

Cord-blood hematopoietic stem and progenitor cells edited near disease-associated SPI1 regions

Publication

PMID:33951726

Pathograph links

Impaired B-Cell Development partially recapitulates SPI1 editing impairs early B-cell and myeloid differentiation in culture.

Limitations: Cord-blood culture and mixed editing outcomes differ from human heterozygous disease. This experiment is separate from RS4;11 ATAC-seq and does not isolate a particular chromatin-mediated causal bridge.

Readouts

B-lineage differentiation output

Direction: DECREASED

Interpretation: Reduced B-lineage differentiation supports a cell-intrinsic developmental role in this culture system.

Show evidence (1 reference)

PMID:33951726 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Introducing disease-similar SPI1 mutations into human hematopoietic stem and progenitor cells impaired early in vitro B cell and myeloid cell differentiation."

Edited cord-blood progenitors carry mixtures of near-variant indels, not precise patient-allele knock-ins; lineage selection supports but does not isolate the chromatin mediator.

Show evidence (1 reference)

PMID:33951726 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Introducing disease-similar SPI1 mutations into human hematopoietic stem and progenitor cells impaired early in vitro B cell and myeloid cell differentiation."

Edited cord-blood progenitors carry mixtures of near-variant indels, not precise patient-allele knock-ins; lineage selection supports but does not isolate the chromatin mediator.

🐁

Animal Models

Slc39a7 hypomorphic mice and mixed marrow chimeras

Global knock-in and engineered hypomorphic alleles cause allele-dependent growth/skin abnormalities and profound B-cell deficiency. P198A is orthologous to human P190A. Mixed WT/mutant marrow chimeras demonstrate a B-cell intrinsic late-pre-B to immature-stage block.

Species

Mouse

Genotype

Slc39a7 P198A homozygous, H199QV homozygous or P198A/H199QV compound heterozygous

Publication

PMID:30718914

Pathograph links

Impaired ZIP7-Dependent B-Cell Maturation recapitulates Recapitulates B-cell intrinsic maturation failure.

Limitations: Stage assignment is based on mouse Hardy fractions; the study cannot exclude an earlier pre-B defect.

Readouts

Late-pre-B to immature B-cell progression

Direction: DECREASED

Interpretation: Recapitulates B-cell intrinsic maturation failure.

Show evidence (1 reference)

PMID:30718914 SUPPORT DIRECT PRIMARY RESULT Model Organism

Mixed marrow chimeras show cell-intrinsic developmental failure strongest at late-pre-B to immature transition.

Show evidence (1 reference)

PMID:30718914 SUPPORT DIRECT PRIMARY RESULT Model Organism

Mixed marrow chimeras show cell-intrinsic developmental failure strongest at late-pre-B to immature transition.

Notes

Null/null and null/hypomorph animals could not be obtained; these are not equivalent to viable complete-null patient models. Few P198A homozygotes survived past six weeks. Oral zinc did not rescue the tested marrow-reconstitution model. BCL2 increased peripheral numbers without relieving the block; B-cell PTEN haploinsufficiency also failed to rescue maturation. Phenotyping was not randomized or blinded.

Show evidence (2 references)

PMID:30718914 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Mice with homozygous (ZIP7P198A/P198A or ZIP7H199QV/H199QV) or compound heterozygous (ZIP7P198A/H199QV) hypomorphic mutations demonstrated profound B cell immunodeficiency"

Global hypomorphic alleles produce B-cell deficiency; H199QV is engineered rather than a human allele.

PMID:30718914 SUPPORT DIRECT PRIMARY RESULT Model Organism

Mixed marrow chimeras show cell-intrinsic developmental failure strongest at late-pre-B to immature transition.

Global Lrrc8a-null and Lrrc8a-null marrow into Rag2-null recipients Mouse Genetic

Global null mice have increased mortality, growth and tissue abnormalities, modest B-cell developmental changes and stronger T-cell defects. Tested B-cell proliferation and antibody responses were largely intact despite reduced peripheral B-cell numbers.

Species

Mouse

Genotype

Global Lrrc8a-null and Lrrc8a-null marrow into Rag2-null recipients

Publication

PMID:24752297

Pathograph links

Impaired B-Cell Development partially recapitulates The null model reproduces only a modest B-development phenotype.

Limitations: Allele, species and viability differ from the human case; it does not recapitulate profound human agammaglobulinemia.

Readouts

B-cell developmental progression

Direction: DECREASED

Interpretation: The null model reproduces only a modest B-development phenotype.

Show evidence (1 reference)

PMID:24752297 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Lrrc8a(-/-) mice displayed a modest block in B cell development but intact intrinsic B cell function."

Global null mice have a different allele mechanism from the single human heterozygous truncation.

Show evidence (1 reference)

PMID:24752297 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Lrrc8a(-/-) mice displayed a modest block in B cell development but intact intrinsic B cell function."

Global null mice have a different allele mechanism from the single human heterozygous truncation.

This is not the human heterozygous truncation. The result neither disproves the reported human association nor establishes dominant interference. The historical proposed ligand/topology mechanism is not promoted as current channel biology.

B-lineage conditional Top2b deletion and a heterozygous disease-associated EE587E allele Mouse Genetic

Conditional mb1-Cre and cd19-Cre deletions and a separate constitutive disease-allele model show B-lineage defects at multiple stages. The heterozygous disease-allele model also has reduced humoral responses. Human marrow stage was not measured in the three families.

Species

Mouse

Genotype

B-lineage conditional Top2b deletion and a heterozygous disease-associated EE587E allele

Publication

PMID:31409799

Pathograph links

Impaired B-Cell Development partially recapitulates The conditional model alters B-cell differentiation and the expression of selected B-lineage regulators.

Limitations: Pax5 reduction is a measured accompanying change, not isolated rescue or mediation; stage and allele effects differ among models.

Readouts

B-lineage Pax5 expression

Direction: DECREASED

Interpretation: The conditional model alters B-cell differentiation and the expression of selected B-lineage regulators.

Show evidence (1 reference)

PMID:31409799 SUPPORT DIRECT PRIMARY RESULT Model Organism

"expression of Pax5, a B-cell speci ﬁc transcription factor expressed at most stages of B-cell develop- ment23– 25, was signi ﬁcantly reduced in B cells derived from Top2b−/−mb1-cre mice while Rag1 expression was unchanged (Fig. 3n, o)."

Conditional Top2b-deficient mouse B cells show altered Pax5 expression, with unchanged Rag1; this is not proof that Pax5 alone mediates the phenotype.

Show evidence (1 reference)

PMID:31409799 SUPPORT DIRECT PRIMARY RESULT Model Organism

Conditional Top2b-deficient mouse B cells show altered Pax5 expression, with unchanged Rag1; this is not proof that Pax5 alone mediates the phenotype.

Conditional deletion and the dominant disease allele are distinct models. B-cell DNA-damage, transcription and survival readouts do not establish a single necessary route, and do not explain human limb or urogenital anomalies. Homozygous disease-allele viability differs from heterozygous patients.

