| 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 (pqac-00000002, pqac-00000003, pqac-00000006) | Classification caveat: this is an umbrella category rather than a single monogenic disease entity (pqac-00000000, pqac-00000002) |
| **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 (pqac-00000001, pqac-00000006) | 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 (pqac-00000002) | Human cohort: novel homozygous frameshifts **p.Val378Alafs*1** and **p.Ile184Serfs*21** in 3 patients; absent/severely reduced B cells **<0.5%** with very low/undetectable immunoglobulins (pqac-00000007, pqac-00000009) |
| **IGLL1 (λ5 surrogate light chain / pre-BCR)** | Autosomal recessive | Pre-BCR assembly defect causing block at the pro-B to pre-B transition (pqac-00000001, pqac-00000006) | Patients with **CD79A, CD79B, IGLL1, or BLNK** defects are described as clinically indistinguishable from BTK deficiency in major features (pqac-00000001) | Identified by review evidence as a recurrent AR cause of agammaglobulinemia/B-cell deficiency; no quantitative patient numbers in available context (pqac-00000002, pqac-00000008) |
| **CD79A (Igα / pre-BCR signaling)** | Autosomal recessive | Complete block in B-cell development from defective Igα-mediated pre-BCR signaling (pqac-00000004, pqac-00000008) | In a human cohort, 2 sisters had undetectable/very low immunoglobulins, absent or severely reduced B cells **<0.5%**, and normal T-cell counts (pqac-00000009) | Novel homozygous nonsense variant **p.Trp66*** (c.197G>A) in extracellular domain; review literature characterizes CD79A defects as causing a complete developmental block (pqac-00000009, pqac-00000004) |
| **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 (pqac-00000004, pqac-00000008) | Clinically grouped with CD79A/IGLL1/BLNK deficiencies as resembling BTK-related agammaglobulinemia (pqac-00000001) | Human case evidence is referenced in reviews, including hypomorphic/leaky defects; no exact variant details available in cited context (pqac-00000004, pqac-00000008) |
| **BLNK (B-cell linker protein)** | Autosomal recessive | Downstream pre-BCR/BCR signal transduction defect; integrated with BTK and PI3K signaling during B-cell development (pqac-00000005) | Review evidence states BLNK-deficient patients are phenotypically similar to BTK/XLA; no quantitative cohort details in available context (pqac-00000001) | Listed in recent reviews among genes causing AR agammaglobulinemia; heterozygous carriers reported healthy, supporting biallelic disease mechanism (pqac-00000005, pqac-00000006) |
| **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 (pqac-00000005, pqac-00000006) | Review evidence highlights **early neutropenia** as notable in **PIK3R1**-related agammaglobulinemia, often improving over time (pqac-00000003) | Included in 2022-2023 reviews as established pathway genes for autosomal agammaglobulinemia/B-cell deficiency; no exact patient-level variants in available context (pqac-00000003, pqac-00000005, pqac-00000006) |
| **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 (pqac-00000001) | Review notes **6 individuals from 5 kindreds** with peripheral B-cell deficiency and preserved T-cell function (pqac-00000001) | Identified in recent reviews as a novel AR cause of agammaglobulinemia/B-cell lymphopenia; no specific variant listed in available context (pqac-00000001) |
| **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 (pqac-00000001, pqac-00000004, pqac-00000008) | Review evidence describes autosomal dominant and recessive agammaglobulinemia, including cases from Pakistan; clinical severity can include agammaglobulinemia and neutropenia-spectrum presentations (pqac-00000008) | Recent reviews note dominant-negative mechanism and BCR-negative B cells; exact variant not provided in available context (pqac-00000004, pqac-00000008) |
| **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 (pqac-00000001) | Primary paper identified **10 individuals from 5 kindreds** with syndromic B-cell immunodeficiency/Hoffman syndrome features including facial dysmorphism, limb anomalies, and urogenital malformations (pqac-00000001) | 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 (pqac-00000001) |
| **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 (pqac-00000010) | **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 (pqac-00000010) | Recent 2023 review highlights FNIP1 as an AR agammaglobulinemia cause with marrow-stage quantitative abnormalities, representing a newer metabolic subtype (pqac-00000010) |


*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.*