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:

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).

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 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

• Entry - #618459 - IMMUNODEFICIENCY 62; IMD62 - OMIM
• Entry - *601855 - RHO GUANINE NUCLEOTIDE EXCHANGE FACTOR 1; ARHGEF1 - OMIM
• Immunodeficiency 62 - NIH Genetic Testing Registry (GTR) - NCBI
• immunodeficiency 62 Disease External Resources - ClinGen
• ClinGen Gene-Disease Validity Curation: ARHGEF1 / Immunodeficiency 62
• Immunodeficiency 62 - MalaCards
• Curate immunodeficiency 62 (MONDO:0032763) · Issue #12797 · monarch-initiative/dismech
• Loss of ARHGEF1 causes a human primary antibody deficiency - PubMed (PMID:30521495)
• Loss of ARHGEF1 causes a human primary antibody deficiency - PMC
• JCI - Loss of ARHGEF1 causes a human primary antibody deficiency
• ARHGEF1 deficiency reveals Gα13-associated GPCRs are critical regulators of human lymphocyte function - PubMed (PMID:30714991)
• ARHGEF1 deficiency reveals Gα13-associated GPCRs are critical regulators of human lymphocyte function - PMC
• JCI - ARHGEF1 deficiency reveals Gα13-associated GPCRs are critical regulators of human lymphocyte function
• Loss of ARHGEF1 causes a human primary antibody deficiency | Semantic Scholar
• Lsc is required for marginal zone B cells, regulation of lymphocyte motility and immune responses - PubMed (PMID:11526402)
• Lsc Regulates Marginal-Zone B Cell Migration and Adhesion and Is Required for the IgM T-Dependent Antibody Response - PubMed (PMID:16286020)
• The influence of Arhgef1 on pulmonary leukocyte function - PubMed (PMID:22941563)
• Arhgef1 is required by T cells for the development of airway hyperreactivity and inflammation - PubMed (PMID:17463415)
• JCI - Leukocyte RhoA exchange factor Arhgef1 mediates vascular inflammation and atherosclerosis (PMID:29130930)
• ARHGEF1 Gene - GeneCards
• ARHGEF1 curation results - ClinGen
• Gene: ARHGEF1 - Genomics England PanelApp
• The 2022 Update of IUIS Phenotypical Classification for Human Inborn Errors of Immunity - PubMed

Reference Validation

Checked with linkml-reference-validator 0.3.0rc1.

All extracted references resolved successfully.

Term Validation

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

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.