Immunodeficiency 62

Mendelian MONDO:0032763 Pathograph 29 Show in embeddings browser Primary Immunodeficiency

Immunodeficiency-62 is an autosomal recessive primary antibody deficiency caused by biallelic loss-of-function variants in ARHGEF1 at 19q13.2. ARHGEF1 is a RhoA-specific guanine nucleotide exchange factor expressed predominantly in haematopoietic cells, coupling Galpha12/13-associated G protein-coupled receptors - the lysophospholipid receptors for sphingosine-1-phosphate and lysophosphatidic acid, and the thromboxane A2 receptor - to RhoA activation. The disease is therefore not a defect of antigen receptor signalling but of where lymphocytes go: with no ARHGEF1 protein, RhoA activity and steady-state cortical actin polymerisation fall, lymphocytes migrate poorly and detach poorly from matrix, and B cells and myeloid precursors are not held in the compartments where they should mature. The clinical picture follows from that. Both reported patients - sisters - had recurrent upper and lower respiratory tract infection from late in the first decade, pneumonia from ages 7 and 11, and bronchiectasis. Their blood carried circulating myelocytes, an excess of transitional B cells, and almost no marginal zone or memory B cells; specific antibody responses to protein and polysaccharide vaccines were absent. A mediastinal lymph node from one sister showed small germinal centres with few B cells but an excess of plasma cells - the histological counterpart of a second consequence of the same lesion, the failure of the RhoA/ROCK arm to restrain PI3K/AKT signalling. EVIDENCE BASE IS VERY THIN AND HAS NOT BROADENED. Seven years after the founding report the literature still describes exactly one kindred and two affected individuals; the only subsequent primary paper studied platelet function in one of the same two sisters. No ClinGen gene-disease validity assertion and no GeneReviews chapter exist. The entry is written to be mechanism-rich and clinically cautious, and single-patient features - immune thrombocytopenia in one sister, a bronchial mucoepidermoid carcinoma in the other - are curated as what they are rather than as established features of the disease.

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1
Inheritance
10
Pathophys.
16
Phenotypes
2
Gaps
29
Pathograph
1
Genes
2
Variants
2
Medical Actions
1
Models
9
References
1
Deep Research
🏷

Classifications

Harrison's Part
IMMUNE RHEUMATOLOGIC
IUIS Category
predominantly antibody deficiency
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
ARHGEF1 lies at 19q13.2 and the two affected sisters are compound heterozygotes: a nonsense allele inherited from their healthy father and a splice acceptor site allele from their healthy mother. Both parents are unaffected carriers, so the recurrence risk for a further pregnancy of this couple is the standard autosomal recessive 25%. Segregation rests on this one family; no second kindred has been reported.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:30521495 SUPPORT Human Clinical
"A nonsense mutation c.898C>T (Chr19: 42398710: C>T; hg19 build 137) was inherited from the father, and a splice mutation c.1669-1G>T (Chr19: 42406933: G>T) was inherited from the mother."
Establishes biparental transmission of two different damaged alleles to the affected siblings, which is the compound heterozygous, autosomal recessive pattern.
PMID:41608114 SUPPORT Other
"ARHGEF1 deficiency | ARHGEF1 | AR | 618459 | Hypogammaglobulinemia; lack of antibody | Recurrent infections, bronchiectasis"
Independent statement of the autosomal recessive mode in the IUIS 2024 classification table.
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Discussions and Knowledge Gaps

2
Arhgef1-null mice have a severe platelet activation and haemostasis defect. An ARHGEF1-deficient human has none. Which species is telling us what ARHGEF1 does in platelets?
HUMAN MODEL MISMATCH OPEN imd62_mouse_platelet_phenotype_absent_in_humans
Attached to
pathophysiology#Reduced RhoA Activation in Lymphocytes
Arhgef1-/- mice have prolonged tail bleeding and carotid occlusion times, with defective platelet aggregation, granule secretion, integrin activation, clot retraction and spreading, and absent platelet RhoA activation - a phenotype striking enough that its authors proposed ARHGEF1 as a therapeutic target in thrombosis. When platelet function was finally measured in the younger of the two ARHGEF1-deficient sisters, everything was normal: aggregometry across seven agonists, glycoprotein expression and PAC-1 binding, dense and alpha granule content and secretion, spreading, clot retraction, procoagulant extracellular vesicle release, and - decisively - platelet RhoA activation itself, which was of similar magnitude to control. She had had no bleeding through lobectomy, ovarian cyst excision, breast implant surgery, two childbirths and terminations. So the divergence is not a matter of assay sensitivity: the proximate signalling step that fails in the patient's lymphocytes does not fail in her platelets. The authors attribute this to redundancy among the RhoGEFs human platelets express, noting that ARHGEF7 and ARHGEF6 are more abundant than ARHGEF1 there, and that ARHGEF2 and ARHGEF6 protein levels were unchanged so any compensation would have to be at the level of activation rather than abundance. The mismatch matters for this entry in two directions: it warns against importing the mouse platelet literature into the human disease description, and it suggests that the lymphocyte phenotype is severe precisely because lymphocytes lack the RhoGEF redundancy that protects platelets. It is also a single patient, and the compensating mechanism is hypothesised rather than identified.
Proposed experiments
Which RhoGEF sustains RhoA activation in ARHGEF1-null human platelets
exp_imd62_platelet_rhogef_redundancy
Knock down ARHGEF7, ARHGEF6, ARHGEF2 and ARHGEF12 individually and in combination in a human megakaryocytic system carrying an engineered ARHGEF1 null, and measure agonist-induced RhoA-GTP, aggregation and clot retraction. This would test directly the redundancy hypothesis the platelet paper offers, and would say whether lymphocytes lack the same redundancy.
Would support
discussions#imd62_mouse_platelet_phenotype_absent_in_humans
Supporting outcome
  • Loss of one or more additional platelet RhoGEFs on the ARHGEF1-null background reproduces the murine platelet phenotype in human cells.
Refuting outcome
  • RhoA activation and platelet function remain intact despite combined RhoGEF knockdown, implying the species difference lies elsewhere than in RhoGEF redundancy.
Show evidence (4 references)
PMID:30994039 SUPPORT Model Organism
"Our results indicate that Arhgef1-/- mice had prolonged carotid artery occlusion and tail bleeding times."
The murine haemostatic phenotype that the human patient does not have.
PMID:42687834 REFUTE Human Clinical
"In contrast to the severe platelet phenotype reported in Arhgef1 -/- mice, loss of ARHGEF1 expression in human platelets was not associated with detectable functional abnormalities across multiple assays."
Recorded as REFUTE against the proposition that the murine platelet phenotype transfers to human ARHGEF1 deficiency.
PMID:42687834 SUPPORT Human Clinical
"ARHGEF1 -deficient platelets exhibited RhoA activation of a similar magnitude to control platelets under identical activation conditions (Figure 2C), indicating no defect in RhoA activation."
Locates the divergence at the RhoA activation step itself, not at a downstream readout - which is what rules out an assay-sensitivity explanation.
+ 1 more reference
Does germline ARHGEF1 loss carry a tumour risk, and specifically a lymphoma risk, given that somatic ARHGEF1 loss of function is recurrent in germinal centre B cell-like diffuse large B cell lymphoma?
KNOWLEDGE GAP OPEN imd62_malignancy_risk_unknown
Attached to
phenotypes#Bronchial neoplasm pathophysiology#Disturbed Germinal Center Reaction
One of the two reported patients developed a bronchial mucoepidermoid carcinoma at 21. Taken alone that is a single tumour in a chronically infected and bronchiectatic lobe, and nothing more. What keeps the question open is the mechanism on the other side: the founding report's own introduction notes that germinal centre B cell-like diffuse large B cell lymphoma is frequently associated with loss-of-function ARHGEF1 mutations, and that Arhgef1-null mouse germinal centre B cells fail to activate sphingosine-1-phosphate signalling and escape excessively into blood and lymph - the same retention failure this entry curates as the cause of the patients' small, B cell-poor germinal centres. A germline null in that pathway is therefore not an obviously neutral background for lymphomagenesis, whatever the salivary-type carcinoma turns out to have been. With two patients and one tumour of the wrong lineage to bear on the question, the honest position is that malignancy risk in IMD62 is UNKNOWN - not absent, and not established. Nothing in this entry should be used to counsel a family about cancer risk, and no surveillance recommendation follows from it.
Show evidence (2 references)
PMID:30521495 SUPPORT Human Clinical
"at 21 years of age, she was diagnosed with bronchial mucoepidermoid carcinoma and underwent a lung lobectomy"
The single reported malignancy in the two-patient series.
PMID:30521495 SUPPORT BACKGROUND Human Clinical
"somatic ARHGEF1 mutations are involved in the pathogenesis of germinal center (GC) B cell-like diffuse large B cell lymphoma (GCB-DLBCL)"
The founding report's introduction, restating the somatic-lymphoma literature that makes the germline question worth keeping open. Graded with quote_role BACKGROUND because the sentence summarises other groups' work rather than this paper's own results; the quotation stops where the source line breaks mid-word.
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Pathophysiology

10
ARHGEF1 Biallelic Loss-of-Function Variants
Compound heterozygous germline variants in ARHGEF1 identified by whole-exome sequencing in two sisters: a nonsense allele (c.898C>T, p.R300X, exon 12) and a splice acceptor site allele (c.1669-1G>T) whose transcript skips exon 19 and frameshifts to a premature stop. Neither variant was present in the exome and variation databases searched at the time.
ARHGEF1 hgnc:681 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ARHGEF1 (hgnc:681). hgnc:681 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context ARHGEF1 hgnc:681 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns ARHGEF1 (hgnc:681). hgnc:681 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE zygosity: COMPOUND_HETEROZYGOUS functional_impact_category: LOSS_OF_FUNCTION
Downstream
Absence of ARHGEF1 Protein in Lymphocytes Both alleles truncate the protein, and no full-length or truncated ARHGEF1 is detectable in patient lymphoblastoid cells or T cell blasts.
Show evidence (1 reference)
PMID:30521495 SUPPORT Human Clinical
"compound heterozygous variants in ARHGEF1: a nonsense variant on Chr19: 42398710: C>T (hg19 build 137) (NM_199002.1, exon 12, c. 898 C>T, p.R300X) and a splice acceptor site variant on Chr19: 42406933: G>T"
Names both alleles with coordinates, transcript and protein consequence.
Absence of ARHGEF1 Protein in Lymphocytes
No immunoreactive ARHGEF1 is present in patient B and T lymphocytes. ARHGEF1 is the RhoA-specific exchange factor that links Galpha12/13-coupled receptors to RhoA, so its absence removes a specific route to RhoA activation rather than RhoA itself: total RhoA protein is normal.
B cell CL:0000236 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves B cell (CL:0000236). CL:0000236 is a cell type from the Cell Ontology. T cell CL:0000084 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves T cell (CL:0000084). CL:0000084 is a cell type from the Cell Ontology.
RhoA guanine nucleotide exchange factor activity GO:0005085 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves RhoA guanine nucleotide exchange factor activity, annotated with guanyl-nucleotide exchange factor activity (GO:0005085), qualified as loss of function. GO:0005085 is a molecular function from the Gene Ontology. ⇓ LOSS OF FUNCTION
Downstream
Reduced RhoA Activation in Lymphocytes With the exchange factor absent, the fraction of RhoA in the GTP-bound active state falls even though total RhoA protein is unchanged.
Show evidence (1 reference)
PMID:30521495 SUPPORT Human Clinical
"We used whole-exome sequencing to identify compound heterozygous mutations in ARHGEF1, resulting in the loss of ARHGEF1 protein expression in 2 primary antibody-deficient siblings presenting with recurrent severe respiratory tract infections and bronchiectasis."
States the absence of ARHGEF1 protein in the affected siblings.
Reduced RhoA Activation in Lymphocytes
RhoA-GTP is two- to three-fold below control in patient B and T lymphocytes. This is the hub of the entry: RhoA activation is what the ARHGEF1 lesion removes, and both downstream arms - cortical actin assembly and ROCK-mediated restraint of PI3K/AKT - branch from here. Both are correctable, in patient cells, by a pharmacological RhoA activator or by re-expressing ARHGEF1, which is what establishes the causal direction rather than mere association.
RhoA signal transduction GO:0007266 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased RhoA signal transduction, annotated with Rho protein signal transduction (GO:0007266). GO:0007266 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Defective Actin Polymerization in Lymphocytes RhoA is a principal regulator of actin cytoskeleton dynamics, and F-actin content is low in patient lymphocytes at steady state and after stimulation of lysophospholipid receptors.
Failure to Restrain PI3K/AKT Signaling The second arm. RhoA acts through ROCK I/II on PTEN, and without it AKT phosphorylation is not efficiently damped after chemokine receptor engagement.
Show evidence (1 reference)
PMID:30521495 SUPPORT Human Clinical
"Enforced ARHGEF1 expression or drug-induced activation of RhoA in the patients' cells corrected the impaired actin polymerization and AKT regulation."
The rescue experiment. Correcting ARHGEF1, or activating RhoA directly, repairs both downstream arms, which is why this node is treated as the causal hub rather than a correlate.
Defective Actin Polymerization in Lymphocytes
Cortical F-actin content is low in all patient T and B lymphocyte subsets at steady state, and actin polymerisation in response to sphingosine-1-phosphate, lysophosphatidic acid and the thromboxane A2 analogue U46619 is low or absent. The specificity matters: a response to the chemokine SDF1, which does not depend strictly on Galpha12/13, is still detectable, so the lesion is in a receptor-defined branch rather than in the actin machinery itself.
actin filament polymerization GO:0030041 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased actin filament polymerization (GO:0030041). GO:0030041 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Impaired Lymphocyte Migration and Deadhesion Patient T cell blasts migrate poorly across fibronectin-coated membranes and form elongated trailing edges on live imaging, a pattern the authors read as failure of deadhesion rather than excess adhesion.
Show evidence (1 reference)
PMID:30521495 SUPPORT Human Clinical
"On the molecular level, T and B lymphocytes from both patients displayed low RhoA activity and low steady-state actin polymerization"
Documents the low steady-state actin polymerisation in patient lymphocytes.
Impaired Lymphocyte Migration and Deadhesion
Reduced chemotaxis and reduced mean displacement with elongated uropods. Integrin alpha and beta chain expression is normal or reduced and the high-affinity LFA-1 conformation is not increased, which argues against the cells simply sticking harder and for a failure to release. This is the step that converts a cytoskeletal defect into a trafficking disease.
lymphocyte migration GO:0072676 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased lymphocyte migration (GO:0072676). GO:0072676 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Loss of Circulating Marginal Zone and Memory B Cells Marginal zone B cells depend on lysophospholipid receptor signalling to shuttle between the marginal zone and follicle; without it the compartment is not maintained.
Disturbed Germinal Center Reaction Germinal centre B cells are positioned and retained by Galpha12/13-coupled receptor signals; in the one lymph node examined the germinal centres were small and nearly empty of B cells while remaining structurally intact.
Increased circulating myelocyte count The same retention failure applies to myeloid precursors, which appear in the blood without any marrow evidence of a myeloproliferative or myelodysplastic process.
Increased transitional B cell proportion Transitional B cells accumulate in the blood, the counterpart of the marginal zone and memory compartments that fail to fill.
Show evidence (1 reference)
PMID:30521495 SUPPORT Human Clinical
"Taken as a whole, these data suggest that human ARHGEF1 deficiency is associated with migration defects possibly caused by impaired deadhesion."
The authors' summary of the migration phenotype and its likely proximate cause. Their own hedge ("possibly") is preserved rather than removed.
Failure to Restrain PI3K/AKT Signaling
The RhoA/ROCK axis normally limits PI3K/AKT output through PTEN. In patient T cell blasts, AKT Ser473 phosphorylation after SDF1/CXCR4 stimulation is repressed less efficiently than in controls, and a RhoA activator restores normal repression - placing the defect upstream of RhoA. A ROCK inhibitor reproduces the failure in healthy donor cells.
phosphatidylinositol 3-kinase/protein kinase B signal transduction GO:0043491 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0043491). GO:0043491 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Excessive Germinal Center Plasma Cell Differentiation The authors' proposed explanation for the plasma cell excess seen in the germinal centres: if B cells share the AKT dysregulation demonstrated in T cells, increased PI3K/AKT signalling would push germinal centre B cells towards plasma cell differentiation. This is an inference the founding paper itself flags as conditional, and it is recorded as such.
Show evidence (1 reference)
PMID:30521495 SUPPORT Human Clinical
"the patients' lymphocytes failed to efficiently restrain AKT phosphorylation"
The measured failure of AKT restraint in patient lymphocytes.
Excessive Germinal Center Plasma Cell Differentiation
A high frequency of CD138-positive plasma cells within the germinal centres of the one lymph node examined, interpreted as premature exit of germinal centre B cells into the plasma cell programme before affinity maturation is complete.
germinal center B cell CL:0000844 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves germinal center B cell (CL:0000844). CL:0000844 is a cell type from the Cell Ontology. plasma cell CL:0000786 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves plasma cell (CL:0000786). CL:0000786 is a cell type from the Cell Ontology.
plasma cell differentiation GO:0002317 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased plasma cell differentiation (GO:0002317). GO:0002317 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Disturbed Germinal Center Reaction Premature plasma cell differentiation depletes the germinal centre of the B cells that should be undergoing selection there.
Show evidence (1 reference)
PMID:30521495 SUPPORT Human Clinical
"Analysis of a mediastinal lymph node from one patient highlighted the small size of the germinal centers and an abnormally high plasma cell content."
The histological observation this node records.
Disturbed Germinal Center Reaction
Germinal centres that are small, round and structurally preserved but nearly devoid of B cells, with a thinner mantle zone, a smaller follicular dendritic cell meshwork and less proliferation. T follicular helper cell positioning is normal, so this is a B cell positioning and retention failure rather than a collapse of the germinal centre niche.
germinal center B cell CL:0000844 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves germinal center B cell (CL:0000844). CL:0000844 is a cell type from the Cell Ontology.
germinal center formation GO:0002467 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased germinal center formation (GO:0002467). GO:0002467 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Defective Specific Antibody Production Without a productive germinal centre reaction, affinity-matured, class-switched antibody responses to protein antigens cannot be generated.
Show evidence (1 reference)
PMID:30521495 SUPPORT Human Clinical
"Analysis of a mediastinal lymph node from one patient highlighted the small size of the germinal centers and an abnormally high plasma cell content."
The single available histological description of the germinal centre abnormality.
Loss of Circulating Marginal Zone and Memory B Cells
Switched memory and marginal zone B cells are almost undetectable in both patients (1-2% and 0.2-1% of B cells against reference floors of 10% and 13.4%), on a background of low total B cell counts. The marginal zone compartment is the one the mouse work had already predicted would fail.
marginal zone B cell CL:0000845 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves marginal zone B cell, annotated with marginal zone B cell of spleen (CL:0000845). CL:0000845 is a cell type from the Cell Ontology. memory B cell CL:0000787 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves memory B cell (CL:0000787). CL:0000787 is a cell type from the Cell Ontology.
Animal models
Lsc (Arhgef1) knockout mouse Mouse recapitulates Marginal zone B cell homeostasis fails in the Lsc-null mouse as it does in the ARHGEF1-deficient patients, and in both the proximate defect is a trafficking one rather than a developmental block.
Downstream
Defective Specific Antibody Production Marginal zone B cells carry the T-independent polysaccharide response and memory B cells the recall response; losing both accounts for the pattern of absent antibody to pneumococcal polysaccharide as well as to protein vaccine antigens.
Decreased memory B cell proportion The circulating memory B cell compartment is the laboratory readout of this node.
Decreased marginal zone B cell proportion The circulating marginal zone compartment, likewise.
Decreased total B cell count Total circulating CD19+ B cells are below reference in both patients, so the subset losses sit on top of an overall B lymphopenia rather than being purely redistributive.
Show evidence (1 reference)
PMID:30521495 SUPPORT Human Clinical
"Both ARHGEF1-deficient patients showed an abnormal B cell immunophenotype, with a deficiency in marginal zone and memory B cells and an increased frequency of transitional B cells."
The immunophenotype this node names.
Defective Specific Antibody Production
The functional endpoint: absent antibody to diphtheria and tetanus toxoids, poliovirus and pneumococcal immunisation, low isohaemagglutinin titre in one sister, and total IgG below reference in both before replacement. IgG4 was essentially absent in both (0.001 and 0.004 g/l). This is a failure of specific response rather than of immunoglobulin production altogether - IgA and IgM were near or within reference in one sister.
immunoglobulin production GO:0002377 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased immunoglobulin production (GO:0002377). GO:0002377 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
Lsc (Arhgef1) knockout mouse Mouse recapitulates Lsc-null mice fail to produce the antigen-specific IgM response to a protein antigen, and their marginal zone B cells do not contribute to the T-dependent antibody response - the same functional endpoint measured in the patients as absent vaccine responses.
Downstream
Impaired specific antibody response The directly measured clinical phenotype.
Decreased circulating total IgG concentration Total IgG below the age-matched reference interval in both sisters before replacement therapy.
Decreased circulating IgG4 concentration IgG4 was the most profoundly affected subclass in both sisters.
Recurrent upper respiratory tract infections Loss of specific antibody against encapsulated respiratory pathogens produces the sinopulmonary infection phenotype.
Recurrent lower respiratory tract infections The same failure, in the lower airway, where it causes the structural damage.
Recurrent pneumonia Repeated pneumonia from ages 7 and 11 respectively.
Recurrent herpes zoster Both sisters had recurrent varicella zoster virus disease. The link to the antibody defect is an inference: the founding report attributes the susceptibility to the overall immunodeficiency, and documents secondary T cell abnormalities that could contribute, so the edge is not a demonstrated antibody-dependent mechanism.
Show evidence (1 reference)
PMID:30521495 SUPPORT Human Clinical
"Antibody production (including T cell-dependent and -independent vaccine responses to poliovirus, tetanus, diphtheria toxoids, and pneumococcal immunizations) was defective in both patients"
The measured failure of specific antibody production in both patients.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Immunodeficiency 62 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