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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 agammaglobulinemia comprises recessive and dominant disorders with severely reduced circulating B cells and antibody production. Defects affect pre-B-cell receptor components, intracellular signaling, transcriptional regulation, zinc transport, or metabolic homeostasis. The developmental stage, residual B-cell output, immunoglobulin concentrations, and accompanying cell defects vary by gene and allele; a single universal pro-B-to-pre-B arrest does not describe the whole group. Recurrent sinopulmonary and invasive bacterial infections are central manifestations, but onset can extend into adulthood. Inflammatory disease and syndromic features occur in selected forms. Immunoglobulin replacement and infection management are the mainstay of care; transplantation requires gene-specific assessment.
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: Biallelic pathogenic variants underlie IGHM, IGLL1, CD79A, CD79B, BLNK, PIK3R1, PIK3CD, SLC39A7, FNIP1 and recessive TCF3 disease. Consanguineous families have contributed substantially to gene discovery, but consanguinity is not required.
  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.
    directness: DIRECT
    quote_role: BACKGROUND
  - 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.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- name: Autosomal dominant inheritance
  description: Dominant TCF3/E47 disease and SPI1 haploinsufficiency can be de novo or familial; SPI1 disease has variable expressivity and incomplete penetrance. TOP2B-related Hoffman syndrome is another dominant B-cell immunodeficiency. The historical LRRC8A association rests on one truncating-translocation case and currently has Limited gene-disease validity.
  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.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - 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.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    reference_title: https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: 6 were apparently unaffected, indicating a disease penetrance of 81.8% with incomplete expressivity.
    explanation: Familial segregation of heterozygous loss-of-function SPI1 variants, including apparently unaffected carriers, gives an estimated 81.8% penetrance; the authors note that ascertainment bias and late onset limit this estimate.
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.
      directness: DIRECT
      quote_role: BACKGROUND
  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: The antibody-deficiency phenotype places this heterogeneous group in the predominantly antibody deficiency category; normal T-cell function is not required for every genotype.
      directness: DIRECT
      quote_role: BACKGROUND
    - reference: PMID:35748970
      reference_title: 'Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: heavy chain deficiency IGHM AR 147020
      explanation: This entry spans multiple IUIS 2022 Table 3 section 1 (agammaglobulinemia) rows, one per subtype gene (IGHM, IGLL1, CD79A, CD79B, BLNK, PIK3R1, TCF3, SLC39A7, SPI1); quoted here is the most representative, the AGM1 mu-heavy-chain row. Its printed label is "mu heavy chain deficiency" - the leading Greek mu was dropped by PDF extraction, so the quote starts at "heavy chain".
      directness: DIRECT
      quote_role: REVIEW_SYNTHESIS
prevalence:
- population: Worldwide
  measure_type: UNKNOWN
  notes: No reliable population rate for this heterogeneous umbrella is established by the cited sources. Historical reviews estimate that XLA accounts for approximately 85% of congenital agammaglobulinemia; the remaining proportion is not a directly measured autosomal population prevalence. Gene discovery, referral patterns, ancestry and later-onset cases affect case composition.
  evidence:
  - reference: PMID:34241796
    reference_title: 'Agammaglobulinemia: from X-linked to Autosomal Forms of Disease.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    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: A review gives an approximate diagnostic share, not an autosomal population prevalence.
has_subtypes:
- name: AGM1
  display_name: Agammaglobulinemia 1, autosomal recessive (IGHM, mu heavy chain)
  description: Biallelic IGHM defects impair the membrane immunoglobulin mu heavy chain. Some early cohorts found more severe disease than XLA; that comparison should not be generalized to all autosomal genes.
  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.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- 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.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- name: AGM3
  display_name: Agammaglobulinemia 3, autosomal recessive (CD79A, Ig-alpha)
  description: Biallelic CD79A deficiency affects Ig-alpha. The original splice-defect case showed profound early B-cell developmental arrest; this observation is not a universal assay of every allele.
  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.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- name: AGM4
  display_name: Agammaglobulinemia 4, autosomal recessive (BLNK)
  description: Biallelic BLNK deficiency affects a cytoplasmic signaling adaptor rather than a structural receptor subunit. The original patient had pro-B cells but no detected pre-B or mature B cells; subsequent phenotypes vary.
  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.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- name: AGM5
  display_name: Agammaglobulinemia 5, autosomal dominant (LRRC8A)
  description: Historical numbered subtype associated with a heterozygous truncating LRRC8A allele from a balanced t(9;20) in one girl. ClinGen currently classifies the LRRC8A-agammaglobulinemia relationship as Limited. Dominant interference is proposed; neither a specific channel defect nor its mediation of the human immune phenotype was demonstrated.
  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 original authors interpreted their single human case and mutant-expression model as causal; current ClinGen validity remains Limited.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- name: AGM6
  display_name: Agammaglobulinemia 6, autosomal recessive (CD79B, Ig-beta)
  description: Biallelic CD79B deficiency affects Ig-beta. The original Q80-stop allele prevented surface receptor assembly in a heterologous mature-BCR reconstitution assay. Other alleles may be hypomorphic; the assay is not a direct measurement of every patient pre-BCR.
  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.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- name: AGM7
  display_name: Agammaglobulinemia 7, autosomal recessive (PIK3R1, p85-alpha)
  description: Biallelic loss of PIK3R1 p85-alpha is distinct from activating PI3K-pathway immunodeficiencies. The original woman had a profound early B-lineage defect, colitis and transient early neutropenia, with preserved measured T-cell function.
  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.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- 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.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- name: AGM8B
  display_name: Agammaglobulinemia 8B, autosomal recessive (TCF3)
  description: Biallelic TCF3 loss affects both E12 and E47, with B-cell deficiency, variable dysmorphic features and reported B-cell acute lymphoblastic leukemia. It is distinct from E47-selective dominant-negative disease and heterozygous TCF3 haploinsufficiency with CVID-like disease.
  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
  evidence:
  - reference: PMID:39073655
    reference_title: Exclusive Characteristics of the p.E555K Dominant-Negative Variant in Autosomal Dominant E47 Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: Complete AR TCF3 deficiency is associated with reduced B cells, hypogammaglobulinemia, dysmorphic phenotypes, and B-cell acute lymphoblastic leukemia (B-ALL)
    explanation: The 2024 article synthesizes the recessive phenotype; the original short report was not available as a substantive cached body.
- name: AGM9
  display_name: Agammaglobulinemia 9, autosomal recessive (SLC39A7/ZIP7)
  description: Hypomorphic SLC39A7 variants impair the zinc transporter ZIP7. Human and mouse evidence supports a B-cell developmental defect involving zinc homeostasis and signaling; the strongest mouse block is late-pre-B to immature B cell. Severe patients can also have skin disease and failure to thrive.
  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.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- name: AGM10
  display_name: Agammaglobulinemia 10, autosomal dominant (SPI1/PU.1 haploinsufficiency)
  description: Heterozygous SPI1 loss reduces PU.1 activity. B-cell and dendritic-cell deficiency can present in infancy or adulthood, and relatives can have mild or no antibody abnormalities. Chromatin-accessibility mechanisms were tested in edited pro-B cell lines rather than directly in every patient lineage.
  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.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    reference_title: https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Of the 11 relatives harboring heterozygous LOF PU.1 variants, 6 were clinically well with laboratory evaluations documenting serum antibody and circulating B-cell concentrations within age- adjusted normal ranges.
    explanation: Variant-carrying relatives with normal antibody and B-cell values support the mild-or-unaffected end of the AGM10 spectrum described here.
  - reference: url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    reference_title: https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: In a cluster of patients, disease onset was delayed, sometimes into adulthood.
    explanation: The expanded SPI1 cohort documents diagnosis and symptom onset extending beyond infancy into adulthood.
- name: FNIP1
  display_name: FNIP1-associated syndrome (autosomal recessive)
  description: Biallelic FNIP1 deficiency is a syndromic B-cell immunodeficiency with hypertrophic cardiomyopathy and variable neutropenia. Patient-cell metabolic and phosphosignaling abnormalities provide mechanistic clues, but do not establish the causal route to cardiomyopathy or a uniform developmental arrest.
  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: url:https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
    reference_title: https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
    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.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- name: TOP2B
  display_name: TOP2B-related Hoffman syndrome
  description: Dominant TOP2B-related B-cell immunodeficiency with variable distal-limb, facial and urogenital anomalies. This syndromic overlap is included in the IUIS agammaglobulinemia category; it is not AGM10, which denotes SPI1 disease.
  genes:
  - preferred_term: TOP2B
    term:
      id: hgnc:11990
      label: TOP2B
  evidence:
  - reference: PMID:31409799
    reference_title: Mutations in topoisomerase IIβ result in a B cell immunodeficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: In three families with Hoffman syndrome 9,10, we identi ﬁed three heterozygous mutations affecting the TOPRIM, or DNA gating, domain of the type II topoisomerase TOP2B.
    explanation: Three families establish the reported human syndrome; mechanistic assays use separate yeast and mouse systems.
- name: PIK3CD
  display_name: Recessive p110-delta deficiency
  description: Biallelic loss of the p110-delta catalytic subunit can cause severe antibody deficiency with reduced B cells. This is distinct from dominant activating PIK3CD variants causing activated PI3K-delta syndrome. The historical numbered AGM series does not exhaust the modern disease spectrum.
  genes:
  - preferred_term: PIK3CD
    term:
      id: hgnc:8977
      label: PIK3CD
  evidence:
  - reference: PMID:34241796
    reference_title: 'Agammaglobulinemia: from X-linked to Autosomal Forms of Disease.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: There are an additional 6 cases of homozygous PIK3CD gene mutation resulting in LOF of PIK3 delta enzyme complex. These patients also displayed hypogammaglobulinemia or agammaglobulinemia as well as decreased B cells [34].
    explanation: The review summarizes recessive p110-delta loss with B-cell and antibody deficiency; activating PIK3CD disease is a distinct mechanism.
pathophysiology:
- name: Impaired Membrane Mu Heavy-Chain Expression
  description: Biallelic IGHM variants disrupt the membrane heavy-chain component required for early B-cell receptor function. Allele-specific residual expression varies.
  biological_scale: MOLECULAR
  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.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  genes:
  - preferred_term: IGHM
    term:
      id: hgnc:5541
      label: IGHM
  downstream:
  - target: Impaired Pre-B-Cell Receptor Assembly
    description: Membrane mu deficiency impairs receptor formation; the human developmental phenotype and receptor biology support this bridge.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:8890099
      reference_title: Mutations in the mu heavy-chain gene in patients with agammaglobulinemia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: This implies that an intact membrane-bound mu chain is essential for B-cell development.
      explanation: The original human report supports the required membrane heavy chain, with receptor assembly inferred.
- name: Defective Lambda5 Surrogate Light Chain
  description: IGLL1 disease disrupts functional lambda5. In the original compound-heterozygous patient, one allele lacked detectable transcript and the tested P142L-containing protein folded and secreted abnormally in COS cells.
  biological_scale: MOLECULAR
  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.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: PMID:9419212
    reference_title: Mutations in the human lambda5/14.1 gene result in B cell deficiency and agammaglobulinemia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: the allele carrying the pseudogene sequence resulted in defective folding and secretion of mutant lambda5/14.1.
    explanation: COS-cell expression showed defective folding/secretion of the P142L-containing allele; this is not a direct patient pre-BCR surface assay.
  genes:
  - preferred_term: IGLL1
    term:
      id: hgnc:5870
      label: IGLL1
  downstream:
  - target: Impaired Pre-B-Cell Receptor Assembly
    description: A defective surrogate light-chain component is expected to limit receptor assembly; this is not a direct assembly assay in the patient marrow.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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: IN_VITRO
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: the allele carrying the pseudogene sequence resulted in defective folding and secretion of mutant lambda5/14.1.
      explanation: COS-cell expression showed defective folding/secretion of the P142L-containing allele; this is not a direct patient pre-BCR surface assay.
- name: Ig-Alpha Deficiency
  description: Biallelic CD79A defects impair the Ig-alpha component. The original splice mutation produced abnormal transcripts and profound early B-cell depletion.
  biological_scale: MOLECULAR
  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.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  genes:
  - preferred_term: CD79A
    term:
      id: hgnc:1698
      label: CD79A
  downstream:
  - target: Impaired Pre-B-Cell Receptor Assembly
    description: Ig-alpha provides a required receptor component; downstream assembly is inferred from structural function and the clinical developmental defect.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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.
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
- name: Ig-Beta Deficiency
  description: Biallelic CD79B defects impair Ig-beta. The original Q80-stop allele prevents association with Ig-alpha and surface BCR reconstitution; later hypomorphic alleles need not have identical residual function.
  biological_scale: MOLECULAR
  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.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: PMID:17709424
    reference_title: Mutations of the Igbeta gene cause agammaglobulinemia in man.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    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: Mixed-species mature-BCR reconstitution in cultured S2 cells establishes an assembly defect for the tested Q80-stop allele; extension to human pre-BCR development is indirect.
  genes:
  - preferred_term: CD79B
    term:
      id: hgnc:1699
      label: CD79B
  downstream:
  - target: Impaired Pre-B-Cell Receptor Assembly
    description: The measured mature-BCR assembly defect supports the pre-BCR route, with a different receptor and cellular context.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:17709424
      reference_title: Mutations of the Igbeta gene cause agammaglobulinemia in man.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      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: Mixed-species mature-BCR reconstitution in cultured S2 cells establishes an assembly defect for the tested Q80-stop allele; extension to human pre-BCR development is indirect.
- name: Impaired Pre-B-Cell Receptor Assembly
  description: Structural-component defects compromise receptor formation. Direct heterologous evidence here concerns the mature BCR containing the CD79B Q80-stop allele, rather than all patient pre-BCR genotypes.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:17709424
    reference_title: Mutations of the Igbeta gene cause agammaglobulinemia in man.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    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: Mixed-species mature-BCR reconstitution in cultured S2 cells establishes an assembly defect for the tested Q80-stop allele; extension to human pre-BCR development is indirect.
  downstream:
  - target: Reduced Receptor-Proximal B-Cell Signaling
    description: Insufficient receptor assembly limits developmental signals; the molecular signaling intermediates were not all assayed in each patient.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:17709424
      reference_title: Mutations of the Igbeta gene cause agammaglobulinemia in man.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      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: Mixed-species mature-BCR reconstitution in cultured S2 cells establishes an assembly defect for the tested Q80-stop allele; extension to human pre-BCR development is indirect.
  protein_complexes:
  - preferred_term: pre-B cell receptor complex
    term:
      id: GO:0035369
      label: pre-B cell receptor complex
- name: BLNK Adaptor Deficiency
  description: BLNK is a cytoplasmic signaling adaptor. Its loss is a signaling defect and does not by itself establish absence of receptor assembly.
  biological_scale: MOLECULAR
  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: The original BLNK patient had a defined early B-lineage developmental block; this is not an estimate of all alleles or a receptor-assembly assay.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  genes:
  - preferred_term: BLNK
    term:
      id: hgnc:14211
      label: BLNK
  downstream:
  - target: Reduced Receptor-Proximal B-Cell Signaling
    description: The adaptor organizes receptor-proximal signals needed for B-cell development; exact stage and residual output vary.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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: The original BLNK patient had a defined early B-lineage developmental block; this is not an estimate of all alleles or a receptor-assembly assay.
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
- name: Reduced Receptor-Proximal B-Cell Signaling
  description: Insufficient signaling through the B-cell developmental checkpoint can follow receptor-component or adaptor defects. This is a shared functional consequence, not proof that all listed genotypes have identical signaling lesions.
  biological_scale: CELLULAR
  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: The original BLNK patient had a defined early B-lineage developmental block; this is not an estimate of all alleles or a receptor-assembly assay.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  downstream:
  - target: Impaired B-Cell Development
    description: Receptor/adaptor defects reduce developmental progression; the original BLNK patient had pro-B cells without detected pre-B or mature B cells.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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: The original BLNK patient had a defined early B-lineage developmental block; this is not an estimate of all alleles or a receptor-assembly assay.
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
  biological_processes:
  - preferred_term: B cell receptor signaling pathway
    term:
      id: GO:0050853
      label: B cell receptor signaling pathway
    modifier: DECREASED
- name: Loss of PI3K p85-Alpha
  description: The original recessive PIK3R1 stop variant eliminated p85-alpha. Reduced p110-delta abundance accompanied its absence in T cells, neutrophils and dendritic cells. These observations do not measure signaling in the missing B-cell population.
  biological_scale: MOLECULAR
  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: IN_VITRO
    snippet: The mutation results in the absence of p85α but normal expression of the p50α and p55α regulatory subunits of PI3K.
    explanation: Patient-cell protein assays distinguish loss of p85-alpha from preserved shorter regulatory isoforms; the assay was not performed in the missing B cells.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: PMID:22351933
    reference_title: Agammaglobulinemia and absent B lineage cells in a patient lacking the p85α subunit of PI3K.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Western blot showed markedly decreased p110δ, as well as absent p85α, in patient T cells, neutrophils, and dendritic cells.
    explanation: Protein abundance was measured in accessible patient lineages, not in the missing B-cell population.
  genes:
  - preferred_term: PIK3R1
    term:
      id: hgnc:8979
      label: PIK3R1
  downstream:
  - target: Impaired B-Cell Development
    description: The homozygous patient had very few early B-lineage cells. The precise lineage-specific pathway from p85-alpha loss remains incompletely resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: Bone marrow aspirates from the patient showed <0.1% CD19(+) B cells with normal percentages of TdT(+)VpreB(+)CD19(-) B cell precursors.
      explanation: The original patient had very few marrow B-lineage cells; this marrow percentage is not a peripheral-blood diagnostic threshold.
  - target: Colitis
    description: Colitis co-occurs in the original patient; the inflammatory route is not resolved by the B-cell assay.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: A homozygous premature stop codon in exon 6 of PIK3R1 was identified in a young woman with colitis and absent B cells.
      explanation: One original patient links the recessive PIK3R1 defect with colitis and B-cell deficiency.
- name: Reduced PI3K p110-Delta Function
  biological_scale: MOLECULAR
  description: Biallelic loss of the p110-delta catalytic subunit can cause severe antibody deficiency with reduced B cells. This is distinct from dominant activating PIK3CD variants causing activated PI3K-delta syndrome. The historical numbered AGM series does not exhaust the modern disease spectrum.
  genes:
  - preferred_term: PIK3CD
    term:
      id: hgnc:8977
      label: PIK3CD
  evidence:
  - reference: PMID:34241796
    reference_title: 'Agammaglobulinemia: from X-linked to Autosomal Forms of Disease.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: There are an additional 6 cases of homozygous PIK3CD gene mutation resulting in LOF of PIK3 delta enzyme complex. These patients also displayed hypogammaglobulinemia or agammaglobulinemia as well as decreased B cells [34].
    explanation: The review summarizes recessive p110-delta loss with B-cell and antibody deficiency; activating PIK3CD disease is a distinct mechanism.
  downstream:
  - target: Impaired B-Cell Development
    description: Recessive catalytic-subunit deficiency is associated with reduced B-cell output; the cited synthesis does not isolate one universal developmental stage or each downstream signal.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34241796
      reference_title: 'Agammaglobulinemia: from X-linked to Autosomal Forms of Disease.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      quote_role: REVIEW_SYNTHESIS
      snippet: There are an additional 6 cases of homozygous PIK3CD gene mutation resulting in LOF of PIK3 delta enzyme complex. These patients also displayed hypogammaglobulinemia or agammaglobulinemia as well as decreased B cells [34].
      explanation: The review summarizes recessive p110-delta loss with B-cell and antibody deficiency; activating PIK3CD disease is a distinct mechanism.
- name: Defective TCF3 Transcription-Factor Activity
  description: Dominant E47 E555K impairs tested E-box binding/transactivation and interferes with wild-type E47. Recessive loss affects both E12 and E47; heterozygous haploinsufficiency can instead produce CVID-like disease. These allele mechanisms are not interchangeable.
  biological_scale: MOLECULAR
  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.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: PMID:24216514
    reference_title: A recurrent dominant negative E47 mutation causes agammaglobulinemia and BCR(-) B cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Although E555K E47 did not bind to the μE5 or creatinine kinase probes as a homodimer, it did allow MyoD to bind to the creatinine kinase probe (Figure 3D).
    explanation: E555K disrupts measured homodimer DNA binding while preserving the tested MyoD heterodimer interaction; it is not loss of all E-protein partnerships.
  - reference: PMID:24216514
    reference_title: A recurrent dominant negative E47 mutation causes agammaglobulinemia and BCR(-) B cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    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: Transfection assays show that E555K interferes with wild-type E47 when bound to DNA as a homodimer.
  - reference: PMID:39073655
    reference_title: Exclusive Characteristics of the p.E555K Dominant-Negative Variant in Autosomal Dominant E47 Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: Complete AR TCF3 deficiency is associated with reduced B cells, hypogammaglobulinemia, dysmorphic phenotypes, and B-cell acute lymphoblastic leukemia (B-ALL)
    explanation: The 2024 article synthesizes the recessive phenotype; the original short report was not available as a substantive cached body.
  genes:
  - preferred_term: TCF3
    term:
      id: hgnc:11633
      label: TCF3
  downstream:
  - target: Impaired B-Cell Development
    description: Reduced or interfering transcription-factor activity impairs B-lineage output. The particular transcriptional targets that mediate each human phenotype are unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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.
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
  - target: B Acute Lymphoblastic Leukemia
    description: Biallelic TCF3 disease has reported leukemia risk, without a uniform oncogenic mechanism established across all TCF3 allele classes.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39073655
      reference_title: Exclusive Characteristics of the p.E555K Dominant-Negative Variant in Autosomal Dominant E47 Deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      quote_role: REVIEW_SYNTHESIS
      snippet: Complete AR TCF3 deficiency is associated with reduced B cells, hypogammaglobulinemia, dysmorphic phenotypes, and B-cell acute lymphoblastic leukemia (B-ALL)
      explanation: The 2024 article synthesizes the recessive phenotype; the original short report was not available as a substantive cached body.
- name: Reduced PU.1 Dosage or Activity
  description: SPI1 haploinsufficiency can arise through protein instability, localization defects or impaired DNA binding, depending on the allele. Reporter coexpression did not demonstrate dominant interference. The human phenotype ranges from unaffected carriers to progressive B-cell aplasia.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:33951726
    reference_title: Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    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: The original SPI1 cohort establishes the human genetic association; later families show inherited variants and milder phenotypes.
  - reference: PMID:33951726
    reference_title: Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Patient SPI1 mutations encoded destabilized PU.1 proteins unable to nuclear localize or bind target DNA.
    explanation: Functional assays identify allele-dependent protein instability, localization or DNA-binding defects; no single defect applies to every variant.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    reference_title: https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: either by destabilizing PU.1, impeding nuclear localization, or directly interfering with transcription.
    explanation: Functional testing of the loss-of-function variants identifies allele-dependent instability, nuclear-localization or transcriptional defects, all acting through reduced PU.1 dosage.
  genes:
  - preferred_term: SPI1
    term:
      id: hgnc:11241
      label: SPI1
  downstream:
  - target: Restricted B-Lineage Chromatin Accessibility
    description: Engineered PU.1 dosage reduction in a pro-B leukemia cell line constrains accessible chromatin; extension to every patient precursor remains indirect.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33951726
      reference_title: Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: PU.1 OCRs were significantly more accessible in SPI1+/+ than SPI1+/− or SPI1−/− cell lines
      explanation: ATAC-seq in edited RS4;11 pro-B leukemia cells shows a PU.1-dose-associated accessibility difference.
  - target: Decreased Dendritic Cell Abundance
    description: Human cohort immunophenotyping also finds conventional and plasmacytoid dendritic-cell depletion, without a uniform monocyte or T-cell deficit.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