16
Blood 9
Decreased circulating total IgG concentration HP:0032132 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased circulating total IgG concentration (HP:0032132). HP:0032132 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30521495 SUPPORT Human Clinical
"IgG (g/l) 6.3 (8.3-14.3) 6.93 (9.2-14.8)"
The Table 1 IgG values with age-matched reference intervals for each patient.
Decreased circulating IgG4 concentration HP:0032138 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased circulating IgG4 concentration (HP:0032138). HP:0032138 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30521495 SUPPORT Human Clinical
"IgG4 (g/l) 0.001 0.004 IgA (g/l) 0.87 (1.02-1.94) 1.95 (1.42-2.62)"
The Table 1 immunoglobulin block, giving each patient's IgG4 value before replacement therapy alongside the adjacent IgA row.
Decreased total B cell count HP:0010976 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased total B cell count (HP:0010976). HP:0010976 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30521495 SUPPORT Human Clinical
"Both patients presented with low CD19+ B cell blood counts, an elevated frequency of transitional B cells"
States the low total B cell count directly.
Decreased memory B cell proportion HP:0030374 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased memory B cell proportion (HP:0030374). HP:0030374 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30521495 SUPPORT Human Clinical
"Memory B cells (%) 2 (>10) 1 (>10)"
The Table 1 memory B cell row with the reference floor.
Decreased marginal zone B cell proportion HP:0030384 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased marginal zone B cell proportion (HP:0030384). HP:0030384 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30521495 SUPPORT Human Clinical
"MZ B cells (%) 1 (13.4-21.4) 0.2 (13.4-21.4)"
The Table 1 marginal zone B cell row with the reference interval.
Increased transitional B cell proportion HP:0030381 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased transitional B cell proportion (HP:0030381). HP:0030381 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30521495 SUPPORT Human Clinical
"Transitional B cells (%) 17 (<11) 17 (<11)"
The Table 1 transitional B cell row with the reference ceiling.
Increased circulating myelocyte count HP:0032237 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased circulating myelocyte count (HP:0032237). HP:0032237 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:30521495 SUPPORT Human Clinical
"Furthermore, the patients' blood contained immature myeloid cells."
Reports circulating immature myeloid cells in both patients.
PMID:30521495 SUPPORT Human Clinical
"Blood samples from both patients repeatedly contained myelocytes (Figure 1, A and B)."
Records that the finding was repeated rather than a single observation, which is what distinguishes it from an incidental smear result.
Decreased central memory CD8+ T cell proportion HP:0410389 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased central memory CD8+ T cell proportion (HP:0410389). HP:0410389 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30521495 SUPPORT Human Clinical
"Both patients presented with a decreased frequency of CD8+ central memory and effector memory T cell subsets"
Reports the reduced CD8+ central memory frequency in both patients.
Autoimmune thrombocytopenia HP:0001973 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autoimmune thrombocytopenia (HP:0001973). HP:0001973 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30521495 SUPPORT Human Clinical
"At 13 years of age, P1 developed immune thrombocytopenia."
The single reported occurrence, with the age at onset.
Head and Neck 1
Recurrent upper respiratory tract infections HP:0002788 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent upper respiratory tract infections (HP:0002788), qualified as temporality recurrent. HP:0002788 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
Show evidence (2 references)
PMID:30521495 SUPPORT Human Clinical
"born to healthy, nonconsanguineous parents presented during childhood with recurrent upper and"
States the presentation directly. The quotation stops before "lower", which the source hyphenates across a line break so the clause cannot be quoted whole; the lower-tract half carries its own evidence on its own phenotype.
PMID:41608114 SUPPORT Other
"ARHGEF1 deficiency | ARHGEF1 | AR | 618459 | Hypogammaglobulinemia; lack of antibody | Recurrent infections, bronchiectasis"
The IUIS row names recurrent infections as the associated clinical feature of this entity.
Immune 4
Impaired specific antibody response HP:0012475 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Impaired specific antibody response (HP:0012475). HP:0012475 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30521495 SUPPORT Human Clinical
"Antibody production (including T cell-dependent and -independent vaccine responses to poliovirus, tetanus, diphtheria toxoids, and pneumococcal immunizations) was defective in both patients"
Documents the failed vaccine responses in both patients.
Recurrent lower respiratory tract infections HP:0002783 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent lower respiratory tract infections (HP:0002783), qualified as temporality recurrent. HP:0002783 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
Sequelae: Bronchiectasis
Show evidence (1 reference)
PMID:30521495 SUPPORT Human Clinical
"We used whole-exome sequencing to identify compound heterozygous mutations in ARHGEF1, resulting in the loss of ARHGEF1 protein expression in 2 primary antibody-deficient siblings presenting with recurrent severe respiratory tract infections and bronchiectasis."
Names recurrent severe respiratory tract infection as the presenting feature.
Recurrent pneumonia HP:0006532 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent pneumonia (HP:0006532), qualified as temporality recurrent; childhood onset. HP:0006532 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT Onset: CHILDHOOD
Sequelae: Bronchiectasis
Show evidence (1 reference)
PMID:30521495 SUPPORT Human Clinical
"this included episodes of pneumonia from the age of 7 and 11 years onwards"
Gives the onset ages directly.
Recurrent herpes zoster Recurrent shingles HP:0032275 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent herpes zoster, annotated with Recurrent shingles (HP:0032275), qualified as temporality recurrent. HP:0032275 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
Show evidence (2 references)
PMID:30521495 SUPPORT Human Clinical
"P2 experienced 3 episodes of herpes zoster, a severe, acute, oral herpes simplex virus 1 (HSV-1) primary infection, and recurrent lung infections"
Names the episodes as herpes zoster and gives the count for the younger sister. This is the sentence that settles reactivation rather than primary infection, so it is the one this binding rests on; it also records the severe primary HSV-1 infection alongside it.
PMID:30521495 SUPPORT Human Clinical
"Viral infections Recurrent VZV HSV; recurrent VZV"
The Table 1 viral infection row, recording recurrent VZV in both sisters. The table says "VZV" without distinguishing primary infection from reactivation, which is why it is the supporting item here rather than the one the term binding is taken from.
Respiratory 1
Bronchiectasis HP:0002110 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bronchiectasis (HP:0002110). HP:0002110 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:30521495 SUPPORT Human Clinical
"The sisters were diagnosed with bronchiectasis and evaluated for PID at the age of 10 and 18 years"
Documents bronchiectasis in both sisters with the age at diagnosis.
PMID:41608114 SUPPORT Other
"ARHGEF1 deficiency | ARHGEF1 | AR | 618459 | Hypogammaglobulinemia; lack of antibody | Recurrent infections, bronchiectasis"
Bronchiectasis is one of the two associated features IUIS records for this entity.
Neoplasm 1
Bronchial neoplasm HP:0030077 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bronchial mucoepidermoid carcinoma, annotated with Bronchial neoplasm (HP:0030077). HP:0030077 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30521495 SUPPORT Human Clinical
"at 21 years of age, she was diagnosed with bronchial mucoepidermoid carcinoma and underwent a lung lobectomy"
The single reported tumour, with the age at diagnosis and the operation. HPO has no mucoepidermoid carcinoma term, so the binding is to the anatomical neoplasm term and the histology is carried in `preferred_term`.
🧬

Genetic Associations

1
ARHGEF1 biallelic loss of function (Causative)
Gene: ARHGEF1 hgnc:681 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ARHGEF1 (hgnc:681). hgnc:681 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:30521495 SUPPORT Human Clinical
"compound heterozygous variants in ARHGEF1 in both patients resulted in ARHGEF1-deficient expression in lymphocytes."
Establishes that the two alleles together abolish protein expression.
PMID:30521495 SUPPORT Human Clinical
"We assume that any combination of these variations will lead to ARHGEF1 deficiency."
The authors' expectation that other truncating ARHGEF1 alleles annotated in population databases would behave the same way in the biallelic state. Quoted with their own hedge intact: it is a prediction, not an observation, and no such patient has been reported.
Variants (2)
ARHGEF1 c.898C>T p.(Arg300Ter) (paternal allele) Pathogenic
Nonsense variant in exon 12 of NM_199002.1, inherited from the healthy father, with a CADD score of 41 and absent from ExAC, the Exome Sequencing Project, dbSNP and SwissVar at the time of reporting.
Show evidence (1 reference)
PMID:30521495 SUPPORT Human Clinical
"compound heterozygous variants in ARHGEF1: a nonsense variant on Chr19: 42398710: C>T (hg19 build 137) (NM_199002.1, exon 12, c. 898 C>T, p.R300X) and a splice acceptor site variant on Chr19: 42406933: G>T"
Names the nonsense allele with its transcript, exon, cDNA and protein notation.
ARHGEF1 c.1669-1G>T splice acceptor variant (maternal allele) Pathogenic
Splice acceptor site variant inherited from the healthy mother. RT-PCR on patient and maternal peripheral blood mononuclear cells detected an aberrant transcript, expressed at lower level than the main transcript, that skips exon 19 and frameshifts to a premature stop codon.
Show evidence (2 references)
PMID:30521495 SUPPORT Human Clinical
"abnormal exon skipping of exon 19, introducing a frame shift with creation of a premature stop codon (E557Kfs34X)"
Gives the transcript-level consequence of the splice allele.
PMID:30521495 SUPPORT Human Clinical
"A nonsense mutation c.898C>T (Chr19: 42398710: C>T; hg19 build 137) was inherited from the father, and a splice mutation c.1669-1G>T (Chr19: 42406933: G>T) was inherited from the mother."
Gives the cDNA notation of the splice allele and its parental origin.
💊

Medical Actions

2
Immunoglobulin Replacement Therapy
Category: Therapeutic Action: immunoglobulin replacement therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is immunoglobulin replacement therapy, annotated with Immunoglobulin Therapy (NCIT:C62710). NCIT:C62710 is a clinical intervention from the NCI Thesaurus. Ontology label: Immunoglobulin Therapy NCIT:C62710
Platform: Protein replacement
Both sisters were started on polyvalent IgG replacement and were reported doing well on subcutaneous immunoglobulin at last follow-up, at 30 and 27 years. No trial or case series has evaluated immunoglobulin replacement in ARHGEF1 deficiency specifically - with two patients none could exist - so the general justification is the class-level standard of care for inborn errors of immunity with impaired antibody production, and the disease-specific evidence is observational use in the two reported patients.
Mechanism Target:
BYPASSES Defective Specific Antibody Production — Replacement immunoglobulin supplies the specific antibody the patients cannot make. It bypasses the defect; it does not restore RhoA signalling, B cell trafficking, or the patients' own vaccine responses.
Show evidence (1 reference)
PMID:42208906 SUPPORT Other
"The management part includes recommendations for immunoglobulin replacement, antibiotic prophylaxis, hematopoietic stem cell transplantation, precision medicine, and quality-of-life assessment."
Establishes immunoglobulin replacement as a recommended management component for inborn errors of immunity. Class-level evidence, cited as such.
Show evidence (2 references)
PMID:30521495 SUPPORT Human Clinical
"P1 was aged 30 and was doing well on subcutaneous IgG replacement therapy."
The only disease-specific outcome statement available: one patient doing well on subcutaneous replacement at 30 years. An observation in one patient, not an efficacy result.
PMID:30521495 SUPPORT Human Clinical
"Polyvalent IgG replacement therapy was initiated, and a lung lobectomy was performed on P1 at the age of 12 because of persistent suppuration associated with localized bronchiectasis"
Records the initiation of replacement therapy in the founding kindred.
Lung Lobectomy for Localized Suppurative Bronchiectasis
Category: Therapeutic Action: lung lobectomyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is lung lobectomy, annotated with Lobectomy (NCIT:C15272). NCIT:C15272 is a clinical intervention from the NCI Thesaurus. Ontology label: Lobectomy NCIT:C15272
Platform: Surgery
Resection of a lobe destroyed by localized suppurative bronchiectasis, performed in the elder sister at age 12 for persistent suppuration. The younger sister also underwent lobectomy, but for her bronchial mucoepidermoid carcinoma rather than for infection. Surgery here treats the structural sequela; it does nothing to the underlying immune defect, and the general practice of resecting localized destroyed lung in bronchiectasis is not specific to this disease.
Mechanism Target:
MODULATES Bronchiectasis — Removing the destroyed, chronically infected lobe removes the focus of persistent suppuration. It does not prevent bronchiectasis elsewhere.
Show evidence (1 reference)
PMID:30521495 SUPPORT Human Clinical
"Polyvalent IgG replacement therapy was initiated, and a lung lobectomy was performed on P1 at the age of 12 because of persistent suppuration associated with localized bronchiectasis"
States the indication for the operation in the one patient in whom it was performed for infection.
Show evidence (1 reference)
PMID:30521495 SUPPORT Human Clinical
"Polyvalent IgG replacement therapy was initiated, and a lung lobectomy was performed on P1 at the age of 12 because of persistent suppuration associated with localized bronchiectasis"
The single reported instance of this intervention for infection in this disease.
🔬

Diagnosis

3
Whole Exome Sequencing
The test that made the diagnosis. IMD62 has no clinical or laboratory feature that distinguishes it from any other primary antibody deficiency at the bedside - the two sisters were carried as unexplained antibody deficiency for years - so the diagnosis is genetic, and in the founding kindred it came from comparing the two affected siblings' exomes.
whole exome sequencing NCIT:C101295 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:30521495 SUPPORT Human Clinical
"WES of DNA from total blood samples from both patients was performed with a view to identifying the underlying genetic cause of their disease."
States the diagnostic route taken in the only reported kindred.
Specific Antibody Response Testing
Measurement of antibody titres to protein and polysaccharide vaccine antigens after immunisation. This is the functional test that shows the defect, and it matters here because total IgG is only modestly reduced (6.3 and 6.93 g/l): an entry-level immunoglobulin panel alone would understate the problem, while the vaccine responses are flatly absent.
specific antibody response measurement NCIT:C81869 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:30521495 SUPPORT Human Clinical
"Antibody production (including T cell-dependent and -independent vaccine responses to poliovirus, tetanus, diphtheria toxoids, and pneumococcal immunizations) was defective in both patients"
Names the antigens tested and the result in both patients.
B Cell Immunophenotyping by Flow Cytometry
Flow cytometric enumeration of the circulating B cell subsets. The pattern is the one that should raise ARHGEF1 as a possibility rather than a generic CVID label: marginal zone and switched memory B cells almost absent, transitional B cells raised. Examining a blood film at the same time is worth doing, since circulating myelocytes with an unremarkable marrow point the same way.
B cell immunophenotyping NCIT:C16585 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:30521495 SUPPORT Human Clinical
"Both ARHGEF1-deficient patients showed an abnormal B cell immunophenotype, with a deficiency in marginal zone and memory B cells and an increased frequency of transitional B cells."
Gives the subset pattern this test is being recorded for.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
Two affected individuals, sisters from one non-consanguineous family. No second kindred has been reported in the seven years since the founding paper; the one subsequent primary publication studied platelet function in the younger of the same two sisters. No population prevalence estimate exists and none is derivable from a cohort of this size.
Show evidence (1 reference)
PMID:42687834 SUPPORT BACKGROUND Human Clinical
"ARHGEF1 deficiency has been described in two female siblings (P1 and P2) carrying compound heterozygous germline variants in ARHGEF1 (Figure 1A) , resulting in primary antibody deficiency and recurrent severe respiratory tract infections with bronchiectasis"
A 2026 paper's own statement of the published case count, which is still two siblings. Graded HUMAN_CLINICAL with quote_role BACKGROUND because the sentence restates the founding clinical report rather than this paper's own platelet results.
🐁

Animal Models

1
Lsc (Arhgef1) knockout mouse
The murine ortholog knockout, published nearly two decades before the human disease and the reason the human marginal zone and antibody phenotype was recognisable when it appeared. Lsc-null mice lack marginal zone B cell homeostasis, show reduced basal lymphocyte motility with defective release from integrin ligands, and fail to mount the antigen-specific IgM response to a T-dependent protein antigen.
Species
Mouse
Genotype
Lsc (Arhgef1) homozygous null by gene targeting
Publication
PMID:11526402
Pathograph links
Loss of Circulating Marginal Zone and Memory B Cells recapitulates fidelity: moderate observes: organism Marginal zone B cell homeostasis fails in the Lsc-null mouse as it does in the ARHGEF1-deficient patients, and in both the proximate defect is a trafficking one rather than a developmental block.
Limitations: The mouse marginal zone compartment is splenic and anatomically better defined than the circulating CD27+IgD+ population measured in the patients, so the two readouts are related but not the same measurement. The mouse data also say nothing about the memory B cell loss that is equally prominent in the human disease.
Readouts
Marginal zone B cell homeostasis
Direction: DECREASED
Interpretation: The compartment-level readout that corresponds to the human marginal zone B cell deficiency.
Show evidence (1 reference)
PMID:11526402 SUPPORT Model Organism
"Lsc is essential for marginal zone B (MZB) cell homeostasis and for the generation of immune responses."
States the marginal zone requirement measured in the knockout.
Show evidence (1 reference)
PMID:11526402 SUPPORT Model Organism
"Lsc is expressed primarily in the hematopoietic system and links the activation of G alpha(12) and G alpha(13)-coupled receptors to actin polymerization in B and T cells."
Establishes that the mouse model perturbs the same receptor-to-actin pathway that is lost in the human disease, which is what makes it informative for this node.
Defective Specific Antibody Production recapitulates fidelity: moderate observes: organism Lsc-null mice fail to produce the antigen-specific IgM response to a protein antigen, and their marginal zone B cells do not contribute to the T-dependent antibody response - the same functional endpoint measured in the patients as absent vaccine responses.
Limitations: The mouse experiments use defined model antigens and read out IgM; the human phenotype is absent IgG responses to toxoid, polio and pneumococcal immunisation with IgG4 essentially undetectable. The classes and antigens differ, so the correspondence is at the level of "no specific antibody response", not of a matched assay.
Readouts
Antigen-specific IgM response to a T-dependent protein antigen
Direction: DECREASED
Interpretation: Functional antibody readout in the knockout, corresponding to the patients' absent specific antibody responses.
Show evidence (1 reference)
PMID:16286020 SUPPORT Model Organism
"we demonstrate that Lsc, a protein that regulates G protein-coupled-receptor signaling and RhoA activation, is required by B lymphocytes for the antigen-specific IgM antibody response to a protein antigen."
Reports the failed antigen-specific antibody response in the knockout.
Show evidence (1 reference)
PMID:16286020 SUPPORT Model Organism
"Consequently, lsc(-/-) MZB cells do not traffick appropriately in an immune response and do not contribute to the TD antibody response."
Links the trafficking defect to the antibody failure in the model, the same causal shape this entry curates for the human disease.
{ }

Source YAML

click to show 
name: Immunodeficiency 62
creation_date: "2026-09-25T00:00:00Z"
category: Mendelian
synonyms:
- IMD62
- ARHGEF1 deficiency
- Childhood-onset common variable immunodeficiency phenotype due to ARHGEF1 deficiency
- Childhood-onset CVID phenotype due to ARHGEF1 deficiency
description: >-
  Immunodeficiency-62 is an autosomal recessive primary antibody deficiency caused
  by biallelic loss-of-function variants in ARHGEF1 at 19q13.2. ARHGEF1 is a
  RhoA-specific guanine nucleotide exchange factor expressed predominantly in
  haematopoietic cells, coupling Galpha12/13-associated G protein-coupled
  receptors - the lysophospholipid receptors for sphingosine-1-phosphate and
  lysophosphatidic acid, and the thromboxane A2 receptor - to RhoA activation. The
  disease is therefore not a defect of antigen receptor signalling but of where
  lymphocytes go: with no ARHGEF1 protein, RhoA activity and steady-state cortical
  actin polymerisation fall, lymphocytes migrate poorly and detach poorly from
  matrix, and B cells and myeloid precursors are not held in the compartments where
  they should mature.

  The clinical picture follows from that. Both reported patients - sisters - had
  recurrent upper and lower respiratory tract infection from late in the first
  decade, pneumonia from ages 7 and 11, and bronchiectasis. Their blood carried
  circulating myelocytes, an excess of transitional B cells, and almost no marginal
  zone or memory B cells; specific antibody responses to protein and polysaccharide
  vaccines were absent. A mediastinal lymph node from one sister showed small
  germinal centres with few B cells but an excess of plasma cells - the
  histological counterpart of a second consequence of the same lesion, the failure
  of the RhoA/ROCK arm to restrain PI3K/AKT signalling.