      reference_title: https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: circulating plasmacytoid DC (pDC) concentrations were also signi ﬁcantly lower in patients than healthy donors (9.2 vs 3.4 cells per μL; P < .001), an immunophenotypic feature not previously appreciated.
      explanation: The expanded cohort adds pDC depletion; this association does not establish an independent causal route to every infection.
  - target: Inflammatory Arthritis
    description: The selected SPI1 cohort documents this associated inflammatory manifestation; cell-specific causal intermediates are unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
      reference_title: https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: juvenile idiopathic arthritis (n = 2); type 1 diabetes mellitus (n = 2); and single cases of immune thrombocytopenia, psoriasis, hidrade- nitis suppurativa, and autoimmune lipodystrophy.
      explanation: These are gene-specific observations in 22 selected SPI1 agammaglobulinemia patients, without disease-wide frequency inference.
  - target: Autoimmune Thrombocytopenia
    description: The selected SPI1 cohort documents this associated inflammatory manifestation; cell-specific causal intermediates are unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
      reference_title: https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: juvenile idiopathic arthritis (n = 2); type 1 diabetes mellitus (n = 2); and single cases of immune thrombocytopenia, psoriasis, hidrade- nitis suppurativa, and autoimmune lipodystrophy.
      explanation: These are gene-specific observations in 22 selected SPI1 agammaglobulinemia patients, without disease-wide frequency inference.
  - target: Type I Diabetes Mellitus
    description: The selected SPI1 cohort documents this associated inflammatory manifestation; cell-specific causal intermediates are unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
      reference_title: https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: juvenile idiopathic arthritis (n = 2); type 1 diabetes mellitus (n = 2); and single cases of immune thrombocytopenia, psoriasis, hidrade- nitis suppurativa, and autoimmune lipodystrophy.
      explanation: These are gene-specific observations in 22 selected SPI1 agammaglobulinemia patients, without disease-wide frequency inference.
- name: Restricted B-Lineage Chromatin Accessibility
  description: ATAC-seq in edited RS4;11 pro-B leukemia cells links reduced PU.1 dose to a less accessible B-lineage regulatory landscape. Cell-line gene-network effects support a developmental model but are not direct chromatin measurements in all patients.
  biological_scale: CELLULAR
  evidence:
  - reference: PMID:33951726
    reference_title: Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: PU.1 OCRs were significantly more accessible in SPI1+/+ than SPI1+/− or SPI1−/− cell lines
    explanation: ATAC-seq in edited RS4;11 pro-B leukemia cells shows a PU.1-dose-associated accessibility difference.
  - reference: PMID:33951726
    reference_title: Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: we employed assay for transposase-accessible chromatin using sequencing (ATAC-seq) to generate genome-wide chromatin accessibility maps of human RS4;11 pro–B cell lines either unedited (SPI1+/+) or CRISPR/Cas9 edited with monoallelic (SPI1+/−) or biallelic (SPI1−/−) SPI1 exon one indels that abolished PU.1 expression.
    explanation: ATAC-seq compared transformed RS4;11 pro-B cell lines with monoallelic or biallelic engineered disruption; these are not patient-cell chromatin maps.
  downstream:
  - target: Impaired B-Cell Development
    description: Chromatin restriction is proposed to constrain the transcriptional program needed for B-cell progression. Patient phenotype and edited HSPC experiments support the model without proving every intervening regulatory target.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33951726
      reference_title: Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: PU.1 OCRs were significantly more accessible in SPI1+/+ than SPI1+/− or SPI1−/− cell lines
      explanation: ATAC-seq in edited RS4;11 pro-B leukemia cells shows a PU.1-dose-associated accessibility difference.
    - reference: PMID:33951726
      reference_title: Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: Introducing disease-similar SPI1 mutations into human hematopoietic stem and progenitor cells impaired early in vitro B cell and myeloid cell differentiation.
      explanation: Edited cord-blood progenitors carry mixtures of near-variant indels, not precise patient-allele knock-ins; lineage selection supports but does not isolate the chromatin mediator.
- name: Decreased Dendritic Cell Abundance
  description: SPI1-related disease can reduce both conventional and plasmacytoid dendritic cells. B-cell and dendritic-cell sample denominators differ; the cohort did not show a consistent monocyte, T-cell or NK-cell reduction.
  biological_scale: CELLULAR
  evidence:
  - reference: url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    reference_title: https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: circulating plasmacytoid DC (pDC) concentrations were also signi ﬁcantly lower in patients than healthy donors (9.2 vs 3.4 cells per μL; P < .001), an immunophenotypic feature not previously appreciated.
    explanation: Flow cytometry supports reduced circulating pDCs in 16 patients compared with 17 controls.
- name: FNIP1 Protein Deficiency
  description: Biallelic FNIP1 variants can eliminate the protein and produce syndromic antibody deficiency. Cardiomyopathy and variable neutropenia co-occur, but their tissue mechanisms are not established by B-cell assays. Complete protein absence was measured in stimulated cultured patient T cells.
  biological_scale: MOLECULAR
  evidence:
  - reference: url:https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
    reference_title: https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
    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.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: url:https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
    reference_title: https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Immunoblotting demonstrated the complete absence of FNIP1 in all the patients (Figure 1D).
    explanation: Protein absence was assayed in stimulated cultured T cells from the three patients, not every affected tissue.
  genes:
  - preferred_term: FNIP1
    term:
      id: hgnc:29418
      label: FNIP1
  downstream:
  - target: Hypertrophic Cardiomyopathy
    description: HCM is a recurrent clinical component of the FNIP1 syndrome; the bridge is genetically associated and has unresolved cardiac intermediates.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
      reference_title: https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
      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.
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
  - target: Neutropenia
    description: Variable neutropenia occurs in the syndrome, without a universal intrinsic granulopoiesis defect demonstrated.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
      reference_title: https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: Two of them also presented with intermittent or severe chronic neutropenia.
      explanation: Two of the original three unrelated patients had neutropenia.
  - target: Impaired B-Cell Development
    description: Human deficiency is associated with impaired B-lineage output, without a discrete universal arrest or an experimentally isolated metabolic mediator.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
      reference_title: https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: B -cell precursors did not show evidence of a maturation block, unlike classical agammaglobulinemia14, although a relative increase of earlier maturation stages (pro-B and pre-B1) and a significant reduction of immature B-cells was observed (Figure 1E and supplemental Figure 8).
      explanation: One patient had altered precursor proportions without a discrete maturation block, limiting a universal pro-B arrest model.
  - target: Increased B-Cell Mitochondrial Abundance
    description: This measured cellular abnormality accompanies FNIP1 deficiency. Its intervening molecular mechanism and necessity for the human developmental phenotype remain unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
      reference_title: https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: Indeed, circulating P1 B-cells exhibited increased numbers of mitochondria and mitochondrial activity relative to healthy control (HC) B-cells (Figure 1F and supplemental Figure 9 ).
      explanation: Mitochondrial dye readouts were measured in rare circulating B cells from one patient compared with a healthy control; they do not establish a general ATP-production flux.
  - target: Increased B-Cell Mitochondrial Activity Signal
    description: This measured cellular abnormality accompanies FNIP1 deficiency. Its intervening molecular mechanism and necessity for the human developmental phenotype remain unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
      reference_title: https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: Indeed, circulating P1 B-cells exhibited increased numbers of mitochondria and mitochondrial activity relative to healthy control (HC) B-cells (Figure 1F and supplemental Figure 9 ).
      explanation: Mitochondrial dye readouts were measured in rare circulating B cells from one patient compared with a healthy control; they do not establish a general ATP-production flux.
  - target: Increased B-Cell AKT Phosphorylation
    description: This measured cellular abnormality accompanies FNIP1 deficiency. Its intervening molecular mechanism and necessity for the human developmental phenotype remain unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
      reference_title: https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: Specifically, p4EBP1 and pAkt473 were significantly activated ( 12.46±1.86 vs 4.00±0.53, p = 0.00 02; 3.82±1.78 vs 0.97±0. 09, p = 0.029). As opposite, no difference could be found in S6 phosphorylation (1.46±0.14 vs 2.70±0.51, p = 0.14).
      explanation: One patient marrow comparison showed increased p4EBP1 and pAKT473 but not pS6; small repeated assays do not expand the donor count.
  - target: Increased B-Cell 4EBP1 Phosphorylation
    description: This measured cellular abnormality accompanies FNIP1 deficiency. Its intervening molecular mechanism and necessity for the human developmental phenotype remain unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
      reference_title: https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: Specifically, p4EBP1 and pAkt473 were significantly activated ( 12.46±1.86 vs 4.00±0.53, p = 0.00 02; 3.82±1.78 vs 0.97±0. 09, p = 0.029). As opposite, no difference could be found in S6 phosphorylation (1.46±0.14 vs 2.70±0.51, p = 0.14).
      explanation: One patient marrow comparison showed increased p4EBP1 and pAKT473 but not pS6; small repeated assays do not expand the donor count.
- name: Truncated LRRC8A Protein
  description: One human balanced translocation generated a truncated LRRC8A protein alongside wild-type protein. The gene-disease relationship remains Limited. Dominant interference is a hypothesis supported by a forced-expression mouse experiment, not an established universal channel mechanism.
  biological_scale: MOLECULAR
  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 original authors interpreted their single human case and mutant-expression model as causal; current ClinGen validity remains Limited.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: url:https://thegencc.org/submissions/SGC-107391.2
    reference_title: LRRC8A | agammaglobulinemia | Autosomal dominant by ClinGen submission information facts
    supports: SUPPORT
    evidence_source: OTHER
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: Since other patients with B cell deficiency and heterozygous LRRC8A have not been identified, the curation is classified as Limited.
    explanation: ClinGen explains the Limited classification by the lack of additional human cases.
  genes:
  - preferred_term: LRRC8A
    term:
      id: hgnc:19027
      label: LRRC8A
  downstream:
  - target: Impaired B-Cell Development
    description: The single human association and experimental mutant expression support a provisional link; the relevant molecular intermediates and replication in additional families remain unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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 original authors interpreted their single human case and mutant-expression model as causal; current ClinGen validity remains Limited.
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
- name: Impaired TOP2B Activity
  description: Heterozygous TOPRIM-domain TOP2B variants cause Hoffman syndrome. Yeast growth and decatenation experiments support loss of activity with partial dominant interference. Human B-cell enzyme activity and marrow arrest stage were not directly measured.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:31409799
    reference_title: Mutations in topoisomerase IIβ result in a B cell immunodeficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
    snippet: In three families with Hoffman syndrome 9,10, we identi ﬁed three heterozygous mutations affecting the TOPRIM, or DNA gating, domain of the type II topoisomerase TOP2B.
    explanation: Identifies the heterozygous TOPRIM-domain TOP2B variants in three Hoffman syndrome families; the loss of enzyme activity itself is shown by the separate yeast assays below.
  - reference: PMID:31409799
    reference_title: Mutations in topoisomerase IIβ result in a B cell immunodeficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: fractions from the strain with only one copy of wild-type TOP2 decatenated kine- toplast DNA more effectively than fractions from strains with one wild-type and one mutant copy of TOP2 (Fig. 2d, Supplementary Fig. 4c).
    explanation: Yeast nuclear-fraction decatenation supports partial dominant interference for tested substitutions; this is not a direct patient B-cell enzyme assay.
  downstream:
  - target: Impaired B-Cell Development
    description: Mouse conditional and disease-allele models impair multiple B-cell stages. DNA topology, damage and transcriptional programs are candidate mediators rather than a single proven human pathway.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31409799
      reference_title: Mutations in topoisomerase IIβ result in a B cell immunodeficiency.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: Immunophenotyping demonstrated that the bone marrow of Top2b−/−mb1-cre mice have fewer PrePro B cells, Pre B, and immature B cells compared to control mice (Fig. 3K).
      explanation: B-cell-specific Top2b deletion reduces several marrow B-cell precursor stages; this is a knockout rather than the patient allele, so it supports the edge indirectly.
  genes:
  - preferred_term: TOP2B
    term:
      id: hgnc:11990
      label: TOP2B
- name: Impaired B-Cell Development
  description: Different autosomal defects reduce B-lineage progression at different stages. A pro-B-to-pre-B block fits several structural/adaptor disorders, but ZIP7, PIK3R1, FNIP1 and progressive SPI1 disease show distinct patterns. The umbrella does not imply a universal complete arrest.
  biological_scale: CELLULAR
  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: The cited source describes the B-cell and antibody-deficiency phenotype. No frequency band or universal complete absence is inferred.
    directness: DIRECT
    quote_role: BACKGROUND
  - 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: The original BLNK patient had a defined early B-lineage developmental block; this is not an estimate of all alleles or a receptor-assembly assay.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: url:https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
    reference_title: https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: B -cell precursors did not show evidence of a maturation block, unlike classical agammaglobulinemia14, although a relative increase of earlier maturation stages (pro-B and pre-B1) and a significant reduction of immature B-cells was observed (Figure 1E and supplemental Figure 8).
    explanation: One patient had altered precursor proportions without a discrete maturation block, limiting a universal pro-B arrest model.
  downstream:
  - target: Reduced Circulating B-Cell Output
    description: Impaired differentiation and survival reduce mature B-cell output, with residual cells and evolving depletion in some alleles.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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: The cited source describes the B-cell and antibody-deficiency phenotype. No frequency band or universal complete absence is inferred.
      directness: INDIRECT
      quote_role: BACKGROUND
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  locations:
  - preferred_term: bone marrow
    term:
      id: UBERON:0002371
      label: bone marrow
  biological_processes:
  - preferred_term: B cell differentiation
    term:
      id: GO:0030183
      label: B cell differentiation
    modifier: DECREASED
- name: Reduced Circulating B-Cell Output
  description: Circulating B cells are severely depleted in established agammaglobulinemia, but are not invariably absent. Plasma-cell absence cannot be assumed without tissue evidence.
  biological_scale: CELLULAR
  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: The cited source describes the B-cell and antibody-deficiency phenotype. No frequency band or universal complete absence is inferred.
    directness: DIRECT
    quote_role: BACKGROUND
  downstream:
  - target: Reduced Immunoglobulin Production
    description: Low B-lineage output limits antibody production, while residual immunoglobulins, maternally acquired IgG and replacement therapy modify measured concentrations.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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: The cited source describes the B-cell and antibody-deficiency phenotype. No frequency band or universal complete absence is inferred.
      directness: INDIRECT
      quote_role: BACKGROUND
  - target: Decreased Total B Cell Count
    description: Peripheral flow cytometry detects this cellular deficit.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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: The cited source describes the B-cell and antibody-deficiency phenotype. No frequency band or universal complete absence is inferred.
      directness: INDIRECT
      quote_role: BACKGROUND
- name: Reduced Immunoglobulin Production
  description: Severely reduced endogenous antibody production compromises humoral defense. The extent differs among isotypes, ages and alleles; replacement IgG does not reconstitute the developmental program.
  biological_scale: CELLULAR
  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: The cited source describes the B-cell and antibody-deficiency phenotype. No frequency band or universal complete absence is inferred.
    directness: DIRECT
    quote_role: BACKGROUND
  downstream:
  - target: Deficient Antibody-Mediated Host Defense
    description: Antibody deficiency reduces protective humoral responses and contributes to infection susceptibility.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
      reference_title: https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: recurrent bacterial sinopulmonary infections including otitis, sinusitis, and/or pneumonia, which were universally experienced by patients before initiation of IRT ( Table 1 ).
      explanation: The expanded SPI1 agammaglobulinemia cohort experienced respiratory infections before replacement; no umbrella frequency is inferred.
  - target: Agammaglobulinemia
    description: The laboratory phenotype reflects reduced endogenous antibody production, interpreted with age and treatment context.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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: The cited source describes the B-cell and antibody-deficiency phenotype. No frequency band or universal complete absence is inferred.
      directness: INDIRECT
      quote_role: BACKGROUND
  - target: Decreased Circulating IgG
    description: The laboratory phenotype reflects reduced endogenous antibody production, interpreted with age and treatment context.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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: The cited source describes the B-cell and antibody-deficiency phenotype. No frequency band or universal complete absence is inferred.
      directness: INDIRECT
      quote_role: BACKGROUND
  - target: Decreased Circulating IgA
    description: The laboratory phenotype reflects reduced endogenous antibody production, interpreted with age and treatment context.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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: The cited source describes the B-cell and antibody-deficiency phenotype. No frequency band or universal complete absence is inferred.
      directness: INDIRECT
      quote_role: BACKGROUND
  - target: Decreased Circulating IgM
    description: The laboratory phenotype reflects reduced endogenous antibody production, interpreted with age and treatment context.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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: The cited source describes the B-cell and antibody-deficiency phenotype. No frequency band or universal complete absence is inferred.
      directness: INDIRECT
      quote_role: BACKGROUND
  biological_processes:
  - preferred_term: immunoglobulin production
    term:
      id: GO:0002377
      label: immunoglobulin production
    modifier: DECREASED
- name: Deficient Antibody-Mediated Host Defense
  conforms_to: "germinal_center_reaction#Clinical Susceptibility to Infection"
  description: Loss of effective antibody defense contributes to recurrent bacterial and selected viral infections. Dendritic-cell depletion in SPI1 disease is not independently assigned as the cause of this entire infection spectrum.
  biological_scale: ORGANISM
  evidence:
  - reference: url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    reference_title: https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: recurrent bacterial sinopulmonary infections including otitis, sinusitis, and/or pneumonia, which were universally experienced by patients before initiation of IRT ( Table 1 ).
    explanation: The expanded SPI1 agammaglobulinemia cohort experienced respiratory infections before replacement; no umbrella frequency is inferred.
  - reference: url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    reference_title: https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Hematogenous spread of streptococcal, Haemophilus, and staphylococcal septicemia and osteomyelitis, arthritis, and meningitis were each reported.
    explanation: Invasive infection manifestations were observed in the SPI1 cohort.
  biological_processes:
  - preferred_term: humoral immune response
    term:
      id: GO:0006959
      label: humoral immune response
    modifier: DECREASED
  downstream:
  - target: Recurrent Infections
    description: The infection phenotype is associated with deficient antibody protection; organism and anatomical susceptibility depend on exposure and host context.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
      reference_title: https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: recurrent bacterial sinopulmonary infections including otitis, sinusitis, and/or pneumonia, which were universally experienced by patients before initiation of IRT ( Table 1 ).
      explanation: The expanded SPI1 agammaglobulinemia cohort experienced respiratory infections before replacement; no umbrella frequency is inferred.
  - target: Recurrent Otitis Media
    description: The infection phenotype is associated with deficient antibody protection; organism and anatomical susceptibility depend on exposure and host context.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
      reference_title: https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: recurrent bacterial sinopulmonary infections including otitis, sinusitis, and/or pneumonia, which were universally experienced by patients before initiation of IRT ( Table 1 ).
      explanation: The expanded SPI1 agammaglobulinemia cohort experienced respiratory infections before replacement; no umbrella frequency is inferred.
  - target: Recurrent Sinusitis
    description: The infection phenotype is associated with deficient antibody protection; organism and anatomical susceptibility depend on exposure and host context.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
      reference_title: https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: recurrent bacterial sinopulmonary infections including otitis, sinusitis, and/or pneumonia, which were universally experienced by patients before initiation of IRT ( Table 1 ).
      explanation: The expanded SPI1 agammaglobulinemia cohort experienced respiratory infections before replacement; no umbrella frequency is inferred.
  - target: Recurrent Pneumonia
    description: The infection phenotype is associated with deficient antibody protection; organism and anatomical susceptibility depend on exposure and host context.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
      reference_title: https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: recurrent bacterial sinopulmonary infections including otitis, sinusitis, and/or pneumonia, which were universally experienced by patients before initiation of IRT ( Table 1 ).
      explanation: The expanded SPI1 agammaglobulinemia cohort experienced respiratory infections before replacement; no umbrella frequency is inferred.
  - target: Sepsis
    description: Invasive or skin infection is a documented complication of the antibody-deficiency phenotype.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
      reference_title: https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: Hematogenous spread of streptococcal, Haemophilus, and staphylococcal septicemia and osteomyelitis, arthritis, and meningitis were each reported.
      explanation: Invasive infection manifestations were observed in the SPI1 cohort.
  - target: Meningitis
    description: Invasive or skin infection is a documented complication of the antibody-deficiency phenotype.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
      reference_title: https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: Hematogenous spread of streptococcal, Haemophilus, and staphylococcal septicemia and osteomyelitis, arthritis, and meningitis were each reported.
      explanation: Invasive infection manifestations were observed in the SPI1 cohort.
  - target: Septic Arthritis
    description: Invasive or skin infection is a documented complication of the antibody-deficiency phenotype.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
      reference_title: https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: Hematogenous spread of streptococcal, Haemophilus, and staphylococcal septicemia and osteomyelitis, arthritis, and meningitis were each reported.
      explanation: Invasive infection manifestations were observed in the SPI1 cohort.
  - target: Cellulitis
    description: Invasive or skin infection is a documented complication of the antibody-deficiency phenotype.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
      reference_title: https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: Staphylococcal skin infec- tions and periorbital cellulitis also occurred.
      explanation: Skin and periorbital cellulitis occurred in the selected SPI1 cohort.
  - target: Infection-Associated Airway Injury
    description: Recurrent lower respiratory infections can contribute to chronic airway injury; timing, treatment and other host factors modify progression.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
      reference_title: https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: Radiographic evidence of bronchiectasis from recurrent respiratory infections was com- mon.
      explanation: Bronchiectasis was observed in a selected SPI1 cohort in association with recurrent respiratory infections.
  - target: Unusual Enteroviral Infection
    description: Deficient antibody protection can contribute to severe or prolonged enteroviral disease, with exposure and host factors modifying the outcome.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
      reference_title: https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: Viral infections, most notably enteroviruses, affected multiple patients.
      explanation: Human antibody-deficiency cohort supports the infection association; virus-specific exposure and intervening antiviral mechanisms are not resolved.
- name: Infection-Associated Airway Injury
  description: Repeated respiratory infections can accompany chronic bronchial injury and bronchiectasis. The selected SPI1 cohort documents their association, without proving every episode or a uniform rate of structural progression.
  biological_scale: TISSUE
  evidence:
  - reference: url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    reference_title: https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Radiographic evidence of bronchiectasis from recurrent respiratory infections was com- mon.
    explanation: Bronchiectasis was observed in a selected SPI1 cohort in association with recurrent respiratory infections.
  downstream:
  - target: Bronchiectasis
    description: Chronic airway injury contributes to bronchial dilatation, with variable clinical course.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
      reference_title: https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: Radiographic evidence of bronchiectasis from recurrent respiratory infections was com- mon.
      explanation: Bronchiectasis was observed in a selected SPI1 cohort in association with recurrent respiratory infections.
  locations:
  - preferred_term: bronchus
    term:
      id: UBERON:0002185
      label: bronchus
- name: Biallelic SLC39A7 Variants
  biological_scale: MOLECULAR