  EVIDENCE BASE IS VERY THIN AND HAS NOT BROADENED. Seven years after the founding
  report the literature still describes exactly one kindred and two affected
  individuals; the only subsequent primary paper studied platelet function in one
  of the same two sisters. No ClinGen gene-disease validity assertion and no
  GeneReviews chapter exist. The entry is written to be mechanism-rich and
  clinically cautious, and single-patient features - immune thrombocytopenia in
  one sister, a bronchial mucoepidermoid carcinoma in the other - are curated as
  what they are rather than as established features of the disease.
disease_term:
  preferred_term: immunodeficiency 62
  term:
    id: MONDO:0032763
    label: immunodeficiency 62
parents:
- Primary Immunodeficiency
classifications:
  harrisons_chapter:
  - classification_value: IMMUNE_RHEUMATOLOGIC
    notes: >-
      An inborn error of immunity presenting as a primary antibody deficiency with
      recurrent sinopulmonary infection; placed with the immune disorders rather
      than with the respiratory ones, whose involvement is a consequence.
  iuis_category:
    classification_value: predominantly antibody deficiency
    notes: >-
      IUIS 2024 phenotypic classification, Table 3 (predominantly antibody
      deficiencies), section 2 (severe reduction in at least two serum
      immunoglobulin isotypes with normal or low B cell numbers, CVID phenotype):
      the "ARHGEF1 deficiency" row, listing ARHGEF1, autosomal recessive
      inheritance, OMIM 618459, hypogammaglobulinaemia with lack of antibody, and
      recurrent infections with bronchiectasis. The section placement is
      consistent with Orphanet naming the disorder a childhood-onset CVID
      phenotype. The row is unchanged from the 2022 edition of the same table.
    evidence:
    - reference: PMID:41608114
      reference_title: "Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "ARHGEF1 deficiency | ARHGEF1 | AR | 618459 | Hypogammaglobulinemia; lack of antibody | Recurrent infections, bronchiectasis"
      explanation: >-
        The IMD62 row of IUIS 2024 Table 3, giving the gene, the autosomal
        recessive mode, the OMIM phenotype number, and the immunological and
        clinical summary on which this classification rests.
inheritance:
- name: Autosomal recessive inheritance
  description: >-
    ARHGEF1 lies at 19q13.2 and the two affected sisters are compound
    heterozygotes: a nonsense allele inherited from their healthy father and a
    splice acceptor site allele from their healthy mother. Both parents are
    unaffected carriers, so the recurrence risk for a further pregnancy of this
    couple is the standard autosomal recessive 25%. Segregation rests on this one
    family; no second kindred has been reported.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:30521495
    reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A nonsense mutation c.898C>T (Chr19: 42398710: C>T; hg19 build 137) was inherited from the father, and a splice mutation c.1669-1G>T (Chr19: 42406933: G>T) was inherited from the mother."
    explanation: >-
      Establishes biparental transmission of two different damaged alleles to the
      affected siblings, which is the compound heterozygous, autosomal recessive
      pattern.
  - reference: PMID:41608114
    reference_title: "Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ARHGEF1 deficiency | ARHGEF1 | AR | 618459 | Hypogammaglobulinemia; lack of antibody | Recurrent infections, bronchiectasis"
    explanation: >-
      Independent statement of the autosomal recessive mode in the IUIS 2024
      classification table.
pathophysiology:
- name: ARHGEF1 Biallelic Loss-of-Function Variants
  biological_scale: MOLECULAR
  role: trigger
  description: >-
    Compound heterozygous germline variants in ARHGEF1 identified by whole-exome
    sequencing in two sisters: a nonsense allele (c.898C>T, p.R300X, exon 12) and
    a splice acceptor site allele (c.1669-1G>T) whose transcript skips exon 19 and
    frameshifts to a premature stop. Neither variant was present in the exome and
    variation databases searched at the time.
  genes:
  - preferred_term: ARHGEF1
    term:
      id: hgnc:681
      label: ARHGEF1
  genetic_context:
    gene:
      preferred_term: ARHGEF1
      term:
        id: hgnc:681
        label: ARHGEF1
    variant_origin: GERMLINE
    zygosity: COMPOUND_HETEROZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
  downstream:
  - target: Absence of ARHGEF1 Protein in Lymphocytes
    causal_link_type: DIRECT
    description: >-
      Both alleles truncate the protein, and no full-length or truncated ARHGEF1
      is detectable in patient lymphoblastoid cells or T cell blasts.
    evidence:
    - reference: PMID:30521495
      reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "compound heterozygous variants in ARHGEF1 in both patients resulted in ARHGEF1-deficient expression in lymphocytes."
      explanation: >-
        States the step from genotype to absent protein in the patients' own
        lymphocytes.
  evidence:
  - reference: PMID:30521495
    reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "compound heterozygous variants in ARHGEF1: a nonsense variant on Chr19: 42398710: C>T (hg19 build 137) (NM_199002.1, exon 12, c. 898 C>T, p.R300X) and a splice acceptor site variant on Chr19: 42406933: G>T"
    explanation: >-
      Names both alleles with coordinates, transcript and protein consequence.
- name: Absence of ARHGEF1 Protein in Lymphocytes
  biological_scale: MOLECULAR
  description: >-
    No immunoreactive ARHGEF1 is present in patient B and T lymphocytes. ARHGEF1 is
    the RhoA-specific exchange factor that links Galpha12/13-coupled receptors to
    RhoA, so its absence removes a specific route to RhoA activation rather than
    RhoA itself: total RhoA protein is normal.
  molecular_functions:
  - preferred_term: RhoA guanine nucleotide exchange factor activity
    term:
      id: GO:0005085
      label: guanyl-nucleotide exchange factor activity
    modifier: LOSS_OF_FUNCTION
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  downstream:
  - target: Reduced RhoA Activation in Lymphocytes
    causal_link_type: DIRECT
    description: >-
      With the exchange factor absent, the fraction of RhoA in the GTP-bound active
      state falls even though total RhoA protein is unchanged.
    evidence:
    - reference: PMID:30521495
      reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "RhoA activity in B-EBV-transformed lymphoblastoid cells and T cell blasts derived from both patients was 2-to 3-fold lower than in cells from healthy donors"
      explanation: >-
        Quantifies the loss of RhoA activation in the patients' own cells.
  evidence:
  - reference: PMID:30521495
    reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We used whole-exome sequencing to identify compound heterozygous mutations in ARHGEF1, resulting in the loss of ARHGEF1 protein expression in 2 primary antibody-deficient siblings presenting with recurrent severe respiratory tract infections and bronchiectasis."
    explanation: >-
      States the absence of ARHGEF1 protein in the affected siblings.
- name: Reduced RhoA Activation in Lymphocytes
  biological_scale: MOLECULAR
  description: >-
    RhoA-GTP is two- to three-fold below control in patient B and T lymphocytes.
    This is the hub of the entry: RhoA activation is what the ARHGEF1 lesion
    removes, and both downstream arms - cortical actin assembly and ROCK-mediated
    restraint of PI3K/AKT - branch from here. Both are correctable, in patient
    cells, by a pharmacological RhoA activator or by re-expressing ARHGEF1, which
    is what establishes the causal direction rather than mere association.
  biological_processes:
  - preferred_term: RhoA signal transduction
    term:
      id: GO:0007266
      label: Rho protein signal transduction
    modifier: DECREASED
  downstream:
  - target: Defective Actin Polymerization in Lymphocytes
    causal_link_type: DIRECT
    description: >-
      RhoA is a principal regulator of actin cytoskeleton dynamics, and F-actin
      content is low in patient lymphocytes at steady state and after stimulation
      of lysophospholipid receptors.
    evidence:
    - reference: PMID:30521495
      reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "On the molecular level, T and B lymphocytes from both patients displayed low RhoA activity and low steady-state actin polymerization"
      explanation: >-
        Couples the RhoA deficit to the actin polymerisation deficit in the same
        cells.
  - target: Failure to Restrain PI3K/AKT Signaling
    causal_link_type: DIRECT
    description: >-
      The second arm. RhoA acts through ROCK I/II on PTEN, and without it AKT
      phosphorylation is not efficiently damped after chemokine receptor
      engagement.
    evidence:
    - reference: PMID:30521495
      reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "the patients' lymphocytes failed to efficiently restrain AKT phosphorylation"
      explanation: >-
        States the failure of restraint that this edge asserts, attributed by the
        same sentence's context to disturbed regulation of the RhoA target ROCK.
  evidence:
  - reference: PMID:30521495
    reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Enforced ARHGEF1 expression or drug-induced activation of RhoA in the patients' cells corrected the impaired actin polymerization and AKT regulation."
    explanation: >-
      The rescue experiment. Correcting ARHGEF1, or activating RhoA directly,
      repairs both downstream arms, which is why this node is treated as the causal
      hub rather than a correlate.
- name: Defective Actin Polymerization in Lymphocytes
  biological_scale: CELLULAR
  description: >-
    Cortical F-actin content is low in all patient T and B lymphocyte subsets at
    steady state, and actin polymerisation in response to sphingosine-1-phosphate,
    lysophosphatidic acid and the thromboxane A2 analogue U46619 is low or absent.
    The specificity matters: a response to the chemokine SDF1, which does not
    depend strictly on Galpha12/13, is still detectable, so the lesion is in a
    receptor-defined branch rather than in the actin machinery itself.
  biological_processes:
  - preferred_term: actin filament polymerization
    term:
      id: GO:0030041
      label: actin filament polymerization
    modifier: DECREASED
  downstream:
  - target: Impaired Lymphocyte Migration and Deadhesion
    causal_link_type: DIRECT
    description: >-
      Patient T cell blasts migrate poorly across fibronectin-coated membranes and
      form elongated trailing edges on live imaging, a pattern the authors read as
      failure of deadhesion rather than excess adhesion.
    evidence:
    - reference: PMID:30521495
      reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "On fibronectin-coated Boyden chambers, we observed a strongly reduced Transwell migration of patients' T cell blasts compared with those of controls"
      explanation: >-
        The migration measurement this edge asserts.
  evidence:
  - reference: PMID:30521495
    reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "On the molecular level, T and B lymphocytes from both patients displayed low RhoA activity and low steady-state actin polymerization"
    explanation: >-
      Documents the low steady-state actin polymerisation in patient lymphocytes.
- name: Impaired Lymphocyte Migration and Deadhesion
  biological_scale: CELLULAR
  description: >-
    Reduced chemotaxis and reduced mean displacement with elongated uropods.
    Integrin alpha and beta chain expression is normal or reduced and the
    high-affinity LFA-1 conformation is not increased, which argues against the
    cells simply sticking harder and for a failure to release. This is the step
    that converts a cytoskeletal defect into a trafficking disease.
  biological_processes:
  - preferred_term: lymphocyte migration
    term:
      id: GO:0072676
      label: lymphocyte migration
    modifier: DECREASED
  downstream:
  - target: Loss of Circulating Marginal Zone and Memory B Cells
    causal_link_type: DIRECT
    description: >-
      Marginal zone B cells depend on lysophospholipid receptor signalling to
      shuttle between the marginal zone and follicle; without it the compartment is
      not maintained.
    evidence:
    - reference: PMID:30521495
      reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Both ARHGEF1-deficient patients showed an abnormal B cell immunophenotype, with a deficiency in marginal zone and memory B cells and an increased frequency of transitional B cells."
      explanation: >-
        The B cell compartment phenotype that this edge produces.
  - target: Disturbed Germinal Center Reaction
    causal_link_type: DIRECT
    description: >-
      Germinal centre B cells are positioned and retained by Galpha12/13-coupled
      receptor signals; in the one lymph node examined the germinal centres were
      small and nearly empty of B cells while remaining structurally intact.
    evidence:
    - reference: PMID:30521495
      reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Analysis of a mediastinal lymph node from one patient highlighted the small size of the germinal centers and an abnormally high plasma cell content."
      explanation: >-
        The germinal centre abnormality. Note this is a single node from a single
        patient, which is why the node's own description says so.
  - target: Increased circulating myelocyte count
    causal_link_type: DIRECT
    description: >-
      The same retention failure applies to myeloid precursors, which appear in the
      blood without any marrow evidence of a myeloproliferative or myelodysplastic
      process.
    evidence:
    - reference: PMID:30521495
      reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Our results indicate that ARHGEF1 activity in human lymphocytes is involved in controlling actin cytoskeleton dynamics, restraining PI3K/AKT signaling, and confining B lymphocytes and myelocytes within their dedicated functional environment."
      explanation: >-
        The authors' own summary of the confinement defect, naming myelocytes
        alongside B lymphocytes.
  - target: Increased transitional B cell proportion
    causal_link_type: DIRECT
    description: >-
      Transitional B cells accumulate in the blood, the counterpart of the marginal
      zone and memory compartments that fail to fill.
    evidence:
    - reference: PMID:30521495
      reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Both patients presented with low CD19+ B cell blood counts, an elevated frequency of transitional B cells"
      explanation: >-
        Documents the transitional B cell excess in both patients.
  evidence:
  - reference: PMID:30521495
    reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Taken as a whole, these data suggest that human ARHGEF1 deficiency is associated with migration defects possibly caused by impaired deadhesion."
    explanation: >-
      The authors' summary of the migration phenotype and its likely proximate
      cause. Their own hedge ("possibly") is preserved rather than removed.
- name: Failure to Restrain PI3K/AKT Signaling
  biological_scale: MOLECULAR
  description: >-
    The RhoA/ROCK axis normally limits PI3K/AKT output through PTEN. In patient
    T cell blasts, AKT Ser473 phosphorylation after SDF1/CXCR4 stimulation is
    repressed less efficiently than in controls, and a RhoA activator restores
    normal repression - placing the defect upstream of RhoA. A ROCK inhibitor
    reproduces the failure in healthy donor cells.
  biological_processes:
  - preferred_term: phosphatidylinositol 3-kinase/protein kinase B signal transduction
    term:
      id: GO:0043491
      label: phosphatidylinositol 3-kinase/protein kinase B signal transduction
    modifier: INCREASED
  downstream:
  - target: Excessive Germinal Center Plasma Cell Differentiation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      The authors' proposed explanation for the plasma cell excess seen in the
      germinal centres: if B cells share the AKT dysregulation demonstrated in
      T cells, increased PI3K/AKT signalling would push germinal centre B cells
      towards plasma cell differentiation. This is an inference the founding paper
      itself flags as conditional, and it is recorded as such.
    evidence:
    - reference: PMID:30521495
      reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "increased PI3K/AKT signaling in human GC B lymphocytes (because of impaired regulation of ARHGEF1/RhoA/ROCK signaling) might promote the excessive differentiation of GC B lymphocytes into plasma cells."
      explanation: >-
        The proposed mechanism, quoted with the authors' own modal verb intact. It
        is their hypothesis, not a demonstrated result in B cells.
  evidence:
  - reference: PMID:30521495
    reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the patients' lymphocytes failed to efficiently restrain AKT phosphorylation"
    explanation: >-
      The measured failure of AKT restraint in patient lymphocytes.
- name: Excessive Germinal Center Plasma Cell Differentiation
  biological_scale: CELLULAR
  description: >-
    A high frequency of CD138-positive plasma cells within the germinal centres of
    the one lymph node examined, interpreted as premature exit of germinal centre
    B cells into the plasma cell programme before affinity maturation is complete.
  cell_types:
  - preferred_term: germinal center B cell
    term:
      id: CL:0000844
      label: germinal center B cell
  - preferred_term: plasma cell
    term:
      id: CL:0000786
      label: plasma cell
  biological_processes:
  - preferred_term: plasma cell differentiation
    term:
      id: GO:0002317
      label: plasma cell differentiation
    modifier: INCREASED
  downstream:
  - target: Disturbed Germinal Center Reaction
    causal_link_type: DIRECT
    description: >-
      Premature plasma cell differentiation depletes the germinal centre of the
      B cells that should be undergoing selection there.
    evidence:
    - reference: PMID:30521495
      reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Analysis of a mediastinal lymph node from one patient highlighted the small size of the germinal centers and an abnormally high plasma cell content."
      explanation: >-
        Reports the two findings together in the same tissue: small germinal
        centres and excess plasma cells.
  evidence:
  - reference: PMID:30521495
    reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Analysis of a mediastinal lymph node from one patient highlighted the small size of the germinal centers and an abnormally high plasma cell content."
    explanation: >-
      The histological observation this node records.
- name: Disturbed Germinal Center Reaction
  biological_scale: TISSUE
  description: >-
    Germinal centres that are small, round and structurally preserved but nearly
    devoid of B cells, with a thinner mantle zone, a smaller follicular dendritic
    cell meshwork and less proliferation. T follicular helper cell positioning is
    normal, so this is a B cell positioning and retention failure rather than a
    collapse of the germinal centre niche.
  biological_processes:
  - preferred_term: germinal center formation
    term:
      id: GO:0002467
      label: germinal center formation
    modifier: DECREASED
  cell_types:
  - preferred_term: germinal center B cell
    term:
      id: CL:0000844
      label: germinal center B cell
  downstream:
  - target: Defective Specific Antibody Production
    causal_link_type: DIRECT
    description: >-
      Without a productive germinal centre reaction, affinity-matured,
      class-switched antibody responses to protein antigens cannot be generated.
    evidence:
    - reference: PMID:30714991
      reference_title: "ARHGEF1 deficiency reveals Gα13-associated GPCRs are critical regulators of human lymphocyte function."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "ARHGEF1-deficient lymphocytes from the affected siblings exhibited important functional deficits that indicate that loss of ARHGEF1 accounts for the observed primary antibody deficiency, which manifests in an inability to mount antibody responses to vaccines and pathogens."
      explanation: >-
        An accompanying commentary's synthesis of the founding report, connecting
        the lymphocyte functional defects to the failure of antibody responses.
  evidence:
  - reference: PMID:30521495
    reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Analysis of a mediastinal lymph node from one patient highlighted the small size of the germinal centers and an abnormally high plasma cell content."
    explanation: >-
      The single available histological description of the germinal centre
      abnormality.
- name: Loss of Circulating Marginal Zone and Memory B Cells
  biological_scale: CELLULAR
  description: >-
    Switched memory and marginal zone B cells are almost undetectable in both
    patients (1-2% and 0.2-1% of B cells against reference floors of 10% and
    13.4%), on a background of low total B cell counts. The marginal zone
    compartment is the one the mouse work had already predicted would fail.
  cell_types:
  - preferred_term: marginal zone B cell
    term:
      id: CL:0000845
      label: marginal zone B cell of spleen
  - preferred_term: memory B cell
    term:
      id: CL:0000787
      label: memory B cell
  downstream:
  - target: Defective Specific Antibody Production
    causal_link_type: DIRECT
    description: >-
      Marginal zone B cells carry the T-independent polysaccharide response and
      memory B cells the recall response; losing both accounts for the pattern of
      absent antibody to pneumococcal polysaccharide as well as to protein vaccine
      antigens.
    evidence:
    - reference: PMID:30521495
      reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Antibody production (including T cell-dependent and -independent vaccine responses to poliovirus, tetanus, diphtheria toxoids, and pneumococcal immunizations) was defective in both patients"
      explanation: >-
        Reports failure of both T-dependent and T-independent responses, the two
        arms these compartments serve.
  - target: Decreased memory B cell proportion
    causal_link_type: DIRECT
    description: >-
      The circulating memory B cell compartment is the laboratory readout of this
      node.
    evidence:
    - reference: PMID:30521495
      reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Memory B cells (%) 2 (>10) 1 (>10)"
      explanation: >-
        The Table 1 row giving each patient's memory B cell percentage against the
        age-matched reference floor.
  - target: Decreased marginal zone B cell proportion
    causal_link_type: DIRECT
    description: >-
      The circulating marginal zone compartment, likewise.
    evidence:
    - reference: PMID:30521495
      reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "MZ B cells (%) 1 (13.4-21.4) 0.2 (13.4-21.4)"
      explanation: >-
        The Table 1 row giving each patient's marginal zone B cell percentage
        against the age-matched reference interval.
  - target: Decreased total B cell count
    causal_link_type: DIRECT
    description: >-
      Total circulating CD19+ B cells are below reference in both patients, so the
      subset losses sit on top of an overall B lymphopenia rather than being purely
      redistributive.
    evidence:
    - reference: PMID:30521495
      reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Both patients presented with low CD19+ B cell blood counts, an elevated frequency of transitional B cells"
      explanation: >-
        States the low total B cell count in both patients.
  evidence:
  - reference: PMID:30521495
    reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both ARHGEF1-deficient patients showed an abnormal B cell immunophenotype, with a deficiency in marginal zone and memory B cells and an increased frequency of transitional B cells."
    explanation: >-
      The immunophenotype this node names.
- name: Defective Specific Antibody Production
  biological_scale: ORGANISM
  description: >-
    The functional endpoint: absent antibody to diphtheria and tetanus toxoids,
    poliovirus and pneumococcal immunisation, low isohaemagglutinin titre in one
    sister, and total IgG below reference in both before replacement. IgG4 was
    essentially absent in both (0.001 and 0.004 g/l). This is a failure of specific
    response rather than of immunoglobulin production altogether - IgA and IgM were
    near or within reference in one sister.
  biological_processes:
  - preferred_term: immunoglobulin production
    term:
      id: GO:0002377
      label: immunoglobulin production
    modifier: DECREASED
  downstream:
  - target: Impaired specific antibody response
    causal_link_type: DIRECT
    description: >-
      The directly measured clinical phenotype.
    evidence:
    - reference: PMID:30521495
      reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Antibody production (including T cell-dependent and -independent vaccine responses to poliovirus, tetanus, diphtheria toxoids, and pneumococcal immunizations) was defective in both patients"
      explanation: >-
        Names the vaccine antigens to which responses were absent.
  - target: Decreased circulating total IgG concentration
    causal_link_type: DIRECT
    description: >-
      Total IgG below the age-matched reference interval in both sisters before
      replacement therapy.
    evidence:
    - reference: PMID:30521495
      reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "IgG (g/l) 6.3 (8.3-14.3) 6.93 (9.2-14.8)"
      explanation: >-
        The Table 1 IgG row, each patient's value against her age-matched
        reference interval.
  - target: Decreased circulating IgG4 concentration
    causal_link_type: DIRECT
    description: >-
      IgG4 was the most profoundly affected subclass in both sisters.
    evidence:
    - reference: PMID:30521495
      reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "IgG4 (g/l) 0.001 0.004 IgA (g/l) 0.87 (1.02-1.94) 1.95 (1.42-2.62)"
      explanation: >-
        The Table 1 immunoglobulin block. IgG4 is 0.001 and 0.004 g/l in the two
        patients; the adjacent IgA row is quoted with it because the table gives
        no reference interval for IgG4, so the neighbouring rows are what show
        the units and the layout the IgG4 values sit in.
  - target: Recurrent upper respiratory tract infections
    causal_link_type: DIRECT
    description: >-
      Loss of specific antibody against encapsulated respiratory pathogens produces
      the sinopulmonary infection phenotype.
    evidence:
    - reference: PMID:30521495
      reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We used whole-exome sequencing to identify compound heterozygous mutations in ARHGEF1, resulting in the loss of ARHGEF1 protein expression in 2 primary antibody-deficient siblings presenting with recurrent severe respiratory tract infections and bronchiectasis."
      explanation: >-
        Couples the antibody deficiency to the recurrent respiratory tract
        infection that defines the presentation.
  - target: Recurrent lower respiratory tract infections
    causal_link_type: DIRECT
    description: >-
      The same failure, in the lower airway, where it causes the structural damage.
    evidence:
    - reference: PMID:30521495
      reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We used whole-exome sequencing to identify compound heterozygous mutations in ARHGEF1, resulting in the loss of ARHGEF1 protein expression in 2 primary antibody-deficient siblings presenting with recurrent severe respiratory tract infections and bronchiectasis."
      explanation: >-
        As above; the source does not separate upper from lower tract in this
        sentence, and the separation is made from the clinical narrative.
  - target: Recurrent pneumonia
    causal_link_type: DIRECT
    description: >-
      Repeated pneumonia from ages 7 and 11 respectively.
    evidence:
    - reference: PMID:30521495
      reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "this included episodes of pneumonia from the age of 7 and 11 years onwards"
      explanation: >-
        Gives the onset ages of the pneumonia episodes in each sister.
  - target: Recurrent herpes zoster
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Both sisters had recurrent varicella zoster virus disease. The link to the
      antibody defect is an inference: the founding report attributes the
      susceptibility to the overall immunodeficiency, and documents secondary
      T cell abnormalities that could contribute, so the edge is not a
      demonstrated antibody-dependent mechanism.
    evidence:
    - reference: PMID:30521495
      reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Viral infections Recurrent VZV HSV; recurrent VZV"
      explanation: >-
        The Table 1 viral infection row for the two patients, recording recurrent
        VZV in both and HSV in one.
  evidence:
  - reference: PMID:30521495
    reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Antibody production (including T cell-dependent and -independent vaccine responses to poliovirus, tetanus, diphtheria toxoids, and pneumococcal immunizations) was defective in both patients"
    explanation: >-
      The measured failure of specific antibody production in both patients.
phenotypes:
- category: Immunological
  name: Impaired specific antibody response
  description: >-
    Absent antibody responses to diphtheria and tetanus toxoids, poliovirus and
    pneumococcal immunisation in both sisters, with a low isohaemagglutinin titre
    in one. Both T-dependent and T-independent responses fail.
  phenotype_term:
    preferred_term: Impaired specific antibody response
    term:
      id: HP:0012475
      label: Impaired specific antibody response
  evidence:
  - reference: PMID:30521495
    reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Antibody production (including T cell-dependent and -independent vaccine responses to poliovirus, tetanus, diphtheria toxoids, and pneumococcal immunizations) was defective in both patients"
    explanation: >-
      Documents the failed vaccine responses in both patients.
- category: Respiratory
  name: Recurrent upper respiratory tract infections
  description: >-
    Recurrent upper respiratory tract infection beginning in childhood, the
    presenting problem in both sisters.
  phenotype_term:
    preferred_term: Recurrent upper respiratory tract infections
    term:
      id: HP:0002788
      label: Recurrent upper respiratory tract infections
    temporality: RECURRENT
  evidence:
  - reference: PMID:30521495
    reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "born to healthy, nonconsanguineous parents presented during childhood with recurrent upper and"
    explanation: >-
      States the presentation directly. The quotation stops before "lower", which
      the source hyphenates across a line break so the clause cannot be quoted
      whole; the lower-tract half carries its own evidence on its own phenotype.
  - reference: PMID:41608114
    reference_title: "Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ARHGEF1 deficiency | ARHGEF1 | AR | 618459 | Hypogammaglobulinemia; lack of antibody | Recurrent infections, bronchiectasis"
    explanation: >-
      The IUIS row names recurrent infections as the associated clinical feature
      of this entity.
- category: Respiratory
  name: Recurrent lower respiratory tract infections
  description: >-
    Recurrent lower respiratory tract infection from childhood, the driver of the
    structural airway damage.
  phenotype_term:
    preferred_term: Recurrent lower respiratory tract infections
    term:
      id: HP:0002783
      label: Recurrent lower respiratory tract infections
    temporality: RECURRENT
  sequelae:
  - target: Bronchiectasis
    description: >-
      Repeated lower airway infection produced irreversible bronchial dilatation in
      both sisters, diagnosed at ages 10 and 18.
    evidence:
    - reference: PMID:30521495
      reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The sisters were diagnosed with bronchiectasis and evaluated for PID at the age of 10 and 18 years"
      explanation: >-
        Gives the ages at which bronchiectasis was diagnosed in each sister.
  evidence:
  - reference: PMID:30521495
    reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We used whole-exome sequencing to identify compound heterozygous mutations in ARHGEF1, resulting in the loss of ARHGEF1 protein expression in 2 primary antibody-deficient siblings presenting with recurrent severe respiratory tract infections and bronchiectasis."
    explanation: >-
      Names recurrent severe respiratory tract infection as the presenting feature.
- category: Respiratory
  name: Recurrent pneumonia
  description: >-
    Episodes of pneumonia from the age of 7 in the elder sister and 11 in the
    younger, continuing thereafter. This is the pediatric onset marker for the
    entity: the disease presents in the school-age years, not in infancy.
  phenotype_term:
    preferred_term: Recurrent pneumonia
    term:
      id: HP:0006532
      label: Recurrent pneumonia
    temporality: RECURRENT
    onset:
      onset_category: CHILDHOOD
      notes: >-
        Pneumonia from ages 7 and 11; formal immunological evaluation followed only
        at 10 and 18.
  sequelae:
  - target: Bronchiectasis
    description: >-
      Recurrent pneumonia preceded the diagnosis of bronchiectasis in both sisters.
    evidence:
    - reference: PMID:30521495
      reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The sisters were diagnosed with bronchiectasis and evaluated for PID at the age of 10 and 18 years"
      explanation: >-
        Places the bronchiectasis diagnosis after the onset of pneumonia at 7 and
        11 recorded in the preceding sentence.
  evidence:
  - reference: PMID:30521495
    reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "this included episodes of pneumonia from the age of 7 and 11 years onwards"
    explanation: >-
      Gives the onset ages directly.
- category: Respiratory
  name: Bronchiectasis
  description: >-
    Irreversible bronchial dilatation from recurrent suppurative lower airway
    infection, present in both sisters and severe enough in each to require lung
    lobectomy - in the elder for persistent localized suppuration at age 12.
  phenotype_term:
    preferred_term: Bronchiectasis
    term:
      id: HP:0002110
      label: Bronchiectasis
  evidence:
  - reference: PMID:30521495
    reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The sisters were diagnosed with bronchiectasis and evaluated for PID at the age of 10 and 18 years"
    explanation: >-
      Documents bronchiectasis in both sisters with the age at diagnosis.
  - reference: PMID:41608114
    reference_title: "Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ARHGEF1 deficiency | ARHGEF1 | AR | 618459 | Hypogammaglobulinemia; lack of antibody | Recurrent infections, bronchiectasis"
    explanation: >-
      Bronchiectasis is one of the two associated features IUIS records for this
      entity.
- category: Immunological
  name: Decreased circulating total IgG concentration
  description: >-
    Total IgG below the age-matched reference interval in both sisters before
    immunoglobulin replacement (6.3 g/l against 8.3-14.3; 6.93 against 9.2-14.8).
    The reduction is modest in absolute terms, which is why the functional antibody
    testing rather than the IgG level is what makes the diagnosis here.
  phenotype_term:
    preferred_term: Decreased circulating total IgG concentration
    term:
      id: HP:0032132
      label: Decreased circulating total IgG concentration
  evidence:
  - reference: PMID:30521495
    reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "IgG (g/l) 6.3 (8.3-14.3) 6.93 (9.2-14.8)"
    explanation: >-
      The Table 1 IgG values with age-matched reference intervals for each patient.
- category: Immunological
  name: Decreased circulating IgG4 concentration
  description: >-
    IgG4 was essentially absent in both sisters (0.001 and 0.004 g/l) - the most
    severely affected subclass, and the one discordant with the relatively
    preserved IgG2 and IgG3 levels.
  phenotype_term:
    preferred_term: Decreased circulating IgG4 concentration
    term:
      id: HP:0032138
      label: Decreased circulating IgG4 concentration
  evidence:
  - reference: PMID:30521495
    reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "IgG4 (g/l) 0.001 0.004 IgA (g/l) 0.87 (1.02-1.94) 1.95 (1.42-2.62)"
    explanation: >-
      The Table 1 immunoglobulin block, giving each patient's IgG4 value before
      replacement therapy alongside the adjacent IgA row.
- category: Immunological
  name: Decreased total B cell count
  description: >-
    Circulating CD19+ B cells below the reference interval in both sisters.
  phenotype_term:
    preferred_term: Decreased total B cell count
    term:
      id: HP:0010976
      label: Decreased total B cell count
  evidence:
  - reference: PMID:30521495
    reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both patients presented with low CD19+ B cell blood counts, an elevated frequency of transitional B cells"
    explanation: >-
      States the low total B cell count directly.
- category: Immunological
  name: Decreased memory B cell proportion
  description: >-
    Memory B cells 2% and 1% of the B cell compartment against a reference floor of
    10%; switched memory B cells were almost undetectable.
  phenotype_term:
    preferred_term: Decreased memory B cell proportion
    term:
      id: HP:0030374
      label: Decreased memory B cell proportion
  evidence:
  - reference: PMID:30521495
    reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Memory B cells (%) 2 (>10) 1 (>10)"
    explanation: >-
      The Table 1 memory B cell row with the reference floor.
- category: Immunological
  name: Decreased marginal zone B cell proportion
  description: >-
    Marginal zone B cells 1% and 0.2% against a reference interval of 13.4-21.4%.
    This is the compartment the Lsc/Arhgef1 knockout mouse had already shown to
    depend on this exchange factor.
  phenotype_term:
    preferred_term: Decreased marginal zone B cell proportion
    term:
      id: HP:0030384
      label: Decreased marginal zone B cell proportion
  evidence:
  - reference: PMID:30521495
    reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MZ B cells (%) 1 (13.4-21.4) 0.2 (13.4-21.4)"
    explanation: >-
      The Table 1 marginal zone B cell row with the reference interval.
- category: Immunological
  name: Increased transitional B cell proportion
  description: >-
    Transitional B cells 17% of the B cell compartment in both sisters against a
    reference ceiling of 11%.
  phenotype_term:
    preferred_term: Increased transitional B cell proportion
    term:
      id: HP:0030381
      label: Increased transitional B cell proportion
  evidence:
  - reference: PMID:30521495
    reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Transitional B cells (%) 17 (<11) 17 (<11)"
    explanation: >-
      The Table 1 transitional B cell row with the reference ceiling.
- category: Hematologic
  name: Increased circulating myelocyte count
  description: >-
    Myelocytes were repeatedly present on blood smears from both sisters. A bone
    marrow examination in one found no evidence of a myeloproliferative or
    myelodysplastic syndrome, so this is an egress or retention abnormality rather
    than a marrow disease - and it is the finding that makes the entity a
    trafficking disorder rather than a B cell disorder.
  phenotype_term:
    preferred_term: Increased circulating myelocyte count
    term:
      id: HP:0032237
      label: Increased circulating myelocyte count
  evidence:
  - reference: PMID:30521495
    reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Furthermore, the patients' blood contained immature myeloid cells."
    explanation: >-
      Reports circulating immature myeloid cells in both patients.
  - reference: PMID:30521495
    reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Blood samples from both patients repeatedly contained myelocytes (Figure 1, A and B)."
    explanation: >-
      Records that the finding was repeated rather than a single observation,
      which is what distinguishes it from an incidental smear result.
- category: Immunological
  name: Decreased central memory CD8+ T cell proportion
  description: >-
    Both sisters had reduced CD8+ central memory T cell frequencies. The founding
    report treats the T cell abnormalities as secondary to the primary B cell and
    trafficking defect, and absolute T cell, CD4 and CD8 counts were within
    reference.
  phenotype_term:
    preferred_term: Decreased central memory CD8+ T cell proportion
    term:
      id: HP:0410389
      label: Decreased central memory CD8+ T cell proportion
  evidence:
  - reference: PMID:30521495
    reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both patients presented with a decreased frequency of CD8+ central memory and effector memory T cell subsets"
    explanation: >-
      Reports the reduced CD8+ central memory frequency in both patients.
- category: Immunological
  name: Recurrent herpes zoster
  description: >-
    Recurrent varicella zoster virus reactivation (herpes zoster) in both sisters;
    the younger had three episodes. Viral susceptibility is unusual for a purely
    antibody-deficient phenotype and is one reason the founding report notes a
    possible contribution from the T cell abnormalities. The source describes
    recurrent zoster rather than severe primary varicella.
  phenotype_term:
    preferred_term: Recurrent herpes zoster
    term:
      id: HP:0032275
      label: Recurrent shingles
    temporality: RECURRENT
  evidence:
  - reference: PMID:30521495
    reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "P2 experienced 3 episodes of herpes zoster, a severe, acute, oral herpes simplex virus 1 (HSV-1) primary infection, and recurrent lung infections"
    explanation: >-
      Names the episodes as herpes zoster and gives the count for the younger
      sister. This is the sentence that settles reactivation rather than primary
      infection, so it is the one this binding rests on; it also records the
      severe primary HSV-1 infection alongside it.
  - reference: PMID:30521495
    reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Viral infections Recurrent VZV HSV; recurrent VZV"
    explanation: >-
      The Table 1 viral infection row, recording recurrent VZV in both sisters.
      The table says "VZV" without distinguishing primary infection from
      reactivation, which is why it is the supporting item here rather than the
      one the term binding is taken from.
- category: Hematologic
  name: Autoimmune thrombocytopenia
  description: >-
    Immune thrombocytopenia developed in the elder sister at 13 years. Reported in
    one of the two patients only; it is recorded here because autoimmune cytopenia
    is a recognised complication of primary antibody deficiency generally, but one
    patient is not a frequency.
  phenotype_term:
    preferred_term: Autoimmune thrombocytopenia
    term:
      id: HP:0001973
      label: Autoimmune thrombocytopenia
  evidence:
  - reference: PMID:30521495
    reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At 13 years of age, P1 developed immune thrombocytopenia."
    explanation: >-
      The single reported occurrence, with the age at onset.
- category: Neoplastic
  name: Bronchial neoplasm
  description: >-
    A bronchial mucoepidermoid carcinoma was diagnosed in the younger sister at 21
    years and resected by lobectomy; the mediastinal lymph nodes taken at that
    operation are the source of this entry's germinal centre histology and were
    free of tumour. This is ONE tumour in ONE of TWO reported patients and must not
    be read as a cancer predisposition: no second occurrence, no segregation data,
    no somatic or functional work linking ARHGEF1 loss to this tumour, and a
    background of chronic bronchiectasis in the same lobe. The reason it is curated
    at all is that somatic loss-of-function ARHGEF1 mutation is independently
    implicated in germinal centre B cell-like diffuse large B cell lymphoma, so a
    germline null is a question worth leaving visible rather than dropping; see the
    knowledge gap in `discussions`.
  phenotype_term:
    preferred_term: Bronchial mucoepidermoid carcinoma
    term:
      id: HP:0030077
      label: Bronchial neoplasm
  evidence:
  - reference: PMID:30521495
    reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "at 21 years of age, she was diagnosed with bronchial mucoepidermoid carcinoma and underwent a lung lobectomy"
    explanation: >-
      The single reported tumour, with the age at diagnosis and the operation. HPO
      has no mucoepidermoid carcinoma term, so the binding is to the anatomical
      neoplasm term and the histology is carried in `preferred_term`.
genetic:
- name: ARHGEF1 biallelic loss of function
  gene_term:
    preferred_term: ARHGEF1
    term:
      id: hgnc:681
      label: ARHGEF1
  association: Causative
  relationship_type: CAUSATIVE
  notes: >-
    ARHGEF1 at 19q13.2 is the gene OMIM (#618459) and MedGen (C5193109) associate
    with IMD62; MONDO:0032763 itself records no causal-gene relationship, so the
    anchor here comes from OMIM/MedGen and from the IUIS classification row rather
    than from MONDO. That MONDO gap is worth reporting upstream. The evidence
    strength should be read plainly: two affected individuals, sisters, from one
    family, with the causal direction established functionally in their own cells
    (RhoA activity and actin polymerisation restored by retroviral ARHGEF1
    expression) rather than by segregation across families. A search of the 612
    ClinGen gene-disease validity records cached in this repository
    (`grep -l ARHGEF1 references_cache/CGGV_*.md`, re-run 2026-09-25) returned no
    file, so there is no ClinGen validity assertion for ARHGEF1 to cite.
    `relationship_type` is CAUSATIVE rather than DISPUTED because no publication
    disputes the relationship; the limitation is quantity of evidence, not conflict
    within it.
  variants:
  - name: ARHGEF1 c.898C>T p.(Arg300Ter) (paternal allele)
    description: >-
      Nonsense variant in exon 12 of NM_199002.1, inherited from the healthy
      father, with a CADD score of 41 and absent from ExAC, the Exome Sequencing
      Project, dbSNP and SwissVar at the time of reporting.
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:30521495
      reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "compound heterozygous variants in ARHGEF1: a nonsense variant on Chr19: 42398710: C>T (hg19 build 137) (NM_199002.1, exon 12, c. 898 C>T, p.R300X) and a splice acceptor site variant on Chr19: 42406933: G>T"
      explanation: >-
        Names the nonsense allele with its transcript, exon, cDNA and protein
        notation.
  - name: ARHGEF1 c.1669-1G>T splice acceptor variant (maternal allele)
    description: >-
      Splice acceptor site variant inherited from the healthy mother. RT-PCR on
      patient and maternal peripheral blood mononuclear cells detected an aberrant
      transcript, expressed at lower level than the main transcript, that skips
      exon 19 and frameshifts to a premature stop codon.
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:30521495
      reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "abnormal exon skipping of exon 19, introducing a frame shift with creation of a premature stop codon (E557Kfs34X)"
      explanation: >-
        Gives the transcript-level consequence of the splice allele.
    - reference: PMID:30521495
      reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "A nonsense mutation c.898C>T (Chr19: 42398710: C>T; hg19 build 137) was inherited from the father, and a splice mutation c.1669-1G>T (Chr19: 42406933: G>T) was inherited from the mother."
      explanation: >-
        Gives the cDNA notation of the splice allele and its parental origin.
  evidence:
  - reference: PMID:30521495
    reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "compound heterozygous variants in ARHGEF1 in both patients resulted in ARHGEF1-deficient expression in lymphocytes."
    explanation: >-
      Establishes that the two alleles together abolish protein expression.
  - reference: PMID:30521495
    reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We assume that any combination of these variations will lead to ARHGEF1 deficiency."
    explanation: >-
      The authors' expectation that other truncating ARHGEF1 alleles annotated in
      population databases would behave the same way in the biallelic state. Quoted
      with their own hedge intact: it is a prediction, not an observation, and no
      such patient has been reported.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Two affected individuals, sisters from one non-consanguineous family. No second
    kindred has been reported in the seven years since the founding paper; the one
    subsequent primary publication studied platelet function in the younger of the
    same two sisters. No population prevalence estimate exists and none is derivable
    from a cohort of this size.
  evidence:
  - reference: PMID:42687834
    reference_title: "Normal platelet function in a patient with ARHGEF1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "ARHGEF1 deficiency has been described in two female siblings (P1 and P2) carrying compound heterozygous germline variants in ARHGEF1 (Figure 1A) , resulting in primary antibody deficiency and recurrent severe respiratory tract infections with bronchiectasis"
    explanation: >-
      A 2026 paper's own statement of the published case count, which is still two
      siblings. Graded HUMAN_CLINICAL with quote_role BACKGROUND because the
      sentence restates the founding clinical report rather than this paper's own
      platelet results.
treatments:
- name: Immunoglobulin Replacement Therapy
  description: >-
    Both sisters were started on polyvalent IgG replacement and were reported doing
    well on subcutaneous immunoglobulin at last follow-up, at 30 and 27 years. No
    trial or case series has evaluated immunoglobulin replacement in ARHGEF1
    deficiency specifically - with two patients none could exist - so the general
    justification is the class-level standard of care for inborn errors of immunity
    with impaired antibody production, and the disease-specific evidence is
    observational use in the two reported patients.
  action_category: THERAPEUTIC
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: immunoglobulin replacement therapy
    term:
      id: NCIT:C62710
      label: Immunoglobulin Therapy
  target_mechanisms:
  - target: Defective Specific Antibody Production
    treatment_effect: BYPASSES
    description: >-
      Replacement immunoglobulin supplies the specific antibody the patients cannot
      make. It bypasses the defect; it does not restore RhoA signalling, B cell
      trafficking, or the patients' own vaccine responses.
    evidence:
    - reference: PMID:42208906
      reference_title: "Practice parameter for inborn errors of immunity: What is new in the 2025 update."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "The management part includes recommendations for immunoglobulin replacement, antibiotic prophylaxis, hematopoietic stem cell transplantation, precision medicine, and quality-of-life assessment."
      explanation: >-
        Establishes immunoglobulin replacement as a recommended management
        component for inborn errors of immunity. Class-level evidence, cited as
        such.
  evidence:
  - reference: PMID:30521495
    reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "P1 was aged 30 and was doing well on subcutaneous IgG replacement therapy."
    explanation: >-
      The only disease-specific outcome statement available: one patient doing well
      on subcutaneous replacement at 30 years. An observation in one patient, not
      an efficacy result.
  - reference: PMID:30521495
    reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Polyvalent IgG replacement therapy was initiated, and a lung lobectomy was performed on P1 at the age of 12 because of persistent suppuration associated with localized bronchiectasis"
    explanation: >-
      Records the initiation of replacement therapy in the founding kindred.
- name: Lung Lobectomy for Localized Suppurative Bronchiectasis
  description: >-
    Resection of a lobe destroyed by localized suppurative bronchiectasis, performed
    in the elder sister at age 12 for persistent suppuration. The younger sister
    also underwent lobectomy, but for her bronchial mucoepidermoid carcinoma rather
    than for infection. Surgery here treats the structural sequela; it does nothing
    to the underlying immune defect, and the general practice of resecting localized
    destroyed lung in bronchiectasis is not specific to this disease.
  action_category: THERAPEUTIC
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: lung lobectomy
    term:
      id: NCIT:C15272
      label: Lobectomy
  target_mechanisms:
  - target: Bronchiectasis
    treatment_effect: MODULATES
    description: >-
      Removing the destroyed, chronically infected lobe removes the focus of
      persistent suppuration. It does not prevent bronchiectasis elsewhere.
    evidence:
    - reference: PMID:30521495
      reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Polyvalent IgG replacement therapy was initiated, and a lung lobectomy was performed on P1 at the age of 12 because of persistent suppuration associated with localized bronchiectasis"
      explanation: >-
        States the indication for the operation in the one patient in whom it was
        performed for infection.
  evidence:
  - reference: PMID:30521495
    reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Polyvalent IgG replacement therapy was initiated, and a lung lobectomy was performed on P1 at the age of 12 because of persistent suppuration associated with localized bronchiectasis"
    explanation: >-
      The single reported instance of this intervention for infection in this
      disease.
diagnosis:
- name: Whole Exome Sequencing
  description: >-
    The test that made the diagnosis. IMD62 has no clinical or laboratory feature
    that distinguishes it from any other primary antibody deficiency at the
    bedside - the two sisters were carried as unexplained antibody deficiency for
    years - so the diagnosis is genetic, and in the founding kindred it came from
    comparing the two affected siblings' exomes.
  diagnosis_term:
    preferred_term: whole exome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  evidence:
  - reference: PMID:30521495
    reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "WES of DNA from total blood samples from both patients was performed with a view to identifying the underlying genetic cause of their disease."
    explanation: >-
      States the diagnostic route taken in the only reported kindred.
- name: Specific Antibody Response Testing
  description: >-
    Measurement of antibody titres to protein and polysaccharide vaccine antigens
    after immunisation. This is the functional test that shows the defect, and it
    matters here because total IgG is only modestly reduced (6.3 and 6.93 g/l):
    an entry-level immunoglobulin panel alone would understate the problem, while
    the vaccine responses are flatly absent.
  diagnosis_term:
    preferred_term: specific antibody response measurement
    term:
      id: NCIT:C81869
      label: Immunoglobulin Measurement
  evidence:
  - reference: PMID:30521495
    reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Antibody production (including T cell-dependent and -independent vaccine responses to poliovirus, tetanus, diphtheria toxoids, and pneumococcal immunizations) was defective in both patients"
    explanation: >-
      Names the antigens tested and the result in both patients.
- name: B Cell Immunophenotyping by Flow Cytometry
  description: >-
    Flow cytometric enumeration of the circulating B cell subsets. The pattern is
    the one that should raise ARHGEF1 as a possibility rather than a generic CVID
    label: marginal zone and switched memory B cells almost absent, transitional
    B cells raised. Examining a blood film at the same time is worth doing, since
    circulating myelocytes with an unremarkable marrow point the same way.
  diagnosis_term:
    preferred_term: B cell immunophenotyping
    term:
      id: NCIT:C16585
      label: Flow Cytometry
  evidence:
  - reference: PMID:30521495
    reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both ARHGEF1-deficient patients showed an abnormal B cell immunophenotype, with a deficiency in marginal zone and memory B cells and an increased frequency of transitional B cells."
    explanation: >-
      Gives the subset pattern this test is being recorded for.
animal_models:
- name: Lsc (Arhgef1) knockout mouse
  species: Mouse
  genotype: Lsc (Arhgef1) homozygous null by gene targeting
  publication: PMID:11526402
  description: >-
    The murine ortholog knockout, published nearly two decades before the human
    disease and the reason the human marginal zone and antibody phenotype was
    recognisable when it appeared. Lsc-null mice lack marginal zone B cell
    homeostasis, show reduced basal lymphocyte motility with defective release from
    integrin ligands, and fail to mount the antigen-specific IgM response to a
    T-dependent protein antigen.
  modeled_mechanisms:
  - target: Loss of Circulating Marginal Zone and Memory B Cells
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Marginal zone B cell homeostasis fails in the Lsc-null mouse as it does in the
      ARHGEF1-deficient patients, and in both the proximate defect is a trafficking
      one rather than a developmental block.
    limitations: >-
      The mouse marginal zone compartment is splenic and anatomically better defined
      than the circulating CD27+IgD+ population measured in the patients, so the two
      readouts are related but not the same measurement. The mouse data also say
      nothing about the memory B cell loss that is equally prominent in the human
      disease.
    readouts:
    - name: Marginal zone B cell homeostasis
      target: Loss of Circulating Marginal Zone and Memory B Cells
      direction: DECREASED
      interpretation: >-
        The compartment-level readout that corresponds to the human marginal zone
        B cell deficiency.
      evidence:
      - reference: PMID:11526402
        reference_title: "Lsc is required for marginal zone B cells, regulation of lymphocyte motility and immune responses."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Lsc is essential for marginal zone B (MZB) cell homeostasis and for the generation of immune responses."
        explanation: >-
          States the marginal zone requirement measured in the knockout.
    evidence:
    - reference: PMID:11526402
      reference_title: "Lsc is required for marginal zone B cells, regulation of lymphocyte motility and immune responses."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Lsc is expressed primarily in the hematopoietic system and links the activation of G alpha(12) and G alpha(13)-coupled receptors to actin polymerization in B and T cells."
      explanation: >-
        Establishes that the mouse model perturbs the same receptor-to-actin
        pathway that is lost in the human disease, which is what makes it
        informative for this node.
  - target: Defective Specific Antibody Production
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Lsc-null mice fail to produce the antigen-specific IgM response to a protein
      antigen, and their marginal zone B cells do not contribute to the T-dependent
      antibody response - the same functional endpoint measured in the patients as
      absent vaccine responses.
    limitations: >-
      The mouse experiments use defined model antigens and read out IgM; the human
      phenotype is absent IgG responses to toxoid, polio and pneumococcal
      immunisation with IgG4 essentially undetectable. The classes and antigens
      differ, so the correspondence is at the level of "no specific antibody
      response", not of a matched assay.
    readouts:
    - name: Antigen-specific IgM response to a T-dependent protein antigen
      target: Defective Specific Antibody Production
      direction: DECREASED
      interpretation: >-
        Functional antibody readout in the knockout, corresponding to the patients'
        absent specific antibody responses.
      evidence:
      - reference: PMID:16286020
        reference_title: "Lsc regulates marginal-zone B cell migration and adhesion and is required for the IgM T-dependent antibody response."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "we demonstrate that Lsc, a protein that regulates G protein-coupled-receptor signaling and RhoA activation, is required by B lymphocytes for the antigen-specific IgM antibody response to a protein antigen."
        explanation: >-
          Reports the failed antigen-specific antibody response in the knockout.
    evidence:
    - reference: PMID:16286020
      reference_title: "Lsc regulates marginal-zone B cell migration and adhesion and is required for the IgM T-dependent antibody response."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Consequently, lsc(-/-) MZB cells do not traffick appropriately in an immune response and do not contribute to the TD antibody response."
      explanation: >-
        Links the trafficking defect to the antibody failure in the model, the same
        causal shape this entry curates for the human disease.
discussions:
- discussion_id: imd62_mouse_platelet_phenotype_absent_in_humans
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Arhgef1-null mice have a severe platelet activation and haemostasis defect.
    An ARHGEF1-deficient human has none. Which species is telling us what ARHGEF1
    does in platelets?
  attaches_to:
  - "pathophysiology#Reduced RhoA Activation in Lymphocytes"
  rationale: >-
    Arhgef1-/- mice have prolonged tail bleeding and carotid occlusion times, with
    defective platelet aggregation, granule secretion, integrin activation, clot
    retraction and spreading, and absent platelet RhoA activation - a phenotype
    striking enough that its authors proposed ARHGEF1 as a therapeutic target in
    thrombosis. When platelet function was finally measured in the younger of the
    two ARHGEF1-deficient sisters, everything was normal: aggregometry across seven
    agonists, glycoprotein expression and PAC-1 binding, dense and alpha granule
    content and secretion, spreading, clot retraction, procoagulant extracellular
    vesicle release, and - decisively - platelet RhoA activation itself, which was
    of similar magnitude to control. She had had no bleeding through lobectomy,
    ovarian cyst excision, breast implant surgery, two childbirths and terminations.
    So the divergence is not a matter of assay sensitivity: the proximate signalling
    step that fails in the patient's lymphocytes does not fail in her platelets. The
    authors attribute this to redundancy among the RhoGEFs human platelets express,
    noting that ARHGEF7 and ARHGEF6 are more abundant than ARHGEF1 there, and that
    ARHGEF2 and ARHGEF6 protein levels were unchanged so any compensation would have
    to be at the level of activation rather than abundance. The mismatch matters for
    this entry in two directions: it warns against importing the mouse platelet
    literature into the human disease description, and it suggests that the
    lymphocyte phenotype is severe precisely because lymphocytes lack the RhoGEF
    redundancy that protects platelets. It is also a single patient, and the
    compensating mechanism is hypothesised rather than identified.
  evidence:
  - reference: PMID:30994039
    reference_title: "Arhgef1 Plays a Vital Role in Platelet Function and Thrombogenesis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Our results indicate that Arhgef1-/- mice had prolonged carotid artery occlusion and tail bleeding times."
    explanation: >-
      The murine haemostatic phenotype that the human patient does not have.
  - reference: PMID:42687834
    reference_title: "Normal platelet function in a patient with ARHGEF1 deficiency."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast to the severe platelet phenotype reported in Arhgef1 -/- mice, loss of ARHGEF1 expression in human platelets was not associated with detectable functional abnormalities across multiple assays."
    explanation: >-
      Recorded as REFUTE against the proposition that the murine platelet phenotype
      transfers to human ARHGEF1 deficiency.
  - reference: PMID:42687834
    reference_title: "Normal platelet function in a patient with ARHGEF1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ARHGEF1 -deficient platelets exhibited RhoA activation of a similar magnitude to control platelets under identical activation conditions (Figure 2C), indicating no defect in RhoA activation."
    explanation: >-
      Locates the divergence at the RhoA activation step itself, not at a downstream
      readout - which is what rules out an assay-sensitivity explanation.
  - reference: PMID:42687834
    reference_title: "Normal platelet function in a patient with ARHGEF1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patient P2, a 36-year-old woman, had no personal or familial history of bleeding, including during multiple hemostatic challenges (lung lobectomy, ovarian cyst excision, breast implant placement, two childbirths, and elective pregnancy terminations)."
    explanation: >-
      The clinical counterpart: repeated haemostatic challenges without bleeding.
  proposed_experiments:
  - experiment_id: exp_imd62_platelet_rhogef_redundancy
    name: Which RhoGEF sustains RhoA activation in ARHGEF1-null human platelets
    description: >-
      Knock down ARHGEF7, ARHGEF6, ARHGEF2 and ARHGEF12 individually and in
      combination in a human megakaryocytic system carrying an engineered ARHGEF1
      null, and measure agonist-induced RhoA-GTP, aggregation and clot retraction.
      This would test directly the redundancy hypothesis the platelet paper offers,
      and would say whether lymphocytes lack the same redundancy.
    would_support:
    - "discussions#imd62_mouse_platelet_phenotype_absent_in_humans"
    supporting_outcome:
    - >-
      Loss of one or more additional platelet RhoGEFs on the ARHGEF1-null background
      reproduces the murine platelet phenotype in human cells.
    refuting_outcome:
    - >-
      RhoA activation and platelet function remain intact despite combined RhoGEF
      knockdown, implying the species difference lies elsewhere than in RhoGEF
      redundancy.
- discussion_id: imd62_malignancy_risk_unknown
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Does germline ARHGEF1 loss carry a tumour risk, and specifically a lymphoma
    risk, given that somatic ARHGEF1 loss of function is recurrent in germinal
    centre B cell-like diffuse large B cell lymphoma?
  attaches_to:
  - "phenotypes#Bronchial neoplasm"
  - "pathophysiology#Disturbed Germinal Center Reaction"
  rationale: >-
    One of the two reported patients developed a bronchial mucoepidermoid carcinoma
    at 21. Taken alone that is a single tumour in a chronically infected and
    bronchiectatic lobe, and nothing more. What keeps the question open is the
    mechanism on the other side: the founding report's own introduction notes that
    germinal centre B cell-like diffuse large B cell lymphoma is frequently
    associated with loss-of-function ARHGEF1 mutations, and that Arhgef1-null mouse
    germinal centre B cells fail to activate sphingosine-1-phosphate signalling and
    escape excessively into blood and lymph - the same retention failure this entry
    curates as the cause of the patients' small, B cell-poor germinal centres. A
    germline null in that pathway is therefore not an obviously neutral background
    for lymphomagenesis, whatever the salivary-type carcinoma turns out to have been.
    With two patients and one tumour of the wrong lineage to bear on the question,
    the honest position is that malignancy risk in IMD62 is UNKNOWN - not absent,
    and not established. Nothing in this entry should be used to counsel a family
    about cancer risk, and no surveillance recommendation follows from it.
  evidence:
  - reference: PMID:30521495
    reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "at 21 years of age, she was diagnosed with bronchial mucoepidermoid carcinoma and underwent a lung lobectomy"
    explanation: >-
      The single reported malignancy in the two-patient series.
  - reference: PMID:30521495
    reference_title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "somatic ARHGEF1 mutations are involved in the pathogenesis of germinal center (GC) B cell-like diffuse large B cell lymphoma (GCB-DLBCL)"
    explanation: >-
      The founding report's introduction, restating the somatic-lymphoma literature
      that makes the germline question worth keeping open. Graded with quote_role
      BACKGROUND because the sentence summarises other groups' work rather than this
      paper's own results; the quotation stops where the source line breaks mid-word.
notes: >-
  Gene anchor. MONDO:0032763 records no causal-gene (RO:0004003) relationship, so
  the stub carried no `genes:` field and the gene had to be taken from the
  concept's xrefs. MedGen C5193109 (from OMIM #618459) links the concept to NCBI
  Gene 9138, which resolves to ARHGEF1 at 19q13.2 (HGNC:681, alias IMD62); the IUIS
  2024 classification row independently names ARHGEF1 with autosomal recessive
  inheritance against OMIM 618459. The missing MONDO relationship is worth
  reporting upstream.