  description: Biallelic hypomorphic or truncating SLC39A7 variants define this genetic subtype. The reported viable patients should not be described as proven complete ZIP7 knockouts.
  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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Six individuals from 5 kindreds of white European, South Asian or Hispanic ancestry, were found to harbor compound heterozygous (4 families) or homozygous (1 family) rare variants in SLC39A7
    explanation: Six affected people from five kindreds carry biallelic variants.
  role: trigger
  downstream:
  - target: Reduced ZIP7 Zinc Transport
    description: Tested human alleles impair transporter function.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30718914
      reference_title: An essential role for the Zn(2+) transporter ZIP7 in B cell development.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: In keeping with hypomorphic behavior, the Zn2+ signal generated by either mutant ZIP7 was significantly reduced compared with WT (Fig. 2h), despite similar amounts of protein expression
      explanation: The P190A and E363K transport assays show reduced reporter signal at comparable protein expression.
  - target: Abnormal Skin Blistering
    description: Severe ZIP7 disease is associated with this clinical feature; organ-specific intermediates are unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: (P1 and P2, family 1) additionally showed severe blistering dermatosis (Fig. 1b), failure to thrive and thrombocytopenia, prompting hematopoietic stem cell transplantation; this resulted in cure of immunologic abnormalities and amelioration of skin disease.
      explanation: Two siblings among six ZIP7-deficient patients had severe skin disease, poor growth and thrombocytopenia; transplantation outcomes are specific to them.
  - target: Thrombocytopenia
    description: Severe ZIP7 disease is associated with this clinical feature; organ-specific intermediates are unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: (P1 and P2, family 1) additionally showed severe blistering dermatosis (Fig. 1b), failure to thrive and thrombocytopenia, prompting hematopoietic stem cell transplantation; this resulted in cure of immunologic abnormalities and amelioration of skin disease.
      explanation: Two siblings among six ZIP7-deficient patients had severe skin disease, poor growth and thrombocytopenia; transplantation outcomes are specific to them.
  - target: Failure to Thrive
    description: Severe ZIP7 disease is associated with this clinical feature; organ-specific intermediates are unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: (P1 and P2, family 1) additionally showed severe blistering dermatosis (Fig. 1b), failure to thrive and thrombocytopenia, prompting hematopoietic stem cell transplantation; this resulted in cure of immunologic abnormalities and amelioration of skin disease.
      explanation: Two siblings among six ZIP7-deficient patients had severe skin disease, poor growth and thrombocytopenia; transplantation outcomes are specific to them.
  genes:
  - preferred_term: SLC39A7
    term:
      id: hgnc:4927
      label: SLC39A7
- name: Reduced ZIP7 Zinc Transport
  biological_scale: MOLECULAR
  description: Reduced zinc transport was measured for human P190A and E363K. Residual expression and ER localization distinguish transport impairment from universal protein absence.
  evidence:
  - reference: PMID:30718914
    reference_title: An essential role for the Zn(2+) transporter ZIP7 in B cell development.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: In keeping with hypomorphic behavior, the Zn2+ signal generated by either mutant ZIP7 was significantly reduced compared with WT (Fig. 2h), despite similar amounts of protein expression
    explanation: The P190A and E363K transport assays show reduced reporter signal at comparable protein expression.
  downstream:
  - target: Reduced B-Cell Cytosolic Free Zinc
    description: Reduced transport is associated with deficient cytosolic zinc in the mouse cellular model; compartmental buffering and compensation were not fully resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:30718914
      reference_title: An essential role for the Zn(2+) transporter ZIP7 in B cell development.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: Cytoplasmic Zn2+ concentrations were indeed lower in mutant compared to WT cells, whereas ER Zn2+ amounts were equivalent
      explanation: FRET-FLIM in IL7-expanded mutant mouse marrow B-cell cultures measures lower free cytosolic zinc with unchanged free ER zinc.
- name: Reduced B-Cell Cytosolic Free Zinc
  biological_scale: CELLULAR
  description: Mutant mouse B-cell cultures have lower free cytosolic zinc. This is not evidence of systemic zinc deficiency, excess free ER zinc or a measured local zinc pulse.
  evidence:
  - reference: PMID:30718914
    reference_title: An essential role for the Zn(2+) transporter ZIP7 in B cell development.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Cytoplasmic Zn2+ concentrations were indeed lower in mutant compared to WT cells, whereas ER Zn2+ amounts were equivalent
    explanation: FRET-FLIM in IL7-expanded mutant mouse marrow B-cell cultures measures lower free cytosolic zinc with unchanged free ER zinc.
  downstream:
  - target: Increased B-Cell Phosphatase Activity
    description: Loss of zinc-mediated phosphatase inhibition is a proposed partial mediator. No selective zinc restoration experiment proves necessity.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:30718914
      reference_title: An essential role for the Zn(2+) transporter ZIP7 in B cell development.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: Our data suggest that ZIP7 hypofunction likewise impedes signalling by the nascent BCR during positive selection, and that this may be in part due to defective Zn2+-dependent inhibition of phosphatase activity.
      explanation: The authors propose partial zinc/phosphatase mediation; PTEN haploinsufficiency did not rescue development.
- name: Increased B-Cell Phosphatase Activity
  biological_scale: CELLULAR
  description: Developing mutant B cells show increased constitutive activity on a broad phosphatase substrate. Specific PTEN hyperactivity is not isolated by this assay.
  evidence:
  - reference: PMID:30718914
    reference_title: An essential role for the Zn(2+) transporter ZIP7 in B cell development.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Constitutive phosphatase activity was indeed higher in ZIP7P198A/P198A compared to WT pre-B and immature B cells, as measured by flow cytometry using a cell-permeable alkaline phosphatase substrate
    explanation: The broad live phosphatase-substrate assay does not isolate PTEN activity.
  downstream:
  - target: Reduced B-Cell Receptor Signaling
    description: Elevated phosphatase activity may contribute to reduced signaling, but multiple pathways remain involved and the PTEN-only rescue experiment was negative.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:30718914
      reference_title: An essential role for the Zn(2+) transporter ZIP7 in B cell development.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: Our data suggest that ZIP7 hypofunction likewise impedes signalling by the nascent BCR during positive selection, and that this may be in part due to defective Zn2+-dependent inhibition of phosphatase activity.
      explanation: The authors propose partial zinc/phosphatase mediation; PTEN haploinsufficiency did not rescue development.
- name: Reduced B-Cell Receptor Signaling
  biological_scale: CELLULAR
  description: Antigen-stimulated immature mutant B cells have reduced phosphorylation of SYK, PLCγ2 and ERK despite equivalent surface receptor expression. These are parallel signaling readouts rather than demonstrated intrinsic kinase defects.
  evidence:
  - reference: PMID:30718914
    reference_title: An essential role for the Zn(2+) transporter ZIP7 in B cell development.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: immature ZIP7P198A/P198A SWHel B cells showed impaired antigen-induced signalling as judged by reduced amounts of multiple phosphorylated intermediates, including SYK, PLCγ2 and ERK
    explanation: Ex-vivo antigen stimulation demonstrates reduced phosphorylation despite comparable surface BCR.
  downstream:
  - target: Impaired ZIP7-Dependent B-Cell Maturation
    description: Deficient nascent-BCR signaling is proposed to impair positive selection. This is not a fully isolated necessary sequence.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:30718914
      reference_title: An essential role for the Zn(2+) transporter ZIP7 in B cell development.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: Our data suggest that ZIP7 hypofunction likewise impedes signalling by the nascent BCR during positive selection, and that this may be in part due to defective Zn2+-dependent inhibition of phosphatase activity.
      explanation: The authors propose partial zinc/phosphatase mediation; PTEN haploinsufficiency did not rescue development.
- name: Impaired ZIP7-Dependent B-Cell Maturation
  biological_scale: CELLULAR
  description: ZIP7 hypofunction blocks B-cell development, most clearly at late pre-B to immature transition in mixed marrow chimeras; an earlier contribution cannot be excluded.
  evidence:
  - reference: PMID:30718914
    reference_title: An essential role for the Zn(2+) transporter ZIP7 in B cell development.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Eight weeks after BM transfer, our analysis confirmed a B cell intrinsic block in development, which was most evident in a failure to progress from the late pre-B (FrD) to immature B (FrE) cell stage, with no residual mutant cells in the recirculating FrF population
    explanation: Mixed marrow chimeras show cell-intrinsic developmental failure strongest at late-pre-B to immature transition.
  role: central_effector
  downstream:
  - target: Reduced Circulating B-Cell Output
    description: Mouse late-pre-B/immature maturation failure and human B-cell depletion support reduced output, without imposing one stage on all autosomal forms.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:30718914
      reference_title: An essential role for the Zn(2+) transporter ZIP7 in B cell development.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: Eight weeks after BM transfer, our analysis confirmed a B cell intrinsic block in development, which was most evident in a failure to progress from the late pre-B (FrD) to immature B (FrE) cell stage, with no residual mutant cells in the recirculating FrF population
      explanation: Mixed marrow chimeras show cell-intrinsic developmental failure strongest at late-pre-B to immature transition.
- name: Increased B-Cell Mitochondrial Abundance
  description: Mitochondrial abundance was increased in rare circulating B cells from one FNIP1-deficient patient. This is not a measure in marrow progenitors or cardiac tissue.
  biological_scale: CELLULAR
  evidence:
  - reference: url:https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
    reference_title: https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Indeed, circulating P1 B-cells exhibited increased numbers of mitochondria and mitochondrial activity relative to healthy control (HC) B-cells (Figure 1F and supplemental Figure 9 ).
    explanation: Mitochondrial dye readouts were measured in rare circulating B cells from one patient compared with a healthy control; they do not establish a general ATP-production flux.
- name: Increased B-Cell Mitochondrial Activity Signal
  description: A mitochondrial activity-associated dye readout was increased in circulating B cells from one FNIP1-deficient patient. It is distinct from mitochondrial abundance and does not establish increased ATP synthesis or respiratory flux.
  biological_scale: CELLULAR
  evidence:
  - reference: url:https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
    reference_title: https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Indeed, circulating P1 B-cells exhibited increased numbers of mitochondria and mitochondrial activity relative to healthy control (HC) B-cells (Figure 1F and supplemental Figure 9 ).
    explanation: Mitochondrial dye readouts were measured in rare circulating B cells from one patient compared with a healthy control; they do not establish a general ATP-production flux.
- name: Increased B-Cell AKT Phosphorylation
  description: Marrow B-cell progenitors from one FNIP1-deficient patient had increased AKT Ser473 phosphorylation relative to a healthy control. This is an observed signaling state, not a direct assay of a unique kinase mechanism.
  biological_scale: CELLULAR
  evidence:
  - reference: url:https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
    reference_title: https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Specifically, p4EBP1 and pAkt473 were significantly activated ( 12.46±1.86 vs 4.00±0.53, p = 0.00 02; 3.82±1.78 vs 0.97±0. 09, p = 0.029). As opposite, no difference could be found in S6 phosphorylation (1.46±0.14 vs 2.70±0.51, p = 0.14).
    explanation: One patient marrow comparison showed increased p4EBP1 and pAKT473 but not pS6; small repeated assays do not expand the donor count.
- name: Increased B-Cell 4EBP1 Phosphorylation
  description: Marrow B-cell progenitors from one FNIP1-deficient patient had increased 4EBP1 phosphorylation; pS6 was not significantly altered. BEZ235 lowered the 4EBP1 readout without demonstrating restored B-cell development or clinical benefit.
  biological_scale: CELLULAR
  evidence:
  - reference: url:https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
    reference_title: https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Specifically, p4EBP1 and pAkt473 were significantly activated ( 12.46±1.86 vs 4.00±0.53, p = 0.00 02; 3.82±1.78 vs 0.97±0. 09, p = 0.029). As opposite, no difference could be found in S6 phosphorylation (1.46±0.14 vs 2.70±0.51, p = 0.14).
    explanation: One patient marrow comparison showed increased p4EBP1 and pAKT473 but not pS6; small repeated assays do not expand the donor count.
phenotypes:
- name: Agammaglobulinemia
  category: Immunologic
  description: Markedly impaired endogenous antibody production defines the severe phenotype. Some isotypes remain measurable, especially in evolving or hypomorphic disease.
  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: The cited source describes the B-cell and antibody-deficiency phenotype. No frequency band or universal complete absence is inferred.
    directness: DIRECT
    quote_role: BACKGROUND
- name: Decreased Total B Cell Count
  category: Immunologic
  description: Severely reduced circulating B cells, assessed by age-aware absolute counts and proportions. Residual cells and progressive loss occur; this finding alone does not distinguish every genetic or acquired cause.
  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: The cited source describes the B-cell and antibody-deficiency phenotype. No frequency band or universal complete absence is inferred.
    directness: DIRECT
    quote_role: BACKGROUND
  - 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).
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- name: Decreased Circulating IgG
  category: Immunologic
  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: The cited source describes the B-cell and antibody-deficiency phenotype. No frequency band or universal complete absence is inferred.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- name: Decreased Circulating IgA
  category: Immunologic
  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.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- name: Decreased Circulating IgM
  category: Immunologic
  description: IgM is often severely reduced but may remain measurable; its concentration is interpreted with the other isotypes, cell counts and molecular diagnosis.
  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.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- name: Recurrent Infections
  category: Immunologic
  description: Recurrent bacterial infections occur across multiple autosomal forms, with variable age at onset.
  phenotype_term:
    preferred_term: Recurrent bacterial infections
    term:
      id: HP:0002718
      label: Recurrent bacterial infections
  evidence:
  - reference: url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    reference_title: https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: recurrent bacterial sinopulmonary infections including otitis, sinusitis, and/or pneumonia, which were universally experienced by patients before initiation of IRT ( Table 1 ).
    explanation: The expanded SPI1 agammaglobulinemia cohort experienced respiratory infections before replacement; no umbrella frequency is inferred.
- name: Recurrent Otitis Media
  category: Otolaryngologic
  description: Recurrent middle-ear infection is documented in the SPI1 cohort and other antibody-deficiency forms.
  phenotype_term:
    preferred_term: Recurrent otitis media
    term:
      id: HP:0000403
      label: Recurrent otitis media
  evidence:
  - reference: url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    reference_title: https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: recurrent bacterial sinopulmonary infections including otitis, sinusitis, and/or pneumonia, which were universally experienced by patients before initiation of IRT ( Table 1 ).
    explanation: The expanded SPI1 agammaglobulinemia cohort experienced respiratory infections before replacement; no umbrella frequency is inferred.
- name: Recurrent Sinusitis
  category: Otolaryngologic
  description: Recurrent sinus infection is part of the documented sinopulmonary infection spectrum.
  phenotype_term:
    preferred_term: Recurrent sinusitis
    term:
      id: HP:0011108
      label: Recurrent sinusitis
  evidence:
  - reference: url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    reference_title: https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: recurrent bacterial sinopulmonary infections including otitis, sinusitis, and/or pneumonia, which were universally experienced by patients before initiation of IRT ( Table 1 ).
    explanation: The expanded SPI1 agammaglobulinemia cohort experienced respiratory infections before replacement; no umbrella frequency is inferred.
- name: Recurrent Pneumonia
  category: Respiratory
  description: Recurrent pneumonia can contribute to chronic pulmonary morbidity; not every patient develops bronchiectasis.
  phenotype_term:
    preferred_term: Recurrent pneumonia
    term:
      id: HP:0006532
      label: Recurrent pneumonia
  evidence:
  - reference: url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    reference_title: https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: recurrent bacterial sinopulmonary infections including otitis, sinusitis, and/or pneumonia, which were universally experienced by patients before initiation of IRT ( Table 1 ).
    explanation: The expanded SPI1 agammaglobulinemia cohort experienced respiratory infections before replacement; no umbrella frequency is inferred.
- name: Bronchiectasis
  category: Respiratory
  description: Chronic bronchial dilatation is a potential respiratory complication. Its frequency and course vary with genotype, infection burden and treatment.
  phenotype_term:
    preferred_term: Bronchiectasis
    term:
      id: HP:0002110
      label: Bronchiectasis
    clinical_course: PROGRESSIVE
  evidence:
  - reference: url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    reference_title: https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Radiographic evidence of bronchiectasis from recurrent respiratory infections was com- mon.
    explanation: Bronchiectasis was observed in a selected SPI1 cohort in association with recurrent respiratory infections.
- name: Sepsis
  category: Immunologic
  description: Invasive bacterial infection is documented in autosomal antibody deficiency.
  phenotype_term:
    preferred_term: Sepsis
    term:
      id: HP:0100806
      label: Sepsis
  evidence:
  - reference: url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    reference_title: https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Hematogenous spread of streptococcal, Haemophilus, and staphylococcal septicemia and osteomyelitis, arthritis, and meningitis were each reported.
    explanation: Invasive infection manifestations were observed in the SPI1 cohort.
- name: Meningitis
  category: Neurologic
  description: Bacterial meningitis is documented; enteroviral disease is a separate important complication of severe antibody deficiency.
  phenotype_term:
    preferred_term: Meningitis
    term:
      id: HP:0001287
      label: Meningitis
  evidence:
  - reference: url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    reference_title: https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Hematogenous spread of streptococcal, Haemophilus, and staphylococcal septicemia and osteomyelitis, arthritis, and meningitis were each reported.
    explanation: Invasive infection manifestations were observed in the SPI1 cohort.
- name: Septic Arthritis
  category: Musculoskeletal
  description: Invasive bacterial joint infection is documented in affected patients.
  phenotype_term:
    preferred_term: Septic arthritis
    term:
      id: HP:0003095
      label: Septic arthritis
  evidence:
  - reference: url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    reference_title: https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Hematogenous spread of streptococcal, Haemophilus, and staphylococcal septicemia and osteomyelitis, arthritis, and meningitis were each reported.
    explanation: Invasive infection manifestations were observed in the SPI1 cohort.
- name: Cellulitis
  category: Dermatologic
  description: Skin and periorbital bacterial cellulitis occur in the selected SPI1 cohort.
  phenotype_term:
    preferred_term: Cellulitis
    term:
      id: HP:0100658
      label: Cellulitis
  evidence:
  - reference: url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    reference_title: https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Staphylococcal skin infec- tions and periorbital cellulitis also occurred.
    explanation: Direct autosomal clinical observation.
- name: Chronic Diarrhea
  category: Gastrointestinal
  description: Chronic diarrhea was reported in a genotyped FNIP1-deficient girl; enteric infection and inflammatory bowel disease require clinical differentiation.
  phenotype_term:
    preferred_term: Chronic diarrhea
    term:
      id: HP:0002028
      label: Chronic diarrhea
    temporality: CHRONIC
  evidence:
  - reference: PMID:39537849
    reference_title: A novel mutation in FNIP1 associated with a syndromic immunodeficiency and cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: hypertrophic cardiomyopathy, recurrent infections, and chronic diarrhea during infancy. Immune workup revealed agammaglobulinemia and a lack of B lymphocytes.
    explanation: One additional genotyped FNIP1 case had chronic diarrhea during infancy; no general frequency is inferred.
  subtype: FNIP1
- name: Conjunctivitis
  category: Ophthalmologic
  description: Conjunctivitis is described in shared agammaglobulinemia clinical guidance, extrapolated here from XLA rather than quantified in an autosomal cohort.
  phenotype_term:
    preferred_term: Conjunctivitis
    term:
      id: HP:0000509
      label: Conjunctivitis
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1453/
    reference_title: X-Linked Agammaglobulinemia - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: Conjunctivitis, sinopulmonary infections, diarrhea, and skin infections are also frequently seen.
    explanation: Shared XLA clinical synthesis is extrapolated to this related antibody-deficiency spectrum.
- name: Absent tonsils
  category: Immunologic
  description: Absent tonsils can be a clinical clue in severe antibody deficiency. Small tonsils or absent cervical nodes are related observations and do not establish absence of all lymphoid tissue; the cited general examination guidance is from XLA.
  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: In context the physical-examination clue refers to X-linked agammaglobulinemia; it is applied to the autosomal forms by extrapolation from the shared early B-cell defect.
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
- name: Neutropenia
  category: Hematologic
  description: Variable neutropenia occurs in FNIP1 and selected other forms. It can be transient during infection; the original PIK3R1 patient improved after immunoglobulin therapy despite persistent protein deficiency.
  phenotype_term:
    preferred_term: Decreased total neutrophil count
    term:
      id: HP:0001875
      label: Decreased total neutrophil count
  evidence:
  - reference: url:https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
    reference_title: https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
    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).
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- name: Hypertrophic Cardiomyopathy
  category: Cardiovascular
  subtype: FNIP1
  description: HCM occurred in the original three FNIP1-deficient patients and an additional reported case. It is a syndromic, gene-specific feature; B-cell metabolic assays do not establish its cardiac mechanism.
  phenotype_term:
    preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  evidence:
  - reference: url:https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
    reference_title: https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: We here investigated three novel patients, including the first known adult, from unrelated families with agammaglobulinemia, recurrent infections, and hypertrophic cardiomyopathy (HCM).
    explanation: All three original unrelated FNIP1 patients had HCM; no umbrella frequency is inferred.
  - reference: PMID:39537849
    reference_title: A novel mutation in FNIP1 associated with a syndromic immunodeficiency and cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: hypertrophic cardiomyopathy, recurrent infections, and chronic diarrhea during infancy. Immune workup revealed agammaglobulinemia and a lack of B lymphocytes.
    explanation: An additional genotyped FNIP1 girl had cardiomyopathy; her deceased brother was not genetically confirmed.
- name: Failure to Thrive
  category: Growth
  subtype: AGM9
  description: Poor growth was reported in severe ZIP7-deficient siblings and can accompany other forms. It is not a mandatory feature or an established direct effect of one shared pathway.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  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
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: (P1 and P2, family 1) additionally showed severe blistering dermatosis (Fig. 1b), failure to thrive and thrombocytopenia, prompting hematopoietic stem cell transplantation; this resulted in cure of immunologic abnormalities and amelioration of skin disease.
    explanation: Two siblings among six ZIP7-deficient patients had severe skin disease, poor growth and thrombocytopenia; transplantation outcomes are specific to them.
- name: Osteomyelitis
  category: Musculoskeletal
  description: Hematogenous bone infection was reported in the SPI1 cohort.
  phenotype_term:
    preferred_term: Osteomyelitis
    term:
      id: HP:0002754
      label: Osteomyelitis
  evidence:
  - reference: url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    reference_title: https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Hematogenous spread of streptococcal, Haemophilus, and staphylococcal septicemia and osteomyelitis, arthritis, and meningitis were each reported.
    explanation: Invasive infection manifestations were observed in the SPI1 cohort.
  subtype: AGM10
- name: Colitis
  category: Gastrointestinal
  description: Colitis was documented in the original PIK3R1 patient. Inflammatory gastrointestinal disease also occurs in SPI1 and FNIP1 disease; the broader category includes conditions beyond colitis.
  phenotype_term:
    preferred_term: Inflammation of the large intestine
    term:
      id: HP:0002037
      label: Inflammation of the large intestine
  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
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: A homozygous premature stop codon in exon 6 of PIK3R1 was identified in a young woman with colitis and absent B cells.
    explanation: One original patient links the recessive PIK3R1 defect with colitis and B-cell deficiency.
  subtype: AGM7
- name: Inflammatory Arthritis
  category: Musculoskeletal
  description: Juvenile idiopathic arthritis occurred in two SPI1 patients and can be difficult to treat. This is distinct from septic arthritis.
  phenotype_term:
    preferred_term: Arthritis
    term:
      id: HP:0001369
      label: Arthritis
  evidence:
  - reference: url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    reference_title: https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: juvenile idiopathic arthritis (n = 2); type 1 diabetes mellitus (n = 2); and single cases of immune thrombocytopenia, psoriasis, hidrade- nitis suppurativa, and autoimmune lipodystrophy.
    explanation: These are gene-specific observations in 22 selected SPI1 agammaglobulinemia patients, without disease-wide frequency inference.
  subtype: AGM10
- name: Autoimmune Thrombocytopenia
  category: Hematologic
  description: One SPI1 cohort patient had immune-mediated thrombocytopenia; other causes of low platelets require separate evaluation.
  phenotype_term:
    preferred_term: Autoimmune thrombocytopenia
    term:
      id: HP:0001973
      label: Autoimmune thrombocytopenia
  evidence:
  - reference: url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    reference_title: https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: juvenile idiopathic arthritis (n = 2); type 1 diabetes mellitus (n = 2); and single cases of immune thrombocytopenia, psoriasis, hidrade- nitis suppurativa, and autoimmune lipodystrophy.
    explanation: These are gene-specific observations in 22 selected SPI1 agammaglobulinemia patients, without disease-wide frequency inference.
  subtype: AGM10
- name: Type I Diabetes Mellitus
  category: Endocrine
  description: Two SPI1 cohort patients had type 1 diabetes. The observation does not establish a shared pancreatic immune mechanism.
  phenotype_term:
    preferred_term: Type I diabetes mellitus
    term:
      id: HP:0100651
      label: Type I diabetes mellitus
  evidence:
  - reference: url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    reference_title: https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: juvenile idiopathic arthritis (n = 2); type 1 diabetes mellitus (n = 2); and single cases of immune thrombocytopenia, psoriasis, hidrade- nitis suppurativa, and autoimmune lipodystrophy.
    explanation: These are gene-specific observations in 22 selected SPI1 agammaglobulinemia patients, without disease-wide frequency inference.
  subtype: AGM10
- name: Neurodevelopmental Delay
  category: Neurodevelopmental
  description: Developmental delay was described in one original FNIP1 patient. The source does not establish a uniform cognitive phenotype or a direct metabolic mechanism in the brain.
  phenotype_term:
    preferred_term: Neurodevelopmental delay
    term:
      id: HP:0012758
      label: Neurodevelopmental delay
  evidence:
  - reference: url:https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
    reference_title: https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: neurologica l examination showed developmental delay associated with MRI abnormalities (supplemental Figure 3).
    explanation: One patient observation; no global-domain assessment is inferred.
  subtype: FNIP1
- name: Abnormal Skin Blistering
  category: Dermatologic
  subtype: AGM9
  description: Severe blistering dermatosis was observed in the two most severely affected ZIP7 siblings. Skin disease improved after transplantation, without a demonstrated direct B-cell-to-skin causal pathway.
  phenotype_term:
    preferred_term: Abnormal blistering of the skin
    term:
      id: HP:0008066
      label: Abnormal blistering of the skin
  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
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: (P1 and P2, family 1) additionally showed severe blistering dermatosis (Fig. 1b), failure to thrive and thrombocytopenia, prompting hematopoietic stem cell transplantation; this resulted in cure of immunologic abnormalities and amelioration of skin disease.
    explanation: Two siblings among six ZIP7-deficient patients had severe skin disease, poor growth and thrombocytopenia; transplantation outcomes are specific to them.
- name: Thrombocytopenia
  category: Hematologic
  subtype: AGM9
  description: Thrombocytopenia accompanied severe ZIP7 disease in two siblings; it is distinct from the immune thrombocytopenia reported in one SPI1 patient.
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
  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
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: (P1 and P2, family 1) additionally showed severe blistering dermatosis (Fig. 1b), failure to thrive and thrombocytopenia, prompting hematopoietic stem cell transplantation; this resulted in cure of immunologic abnormalities and amelioration of skin disease.
    explanation: Two siblings among six ZIP7-deficient patients had severe skin disease, poor growth and thrombocytopenia; transplantation outcomes are specific to them.
- name: B Acute Lymphoblastic Leukemia
  category: Hematologic
  subtype: AGM8B
  description: B-ALL has been reported in recessive TCF3 deficiency. This complication should not be assigned to every TCF3 mechanism or every autosomal agammaglobulinemia subtype.
  phenotype_term:
    preferred_term: B Acute Lymphoblastic Leukemia
    term:
      id: HP:0004812
      label: B Acute Lymphoblastic Leukemia
  evidence:
  - reference: PMID:39073655
    reference_title: Exclusive Characteristics of the p.E555K Dominant-Negative Variant in Autosomal Dominant E47 Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: Complete AR TCF3 deficiency is associated with reduced B cells, hypogammaglobulinemia, dysmorphic phenotypes, and B-cell acute lymphoblastic leukemia (B-ALL)
    explanation: The 2024 article synthesizes the recessive phenotype; the original short report was not available as a substantive cached body.
- name: Unusual Enteroviral Infection
  category: Immunologic
  description: Enteroviral infections can be severe or prolonged in autosomal antibody deficiency. The expanded SPI1 cohort includes prolonged echoviremia and one case of vaccine-associated paralytic poliomyelitis; these selected observations are not a population frequency.
  phenotype_term:
    preferred_term: Unusual enterovirus infection
    term:
      id: HP:5210314
      label: Unusual enterovirus infection
  evidence:
  - reference: url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    reference_title: https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Viral infections, most notably enteroviruses, affected multiple patients.
    explanation: Direct SPI1 cohort observation; prolonged echoviremia and vaccine-associated poliomyelitis illustrate severity without defining an umbrella frequency.
  - reference: url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    reference_title: https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Patient A.II.2 experienced reactive arthritis during a prolonged period of echoviremia.
    explanation: Prolonged enteroviral infection in one SPI1 patient supports the unusual-infection scope, without assuming recurrent episodes in every patient.
- name: Abnormal Facial Shape
  category: Craniofacial
  subtype: TOP2B
  description: Facial dysmorphism is described in the TOP2B-associated Hoffman syndrome phenotype. It is not a universal feature of autosomal agammaglobulinemia.
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:34241796
    reference_title: 'Agammaglobulinemia: from X-linked to Autosomal Forms of Disease.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: Autosomal dominant mutations in TOP2B, a gene coding for a type II topoisomerase, has been reported in patients with recurrent infections with encapsulated organisms, absent B cells, and agammaglobulinemia, in addition to facial dysmorphism and limb abnormalities
    explanation: Review summarizes TOP2B-associated syndromic findings; this broad term preserves the unspecific facial description and is limited to the TOP2B subtype.
biochemical:
- name: Serum IgG
  presence: Decreased
  context: Interpret serum IgG against age-specific laboratory intervals, maternal IgG in infancy, infection status and immunoglobulin replacement. Residual or previously normal IgG occurs in later-onset and hypomorphic disease; no single unsupported threshold is imposed here.
  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.
    directness: DIRECT
    quote_role: BACKGROUND
- name: Serum IgA
  presence: Decreased
  context: Often very low or undetectable, but residual and age-dependent values occur. Serum concentration does not directly measure mucosal secretory IgA.
  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.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- name: Serum IgM
  presence: Decreased
  context: Often severely reduced or undetectable; residual IgM does not exclude a hypomorphic or evolving autosomal form.
  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.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- name: Peripheral blood CD19+ B cell percentage
  presence: Decreased
  context: Quantify absolute B-cell counts and percentage together with age-aware T/NK subsets. Profound depletion supports the phenotype but is not unique to autosomal agammaglobulinemia; counts may decline over time. Marrow precursor percentages cannot be substituted for peripheral-blood thresholds.
  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
  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.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- name: Circulating dendritic-cell counts in SPI1 disease
  presence: Decreased
  context: The expanded SPI1 cohort found reduced conventional and plasmacytoid dendritic-cell counts in 16 patients compared with 17 controls; no consistent monocyte/T/NK reduction was found. This is not an umbrella diagnostic threshold.
  evidence:
  - reference: url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    reference_title: https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: circulating plasmacytoid DC (pDC) concentrations were also signi ﬁcantly lower in patients than healthy donors (9.2 vs 3.4 cells per μL; P < .001), an immunophenotypic feature not previously appreciated.
    explanation: Gene-specific flow-cytometric observation.
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: Biallelic IGHM defects impair the membrane immunoglobulin mu heavy chain. Some early cohorts found more severe disease than XLA; that comparison should not be generalized to all autosomal genes.
  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.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - 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.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- name: IGLL1
  gene_term:
    preferred_term: IGLL1
    term:
      id: hgnc:5870
      label: IGLL1
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: AGM2
  notes: Deficiency of lambda5/14.1, the surrogate light chain component that pairs with the mu heavy chain to form 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.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- name: CD79A
  gene_term:
    preferred_term: CD79A
    term:
      id: hgnc:1698
      label: CD79A
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: AGM3
  notes: Biallelic CD79A deficiency affects Ig-alpha. The original splice-defect case showed profound early B-cell developmental arrest; this observation is not a universal assay of every allele.
  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.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- name: CD79B
  gene_term:
    preferred_term: CD79B
    term:
      id: hgnc:1699
      label: CD79B
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: AGM6
  notes: Biallelic CD79B deficiency affects Ig-beta. The original Q80-stop allele prevented surface receptor assembly in a heterologous mature-BCR reconstitution assay. Other alleles may be hypomorphic; the assay is not a direct measurement of every patient pre-BCR.
  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.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- name: BLNK
  gene_term:
    preferred_term: BLNK
    term:
      id: hgnc:14211
      label: BLNK
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: AGM4
  notes: Biallelic BLNK deficiency affects a cytoplasmic signaling adaptor rather than a structural receptor subunit. The original patient had pro-B cells but no detected pre-B or mature B cells; subsequent phenotypes vary.
  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: The original BLNK patient had a defined early B-lineage developmental block; this is not an estimate of all alleles or a receptor-assembly assay.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- name: LRRC8A
  gene_term:
    preferred_term: LRRC8A
    term:
      id: hgnc:19027
      label: LRRC8A
  association: Limited gene-disease evidence
  variant_origin: GERMLINE
  subtype: AGM5
  notes: Historical numbered subtype associated with a heterozygous truncating LRRC8A allele from a balanced t(9;20) in one girl. ClinGen currently classifies the LRRC8A-agammaglobulinemia relationship as Limited. Dominant interference is proposed; neither a specific channel defect nor its mediation of the human immune phenotype was demonstrated.
  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 original authors interpreted their single human case and mutant-expression model as causal; current ClinGen validity remains Limited.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: url:https://thegencc.org/submissions/SGC-107391.2
    reference_title: LRRC8A | agammaglobulinemia | Autosomal dominant by ClinGen submission information facts
    supports: SUPPORT
    evidence_source: OTHER
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: Since other patients with B cell deficiency and heterozygous LRRC8A have not been identified, the curation is classified as Limited.
    explanation: ClinGen explains the Limited classification by the lack of additional human cases.
- name: PIK3R1
  gene_term:
    preferred_term: PIK3R1
    term:
      id: hgnc:8979
      label: PIK3R1
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: AGM7
  notes: Biallelic loss of PIK3R1 p85-alpha is distinct from activating PI3K-pathway immunodeficiencies. The original woman had a profound early B-lineage defect, colitis and transient early neutropenia, with preserved measured T-cell function.
  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
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: A homozygous premature stop codon in exon 6 of PIK3R1 was identified in a young woman with colitis and absent B cells.
    explanation: One original patient links the recessive PIK3R1 defect with colitis and B-cell deficiency.
  - reference: PMID:22351933
    reference_title: Agammaglobulinemia and absent B lineage cells in a patient lacking the p85α subunit of PI3K.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The mutation results in the absence of p85α but normal expression of the p50α and p55α regulatory subunits of PI3K.
    explanation: Patient-cell protein assays distinguish loss of p85-alpha from preserved shorter regulatory isoforms; the assay was not performed in the missing B cells.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- name: TCF3
  gene_term:
    preferred_term: TCF3
    term:
      id: hgnc:11633
      label: TCF3
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: AGM8
  notes: Dominant-negative E47 variants, recessive loss of both isoforms, and heterozygous haploinsufficiency have different phenotypes. The numbered AGM8 and AGM8B subtypes should not be collapsed into one mechanism.
  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.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - 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.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: PMID:39073655
    reference_title: Exclusive Characteristics of the p.E555K Dominant-Negative Variant in Autosomal Dominant E47 Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: Complete AR TCF3 deficiency is associated with reduced B cells, hypogammaglobulinemia, dysmorphic phenotypes, and B-cell acute lymphoblastic leukemia (B-ALL)
    explanation: The 2024 article synthesizes the recessive phenotype; the original short report was not available as a substantive cached body.
- name: SLC39A7
  gene_term:
    preferred_term: SLC39A7
    term:
      id: hgnc:4927
      label: SLC39A7
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: AGM9
  notes: Hypomorphic SLC39A7 variants impair the zinc transporter ZIP7. Human and mouse evidence supports a B-cell developmental defect involving zinc homeostasis and signaling; the strongest mouse block is late-pre-B to immature B cell. Severe patients can also have skin disease and failure to thrive.
  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.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - 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.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- name: SPI1
  gene_term:
    preferred_term: SPI1
    term:
      id: hgnc:11241
      label: SPI1
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: AGM10
  notes: Heterozygous SPI1 loss reduces PU.1 activity. B-cell and dendritic-cell deficiency can present in infancy or adulthood, and relatives can have mild or no antibody abnormalities. Chromatin-accessibility mechanisms were tested in edited pro-B cell lines rather than directly in every patient lineage.
  evidence:
  - reference: PMID:33951726
    reference_title: Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    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: The original SPI1 cohort establishes the human genetic association; later families show inherited variants and milder phenotypes.
  - reference: PMID:33951726
    reference_title: Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Patient SPI1 mutations encoded destabilized PU.1 proteins unable to nuclear localize or bind target DNA.
    explanation: Functional assays identify allele-dependent protein instability, localization or DNA-binding defects; no single defect applies to every variant.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    reference_title: https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Of the 11 relatives harboring heterozygous LOF PU.1 variants, 6 were clinically well with laboratory evaluations documenting serum antibody and circulating B-cell concentrations within age- adjusted normal ranges.
    explanation: Variant-carrying relatives with normal antibody and B-cell values support the statement that relatives can have no antibody abnormality.
  - reference: url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    reference_title: https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: In a cluster of patients, disease onset was delayed, sometimes into adulthood.
    explanation: The expanded SPI1 cohort documents diagnosis and symptom onset extending beyond infancy into adulthood.
- name: FNIP1
  gene_term:
    preferred_term: FNIP1
    term:
      id: hgnc:29418
      label: FNIP1
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: FNIP1
  notes: Biallelic FNIP1 deficiency is a syndromic B-cell immunodeficiency with hypertrophic cardiomyopathy and variable neutropenia. Patient-cell metabolic and phosphosignaling abnormalities provide mechanistic clues, but do not establish the causal route to cardiomyopathy or a uniform developmental arrest.
  evidence:
  - reference: url:https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
    reference_title: https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
    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.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- name: TOP2B
  gene_term:
    preferred_term: TOP2B
    term:
      id: hgnc:11990
      label: TOP2B
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: TOP2B
  notes: Dominant TOP2B-related B-cell immunodeficiency with variable distal-limb, facial and urogenital anomalies. This syndromic overlap is included in the IUIS agammaglobulinemia category; it is not AGM10, which denotes SPI1 disease.
  evidence:
  - reference: PMID:31409799
    reference_title: Mutations in topoisomerase IIβ result in a B cell immunodeficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: In three families with Hoffman syndrome 9,10, we identi ﬁed three heterozygous mutations affecting the TOPRIM, or DNA gating, domain of the type II topoisomerase TOP2B.
    explanation: Three families establish the reported human syndrome; mechanistic assays use separate yeast and mouse systems.
- name: PIK3CD
  gene_term:
    preferred_term: PIK3CD
    term:
      id: hgnc:8977
      label: PIK3CD
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: PIK3CD
  notes: Biallelic loss of the p110-delta catalytic subunit can cause severe antibody deficiency with reduced B cells. This is distinct from dominant activating PIK3CD variants causing activated PI3K-delta syndrome. The historical numbered AGM series does not exhaust the modern disease spectrum.
  evidence:
  - reference: PMID:34241796
    reference_title: 'Agammaglobulinemia: from X-linked to Autosomal Forms of Disease.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: There are an additional 6 cases of homozygous PIK3CD gene mutation resulting in LOF of PIK3 delta enzyme complex. These patients also displayed hypogammaglobulinemia or agammaglobulinemia as well as decreased B cells [34].
    explanation: The review summarizes recessive p110-delta loss with B-cell and antibody deficiency; activating PIK3CD disease is a distinct mechanism.
differential_diagnoses:
- name: X-linked agammaglobulinemia (BTK)
  description: BTK-related XLA shares severe B-cell and antibody deficiency and is usually male, but rare heterozygous females are affected. Sex, consanguinity and age alone do not distinguish it from all autosomal forms; molecular testing determines the cause.
  disease_term:
    preferred_term: Bruton-type agammaglobulinemia
    term:
      id: MONDO:0010421
      label: Bruton-type agammaglobulinemia
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1453/
    reference_title: X-Linked Agammaglobulinemia - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: Females with a heterozygous pathogenic variant in <i>BTK</i> extremely rarely have clinical and laboratory findings of XLA.
    explanation: The chapter explicitly recognizes rare affected females, correcting an absolute male-only boundary.
- name: Common variable immunodeficiency
  description: CVID generally retains B cells with impaired antibody function, but some autosomal transcription-factor disorders can begin with a CVID-like phenotype and later lose B cells. This is a molecular and longitudinal distinction, not a single universal count threshold.
  disease_term:
    preferred_term: common variable immunodeficiency
    term:
      id: MONDO:0015517
      label: common variable immunodeficiency
  evidence:
  - reference: PMID:39073655
    reference_title: Exclusive Characteristics of the p.E555K Dominant-Negative Variant in Autosomal Dominant E47 Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: TCF3 haploinsufficiency (HI) also impacts both TCF3 isoforms, resulting in common variable immunodeficiency (CVID) with low B cells and hypogammaglobulinemia
    explanation: TCF3 allele mechanism can yield an overlapping phenotype.
- name: Severe combined immunodeficiency
  description: Major T-cell deficiency or dysfunction suggests combined immunodeficiency rather than an isolated antibody defect. Some syndromic autosomal forms have additional immune abnormalities, so comprehensive phenotyping and molecular diagnosis remain necessary.
  disease_term:
    preferred_term: severe combined immunodeficiency
    term:
      id: MONDO:0015974
      label: severe combined immunodeficiency
  evidence:
  - reference: PMID:37273190
    reference_title: Inborn errors of human B cell development, differentiation, and function.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: variants in RAG1 or RAG2 cause severe combined immunodeficiency (SCID) because recombination of TCR chains during thymic development is also compromised.
    explanation: RAG-related T- and B-cell developmental failure distinguishes an important combined-immunodeficiency mechanism.
- name: Transient hypogammaglobulinemia of infancy
  description: Transient hypogammaglobulinemia of infancy typically retains B cells and is confirmed by subsequent recovery. Severe infections or profound B-cell depletion require evaluation for persistent genetic disease rather than assuming a transient state.
  disease_term:
    preferred_term: transient hypogammaglobulinemia of infancy
    term:
      id: MONDO:0015698
      label: transient hypogammaglobulinemia of infancy
- name: Good syndrome (thymoma with immunodeficiency)
  description: Adult-onset antibody and B-cell deficiency associated with thymoma is an acquired syndromic differential. Adult onset alone does not exclude inherited SPI1 disease.
  disease_term:
    preferred_term: Good syndrome
    term:
      id: MONDO:0015696
      label: Good syndrome
- name: Secondary hypogammaglobulinemia after B-cell-depleting therapy
  description: Prior B-cell-depleting therapy can cause prolonged secondary antibody deficiency. Drug exposure, pre-treatment immune history and longitudinal recovery help distinguish it from inherited disease. The cited Greek cohort is broader PAD, not an autosomal agammaglobulinemia prevalence study.
  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.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- name: POU2AF1 (BOB1) deficiency
  description: BOB1 deficiency can cause agammaglobulinemia despite preserved peripheral B-cell numbers, reflecting a later functional differentiation defect rather than the B-cell-poor pattern emphasized here.
  disease_term:
    preferred_term: agammaglobulinemia, autosomal recessive, due to BOB1 deficiency
    term:
      id: MONDO:0800146
      label: agammaglobulinemia, autosomal recessive, due to BOB1 deficiency
  evidence:
  - reference: PMID:37273190
    reference_title: Inborn errors of human B cell development, differentiation, and function.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: Despite normal numbers of peripheral B cells, the OBF-1–deficient patient presented with recurrent respiratory infection, agammaglobulinemia, and an absence of class switched memory B cells (Kury et al., 2021).
    explanation: A review summarizes the reported BOB1 patient; the original brief report had no substantive retrievable cached text.
- name: Hyper-IgM syndrome
  description: Class-switch defects usually preserve B-cell numbers and IgM relative to IgG/IgA. Residual IgM alone does not exclude evolving autosomal agammaglobulinemia; use the full immunophenotype and genotype.
  disease_term:
    preferred_term: hyper-IgM syndrome
    term:
      id: MONDO:0003947
      label: hyper-IgM syndrome
treatments:
- name: Immunoglobulin Replacement Therapy
  description: IVIG or SCIG is standard supportive treatment for clinically significant antibody deficiency. Dose and interval are individualized to infections, trough concentrations and lung disease. It supplies passive IgG without restoring the underlying B-cell program; infections and noninfectious complications may persist. The route schedule is extrapolated from XLA guidance, with direct autosomal cohort evidence of continuing replacement dependence.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: Immunoglobulin Therapy
    term:
      id: NCIT:C62710
      label: Immunoglobulin Therapy
  target_mechanisms:
  - target: Reduced Immunoglobulin Production
    treatment_effect: BYPASSES
    description: Passive antibody supplies an effector product without correcting endogenous production or B-cell development.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1453/
      reference_title: X-Linked Agammaglobulinemia - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      quote_role: REVIEW_SYNTHESIS
      snippet: The mainstay of treatment is gammaglobulin substitution therapy (by weekly subcutaneous injection or intravenous infusion every two to four weeks) to prevent bacterial infections.
      explanation: GeneReviews expert guidance is for XLA; shared antibody-replacement principles are extrapolated to autosomal disease.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1453/
    reference_title: X-Linked Agammaglobulinemia - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: The mainstay of treatment is gammaglobulin substitution therapy (by weekly subcutaneous injection or intravenous infusion every two to four weeks) to prevent bacterial infections.
    explanation: GeneReviews expert guidance is for XLA; shared antibody-replacement principles are extrapolated to autosomal disease.
  - reference: url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    reference_title: https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: All patients with PU.MA were IRT dependent
    explanation: All 22 affected patients in the expanded SPI1 cohort used replacement.
- name: Antibiotic Therapy and Prophylaxis
  description: Treat suspected or proven bacterial infection promptly. Selected patients with recurrent infections despite replacement may receive specialist-directed prophylaxis; it is not mandatory for every genotype or patient.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Antibiotic Therapy
    term:
      id: NCIT:C15620
      label: Antibiotic Therapy
  target_mechanisms:
  - target: Recurrent Infections
    treatment_effect: INHIBITS
    description: Antimicrobial treatment addresses infection and selected prophylaxis reduces recurrence.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1453/
      reference_title: X-Linked Agammaglobulinemia - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      quote_role: REVIEW_SYNTHESIS
      snippet: Generous use of antibiotics can decrease the incidence of chronic sinusitis and lung disease. Prophylactic antibiotics can be considered to prevent infections.
      explanation: XLA management synthesis supports prompt treatment and selected prophylaxis; autosomal treatment is individualized.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1453/
    reference_title: X-Linked Agammaglobulinemia - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: Generous use of antibiotics can decrease the incidence of chronic sinusitis and lung disease. Prophylactic antibiotics can be considered to prevent infections.
    explanation: XLA management synthesis supports prompt treatment and selected prophylaxis; autosomal treatment is individualized.
- name: Avoidance of Live Attenuated Vaccines (Agents to Avoid)
  description: Avoid live viral vaccines, especially oral polio vaccine, in severe antibody deficiency under immunology guidance. Inactivated polio vaccine is used for affected people and family contacts. The SPI1 cohort directly documents vaccine-associated paralytic poliomyelitis; this does not quantify all vaccines or all genotypes.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Preventive Intervention
    term:
      id: NCIT:C15843
      label: Preventive Intervention
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1453/
    reference_title: X-Linked Agammaglobulinemia - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: Live viral vaccines, particularly oral polio vaccine.
    explanation: GeneReviews lists these among agents to avoid in XLA; severe autosomal antibody deficiency shares the relevant concern.
  - reference: url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    reference_title: https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: One (D.II.1) of 5 patients receiving live-attenuated oral polio vaccine developed iatrogenic paralytic poliomyelitis.
    explanation: Direct SPI1 cohort evidence of a live oral polio vaccine complication; the small exposed denominator is not a general vaccine-risk estimate.
- name: Clinical and Respiratory Surveillance
  description: Monitor infections, blood counts and immunoglobulins; assess chronic lung or sinus disease when clinically indicated. Follow genotype-specific skin, cardiac, gastrointestinal and inflammatory complications. Surveillance detects complications; it does not itself inhibit the molecular defect.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1453/
    reference_title: X-Linked Agammaglobulinemia - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    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: XLA surveillance schedule provides a clinical framework, adapted for genotype, age, complications and treatment.