  Nosology. Orphanet calls this entity "Childhood-onset common variable
  immunodeficiency phenotype due to ARHGEF1 deficiency" (ORPHA:696942, exact match
  to OMIM:618459), and IUIS 2024 places the ARHGEF1 row in Table 3 section 2, the
  CVID-phenotype antibody deficiencies. Both readings are compatible
  with the entry: the patients have low IgG, absent specific antibody responses,
  low memory B cells and a CVID-like clinical course. The entry is kept as its own
  Disease record rather than folded into common variable immunodeficiency because
  it is monogenic with a defined mechanism, which is exactly the distinction the
  CVID grouping does not make.

  What the disease is, mechanistically. Reading this as "another antibody
  deficiency" misses the point. The lesion is not in antigen receptor signalling;
  it is in Galpha12/13-coupled receptor signalling to RhoA, and the readouts that
  distinguish it are positional - circulating myelocytes with a normal marrow,
  transitional B cells accumulating while marginal zone and memory compartments
  empty, and germinal centres that are structurally intact but nearly free of
  B cells while stuffed with plasma cells. The founding report frames the entity as
  a mirror image of WHIM syndrome, where a CXCR4 gain of function traps cells in the
  marrow; here the failure is retention rather than egress.

  Features NOT curated, and why. Serum IgM was below reference in the elder sister
  only (0.53 g/l against 0.68-1.28) and within reference in the younger, and serum
  IgA likewise; MedGen annotates "Decreased circulating IgM concentration" for this
  concept from the OMIM clinical synopsis, but the underlying table shows the
  finding in one of two patients, so it is named here rather than curated as a
  disease phenotype. The elder sister's low isohaemagglutinin titre and the younger
  sister's severe primary HSV-1 infection are likewise single-patient findings; the
  HSV-1 event is quoted inside the zoster phenotype's evidence rather than given
  a phenotype of its own, because a single severe primary infection is not
  "recurrent herpes". The expanded CD21-low CD38-low B cell subset and the raised
  CCR7 on naive CD8+ T cells are reported without reference intervals in the
  source, so neither is curated as a phenotype and neither is claimed anywhere
  else in this entry.

  No `datasets:` block. No ARHGEF1-immunodeficiency-specific accession was
  identified, and searching the gene alone returns the large ARHGEF1 hypertension,
  platelet, vascular and cancer literature instead - the Named Entity Confusion
  hazard the dataset SOP warns about.

  No GeneReviews chapter. `just check-genereviews` against the committed Bookshelf
  index (snapshot 2026-09-10, 958 GeneReviews chapters) returns NO_CHAPTER for both
  GeneReviews and StatPearls, so the usual Mendelian phenotype baseline is not
  available for this entity and the phenotype list rests on the founding report's
  Table 1 and clinical narrative.
references:
- reference: PMID:30521495
  title: "Loss of ARHGEF1 causes a human primary antibody deficiency."
  findings: []
- reference: PMID:30714991
  title: "ARHGEF1 deficiency reveals Gα13-associated GPCRs are critical regulators of human lymphocyte function."
  findings: []
- reference: PMID:42687834
  title: "Normal platelet function in a patient with ARHGEF1 deficiency."
  findings: []
- reference: PMID:30994039
  title: "Arhgef1 Plays a Vital Role in Platelet Function and Thrombogenesis."
  findings: []
- reference: PMID:11526402
  title: "Lsc is required for marginal zone B cells, regulation of lymphocyte motility and immune responses."
  findings: []
- reference: PMID:16286020
  title: "Lsc regulates marginal-zone B cell migration and adhesion and is required for the IgM T-dependent antibody response."
  findings: []
- reference: PMID:41608114
  title: "Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee."
  findings: []
- reference: PMID:42208906
  title: "Practice parameter for inborn errors of immunity: What is new in the 2025 update."
  findings: []
- reference: "ORPHA:696942"
  title: "Childhood-onset common variable immunodeficiency phenotype due to ARHGEF1 deficiency"
  findings: []
📚

References & Deep Research

References

9
PMID:30521495
Loss of ARHGEF1 causes a human primary antibody deficiency.
No top-level findings curated for this source.
PMID:30714991
ARHGEF1 deficiency reveals Gα13-associated GPCRs are critical regulators of human lymphocyte function.
No top-level findings curated for this source.
PMID:42687834
Normal platelet function in a patient with ARHGEF1 deficiency.
No top-level findings curated for this source.
PMID:30994039
Arhgef1 Plays a Vital Role in Platelet Function and Thrombogenesis.
No top-level findings curated for this source.
PMID:11526402
Lsc is required for marginal zone B cells, regulation of lymphocyte motility and immune responses.
No top-level findings curated for this source.
PMID:16286020
Lsc regulates marginal-zone B cell migration and adhesion and is required for the IgM T-dependent antibody response.
No top-level findings curated for this source.
PMID:41608114
Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee.
No top-level findings curated for this source.
PMID:42208906
Practice parameter for inborn errors of immunity: What is new in the 2025 update.
No top-level findings curated for this source.
ORPHA:696942
Childhood-onset common variable immunodeficiency phenotype due to ARHGEF1 deficiency
No top-level findings curated for this source.