- name: Allogeneic Hematopoietic Cell Transplantation
  description: Consider HSCT only through individualized specialist assessment of the genetic disorder, morbidity, donor genotype and transplant risk. Two severely affected ZIP7 siblings had correction of immunologic abnormalities and improvement of skin disease. In SPI1 disease, one recipient remained replacement-dependent five years after full trilineage donor engraftment; another failed engraftment after receiving cells from an unknowingly variant-carrying sister. These contrasting small series do not establish a uniform curative strategy.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: Hematopoietic Cell Transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  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
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: (P1 and P2, family 1) additionally showed severe blistering dermatosis (Fig. 1b), failure to thrive and thrombocytopenia, prompting hematopoietic stem cell transplantation; this resulted in cure of immunologic abnormalities and amelioration of skin disease.
    explanation: Two siblings among six ZIP7-deficient patients had severe skin disease, poor growth and thrombocytopenia; transplantation outcomes are specific to them.
  - reference: url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    reference_title: https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Five years after transplantation, he remains IRT dependent because of undetectable serum immunoglobulin (IgA) and IgM despite naïve B-cell reconstitution and >99% donor peripheral blood engraftment in B-cell, T-cell, and myeloid cell compart- ments.
    explanation: Long-term SPI1 follow-up documents persistent antibody-production failure despite donor engraftment.
  - reference: url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    reference_title: https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: The second patient (L.II.1) who received HSCT received stem cells from her healthy sister (L.II.2) at the age of 16 but failed to engraft. 18 Unbeknown at the time of HSCT, the donor harbored the same PU.1 variant as the recipient.
    explanation: The second SPI1 attempt failed; donor variant status was recognized retrospectively.
- name: Genetic Counseling and Family Testing
  description: Explain gene- and allele-specific inheritance, test at-risk relatives after a molecular diagnosis, and reassess initially mild SPI1 carriers over time. A clinically healthy related donor can carry the familial variant; donor assessment should include this possibility.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    reference_title: https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
    snippet: PU.1 variant carriers now counted as unaffected could later develop antibody de ﬁciency or frank agammaglobulinemia.
    explanation: The authors caution that apparently unaffected carriers may develop disease later, which supports reassessing initially mild or unaffected carriers over time.
  - reference: url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    reference_title: https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
    snippet: Unbeknown at the time of HSCT, the donor harbored the same PU.1 variant as the recipient.
    explanation: Retrospective donor genotyping illustrates the relevance of variable expressivity to family and donor assessment.
- name: Individualized Management of Inflammatory Complications
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  description: Treat inflammatory complications according to the affected organ and infection risk. In the SPI1 cohort, mesalamine, mycophenolate and adalimumab were reported for bowel inflammation, whereas multiple agents had limited success in one refractory arthritis case. These are uncontrolled treatment experiences, not comparative efficacy evidence or a disease-wide regimen.
  evidence:
  - reference: url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    reference_title: https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Immune modulating treatments successfully used for inﬂammatory bowel disorder included mesalamine, mycophenolate, and tumor necrosis factor inhibition (adalimumab). A series of therapies (methotrexate, hydroxychloroquine, etanercept, tocilizumab, abatacept, and canakinumab) were trialed with limited success in 1 patient with recalcitrant juvenile idiopathic arthritis (S.II.1).
    explanation: Retrospective case-level treatment experience; no controlled efficacy estimate.
diagnosis:
- name: Quantitative serum immunoglobulins
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  description: Measure IgG, IgA and IgM with age-specific laboratory interpretation. Maternal IgG, replacement therapy and residual or evolving antibody production affect results.
  markers: Serum IgG, IgA and IgM
  results: Severely reduced endogenous antibody concentrations support the phenotype, with variable residual values.
  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.
    directness: DIRECT
    quote_role: BACKGROUND
- name: Lymphocyte subset flow cytometry
  diagnosis_term:
    preferred_term: flow cytometry
    term:
      id: NCIT:C16585
      label: Flow Cytometry
  description: Assess absolute and proportional B cells plus T/NK subsets; add lineage-specific studies when indicated. Normal T cells are common but not universal. Repeat testing may reveal progressive B-cell depletion.
  markers: CD19+ B cell percentage; CD3/CD4/CD8 T cell counts
  results: Profoundly low B cells, with genotype-dependent accompanying abnormalities.
  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: The cited source describes the B-cell and antibody-deficiency phenotype. No frequency band or universal complete absence is inferred.
    directness: DIRECT
    quote_role: BACKGROUND
  - reference: url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    reference_title: https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: The delayed and progressive B-cell loss seen in some patients with PU.MA
    explanation: Delayed and progressive B-cell loss in some SPI1 patients supports repeat lymphocyte-subset testing when initial B-cell counts are not diagnostic.
- name: Molecular genetic testing (IEI panel or exome sequencing)
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: Use phenotype-informed gene testing, multigene panels or exome/genome approaches as appropriate. Evaluate inheritance, copy-number/splice variants and functional evidence; a VUS or a historical gene label alone does not establish causality.
  results: Pathogenic or likely pathogenic variants consistent with the clinical phenotype and inheritance; both inherited and de novo dominant disease occur.
  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.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - 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.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- name: KREC-based newborn screening
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  description: KREC testing can detect deficient B-cell output before symptoms in some screening settings. It is a screening adjunct requiring immunophenotypic and molecular confirmation; later-onset forms may not be recognized at birth.
  markers: KREC copy number (with TREC as the T-cell comparator)
  results: Low KRECs suggest impaired new B-cell output, without identifying a specific gene.
  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.
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
  notes: Residual vaccine titers can persist in evolving SPI1 disease and do not exclude it. Serology is also affected by maternal or replacement antibodies. Do not use live-vaccine challenge to investigate severe antibody deficiency.
- name: Respiratory complication assessment
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  description: Assess chest and sinus disease using imaging when indicated, and obtain baseline pulmonary function testing when the patient can cooperate. This evaluates complications rather than establishing the molecular diagnosis. The XLA GeneReviews framework is extrapolated to autosomal antibody deficiency and individualized to age and clinical course.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1453/
    reference_title: X-Linked Agammaglobulinemia - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    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: XLA guidance supports chest and sinus imaging for suspected chronic disease; application to autosomal antibody deficiency is extrapolated.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1453/
    reference_title: X-Linked Agammaglobulinemia - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: Baseline chest &#x00026; sinus radiographs ... Baseline pulmonary function tests ... If able to cooperate w/testing
    explanation: XLA guidance recommends pulmonary function testing in those able to cooperate; its application here is extrapolated.
progression:
- phase: Variable onset and evolving B-cell deficiency
  age_range: Infancy through adulthood
  evidence:
  - reference: url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    reference_title: https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: The 7 remaining late diagnoses developed infectious symptoms later in life, sometimes well into adulthood (range, aged 4-33 years).
    explanation: Seven late-diagnosed SPI1 patients developed infectious symptoms later in life; this is a selected gene-specific cohort.
  notes: Many structural pre-BCR defects present early. SPI1 and some TCF3 cases can retain B cells or antibody responses for years before progressing. Diagnostic delay and genuinely later biological onset are distinct.
- phase: Long-term treated disease
  evidence:
  - reference: url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    reference_title: https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: All patients with PU.MA were IRT dependent
    explanation: All 22 agammaglobulinemic patients in this expanded SPI1 cohort required replacement; this is not a trial estimate of all autosomal forms.
  notes: Immunoglobulin replacement often improves infection control, while bronchiectasis, inflammatory complications and gene-specific syndromic findings can persist. The long-term course cannot be summarized as uniformly more severe than XLA.
clinical_burden:
  burden_level: HIGH
  rationale: Severe infection risk, repeated immunoglobulin infusions and ongoing monitoring impose substantial burden. Chronic lung disease and selected inflammatory or syndromic complications add morbidity. Age at onset, severity and transplant suitability differ by genotype; the umbrella is not uniformly more severe than XLA.
notes: This entry covers the autosomal B-cell-poor agammaglobulinemia spectrum, including historical numbered subtypes, recessive PIK3CD deficiency and selected syndromic overlaps. The numbering is not an exhaustive modern gene list. Related PAX5, IKZF3 and other antibody deficiencies require phenotype- and allele-specific assessment. GeneReviews X-linked agammaglobulinemia guidance is explicitly extrapolated where used for shared antibody-deficiency care. The genuine full papers PMID32905580, PMID40294836 and PMID39854693 are cited through generated author/repository URL caches because canonical PMID retrieval did not recover their full bodies. The 2026 correction to PMID39854693 restores missing supplemental tables; the main article was reviewed, but those separate supplementary objects were not independently examined. No population phenotype frequencies are inferred from small gene-specific families or selected clinical cohorts.
experimental_models:
- name: IGLL1 folding and secretion in COS cells
  experimental_model_type: CELL_LINE
  cell_source: COS cells expressing wild-type or patient P142L-containing lambda5 with VpreB
  publication: PMID:9419212
  description: Heterologous expression compares mutant folding and secretion. The mutant retains VpreB association but is not normally secreted; the patient also carried a separate premature-stop allele with no detected transcript.
  modeled_mechanisms:
  - target: Defective Lambda5 Surrogate Light Chain
    relationship: MEASURES
    description: Mutant lambda5 has abnormal folding and secretion.
    limitations: COS expression is not a patient marrow receptor-assembly assay; protein degradation is inferred.
    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: IN_VITRO
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: the allele carrying the pseudogene sequence resulted in defective folding and secretion of mutant lambda5/14.1.
      explanation: COS-cell expression showed defective folding/secretion of the P142L-containing allele; this is not a direct patient pre-BCR surface assay.
    readouts:
    - name: Secreted lambda5
      target: Defective Lambda5 Surrogate Light Chain
      direction: DECREASED
      interpretation: Mutant lambda5 has abnormal folding and secretion.
      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: IN_VITRO
        directness: DIRECT
        quote_role: PRIMARY_RESULT
        snippet: the allele carrying the pseudogene sequence resulted in defective folding and secretion of mutant lambda5/14.1.
        explanation: COS-cell expression showed defective folding/secretion of the P142L-containing allele; this is not a direct patient pre-BCR surface assay.
- name: CD79B mature-BCR reconstitution in S2 cells
  experimental_model_type: CELL_LINE
  cell_source: Cultured Drosophila S2 Schneider cells with mixed mouse and human BCR components
  publication: PMID:17709424
  description: Reconstitution uses a mature BCR containing mu heavy chain, conventional light chain, Ig-alpha and wild-type or mutant Ig-beta. The Q80-stop allele prevents surface complex assembly. These cultured cells are not an in-vivo fly immune model.
  modeled_mechanisms:
  - target: Impaired Pre-B-Cell Receptor Assembly
    relationship: MEASURES
    description: The tested Ig-beta mutation prevents mature BCR surface assembly, supporting a receptor-component defect.
    limitations: Mature BCR rather than pre-BCR, heterologous species mixture, and one tested allele; extension to the human pre-B checkpoint is indirect.
    evidence:
    - reference: PMID:17709424
      reference_title: Mutations of the Igbeta gene cause agammaglobulinemia in man.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      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: Mixed-species mature-BCR reconstitution in cultured S2 cells establishes an assembly defect for the tested Q80-stop allele; extension to human pre-BCR development is indirect.
    readouts:
    - name: Surface BCR expression
      target: Impaired Pre-B-Cell Receptor Assembly
      direction: DECREASED
      interpretation: The tested Ig-beta mutation prevents mature BCR surface assembly, supporting a receptor-component defect.
      evidence:
      - reference: PMID:17709424
        reference_title: Mutations of the Igbeta gene cause agammaglobulinemia in man.
        supports: SUPPORT
        evidence_source: IN_VITRO
        directness: INDIRECT
        quote_role: PRIMARY_RESULT
        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: Mixed-species mature-BCR reconstitution in cultured S2 cells establishes an assembly defect for the tested Q80-stop allele; extension to human pre-BCR development is indirect.
- name: TCF3 E47 binding and reporter assays
  experimental_model_type: CELL_LINE
  cell_source: Patient EBV-transformed lines and transfected HEK293 cells
  publication: PMID:24216514
  description: Nuclear extracts and reporter coexpression compare E555K with wild-type E47. The mutant impairs tested E-box binding and interferes with wild-type activity, while localization and the tested MyoD heterodimer interaction are preserved.
  modeled_mechanisms:
  - target: Defective TCF3 Transcription-Factor Activity
    relationship: MEASURES
    description: E555K fails the tested homodimer DNA-binding assay while supporting MyoD heterodimer binding.
    limitations: Transformed-cell and overexpression assays; not loss of every partner interaction or a complete explanation of all TCF3 allele classes.
    evidence:
    - reference: PMID:24216514
      reference_title: A recurrent dominant negative E47 mutation causes agammaglobulinemia and BCR(-) B cells.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: Although E555K E47 did not bind to the μE5 or creatinine kinase probes as a homodimer, it did allow MyoD to bind to the creatinine kinase probe (Figure 3D).
      explanation: E555K disrupts measured homodimer DNA binding while preserving the tested MyoD heterodimer interaction; it is not loss of all E-protein partnerships.
    readouts:
    - name: E47 homodimer DNA binding
      target: Defective TCF3 Transcription-Factor Activity
      direction: DECREASED
      interpretation: E555K fails the tested homodimer DNA-binding assay while supporting MyoD heterodimer binding.
      evidence:
      - reference: PMID:24216514
        reference_title: A recurrent dominant negative E47 mutation causes agammaglobulinemia and BCR(-) B cells.
        supports: SUPPORT
        evidence_source: IN_VITRO
        directness: DIRECT
        quote_role: PRIMARY_RESULT
        snippet: Although E555K E47 did not bind to the μE5 or creatinine kinase probes as a homodimer, it did allow MyoD to bind to the creatinine kinase probe (Figure 3D).
        explanation: E555K disrupts measured homodimer DNA binding while preserving the tested MyoD heterodimer interaction; it is not loss of all E-protein partnerships.
- name: SPI1 dosage-edited RS4;11 pro-B cells
  experimental_model_type: CELL_LINE
  cell_source: Human RS4;11 pro-B leukemia cell lines with monoallelic or biallelic CRISPR SPI1 disruption
  publication: PMID:33951726
  description: ATAC-seq and transcriptomics compare engineered PU.1 dosage states with unedited cells. This model supplies chromatin evidence; the patient marrow transcriptomic comparison is a separate experiment involving one affected child and one control.
  modeled_mechanisms:
  - target: Restricted B-Lineage Chromatin Accessibility
    relationship: MEASURES
    description: Reduced PU.1 dosage accompanies lower accessibility at PU.1-associated regulatory regions.
    limitations: Transformed cells with engineered indels are not exact patient alleles. Accessibility and expression changes do not isolate every necessary mediator of differentiation.
    evidence:
    - reference: PMID:33951726
      reference_title: Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: PU.1 OCRs were significantly more accessible in SPI1+/+ than SPI1+/− or SPI1−/− cell lines
      explanation: ATAC-seq in edited RS4;11 pro-B leukemia cells shows a PU.1-dose-associated accessibility difference.
    readouts:
    - name: PU.1-associated chromatin accessibility
      target: Restricted B-Lineage Chromatin Accessibility
      direction: DECREASED
      interpretation: Reduced PU.1 dosage accompanies lower accessibility at PU.1-associated regulatory regions.
      evidence:
      - reference: PMID:33951726
        reference_title: Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients.
        supports: SUPPORT
        evidence_source: IN_VITRO
        directness: DIRECT
        quote_role: PRIMARY_RESULT
        snippet: PU.1 OCRs were significantly more accessible in SPI1+/+ than SPI1+/− or SPI1−/− cell lines
        explanation: ATAC-seq in edited RS4;11 pro-B leukemia cells shows a PU.1-dose-associated accessibility difference.
- name: Expanded PU.1 variant reporter panel
  experimental_model_type: CELL_LINE
  cell_source: HEK-based expression, localization and PU.1-responsive reporter systems
  publication: url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
  description: The 2025 study tested 134 rare or novel PU.1 variants, rather than 134 patients. Instability, localization and transcriptional impairment differ by allele; some low monoclonal-antibody signals reflected epitope changes. Coexpression did not show dominant interference for tested loss-of-function variants.
  modeled_mechanisms:
  - target: Reduced PU.1 Dosage or Activity
    relationship: MEASURES
    description: Tested loss-of-function alleles reduce effective PU.1 activity without demonstrated dominant-negative action.
    limitations: An empirically calibrated reporter threshold and a low gnomAD-tail value alone do not establish clinical pathogenicity. The clinical cohort contains 22 agammaglobulinemic patients plus 11 relatives.
    evidence:
    - reference: url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
      reference_title: https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: Regardless of location, all tested LOF variants conveyed effects via haploinsuf ﬁciency.
      explanation: HEK-based expression/reporters and coexpression assays support haploinsufficiency for the tested loss-of-function variants, with assay-calibrated pathogenicity limits.
    readouts:
    - name: PU.1 reporter activity
      target: Reduced PU.1 Dosage or Activity
      direction: DECREASED
      interpretation: Tested loss-of-function alleles reduce effective PU.1 activity without demonstrated dominant-negative action.
      evidence:
      - reference: url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
        reference_title: https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
        supports: SUPPORT
        evidence_source: IN_VITRO
        directness: DIRECT
        quote_role: PRIMARY_RESULT
        snippet: Regardless of location, all tested LOF variants conveyed effects via haploinsuf ﬁciency.
        explanation: HEK-based expression/reporters and coexpression assays support haploinsufficiency for the tested loss-of-function variants, with assay-calibrated pathogenicity limits.
- name: FNIP1 patient-cell metabolic assays
  experimental_model_type: PRIMARY_CELL_CULTURE
  cell_source: Stimulated T cells from three patients; rare peripheral B cells and marrow B-cell progenitors from patient 1, with healthy-control comparisons
  publication: url:https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
  description: Separate assays measured protein absence in cultured T cells, increased mitochondrial abundance/activity signals in rare circulating B cells, and altered phosphorylation in marrow progenitors. The metabolic experiments center on patient 1; repeated assays do not expand the donor count. No serial mitochondrial-to-phosphosignaling mechanism or developmental rescue was demonstrated.
  modeled_mechanisms:
  - target: Increased B-Cell Mitochondrial Abundance
    relationship: MEASURES
    description: Mitochondrial abundance was increased in rare circulating B cells from one FNIP1-deficient patient. This is not a measure in marrow progenitors or cardiac tissue.
    limitations: Small patient/control comparisons in distinct cell populations; no selective developmental rescue, cardiac mediation or human treatment efficacy demonstrated.
    evidence:
    - reference: url:https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
      reference_title: https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: Indeed, circulating P1 B-cells exhibited increased numbers of mitochondria and mitochondrial activity relative to healthy control (HC) B-cells (Figure 1F and supplemental Figure 9 ).
      explanation: Mitochondrial dye readouts were measured in rare circulating B cells from one patient compared with a healthy control; they do not establish a general ATP-production flux.
    readouts:
    - name: Mitochondrial abundance signal
      target: Increased B-Cell Mitochondrial Abundance
      direction: INCREASED
      interpretation: Mitochondrial abundance was increased in rare circulating B cells from one FNIP1-deficient patient. This is not a measure in marrow progenitors or cardiac tissue.
      evidence:
      - reference: url:https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
        reference_title: https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
        supports: SUPPORT
        evidence_source: IN_VITRO
        directness: DIRECT
        quote_role: PRIMARY_RESULT
        snippet: Indeed, circulating P1 B-cells exhibited increased numbers of mitochondria and mitochondrial activity relative to healthy control (HC) B-cells (Figure 1F and supplemental Figure 9 ).
        explanation: Mitochondrial dye readouts were measured in rare circulating B cells from one patient compared with a healthy control; they do not establish a general ATP-production flux.
  - target: Increased B-Cell Mitochondrial Activity Signal
    relationship: MEASURES
    description: A mitochondrial activity-associated dye readout was increased in circulating B cells from one FNIP1-deficient patient. It is distinct from mitochondrial abundance and does not establish increased ATP synthesis or respiratory flux.
    limitations: Small patient/control comparisons in distinct cell populations; no selective developmental rescue, cardiac mediation or human treatment efficacy demonstrated.
    evidence:
    - reference: url:https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
      reference_title: https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: Indeed, circulating P1 B-cells exhibited increased numbers of mitochondria and mitochondrial activity relative to healthy control (HC) B-cells (Figure 1F and supplemental Figure 9 ).
      explanation: Mitochondrial dye readouts were measured in rare circulating B cells from one patient compared with a healthy control; they do not establish a general ATP-production flux.
    readouts:
    - name: Mitochondrial activity-associated dye signal
      target: Increased B-Cell Mitochondrial Activity Signal
      direction: INCREASED
      interpretation: A mitochondrial activity-associated dye readout was increased in circulating B cells from one FNIP1-deficient patient. It is distinct from mitochondrial abundance and does not establish increased ATP synthesis or respiratory flux.
      evidence:
      - reference: url:https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
        reference_title: https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
        supports: SUPPORT
        evidence_source: IN_VITRO
        directness: DIRECT
        quote_role: PRIMARY_RESULT
        snippet: Indeed, circulating P1 B-cells exhibited increased numbers of mitochondria and mitochondrial activity relative to healthy control (HC) B-cells (Figure 1F and supplemental Figure 9 ).
        explanation: Mitochondrial dye readouts were measured in rare circulating B cells from one patient compared with a healthy control; they do not establish a general ATP-production flux.
  - target: Increased B-Cell AKT Phosphorylation
    relationship: MEASURES
    description: Marrow B-cell progenitors from one FNIP1-deficient patient had increased AKT Ser473 phosphorylation relative to a healthy control. This is an observed signaling state, not a direct assay of a unique kinase mechanism.
    limitations: Small patient/control comparisons in distinct cell populations; no selective developmental rescue, cardiac mediation or human treatment efficacy demonstrated.
    evidence:
    - reference: url:https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
      reference_title: https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: Specifically, p4EBP1 and pAkt473 were significantly activated ( 12.46±1.86 vs 4.00±0.53, p = 0.00 02; 3.82±1.78 vs 0.97±0. 09, p = 0.029). As opposite, no difference could be found in S6 phosphorylation (1.46±0.14 vs 2.70±0.51, p = 0.14).
      explanation: One patient marrow comparison showed increased p4EBP1 and pAKT473 but not pS6; small repeated assays do not expand the donor count.
    readouts:
    - name: AKT Ser473 phosphorylation
      target: Increased B-Cell AKT Phosphorylation
      direction: INCREASED
      interpretation: Marrow B-cell progenitors from one FNIP1-deficient patient had increased AKT Ser473 phosphorylation relative to a healthy control. This is an observed signaling state, not a direct assay of a unique kinase mechanism.
      evidence:
      - reference: url:https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
        reference_title: https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
        supports: SUPPORT
        evidence_source: IN_VITRO
        directness: DIRECT
        quote_role: PRIMARY_RESULT
        snippet: Specifically, p4EBP1 and pAkt473 were significantly activated ( 12.46±1.86 vs 4.00±0.53, p = 0.00 02; 3.82±1.78 vs 0.97±0. 09, p = 0.029). As opposite, no difference could be found in S6 phosphorylation (1.46±0.14 vs 2.70±0.51, p = 0.14).
        explanation: One patient marrow comparison showed increased p4EBP1 and pAKT473 but not pS6; small repeated assays do not expand the donor count.
  - target: Increased B-Cell 4EBP1 Phosphorylation
    relationship: MEASURES
    description: Marrow B-cell progenitors from one FNIP1-deficient patient had increased 4EBP1 phosphorylation; pS6 was not significantly altered. BEZ235 lowered the 4EBP1 readout without demonstrating restored B-cell development or clinical benefit.
    limitations: Small patient/control comparisons in distinct cell populations; no selective developmental rescue, cardiac mediation or human treatment efficacy demonstrated.
    evidence:
    - reference: url:https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
      reference_title: https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: Specifically, p4EBP1 and pAkt473 were significantly activated ( 12.46±1.86 vs 4.00±0.53, p = 0.00 02; 3.82±1.78 vs 0.97±0. 09, p = 0.029). As opposite, no difference could be found in S6 phosphorylation (1.46±0.14 vs 2.70±0.51, p = 0.14).
      explanation: One patient marrow comparison showed increased p4EBP1 and pAKT473 but not pS6; small repeated assays do not expand the donor count.
    readouts:
    - name: 4EBP1 phosphorylation
      target: Increased B-Cell 4EBP1 Phosphorylation
      direction: INCREASED
      interpretation: Marrow B-cell progenitors from one FNIP1-deficient patient had increased 4EBP1 phosphorylation; pS6 was not significantly altered. BEZ235 lowered the 4EBP1 readout without demonstrating restored B-cell development or clinical benefit.
      evidence:
      - reference: url:https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
        reference_title: https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
        supports: SUPPORT
        evidence_source: IN_VITRO
        directness: DIRECT
        quote_role: PRIMARY_RESULT