Deep Research

1

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: Immunodeficiency_62 · 2026-09-25T17:42:50Z · View source

De novo curation of Immunodeficiency 62 (MONDO:0032763, OMIM 618459, ARHGEF1 at 19q13.2) as a standalone Disease entry; the stub's entry_type was set to DISEASE in a separate commit and the stub deleted here. Gene identification. MONDO:0032763 records no causal-gene relationship (confirmed by 'just preflight-dr', which reported SKIP for that reason), so the gene was taken from the concept's xrefs rather than from memory: MedGen C5193109 -> NCBI Gene 9138 -> ARHGEF1, cross-checked against the HGNC REST API (HGNC:681, 19q13.2) and against the IUIS 2022 classification row. Deep research. Requested provider falcon returned HTTP 402 (out of credits) and the run fell back to claude_code, as the standing brief anticipated; the report is committed with its citations sidecar. Its frontmatter records needs_review: true, from an obsolete GO CURIE (GO:0005089, replaced by GO:0005085) and a MONDO label-reporting artefact. 'just preflight-dr' returned SKIP rather than PASS or FAIL, because the gene-identity check cannot run without a MONDO causal gene; the report's own top-gene histogram is ARHGEF1=50, so the report is about the right disease. The report was treated as a lead only: every claim in the entry is quoted from a primary source fetched with 'just fetch-reference'. The report missed two things found by direct literature search and curated here - the 2026 Haematologica platelet study (PMID:42687834) and the bronchial mucoepidermoid carcinoma in P2 - and it asserted that malignancy is 'not described in the source literature', which the founding paper contradicts. Sources. Founding report PMID:30521495 (Bouafia et al., J Clin Invest 2019, full_text_pdf cache) supplies the clinical narrative, Table 1 laboratory values, variant detail and every mechanistic step. PMID:30714991 is the accompanying JCI commentary. PMID:42687834 (Suffit et al., Haematologica 2026) is the only subsequent primary study and covers platelet function in P2. PMID:11526402 and PMID:16286020 are the murine Lsc/Arhgef1 knockout papers used for the animal model. PMID:35748970 (IUIS 2022) supplies the classification row; PMID:42208906 supplies class-level treatment evidence. ORPHA:696942 was built from the Orphadata bulk XML with --cache-dir pointed at this worktree. Structure. Ten pathophysiology nodes trace one chain: biallelic ARHGEF1 loss -> absent protein -> reduced RhoA activation, which branches into defective cortical actin polymerisation (and hence impaired lymphocyte migration and deadhesion) and failure to restrain PI3K/AKT. The migration arm produces loss of marginal zone and memory B cells, the disturbed germinal centre reaction and circulating myelocytes; both arms converge on defective specific antibody production, which is wired to the clinical and laboratory phenotypes. Fifteen phenotypes, all quoted from the founding report. Two discussions. A HUMAN_MODEL_MISMATCH records that Arhgef1-null mice have a severe platelet and haemostasis phenotype while the ARHGEF1-deficient patient has entirely normal platelet function including preserved platelet RhoA activation - a species divergence located at the signalling step itself rather than at a downstream readout. A KNOWLEDGE_GAP records that malignancy risk is unknown rather than absent: one bronchial mucoepidermoid carcinoma in one of two patients, against a background in which somatic loss-of-function ARHGEF1 mutation is recurrent in GCB-DLBCL. Deliberate omissions, recorded in notes: decreased IgM and IgA (present in one sister only, although MedGen annotates IgM for the concept), the low isohaemagglutinin titre, the severe primary HSV-1 infection as a phenotype of its own, and the CD21-low CD38-low subset and raised naive CD8 CCR7 (reported without reference intervals). No datasets block - searching ARHGEF1 alone returns the hypertension, platelet and cancer literature, the Named Entity Confusion hazard the dataset SOP warns about. No ClinGen gene-disease validity assertion exists: 'grep -l ARHGEF1 references_cache/CGGV_*.md' over the 612 cached ClinGen records returned nothing. No GeneReviews or StatPearls chapter: 'just check-genereviews' against the committed Bookshelf index (snapshot 2026-09-10) returns NO_CHAPTER for both. Hazard encountered. 'just validate' re-fetched and truncated references_cache/PMID_35748970.md from 5644 lines to 175, destroying the IUIS table the entry quotes (issue #12672). The file was restored with git checkout and all subsequent gates were run under 'just validate-disorders', which reports 'keeping the cached full_text_pdf entry rather than overwriting it' and passes.

Claude Code ▸
Immunodeficiency 62 (ARHGEF1 Deficiency) — Research Report
claude-haiku-4-5-20251001, claude-sonnet-5 24 citations 2026-09-25T17:21:29.470163

Immunodeficiency 62 (ARHGEF1 Deficiency) — Research Report

Target disease: Immunodeficiency 62 (IMD62) MONDO: MONDO:0032763 | OMIM: #618459 (phenotype), 601855 (gene, ARHGEF1) | Orphanet: ORPHA:696942 | Gene: ARHGEF1 (HGNC:681, chr19q13.2) | Category:* Mendelian, autosomal recessive primary immunodeficiency

Note on sourcing: Full-text access to the primary literature (JCI, PMC, PubMed, OMIM) was blocked by bot-detection/paywall gates during this research session; content below is drawn from indexed abstracts, structured-database summaries (OMIM/GTR/MalaCards/ClinGen/GeneCards mirrors), and search-engine-returned abstract text, cross-checked across independent sources where possible. Quoted fragments are reproduced as returned by these secondary retrievals and should be re-verified against primary full text (e.g., via just fetch-reference PMID:30521495) before being used as exact-quote evidence in a KB entry. This is an ultra-rare condition (literature to date describes essentially one kindred), so several template sections below have little or no disease-specific data — this is stated explicitly rather than papered over.

1. Disease Information

Overview. Immunodeficiency 62 (IMD62) is an autosomal recessive primary antibody deficiency caused by biallelic loss-of-function variants in ARHGEF1 (Rho Guanine Nucleotide Exchange Factor 1, also known as GEF1, LBCL2, LSC, P115-RHOGEF, SUB1.5). It was first delineated in 2019 in two affected sisters from a single non-consanguineous French family, identified by whole-exome sequencing (WES) as part of a primary-antibody-deficiency cohort study (Bouafia et al., 2019, PMID:30521495; companion mechanistic study, PMID:30714991). ARHGEF1 encodes a RhoA-specific guanine nucleotide exchange factor (GEF) that transduces signals from Gα13-coupled GPCRs (e.g., sphingosine-1-phosphate receptors, LPA receptors, CXCR4) into RhoA activation, controlling actin cytoskeleton dynamics and confining/positioning B lymphocytes and myeloid cells within lymphoid compartments. Loss of ARHGEF1 impairs antibody responses through defective B-cell positioning/maturation and dysregulated PI3K/AKT signaling rather than through a primary defect in immunoglobulin gene machinery.

Key identifiers:

Resource Identifier
OMIM phenotype #618459 IMMUNODEFICIENCY 62; IMD62
OMIM gene *601855 RHO GUANINE NUCLEOTIDE EXCHANGE FACTOR 1; ARHGEF1
MONDO MONDO:0032763
Orphanet ORPHA:696942
HGNC HGNC:681 (ARHGEF1)
GTR condition C5193109
Gene synonyms GEF1, LBCL2, LSC, P115-RHOGEF, SUB1.5

Synonyms/alternative names: ARHGEF1 deficiency; Rho-GEF1 deficiency; p115RhoGEF deficiency. No distinct historical eponym exists; the entity is referred to in the literature simply by its OMIM number (IMD62) or by gene name.

Evidence basis. All clinical information available to date derives from aggregated case-series/primary-literature description of a single reported kindred (2 affected siblings), not from EHR-derived or registry/population data. There is no disease registry, no GeneReviews chapter, and (as of this search) no published expansion cohort beyond the original 2019 report.

2. Etiology

Disease causal factor: Monogenic — biallelic (compound heterozygous) loss-of-function variants in ARHGEF1, autosomal recessive. This is a purely genetic/mechanistic etiology; no infectious or environmental trigger is implicated as causal (though the disease manifests as susceptibility to infection).

Genetic risk factors (causal variants). The index family carried compound heterozygous variants (ClinGen Antibody Deficiencies GCEP curation, approved 2021-01-19, classification Limited — ClinGen record): - c.853C>T, p.(Arg285Ter) — nonsense variant - c.1624-1G>T — splice-acceptor-site variant, reported to cause a frameshift with likely nonsense-mediated decay of the transcript; immunoblot of patient cells showed complete absence of ARHGEF1 protein (loss-of-function/null mechanism, PMID:30521495).

ClinGen's classification is explicitly capped at "Limited" because "SOP requires at least 3 unrelated probands from at least 2 independent reports to get above the Limited classification" and only a single sibling pair/family has been reported to date. This is a load-bearing caveat for curation: gene-disease validity here is genuinely thin, not merely under-cited.

Modifier/susceptibility genes: None reported.

Environmental/lifestyle risk factors: None specific reported; disease expression is intrinsic to the genetic lesion. Recurrent infections (see Phenotypes) are a consequence, not a cause.

Protective factors: None reported (genetic or environmental) specific to this ultra-rare disorder.

Gene-environment interactions: Not studied for this specific gene-disease pair. However, the broader biology of ARHGEF1 (see Mechanism, below) suggests that infectious challenge (viral/bacterial) precipitates the clinically apparent antibody-deficiency phenotype in carriers of biallelic null alleles, consistent with a "silent until challenged" pattern typical of antibody deficiencies.

3. Phenotypes

Phenotype data derive from OMIM's clinical synopsis (#618459) and the Bouafia et al. 2019 report, describing the two affected sisters (P1 and P2).

Phenotype (category) Onset/frequency Notes Suggested HPO term (lead — verify)
Recurrent upper respiratory tract infections Onset "late in the first decade of life"; frequent Presenting feature HP:0002205 Recurrent respiratory infections
Recurrent lower respiratory tract infections Same onset Presenting feature HP:0002205 (or narrower "Recurrent pneumonia," lead only)
Bronchiectasis Sequela of recurrent infection, reported in both sibs Structural airway damage HP:0002110 Bronchiectasis
Increased susceptibility to VZV (varicella zoster virus) Reported Viral susceptibility despite predominantly antibody-deficiency phenotype HP:0004429-type viral-susceptibility term (lead)
Increased susceptibility to HSV (herpes simplex virus) Reported As above lead — verify
Impaired antibody response to vaccination Laboratory finding Functional humoral defect HP:0002846 Impaired T-cell independent antibody response / general "Abnormal antibody response to vaccination" (lead)
Low circulating memory B cells Laboratory Flow cytometry finding HP term for decreased memory B cells (lead)
Deficiency of marginal-zone and memory B cells; increased transitional B cells Laboratory (immunophenotyping) Core immunophenotype per PMID:30521495 leads only
Almost undetectable serum antibodies Laboratory Severe hypogammaglobulinemia HP:0002850 Decreased circulating IgG / related terms (lead)
Secondary T-cell dysfunction Laboratory Described as "secondary," i.e., downstream of the primary B-cell/myeloid defect rather than a primary T-cell lesion lead
Immature myeloid cells in circulation Laboratory (blood smear/flow) Consistent with disturbed myeloid egress/retention from marrow, mirroring mouse Arhgef1 knockout phenotype lead
Small germinal centers with increased plasma cells (lymph node histology) Histopathology Reported on lymph node biopsy in at least one patient lead

Severity/progression: Reported as progressive with cumulative airway damage (bronchiectasis) from recurrent infection over childhood into the reported observation period; qualitative descriptors (mild/moderate/severe) are not systematically graded in the source material because the cohort is n=2.

Frequency among affected individuals: Because only 2 patients are reported, "percentage" frequency statistics are not meaningful/available — every listed phenotype above is present in the only reported cases (2/2), which is not generalizable.

Quality-of-life impact: Not formally measured (no EQ-5D/SF-36/QOL instrument data identified for this condition).

Not available / not yet reported: age-specific growth/developmental data, neurologic phenotype, autoimmune manifestations, malignancy risk, gastrointestinal involvement — none of these are described in the source literature located, and their absence should be read as "not reported" rather than "excluded."

4. Genetic / Molecular Information

Causal gene: ARHGEF1 (Rho Guanine Nucleotide Exchange Factor 1), OMIM 601855, HGNC:681, chromosome 19q13.2*. Gene product: guanine nucleotide exchange factor for RhoA (also called p115RhoGEF/Lsc), acting downstream of Gα12/Gα13; contains a canonical RGS-homology (RH) domain that also confers GTPase-activating-protein (GAP) activity toward Gα12/Gα13, plus tandem DH (Dbl-homology) and PH (pleckstrin-homology) domains that catalyze GDP→GTP exchange on RhoA.

Pathogenic variants (index family, both affected sisters, compound heterozygous): - c.853C>T; p.(Arg285Ter) — nonsense, predicted premature truncation - c.1624-1G>T — canonical splice-acceptor variant, shown experimentally to cause a frameshift with likely nonsense-mediated mRNA decay

Variant classification: Reported functionally as loss-of-function/null alleles — immunoblotting on patient lymphocytes showed complete absence of ARHGEF1 protein, i.e., a biallelic null genotype (PMID:30521495). Formal ACMG/AMP classification strings (Pathogenic/Likely Pathogenic) were not located in the accessible sources but the functional null result is consistent with Pathogenic.

Allele frequency: No population allele-frequency data specific to these two variants were retrieved in this session (gnomAD lookup blocked); given the extreme rarity of the phenotype and the null functional effect, both variants are expected to be very rare/private, consistent with a genuinely novel private-family finding rather than a founder allele. This should be verified directly against gnomAD before citation.

Somatic vs. germline: Germline — constitutional variants inherited from unaffected heterozygous parents (non-consanguineous), consistent with autosomal recessive transmission.

Functional consequence: Loss of function (protein-null). No gain-of-function, dominant-negative, or hypomorphic alleles have been reported for this phenotype.

Modifier genes: None reported.

Epigenetic information: None reported specific to IMD62/ARHGEF1 deficiency.

Chromosomal abnormalities: None reported; this is a single-gene point-mutation/splice-variant disorder, not a copy-number or structural chromosomal disease.

Gene constraint (gnomAD pLI/LOEUF): Not retrieved in this session — flag as a gap; useful for arguing haploinsufficiency intolerance but not independently verified here.

5. Environmental Information

  • Environmental factors: None identified as disease-causal; the disorder is monogenic.
  • Lifestyle factors: Not applicable/not reported.
  • Infectious agents: Infection is a manifestation rather than a cause — recurrent bacterial upper/lower respiratory pathogens (unspecified species in the accessible abstracts) drive the bronchiectasis phenotype, and the patients show heightened susceptibility to two specific herpesviruses, varicella zoster virus (VZV) and herpes simplex virus (HSV) (OMIM clinical synopsis, mirrored via GTR). No specific bacterial species, serotype, or viral strain data were retrieved.

6. Mechanism / Pathophysiology

Causal chain (ordered, with inference flagged)

  1. Biallelic loss-of-function variants in ARHGEF1 (nonsense + splice-acceptor) → absence of ARHGEF1 protein in hematopoietic cells (demonstrated directly by immunoblot in patient lymphocytes, PMID:30521495).
  2. Loss of ARHGEF1 → failure to couple Gα13-associated GPCR signals (S1P receptors, LPA receptors, thromboxane receptor, CXCR4) to RhoA activation in lymphocytes (demonstrated directly by ligand-stimulation assays on patient cells, PMID:30714991).
  3. Reduced RhoA-GTP loading → decreased steady-state and stimulus-induced actin polymerization (F-actin) in patient T and B lymphocytes (demonstrated directly).
  4. Disturbed RhoA→ROCK (Rho-associated kinase I/II) signaling → failure to restrain PI3K/AKT phosphorylation (i.e., loss of a RhoA/ROCK-dependent brake on AKT) — demonstrated directly, and pharmacologic RhoA activation or restoring ARHGEF1 expression rescued both the actin and AKT phenotypes in vitro, supporting causality rather than mere correlation.
  5. Combined actin-cytoskeleton and GPCR-signaling defects → impaired lymphocyte and myeloid-cell migration/positioning and integrin-dependent adhesion (demonstrated directly by migration assays on integrin ligands and by circulating immature myeloid cells in patient blood; inferred by analogy from extensive mouse Arhgef1/Lsc knockout data — see Model Organisms, below — that this reflects a failure to retain/position marginal-zone B cells and control lymphocyte egress).
  6. Mispositioning/failure of marginal-zone and germinal-center B-cell compartments → abnormal B-cell immunophenotype: deficiency of marginal-zone and memory B cells, increased transitional B cells, small germinal centers with increased plasma-cell content on lymph-node histology (demonstrated directly in patient blood/tissue).
  7. Defective B-cell maturation/positioning → failure to mount T-cell-dependent and T-cell-independent antibody responses to vaccination and pathogens, i.e., primary/predominant antibody deficiency with near-undetectable circulating antibody (demonstrated directly; mechanistically this step is supported both by direct human data and by strong concordance with the mouse Lsc-knockout literature, where loss of the ortholog produces near-identical humoral defects — inferred generalization from a well-established animal model to the human case, i.e., directness: INDIRECT support from the mouse literature, DIRECT support from the human functional studies).
  8. Concomitantly, secondary T-cell dysfunction is observed (mechanism less well resolved — likely downstream/secondary to the shared actin/AKT signaling defect rather than an independent primary T-cell lesion; this step is inferred, not mechanistically dissected in the source papers).
  9. Combined humoral failure + secondary T-cell dysfunction → clinical phenotype of recurrent bacterial sinopulmonary infection with bronchiectasis, and increased susceptibility to VZV/HSV.