        snippet: Specifically, p4EBP1 and pAkt473 were significantly activated ( 12.46±1.86 vs 4.00±0.53, p = 0.00 02; 3.82±1.78 vs 0.97±0. 09, p = 0.029). As opposite, no difference could be found in S6 phosphorylation (1.46±0.14 vs 2.70±0.51, p = 0.14).
        explanation: One patient marrow comparison showed increased p4EBP1 and pAKT473 but not pS6; small repeated assays do not expand the donor count.
  notes: The patient marrow showed a relative shift toward earlier precursors and fewer immature cells, without a discrete maturation block in the reported analysis.
- name: TOP2B yeast complementation and decatenation
  experimental_model_type: OTHER
  cell_source: Saccharomyces cerevisiae strains and extracted nuclear fractions
  publication: PMID:31409799
  description: Human/mouse chimeric constructs and corresponding yeast substitutions are used in complementation and biochemical assays. Growth and nuclear-fraction decatenation support loss of function and partial dominant interference.
  modeled_mechanisms:
  - target: Impaired TOP2B Activity
    relationship: MEASURES
    description: Mutant-plus-wild-type yeast fractions decatenate less effectively than the single-wild-type-copy comparator.
    limitations: Yeast ortholog/context and extracted fractions do not directly measure human B-cell topoisomerase function or establish a specific downstream transcriptional mediator.
    evidence:
    - reference: PMID:31409799
      reference_title: Mutations in topoisomerase IIβ result in a B cell immunodeficiency.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: fractions from the strain with only one copy of wild-type TOP2 decatenated kine- toplast DNA more effectively than fractions from strains with one wild-type and one mutant copy of TOP2 (Fig. 2d, Supplementary Fig. 4c).
      explanation: Yeast nuclear-fraction decatenation supports partial dominant interference for tested substitutions; this is not a direct patient B-cell enzyme assay.
    readouts:
    - name: DNA decatenation activity
      target: Impaired TOP2B Activity
      direction: DECREASED
      interpretation: Mutant-plus-wild-type yeast fractions decatenate less effectively than the single-wild-type-copy comparator.
      evidence:
      - reference: PMID:31409799
        reference_title: Mutations in topoisomerase IIβ result in a B cell immunodeficiency.
        supports: SUPPORT
        evidence_source: IN_VITRO
        directness: DIRECT
        quote_role: PRIMARY_RESULT
        snippet: fractions from the strain with only one copy of wild-type TOP2 decatenated kine- toplast DNA more effectively than fractions from strains with one wild-type and one mutant copy of TOP2 (Fig. 2d, Supplementary Fig. 4c).
        explanation: Yeast nuclear-fraction decatenation supports partial dominant interference for tested substitutions; this is not a direct patient B-cell enzyme assay.
- name: ZIP7-mutant mouse B-cell signaling and zinc assays
  experimental_model_type: PRIMARY_CELL_CULTURE
  cell_source: IL7-expanded P198A homozygous and wild-type mouse marrow B cells; ex-vivo SWHEL immature B cells
  publication: PMID:30718914
  description: Compartment-targeted FRET-FLIM measures free zinc in expanded cultures. Separate ex-vivo assays measure broad phosphatase activity and antigen-induced phosphorylation with equivalent surface BCR expression. These assays support several linked abnormalities without proving one necessary PTEN-mediated sequence.
  notes: The cultured zinc assay and ex-vivo signaling assays use different preparations. No UPR transcriptional signature or altered Xbp1 splicing was observed; there was no measured ER free-zinc overload. PTEN haploinsufficiency failed to rescue maturation. Findings do not establish human zinc treatment efficacy.
  evidence:
  - reference: PMID:30718914
    reference_title: An essential role for the Zn(2+) transporter ZIP7 in B cell development.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Cytoplasmic Zn2+ concentrations were indeed lower in mutant compared to WT cells, whereas ER Zn2+ amounts were equivalent
    explanation: FRET-FLIM in IL7-expanded mutant mouse marrow B-cell cultures measures lower free cytosolic zinc with unchanged free ER zinc.
  - reference: PMID:30718914
    reference_title: An essential role for the Zn(2+) transporter ZIP7 in B cell development.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Constitutive phosphatase activity was indeed higher in ZIP7P198A/P198A compared to WT pre-B and immature B cells, as measured by flow cytometry using a cell-permeable alkaline phosphatase substrate
    explanation: The broad live phosphatase-substrate assay does not isolate PTEN activity.
  - reference: PMID:30718914
    reference_title: An essential role for the Zn(2+) transporter ZIP7 in B cell development.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: immature ZIP7P198A/P198A SWHel B cells showed impaired antigen-induced signalling as judged by reduced amounts of multiple phosphorylated intermediates, including SYK, PLCγ2 and ERK
    explanation: Ex-vivo antigen stimulation demonstrates reduced phosphorylation despite comparable surface BCR.
  modeled_mechanisms:
  - target: Reduced B-Cell Cytosolic Free Zinc
    relationship: MEASURES
    description: Measures reduced free cytosolic zinc.
    limitations: ER free zinc was unchanged; local or dynamic pulses exceed the measurement resolution.
    evidence:
    - reference: PMID:30718914
      reference_title: An essential role for the Zn(2+) transporter ZIP7 in B cell development.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Cytoplasmic Zn2+ concentrations were indeed lower in mutant compared to WT cells, whereas ER Zn2+ amounts were equivalent
      explanation: FRET-FLIM in IL7-expanded mutant mouse marrow B-cell cultures measures lower free cytosolic zinc with unchanged free ER zinc.
    readouts:
    - name: Free cytosolic zinc
      target: Reduced B-Cell Cytosolic Free Zinc
      direction: DECREASED
      interpretation: Measures reduced free cytosolic zinc.
      evidence:
      - reference: PMID:30718914
        reference_title: An essential role for the Zn(2+) transporter ZIP7 in B cell development.
        supports: SUPPORT
        evidence_source: IN_VITRO
        quote_role: PRIMARY_RESULT
        directness: DIRECT
        snippet: Cytoplasmic Zn2+ concentrations were indeed lower in mutant compared to WT cells, whereas ER Zn2+ amounts were equivalent
        explanation: FRET-FLIM in IL7-expanded mutant mouse marrow B-cell cultures measures lower free cytosolic zinc with unchanged free ER zinc.
  - target: Increased B-Cell Phosphatase Activity
    relationship: MEASURES
    description: Measures increased broad substrate activity.
    limitations: No PTEN-specific catalytic assay.
    evidence:
    - reference: PMID:30718914
      reference_title: An essential role for the Zn(2+) transporter ZIP7 in B cell development.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Constitutive phosphatase activity was indeed higher in ZIP7P198A/P198A compared to WT pre-B and immature B cells, as measured by flow cytometry using a cell-permeable alkaline phosphatase substrate
      explanation: The broad live phosphatase-substrate assay does not isolate PTEN activity.
    readouts:
    - name: Phosphatase-substrate activity
      target: Increased B-Cell Phosphatase Activity
      direction: INCREASED
      interpretation: Measures increased broad substrate activity.
      evidence:
      - reference: PMID:30718914
        reference_title: An essential role for the Zn(2+) transporter ZIP7 in B cell development.
        supports: SUPPORT
        evidence_source: IN_VITRO
        quote_role: PRIMARY_RESULT
        directness: DIRECT
        snippet: Constitutive phosphatase activity was indeed higher in ZIP7P198A/P198A compared to WT pre-B and immature B cells, as measured by flow cytometry using a cell-permeable alkaline phosphatase substrate
        explanation: The broad live phosphatase-substrate assay does not isolate PTEN activity.
  - target: Reduced B-Cell Receptor Signaling
    relationship: MEASURES
    description: Measures reduced antigen-induced phosphorylation.
    limitations: Does not establish a serial SYK-to-PLCγ2-to-ERK necessity chain or generalized T-cell signaling defect.
    evidence:
    - reference: PMID:30718914
      reference_title: An essential role for the Zn(2+) transporter ZIP7 in B cell development.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: immature ZIP7P198A/P198A SWHel B cells showed impaired antigen-induced signalling as judged by reduced amounts of multiple phosphorylated intermediates, including SYK, PLCγ2 and ERK
      explanation: Ex-vivo antigen stimulation demonstrates reduced phosphorylation despite comparable surface BCR.
    readouts:
    - name: Antigen-induced phosphoprotein signal
      target: Reduced B-Cell Receptor Signaling
      direction: DECREASED
      interpretation: Measures reduced antigen-induced phosphorylation.
      evidence:
      - reference: PMID:30718914
        reference_title: An essential role for the Zn(2+) transporter ZIP7 in B cell development.
        supports: SUPPORT
        evidence_source: IN_VITRO
        quote_role: PRIMARY_RESULT
        directness: DIRECT
        snippet: immature ZIP7P198A/P198A SWHel B cells showed impaired antigen-induced signalling as judged by reduced amounts of multiple phosphorylated intermediates, including SYK, PLCγ2 and ERK
        explanation: Ex-vivo antigen stimulation demonstrates reduced phosphorylation despite comparable surface BCR.
- name: SPI1-edited human hematopoietic progenitor differentiation
  experimental_model_type: PRIMARY_CELL_CULTURE
  cell_source: Cord-blood hematopoietic stem and progenitor cells edited near disease-associated SPI1 regions
  publication: PMID:33951726
  description: In-vitro B-cell, myeloid and T-cell differentiation compares edited and control progenitors. Editing introduces mixtures of monoallelic and biallelic indels rather than precise patient variants; allele enrichment among surviving differentiated cells is distinct from a universal lineage arrest.
  modeled_mechanisms:
  - target: Impaired B-Cell Development
    relationship: PARTIALLY_RECAPITULATES
    description: SPI1 editing impairs early B-cell and myeloid differentiation in culture.
    limitations: Cord-blood culture and mixed editing outcomes differ from human heterozygous disease. This experiment is separate from RS4;11 ATAC-seq and does not isolate a particular chromatin-mediated causal bridge.
    evidence:
    - reference: PMID:33951726
      reference_title: Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: Introducing disease-similar SPI1 mutations into human hematopoietic stem and progenitor cells impaired early in vitro B cell and myeloid cell differentiation.
      explanation: Edited cord-blood progenitors carry mixtures of near-variant indels, not precise patient-allele knock-ins; lineage selection supports but does not isolate the chromatin mediator.
    readouts:
    - name: B-lineage differentiation output
      target: Impaired B-Cell Development
      direction: DECREASED
      interpretation: Reduced B-lineage differentiation supports a cell-intrinsic developmental role in this culture system.
      evidence:
      - reference: PMID:33951726
        reference_title: Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients.
        supports: SUPPORT
        evidence_source: IN_VITRO
        directness: DIRECT
        quote_role: PRIMARY_RESULT
        snippet: Introducing disease-similar SPI1 mutations into human hematopoietic stem and progenitor cells impaired early in vitro B cell and myeloid cell differentiation.
        explanation: Edited cord-blood progenitors carry mixtures of near-variant indels, not precise patient-allele knock-ins; lineage selection supports but does not isolate the chromatin mediator.
animal_models:
- name: Slc39a7 hypomorphic mice and mixed marrow chimeras
  species: Mouse
  genotype: Slc39a7 P198A homozygous, H199QV homozygous or P198A/H199QV compound heterozygous
  description: Global knock-in and engineered hypomorphic alleles cause allele-dependent growth/skin abnormalities and profound B-cell deficiency. P198A is orthologous to human P190A. Mixed WT/mutant marrow chimeras demonstrate a B-cell intrinsic late-pre-B to immature-stage block.
  publication: PMID:30718914
  notes: Null/null and null/hypomorph animals could not be obtained; these are not equivalent to viable complete-null patient models. Few P198A homozygotes survived past six weeks. Oral zinc did not rescue the tested marrow-reconstitution model. BCL2 increased peripheral numbers without relieving the block; B-cell PTEN haploinsufficiency also failed to rescue maturation. Phenotyping was not randomized or blinded.
  evidence:
  - reference: PMID:30718914
    reference_title: An essential role for the Zn(2+) transporter ZIP7 in B cell development.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Mice with homozygous (ZIP7P198A/P198A or ZIP7H199QV/H199QV) or compound heterozygous (ZIP7P198A/H199QV) hypomorphic mutations demonstrated profound B cell immunodeficiency
    explanation: Global hypomorphic alleles produce B-cell deficiency; H199QV is engineered rather than a human allele.
  - reference: PMID:30718914
    reference_title: An essential role for the Zn(2+) transporter ZIP7 in B cell development.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Eight weeks after BM transfer, our analysis confirmed a B cell intrinsic block in development, which was most evident in a failure to progress from the late pre-B (FrD) to immature B (FrE) cell stage, with no residual mutant cells in the recirculating FrF population
    explanation: Mixed marrow chimeras show cell-intrinsic developmental failure strongest at late-pre-B to immature transition.
  modeled_mechanisms:
  - target: Impaired ZIP7-Dependent B-Cell Maturation
    relationship: RECAPITULATES
    description: Recapitulates B-cell intrinsic maturation failure.
    limitations: Stage assignment is based on mouse Hardy fractions; the study cannot exclude an earlier pre-B defect.
    evidence:
    - reference: PMID:30718914
      reference_title: An essential role for the Zn(2+) transporter ZIP7 in B cell development.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Eight weeks after BM transfer, our analysis confirmed a B cell intrinsic block in development, which was most evident in a failure to progress from the late pre-B (FrD) to immature B (FrE) cell stage, with no residual mutant cells in the recirculating FrF population
      explanation: Mixed marrow chimeras show cell-intrinsic developmental failure strongest at late-pre-B to immature transition.
    readouts:
    - name: Late-pre-B to immature B-cell progression
      target: Impaired ZIP7-Dependent B-Cell Maturation
      direction: DECREASED
      interpretation: Recapitulates B-cell intrinsic maturation failure.
      evidence:
      - reference: PMID:30718914
        reference_title: An essential role for the Zn(2+) transporter ZIP7 in B cell development.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        quote_role: PRIMARY_RESULT
        directness: DIRECT
        snippet: Eight weeks after BM transfer, our analysis confirmed a B cell intrinsic block in development, which was most evident in a failure to progress from the late pre-B (FrD) to immature B (FrE) cell stage, with no residual mutant cells in the recirculating FrF population
        explanation: Mixed marrow chimeras show cell-intrinsic developmental failure strongest at late-pre-B to immature transition.
- species: Mouse
  genotype: Global Lrrc8a-null and Lrrc8a-null marrow into Rag2-null recipients
  category: Genetic
  publication: PMID:24752297
  description: Global null mice have increased mortality, growth and tissue abnormalities, modest B-cell developmental changes and stronger T-cell defects. Tested B-cell proliferation and antibody responses were largely intact despite reduced peripheral B-cell numbers.
  notes: This is not the human heterozygous truncation. The result neither disproves the reported human association nor establishes dominant interference. The historical proposed ligand/topology mechanism is not promoted as current channel biology.
  modeled_mechanisms:
  - target: Impaired B-Cell Development
    relationship: PARTIALLY_RECAPITULATES
    description: The null model reproduces only a modest B-development phenotype.
    limitations: Allele, species and viability differ from the human case; it does not recapitulate profound human agammaglobulinemia.
    evidence:
    - reference: PMID:24752297
      reference_title: Leucine-rich repeat containing 8A (LRRC8A) is essential for T lymphocyte development and function.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: Lrrc8a(-/-) mice displayed a modest block in B cell development but intact intrinsic B cell function.
      explanation: Global null mice have a different allele mechanism from the single human heterozygous truncation.
    readouts:
    - name: B-cell developmental progression
      target: Impaired B-Cell Development
      direction: DECREASED
      interpretation: The null model reproduces only a modest B-development phenotype.
      evidence:
      - reference: PMID:24752297
        reference_title: Leucine-rich repeat containing 8A (LRRC8A) is essential for T lymphocyte development and function.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        directness: DIRECT
        quote_role: PRIMARY_RESULT
        snippet: Lrrc8a(-/-) mice displayed a modest block in B cell development but intact intrinsic B cell function.
        explanation: Global null mice have a different allele mechanism from the single human heterozygous truncation.
- species: Mouse
  genotype: B-lineage conditional Top2b deletion and a heterozygous disease-associated EE587E allele
  category: Genetic
  publication: PMID:31409799
  description: Conditional mb1-Cre and cd19-Cre deletions and a separate constitutive disease-allele model show B-lineage defects at multiple stages. The heterozygous disease-allele model also has reduced humoral responses. Human marrow stage was not measured in the three families.
  notes: Conditional deletion and the dominant disease allele are distinct models. B-cell DNA-damage, transcription and survival readouts do not establish a single necessary route, and do not explain human limb or urogenital anomalies. Homozygous disease-allele viability differs from heterozygous patients.
  modeled_mechanisms:
  - target: Impaired B-Cell Development
    relationship: PARTIALLY_RECAPITULATES
    description: The conditional model alters B-cell differentiation and the expression of selected B-lineage regulators.
    limitations: Pax5 reduction is a measured accompanying change, not isolated rescue or mediation; stage and allele effects differ among models.
    evidence:
    - reference: PMID:31409799
      reference_title: Mutations in topoisomerase IIβ result in a B cell immunodeficiency.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: expression of Pax5, a B-cell speci ﬁc transcription factor expressed at most stages of B-cell develop- ment23– 25, was signi ﬁcantly reduced in B cells derived from Top2b−/−mb1-cre mice while Rag1 expression was unchanged (Fig. 3n, o).
      explanation: Conditional Top2b-deficient mouse B cells show altered Pax5 expression, with unchanged Rag1; this is not proof that Pax5 alone mediates the phenotype.
    readouts:
    - name: B-lineage Pax5 expression
      target: Impaired B-Cell Development
      direction: DECREASED
      interpretation: The conditional model alters B-cell differentiation and the expression of selected B-lineage regulators.
      evidence:
      - reference: PMID:31409799
        reference_title: Mutations in topoisomerase IIβ result in a B cell immunodeficiency.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        directness: DIRECT
        quote_role: PRIMARY_RESULT
        snippet: expression of Pax5, a B-cell speci ﬁc transcription factor expressed at most stages of B-cell develop- ment23– 25, was signi ﬁcantly reduced in B cells derived from Top2b−/−mb1-cre mice while Rag1 expression was unchanged (Fig. 3n, o).
        explanation: Conditional Top2b-deficient mouse B cells show altered Pax5 expression, with unchanged Rag1; this is not proof that Pax5 alone mediates the phenotype.
discussions:
- discussion_id: gap_autosomal_agamma_lrrc8a
  kind: KNOWLEDGE_GAP
  prompt: Does the historical LRRC8A truncation define a reproducible dominant agammaglobulinemia mechanism?
  rationale: The human claim rests on a single balanced-translocation case. ClinGen labels the relationship Limited. Forced mutant expression and global null mouse studies use different allele mechanisms; preserved null-mouse antibody function cannot establish or refute a dominant human effect. Additional unrelated families and allele-specific functional evidence are needed.
  attaches_to:
  - pathophysiology#Truncated LRRC8A Protein
  evidence:
  - reference: url:https://thegencc.org/submissions/SGC-107391.2
    reference_title: LRRC8A | agammaglobulinemia | Autosomal dominant by ClinGen submission information facts
    supports: SUPPORT
    evidence_source: OTHER
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: Since other patients with B cell deficiency and heterozygous LRRC8A have not been identified, the curation is classified as Limited.
    explanation: ClinGen explains the Limited classification by the lack of additional human cases.
  - reference: PMID:24752297
    reference_title: Leucine-rich repeat containing 8A (LRRC8A) is essential for T lymphocyte development and function.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Lrrc8a(-/-) mice displayed a modest block in B cell development but intact intrinsic B cell function.
    explanation: Global null mice have a different allele mechanism from the single human heterozygous truncation.
- discussion_id: gap_autosomal_agamma_spi1_penetrance
  kind: KNOWLEDGE_GAP
  prompt: What predicts onset, expressivity and long-term risk in SPI1 carriers?
  rationale: The 2025 cohort has 22 agammaglobulinemic patients, 5 relatives with milder antibody abnormalities and 6 apparently unaffected relatives. Its 81.8% estimate concerns any antibody phenotype and is affected by familial ascertainment and possible later onset. No hematologic malignancy was observed over 514 patient-years, but the small cohort cannot establish zero risk. The L180F family has marked within-family variation; a simple PU.1 abundance-to-severity relationship is not established.
  attaches_to:
  - pathophysiology#Reduced PU.1 Dosage or Activity
  evidence:
  - reference: url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    reference_title: https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Of the 11 relatives harboring heterozygous LOF PU.1 variants, 6 were clinically well with laboratory evaluations documenting serum antibody and circulating B-cell concentrations within age- adjusted normal ranges.
    explanation: Six heterozygous relatives had normal clinical and laboratory findings at assessment, which is the variable-penetrance observation this knowledge gap asks to explain.
  - reference: url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    reference_title: https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: our cohort remains too small to conclude that inborn LOF PU.1 variants convey 0 malignancy risks.
    explanation: The authors explicitly limit inference from the absence of observed blood cancers.
- discussion_id: gap_autosomal_agamma_transplant
  kind: KNOWLEDGE_GAP
  prompt: Which genetic forms benefit from transplantation, and which compartments must be corrected?
  rationale: ZIP7 sibling outcomes contrast with two SPI1 attempts that did not achieve independence from replacement. Persistent tissue-resident macrophages and donor competitive advantage are proposed explanations in SPI1, not demonstrated mechanisms. Gene-specific outcome data and donor genotype matter; immunologic improvement must be distinguished from skin or other organ recovery.
  attaches_to:
  - treatments#Allogeneic Hematopoietic Cell Transplantation
  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
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: (P1 and P2, family 1) additionally showed severe blistering dermatosis (Fig. 1b), failure to thrive and thrombocytopenia, prompting hematopoietic stem cell transplantation; this resulted in cure of immunologic abnormalities and amelioration of skin disease.
    explanation: Two siblings among six ZIP7-deficient patients had severe skin disease, poor growth and thrombocytopenia; transplantation outcomes are specific to them.
  - reference: url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    reference_title: https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Five years after transplantation, he remains IRT dependent because of undetectable serum immunoglobulin (IgA) and IgM despite naïve B-cell reconstitution and >99% donor peripheral blood engraftment in B-cell, T-cell, and myeloid cell compart- ments.
    explanation: Long-term SPI1 follow-up documents persistent antibody-production failure despite donor engraftment.
- discussion_id: gap_autosomal_agamma_fnip_cardio
  kind: KNOWLEDGE_GAP
  prompt: How does FNIP1 deficiency produce cardiomyopathy and variable neutropenia?
  rationale: The clinical syndrome is genetically associated with these features, but small B-cell metabolic assays do not establish heart or granulocyte causal pathways. The original marrow observation lacks a discrete block, and later cases differ in neutrophil number and stimulus-dependent function.
  attaches_to:
  - pathophysiology#FNIP1 Protein Deficiency
  - pathophysiology#Increased B-Cell Mitochondrial Abundance
  - pathophysiology#Increased B-Cell Mitochondrial Activity Signal
  - pathophysiology#Increased B-Cell AKT Phosphorylation
  - pathophysiology#Increased B-Cell 4EBP1 Phosphorylation
  evidence:
  - reference: url:https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
    reference_title: https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Specifically, p4EBP1 and pAkt473 were significantly activated ( 12.46±1.86 vs 4.00±0.53, p = 0.00 02; 3.82±1.78 vs 0.97±0. 09, p = 0.029). As opposite, no difference could be found in S6 phosphorylation (1.46±0.14 vs 2.70±0.51, p = 0.14).
    explanation: One patient marrow comparison showed increased p4EBP1 and pAKT473 but not pS6; small repeated assays do not expand the donor count.
  - reference: url:https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
    reference_title: https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: B -cell precursors did not show evidence of a maturation block, unlike classical agammaglobulinemia14, although a relative increase of earlier maturation stages (pro-B and pre-B1) and a significant reduction of immature B-cells was observed (Figure 1E and supplemental Figure 8).
    explanation: One patient had altered precursor proportions without a discrete maturation block, limiting a universal pro-B arrest model.
  - reference: url:https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
    reference_title: https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Indeed, circulating P1 B-cells exhibited increased numbers of mitochondria and mitochondrial activity relative to healthy control (HC) B-cells (Figure 1F and supplemental Figure 9 ).
    explanation: Mitochondrial dye readouts were measured in rare circulating B cells from one patient compared with a healthy control; they do not establish a general ATP-production flux.
references:
- reference: PMID:10525050
  title: Mutations in Igalpha (CD79a) result in a complete block in B-cell development.
- reference: PMID:10583958
  title: An essential role for BLNK in human B cell development.
- reference: PMID:14660746
  title: A congenital mutation of the novel gene LRRC8 causes agammaglobulinemia in humans.
- reference: PMID:14752335
  title: Early defects in B cell development.
- reference: PMID:17709424
  title: Mutations of the Igbeta gene cause agammaglobulinemia in man.
- reference: PMID:22351933
  title: Agammaglobulinemia and absent B lineage cells in a patient lacking the p85α subunit of PI3K.
- reference: PMID:24216514
  title: A recurrent dominant negative E47 mutation causes agammaglobulinemia and BCR(-) B cells.
- reference: PMID:24752297
  title: Leucine-rich repeat containing 8A (LRRC8A) is essential for T lymphocyte development and function.
- reference: PMID:30718914
  title: An essential role for the Zn(2+) transporter ZIP7 in B cell development.
- reference: PMID:31409799
  title: Mutations in topoisomerase IIβ result in a B cell immunodeficiency.
- reference: PMID:31696364
  title: Genetic Approaches for Definitive Diagnosis of Agammaglobulinemia in Consanguineous Families.
- reference: PMID:33951726
  title: Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients.
- reference: PMID:34241796
  title: 'Agammaglobulinemia: from X-linked to Autosomal Forms of Disease.'
- reference: PMID:35748970
  title: 'Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee.'
- reference: PMID:37273190
  title: Inborn errors of human B cell development, differentiation, and function.
- reference: PMID:38792965
  title: A Nationwide Study of the Delayed Diagnosis and the Clinical Manifestations of Predominantly Antibody Deficiencies and CTLA4-Mediated Immune Dysregulation Syndrome in Greece.
- reference: PMID:39073655
  title: Exclusive Characteristics of the p.E555K Dominant-Negative Variant in Autosomal Dominant E47 Deficiency.
- reference: PMID:39537849
  title: A novel mutation in FNIP1 associated with a syndromic immunodeficiency and cardiomyopathy.
- reference: PMID:8890099
  title: Mutations in the mu heavy-chain gene in patients with agammaglobulinemia.
- reference: PMID:9419212
  title: Mutations in the human lambda5/14.1 gene result in B cell deficiency and agammaglobulinemia.
- reference: url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
  title: https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf
- reference: url:https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
  title: https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content
- reference: url:https://thegencc.org/submissions/SGC-107391.2
  title: LRRC8A | agammaglobulinemia | Autosomal dominant by ClinGen submission information facts
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1453/
  title: X-Linked Agammaglobulinemia - GeneReviews® - NCBI Bookshelf
  tags:
  - GeneReviews
- reference: PMID:32905580
  title: Absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in folliculin-interacting protein 1 deficiency.

📚

References & Deep Research

References

PMID:10525050

Mutations in Igalpha (CD79a) result in a complete block in B-cell development.

No top-level findings curated for this source.

PMID:10583958

An essential role for BLNK in human B cell development.

No top-level findings curated for this source.

PMID:14660746

A congenital mutation of the novel gene LRRC8 causes agammaglobulinemia in humans.

No top-level findings curated for this source.

PMID:14752335

Early defects in B cell development.

No top-level findings curated for this source.

PMID:17709424

Mutations of the Igbeta gene cause agammaglobulinemia in man.

No top-level findings curated for this source.

PMID:22351933

Agammaglobulinemia and absent B lineage cells in a patient lacking the p85α subunit of PI3K.

No top-level findings curated for this source.

PMID:24216514

A recurrent dominant negative E47 mutation causes agammaglobulinemia and BCR(-) B cells.

No top-level findings curated for this source.

PMID:24752297

Leucine-rich repeat containing 8A (LRRC8A) is essential for T lymphocyte development and function.

No top-level findings curated for this source.

PMID:30718914

An essential role for the Zn(2+) transporter ZIP7 in B cell development.

No top-level findings curated for this source.

PMID:31409799

Mutations in topoisomerase IIβ result in a B cell immunodeficiency.

No top-level findings curated for this source.

PMID:31696364

Genetic Approaches for Definitive Diagnosis of Agammaglobulinemia in Consanguineous Families.

No top-level findings curated for this source.

PMID:33951726

Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients.

No top-level findings curated for this source.

PMID:34241796

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

No top-level findings curated for this source.

PMID:35748970

Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee.

No top-level findings curated for this source.

PMID:37273190

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

No top-level findings curated for this source.

PMID:38792965

A Nationwide Study of the Delayed Diagnosis and the Clinical Manifestations of Predominantly Antibody Deficiencies and CTLA4-Mediated Immune Dysregulation Syndrome in Greece.

No top-level findings curated for this source.

PMID:39073655

Exclusive Characteristics of the p.E555K Dominant-Negative Variant in Autosomal Dominant E47 Deficiency.

No top-level findings curated for this source.

PMID:39537849

A novel mutation in FNIP1 associated with a syndromic immunodeficiency and cardiomyopathy.

No top-level findings curated for this source.

PMID:8890099

Mutations in the mu heavy-chain gene in patients with agammaglobulinemia.

No top-level findings curated for this source.

PMID:9419212

Mutations in the human lambda5/14.1 gene result in B cell deficiency and agammaglobulinemia.

No top-level findings curated for this source.

url:https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf

https://pure.eur.nl/ws/portalfiles/portal/198591090/1-s2.0-S0006497125002174-main.pdf

No top-level findings curated for this source.

url:https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content

https://repositorio.udd.cl/server/api/core/bitstreams/a9d54a3e-518c-4beb-ac3d-b570765e7314/content

No top-level findings curated for this source.

url:https://thegencc.org/submissions/SGC-107391.2

LRRC8A | agammaglobulinemia | Autosomal dominant by ClinGen submission information facts

No top-level findings curated for this source.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1453/

X-Linked Agammaglobulinemia - GeneReviews® - NCBI Bookshelf

No top-level findings curated for this source.

PMID:32905580

Absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in folliculin-interacting protein 1 deficiency.

No top-level findings curated for this source.

Deep Research

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

Evaluations and curation notes (1)

Create: Autosomal Agammaglobulinemia (MONDO:0011096) · 2026-08-01T09:40:32Z · View source

De novo curation of autosomal (non-Bruton) agammaglobulinemia for issue #7568. Deep research via Edison/Falcon (553 s); its 17 citations resolved to only four distinct works, so the entry was built primarily from an independent PubMed E-utilities sweep of the primary gene-discovery literature (Yel 1996 IGHM, Minegishi 1998 IGLL1, Minegishi 1999 CD79A and BLNK, Ferrari 2007 CD79B, Conley 2012 PIK3R1, Boisson 2013 TCF3, Anzilotti 2019 SLC39A7, Le Coz 2021 SPI1, Sawada 2003 LRRC8A). Gene-to-numbered-subtype mapping was re-derived independently from MONDO/OMIM with OAK rather than taken from the brief: two corrections resulted, LRRC8A is AGM5 (omitted from the supplied gene list) and AGM10 is SPI1 not TOP2B (TOP2B causes the separate syndromic MONDO:0012243). Two Falcon-supplied HP identifiers were semantically wrong on OAK check (HP:0030245 is Intrapartum fever, HP:0031693 is Severe Epstein Barr virus infection) and were discarded. GeneReviews has no chapter for the autosomal forms; the X-linked chapter (PMID:20301626) was mined for shared clinical and management content, always tagged supports PARTIAL. XLA is handled as a cross-referenced differential diagnosis rather than duplicated. A hostile pre-PR red-team pass (dismech-pr-review checklist, fresh-context subagent) found one CRITICAL and several IMPORTANT issues, all fixed before opening the PR: POU2AF1/BOB1 was scoped OUT of the entry (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 moved to differential_diagnoses; the LRRC8A snippet was replaced (the original was verbatim but a vacuous mid-sentence fragment); MONDO-parentage claims for AGM8B and AGM10 were corrected (both sit under MONDO:0015977, not MONDO:0011096); an intrinsic germline myeloid defect was moved off an infection-to-neutropenia edge onto its own parallel edge; FNIP1 gained a subtype bound to MONDO:0100432 plus its cardinal hypertrophic cardiomyopathy phenotype; a diagnosis section was added (quantitative immunoglobulins, lymphocyte flow cytometry, IEI panel/exome, KREC newborn screening); Recurrent Infections was retermed to HP:0002718; and several prose overstatements were corrected. Validation: just validate PASS (95/95 snippets verified), just validate-terms PASS, just validate-references PASS, phenotype connectivity 19/19 (100 percent), gene-to-mechanism wiring 12/12 (100 percent).

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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Classifications

Inheritance

Subtypes

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Biochemical Markers

Diagnosis

Progression

Prevalence

Clinical Burden

Differential Diagnoses

Experimental Models

Animal Models

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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

Artifacts