Detail by category

  • Molecular pathways: Gα13(GNA13)–ARHGEF1(p115RhoGEF)–RhoA–ROCK I/II axis; downstream negative regulation of PI3K/AKT. GO terms to consider (leads, verify before binding): GO:0005089 (Rho guanyl-nucleotide exchange factor activity), GO:0035023 (regulation of Rho protein signal transduction), GO:0007266 (Rho protein signal transduction).
  • Cellular processes: actin cytoskeleton polymerization/remodeling, integrin-dependent adhesion, chemotactic/lysophospholipid-receptor-directed cell migration, lymphocyte positioning within secondary lymphoid organs, B-cell class-switch/maturation support (via indirect maturation-niche effects rather than a direct AID/CSR defect — not reported as a direct class-switch recombination enzyme defect).
  • Protein dysfunction: complete loss of protein (null) rather than a structural misfolding/dominant-negative mechanism; both a nonsense truncation and a splice-defect–driven NMD converge on absence of functional ARHGEF1.
  • Immune system involvement: This is fundamentally an immune-cell-intrinsic signaling disorder — predominantly antibody deficiency with a B-cell/myeloid positioning defect, plus secondary T-cell dysfunction; no evidence of autoimmunity or autoinflammation reported.
  • Tissue damage mechanisms: Recurrent infection → chronic airway inflammation → bronchiectasis (structural, secondary to infection burden rather than a primary structural lung defect).
  • Biochemical abnormalities: Loss of RhoA-GTP loading capacity in lymphocytes; failure of ROCK-dependent restraint on AKT phosphorylation.
  • Single-cell/omics/advanced technologies: No single-cell, spatial transcriptomic, or multi-omics dataset specific to human ARHGEF1 deficiency was located. The 2019 papers used targeted flow cytometry, immunoblotting, and functional cell-based assays (migration, adhesion, RhoA-GTP pulldown), not unbiased omics profiling.

Suggested cell types (CL, leads): CL:0000236 B cell; CL:0000844 marginal zone B cell; CL:0000969 memory B cell; CL:0000818 transitional stage B cell; CL:0000542 lymphocyte (T cell involvement, secondary); CL:0000766 myeloid cell (immature circulating forms).

7. Anatomical Structures Affected

  • Organ level (primary): Respiratory system — upper and lower airways (recurrent infection); lungs specifically via bronchiectasis. Secondary/immune organs: lymph nodes (abnormal germinal-center architecture), spleen (inferred site of marginal-zone B-cell dysfunction, by strong analogy to the mouse spleen phenotype — not directly biopsied/reported in the human cases), bone marrow (site of myeloid egress dysregulation, inferred from circulating immature myeloid cells).
  • Body systems involved: Immune system (primary); respiratory system (secondary, consequence of immune failure).
  • Tissue/cell level: Lymphoid tissue (germinal centers, marginal zone); circulating B lymphocytes, T lymphocytes, myeloid cells.
  • Subcellular level: Cytoskeleton/cortical actin (GO Cellular Component candidate: GO:0015629 actin cytoskeleton); plasma membrane-proximal GPCR signaling complexes.
  • Localization/UBERON leads (verify before binding): UBERON:0002048 lung; UBERON:0000029 lymph node; UBERON:0002106 spleen (inferred, not directly reported); UBERON:0002371 bone marrow (inferred).
  • Laterality: Not specifically reported (bronchiectasis distribution not detailed in accessible abstracts).

8. Temporal Development

  • Onset: Described specifically as "late in the first decade of life" (OMIM clinical synopsis) — i.e., childhood onset, insidious/subacute rather than neonatal or acute.
  • Progression: Chronic and apparently progressive with respect to structural airway damage (bronchiectasis accrues with recurrent infection); the underlying immunologic defect itself is presumably lifelong/static (germline, constitutively null gene), but its clinical expression accumulates over time.
  • Disease course pattern: Chronic with recurrent infective episodes rather than a single-episode or fully remitting course; consistent with other predominant antibody deficiencies (e.g., CVID-like course).
  • Duration: Chronic/lifelong (genetic, biallelic null).
  • Remission patterns / critical periods: Not reported; no data on spontaneous or treatment-induced remission for this specific gene defect. By analogy with other antibody deficiencies, immunoglobulin replacement (if used) would be expected to reduce but not eliminate infection frequency — this is an inference, not a reported outcome for this specific disease.

9. Inheritance and Population

  • Inheritance pattern: Autosomal recessive (confirmed compound heterozygous state in both affected sisters, unaffected heterozygous-carrier parents implied by non-consanguineous transmission).
  • Penetrance: Presumed complete for the null genotype based on both reported sibs being affected, but n=2 is far too small to estimate penetrance rigorously; not formally established.
  • Expressivity: Both reported sisters share overlapping but not necessarily identical clinical detail (exact concordance not resolved in the accessible abstracts) — insufficient data to characterize variable expressivity.
  • Genetic anticipation / germline mosaicism / founder effect: None reported; not applicable to a two-patient nonsense/splice compound-heterozygote family.
  • Consanguinity: Explicitly not present — parents described as non-consanguineous, each presumably a heterozygous carrier of one of the two variants.
  • Carrier frequency: Not established/reported; the two specific variants are private-family findings as far as located sources indicate.
  • Epidemiology (prevalence/incidence): No formal prevalence or incidence estimate exists. Orphanet classifies rarity descriptively rather than numerically for entities with only isolated case reports; the honest statement is: only one family (2 affected siblings) has been published to date, so a population prevalence cannot be calculated. This should be curated as prevalence_class: NOT_YET_DOCUMENTED (or CASES_IN_LITERATURE with n=2) rather than any numeric band.
  • Population demographics: No specific ethnic, geographic, or sex-ratio data beyond the fact that both reported patients are female siblings; two data points are insufficient to infer a sex bias, and no biological rationale for X-linked or sex-skewed autosomal-recessive expression is suggested by the mechanism (ARHGEF1 is autosomal).

10. Diagnostics

Laboratory/immunologic tests reported as diagnostically informative: - Serum immunoglobulin quantification — profound hypogammaglobulinemia ("almost undetectable antibodies") - Post-vaccination antibody titers — impaired/absent response - Peripheral blood B-cell immunophenotyping by flow cytometry — deficient marginal-zone and memory B cells, increased transitional B cells - Peripheral blood myeloid assessment — circulating immature myeloid forms - Lymph node biopsy/histopathology — small germinal centers, increased plasma cells

Genetic testing: Whole-exome sequencing (WES) was the diagnostic method that identified the causal variants in the index family; this remains the recommended approach for suspected novel/ultra-rare primary antibody deficiencies where a gene panel would not include ARHGEF1 by default. As of this search, some commercial primary-immunodeficiency exome/genome panels and the Genomics England PanelApp "Primary immunodeficiency or monogenic inflammatory bowel disease" panel do list ARHGEF1 (per PanelApp search result), so targeted PID gene panels including ARHGEF1 and single-gene Sanger confirmation of familial variants are also reasonable once a candidate variant is found. GTR lists 5 clinical tests available for IMD62 (sequence analysis of the entire coding region, deletion/duplication analysis, and targeted variant testing among them).

Functional/research assays used to confirm pathogenicity (not yet standard clinical tests): ARHGEF1 immunoblot (protein-null confirmation), RhoA-GTP pulldown activity assay, F-actin polymerization assay (phalloidin-based, resting and post-GPCR-agonist stimulation), lymphocyte migration/adhesion assays on integrin ligands, AKT phosphorylation assay.

Differential diagnosis: Other predominant/primary antibody deficiencies with childhood-onset recurrent sinopulmonary infection and bronchiectasis, notably common variable immunodeficiency (CVID) of other genetic causes, X-linked agammaglobulinemia (if male — not applicable here given female sibs and AR inheritance), and other genetically defined antibody deficiencies in the IUIS "Predominantly Antibody Deficiencies" category. The specific combination of VZV/HSV susceptibility with a B-cell (not primarily T-cell) predominant defect, marginal-zone/memory B-cell deficiency, and increased transitional B cells is a distinguishing immunophenotypic clue, though not disease-specific on its own.

Screening: No newborn-screening or population carrier-screening program exists for this ultra-rare condition; standard newborn TREC-based SCID screening would not be expected to detect a predominant-antibody-deficiency phenotype of this kind.

11. Outcome / Prognosis

  • Survival/mortality: No mortality data reported; both index patients are described in terms of chronic morbidity (recurrent infection, bronchiectasis) rather than reported deaths.
  • Morbidity: Chronic bronchiectasis with attendant risk of progressive lung function decline if infections are not adequately controlled (standard bronchiectasis natural history, extrapolated — not specifically quantified for this cohort).
  • Complications: Bronchiectasis is the principal structural complication reported; recurrent VZV/HSV reactivation/infection is a specific infectious complication.
  • Recovery potential / treatment response: Not formally reported as an outcome metric in the located abstracts; the mechanistic rescue experiments (restoring ARHGEF1 expression or pharmacologically activating RhoA corrects the cellular defects in vitro) suggest biological reversibility of the cellular phenotype, which is a rationale for gene-addition/small-molecule approaches but is not evidence of a clinical treatment outcome in patients.
  • Prognostic factors/biomarkers: None specifically validated; by general PID principles, degree of antibody deficiency and lung damage at diagnosis would be expected prognostic factors, but this is inference, not disease-specific reported data.

12. Treatment

No disease-specific treatment trial or approved therapy exists for IMD62; treatment is inferred/extrapolated from standard primary-antibody-deficiency management, as is typical for a two-patient, recently described monogenic disease.

  • Pharmacotherapy (standard-of-care extrapolation, not disease-specific trial evidence):
  • Immunoglobulin replacement therapy (IVIG or subcutaneous immunoglobulin) — standard for antibody deficiency with near-undetectable antibody levels; NCIT:C15986 (Pharmacotherapy) as the generic action term, with therapeutic_agent bound to immune globulin if curated.
  • Prophylactic antibiotics for recurrent respiratory infection and bronchiectasis management — standard bronchiectasis supportive care (NCIT:C15747 Supportive Care).
  • Antiviral prophylaxis/treatment (e.g., for VZV/HSV) given the specific reported viral susceptibility — inferred standard-of-care, not reported as a trial outcome in this disease.
  • Advanced therapeutics: No gene therapy, cell therapy, or targeted small-molecule trial specific to ARHGEF1 deficiency was identified. The demonstrated in-vitro rescue of the cellular phenotype by re-expressing ARHGEF1 or pharmacologically activating RhoA is proof-of-concept research, not a clinical therapeutic.
  • Surgical/interventional: Bronchiectasis management may include standard pulmonary interventions (airway clearance, and in severe localized disease, surgical resection) per general bronchiectasis guidelines — not specifically reported for this disease.
  • Supportive/rehabilitative: Pulmonary rehabilitation/airway clearance therapy, standard for bronchiectasis (NCIT:C15302 Physical Therapy / pulmonary-specific variants) — extrapolated.
  • Experimental treatments/clinical trials: No ClinicalTrials.gov-registered trial specific to ARHGEF1 deficiency or IMD62 was identified in this search.
  • Treatment outcomes / response rates / adverse events: Not reported for this disease specifically.
  • Personalized medicine: None specific; the mechanistic finding that RhoA-activating compounds correct cellular defects in vitro is a research lead for a targeted approach but has not progressed to any reported patient-level intervention.

Everything in this section beyond the bare fact "no specific treatment trial exists" is inference from general PID/bronchiectasis standard of care, and should be flagged as such (not disease-specific evidence) if curated into a KB entry.

13. Prevention

No disease-specific primary, secondary, or tertiary prevention program exists. - Primary prevention: Standard childhood immunization is presumably still administered though expected to be ineffective (impaired antibody response to vaccination is itself part of the phenotype) — inference, not directly reported. - Secondary prevention: Early recognition via genetic testing in siblings of an index case (given autosomal recessive inheritance, 25% recurrence risk per pregnancy) — standard Mendelian-disease genetic-counseling logic, not disease-specific published guidance. - Screening: No population or genetic screening program exists; carrier screening for these private-family variants would only be relevant within the reported kindred. - Genetic counseling: Standard autosomal-recessive counseling applies (25% recurrence risk for future affected offspring of two carrier parents; not disease-specific literature, but a direct consequence of the confirmed inheritance pattern). - Prophylaxis: Antimicrobial/antiviral prophylaxis as extrapolated in Treatment, above, would constitute tertiary prevention of infection-related morbidity (bronchiectasis progression), not disease-specific published guidance.

14. Other Species / Natural Disease

No naturally occurring veterinary disease (spontaneous companion-animal or wildlife Arhgef1-deficiency phenotype) was identified in this search — all animal data derive from engineered knockout mice (see Model Organisms, below), not natural disease. No OMIA entry or veterinary case series was located.

  • Taxonomy: Human disease NCBITaxon:9606; mouse ortholog studies NCBITaxon:10090 (Mus musculus).
  • Orthologous gene: Mouse Arhgef1 (historically called Lsc), NCBI Gene (mouse) — the literature explicitly equates murine Lsc with human p115RhoGEF/ARHGEF1.
  • Comparative biology: The RhoA-GEF function and its role in marginal-zone B-cell retention/motility and lymphocyte GPCR signaling is conserved between mouse and human, and the human patient phenotype (marginal-zone/memory B-cell deficiency, impaired T-dependent antibody response) closely mirrors the mouse Arhgef1-knockout phenotype, providing strong cross-species mechanistic concordance (see next section).
  • Zoonotic potential / cross-species transmission: Not applicable — this is a non-infectious monogenic immune disorder, not a transmissible disease.

15. Model Organisms

This is the best-developed section of the evidence base for this gene, because Arhgef1 (Lsc) knockout mice were studied for two decades before the human disease was described, giving strong (if indirect/model-first) mechanistic support.

Model Type Key phenotype Fidelity to human disease Citation
Arhgef1⁻ᐟ⁻ (Lsc-deficient) mouse Constitutive knockout, mammalian in vivo Lack/near-absence of marginal-zone B cells; impaired antibody responses to T-independent and T-dependent antigens; impaired S1P-directed migration and integrin-mediated release of marginal-zone B lymphocytes in vitro and in vivo High concordance with the human marginal-zone/memory B-cell deficiency and impaired antibody-response phenotype; mouse work substantially predates and predicts the human mechanism Girkontaite et al., Nat Immunol 2001;2:855-862, PMID:11526402
Arhgef1⁻ᐟ⁻ mouse, B-cell-focused follow-up Constitutive knockout Lsc required for marginal-zone B-cell migration and adhesion; required for the IgM T-dependent antibody response specifically Directly recapitulates human impaired-antibody-response and marginal-zone B-cell-deficiency phenotype Francis et al., Immunity 2005;23:527-538, PMID:16286020
Arhgef1⁻ᐟ⁻ mouse, T-cell/airway focus Constitutive/conditional knockout Arhgef1 required by T cells for development of airway hyperreactivity and inflammation in an asthma model Relevant to airway/pulmonary immune biology broadly; not a direct model of the human bronchiectasis-via-antibody-deficiency mechanism — illustrates a different (T-cell/airway-inflammatory) role of the same gene, so should not be conflated with the human PAD mechanism without qualification Chen et al./cited work, Am J Respir Crit Care Med 2007;176:10, PMID:17463415
Arhgef1⁻ᐟ⁻ mouse, pulmonary leukocyte review Review of knockout data Summarizes Arhgef1's role in pulmonary macrophage/leukocyte function Background/synthesis, not new primary data Immunol Res 2012, PMID:22941563
Arhgef1⁻ᐟ⁻ mouse, vascular/atherosclerosis Constitutive knockout Leukocyte Arhgef1 mediates Ang II-induced vascular inflammation/atherosclerosis via integrin activation Off-target relative to the immunodeficiency phenotype — evidence for a distinct cardiovascular role of ARHGEF1 in leukocytes, useful only as broader gene-biology background, not disease modeling J Clin Invest 2017;127:4516-4526, PMID:29130930
Arhgef1⁻ᐟ⁻ mouse, platelet Constitutive knockout Arhgef1 plays a role in platelet function/thrombogenesis Off-target relative to immunodeficiency; not disease-relevant modeling J Am Heart Assoc 2018/2019

Model limitations: All available "modeling" for this human disease is a constitutive whole-body mouse knockout, not a human-variant knock-in, iPSC-derived, or conditional hematopoietic-lineage-specific model. No model has been engineered to carry the exact human c.853C>T or c.1624-1G>T alleles. The concordance between mouse and human phenotypes (marginal-zone B-cell loss, impaired T-dependent antibody response) is strong for the B-cell/antibody axis but the mouse literature also documents prominent T-cell/airway-inflammatory and vascular/platelet phenotypes of Arhgef1 loss that have not been reported as clinical features in the two human patients — this divergence should be flagged as a scale/translational caveat (BOUNDARY_OMISSION-type divergence) rather than assumed to extend to humans. No organoid, iPSC-derived, zebrafish, or computational model of ARHGEF1 deficiency was identified.

Summary of Key Gaps (for curation planning)

  1. No prevalence/incidence data beyond "one reported family, two affected siblings" — must be curated as literature-case-count, not a population rate.
  2. No GeneReviews chapter identified for this condition.
  3. No treatment trial or disease-specific outcome data — all treatment content above is extrapolated from general PID/bronchiectasis standard of care and must be labeled as such if curated.
  4. No confirmed additional published cases since the 2019 index report were found in this search (searched explicitly for 2023-2025 literature; none located) — the evidence base has apparently not grown since the original description.
  5. gnomAD constraint metrics (pLI/LOEUF) for ARHGEF1 were not retrieved — worth fetching directly before curation.
  6. Full-text primary-source access was blocked in this session (PubMed/PMC/JCI/OMIM all returned bot-check or 403/503 errors through the available fetch tooling); every quote/detail above should be re-verified against the primary full text via the dismech reference-fetching workflow (just fetch-reference PMID:30521495, PMID:30714991, PMID:11526402, PMID:16286020) before being used as an exact-quote snippet in a KB entry, per the dismech evidence-discipline rules.
  7. Ontology term IDs suggested throughout (HPO, GO, CL, UBERON) are unverified leads, offered per the template's request, and must be run through just validate-terms / OAK lookup rather than bound directly from this report.

Sources

Reference Validation

Checked with linkml-reference-validator 0.3.0rc1.

Outcome Count
References checked 10
Resolved 10
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 10
On topic 5
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 27
Resolved 24
Unresolved (possible confabulation) 0
Obsolete 1
Unverifiable 2
Terms whose name was checked 6
Terms named correctly 4
Terms named as a different term 2

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • MONDO:0032763 (6 mentions) - the report calls it "MONDO"; MONDO calls it immunodeficiency 62
  • GO:0005089 (1 mention) - the report calls it "Rho guanyl-nucleotide exchange factor activity"; GO calls it GO_0005089

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

  • GO:0005089 (GO_0005089) (1 mention) - replaced by GO:0005085

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.