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Inheritance

1

Autosomal dominant inheritance HP:0000006

A single heterozygous dominant-activating RAC2 allele is sufficient. Reported variants are private missense changes, frequently de novo, and vertical transmission from an affected parent has been documented.

Autosomal dominant inheritance De novo rate: Frequently de novo; vertical transmission also documented

Show evidence (1 reference)

PMID:30723080 SUPPORT Human Clinical

"mutations resulting in severe T- and B-cell lymphopenia, myeloid dysfunction, and recurrent respiratory infections"

Three unrelated de novo heterozygous cases establish the dominant, single-allele mechanism.

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Discussions and Knowledge Gaps

2

By what route does constitutive RAC2 activation in the cytoskeletal and oxidase arms produce reduced thymic and bone-marrow lymphocyte output?

KNOWLEDGE GAP imd73b_lymphopenia_mechanism

Attached to

pathophysiology#T and B Lymphopenia with Impaired Lymphocyte Output

Low TRECs and KRECs establish that output is reduced rather than that peripheral cells are being consumed, and accelerated caspase-3-positive apoptosis is measured in patient lymphocytes. What is missing is the step between them, since no patient thymus or marrow study demonstrates where in development the loss occurs. This entry therefore types the edge from apoptosis to lymphopenia as having unknown intermediates rather than asserting a pathway.

Show evidence (1 reference)

PMID:31071452 SUPPORT Human Clinical

"Immunologic investigation revealed low numbers of TRECs/KRECs, a severe reduction of memory B cells, absence of isohemagglutinins, and low IgG levels."

Establishes that output is reduced, which is the observation the missing mechanism has to explain.

Where exactly is the boundary between the dominant-activating alleles that cause IMD73B and the constitutively active RAS-like alleles that cause neonatal SCID?

KNOWLEDGE GAP imd73b_allele_class_boundary

Attached to

genetic#RAC2

The cohort framework treats activity level as a continuum that maps onto discrete syndromes, but individual reports do not always sort cleanly. The G12R allele is described biochemically as gain of function while its three reported newborns presented with profound leukopenia and a severe autosomal-dominant SCID picture rather than the later-onset combined immunodeficiency of this entry. Until functional thresholds are standardized, assigning a new activating allele to IMD73B rather than to the SCID arm is a clinical judgement, not a measurement.

Show evidence (2 references)

PMID:31919089 SUPPORT Human Clinical

"In three newborns presenting with frequent infections and profound leukopenia, we identified a private, heterozygous mutation in the RAC2 gene (p.G12R)."

A gain-of-function allele presenting at the SCID end rather than as later-onset CID, which is the boundary problem this gap records.

PMID:38194689 SUPPORT In Vitro

"All tested RAC2 mutant proteins exhibited aberrant function; no single assay was sufficient to determine functional consequence."

Confirms that no single functional measurement settles the class of a new allele.

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Pathophysiology

8

RAC2 Dominant-Activating Missense Variant

A heterozygous germline missense change, typically in a switch region or the nucleotide-binding pocket, that shifts RAC2 toward its active state. For E62K the defect is specific and measurable, in that intrinsic hydrolysis is preserved but GTPase-activating protein no longer accelerates it.

RAC2 hgnc:9802 ⇑ GAIN OF FUNCTION

GTPase activity GO:0003924 ↓ DECREASED

Downstream

Constitutive GTP-Loading of RAC2

Show evidence (1 reference)

PMID:30723080 SUPPORT In Vitro

"retains intrinsic GTP hydrolysis; however, GTPase-activating protein failed to accelerate hydrolysis resulting in prolonged active GTP-bound RAC2."

The measured biochemical lesion behind this node.

Constitutive GTP-Loading of RAC2

RAC2 is a molecular switch whose function depends on cycling, not on being on. Holding it in the GTP-bound state engages its effector modules at rest. Because superoxide production and chemotaxis run through separable effector pathways, the lesion branches here rather than producing a single graded output.

GTP-bound occupancy of RAC2 GO:0005525 ↑ INCREASED

Animal models

Rac2-null mouse Mouse fails to recapitulate The null mouse cannot model constitutive activation, and is cited here for the separability of the two effector arms rather than for the disease state.

Downstream

Excessive NADPH Oxidase Superoxide Production The oxidase arm, engaged through p67phox.

Dysregulated F-Actin Assembly and Loss of Polarization The cytoskeletal arm, engaged through PAK1 and POR1/Arfaptin 2.

Accelerated Lymphocyte and Neutrophil Apoptosis

Show evidence (2 references)

PMID:35596857 SUPPORT Other

"RAC2 undergoes a tightly regulated GTP-binding/GTP-hydrolysis cycle, enabling it to function as a molecular switch."

States the switch behaviour that constitutive GTP-loading subverts. Graded OTHER because the sentence is the paper's background statement of established RAC2 biochemistry rather than a result of the case it reports.

PMID:15814684 SUPPORT Model Organism

"In this study, we demonstrate that Rac2 controls chemotaxis and superoxide production via distinct pathways and is critical for development of myeloid colonies in vitro."

The separability of the two effector arms is what makes this node a branch point rather than a single downstream chain.

Excessive NADPH Oxidase Superoxide Production

Superoxide is elevated both at rest and on stimulation. The clinically relevant defect is dysregulation rather than excess as such, since an oxidative burst that cannot be timed is not an effective one.

neutrophil CL:0000775

superoxide anion generation GO:0042554 ↑ INCREASED

Downstream

Myeloid Effector Dysfunction

Show evidence (1 reference)

PMID:31071452 SUPPORT In Vitro

"enhanced NADPH oxidase-derived superoxide production both at rest and in response to PMA"

Records that the elevation is present at rest as well as on stimulation.

Dysregulated F-Actin Assembly and Loss of Polarization

F-actin content rises while polarization is lost. This is the step at which a gain of GTPase activity becomes a functional loss, because directed migration requires an asymmetric, dynamically remodelled cytoskeleton rather than more polymer.

neutrophil CL:0000775

regulation of actin cytoskeleton organization GO:0032956 ⚠ ABNORMAL

Animal models

Rac2 E62K heterozygous knock-in mouse Mouse recapitulates Neutrophil F-actin is increased in the knock-in, matching the patient finding.

Downstream

Absent Neutrophil Chemotaxis

Show evidence (1 reference)

PMID:35596857 SUPPORT Human Clinical

"elevated F-actin content, and increased RAC2 protein expression in neutrophils"

The raised F-actin content this node asserts, measured in patient neutrophils.

Absent Neutrophil Chemotaxis

Directed migration toward fMLP is not merely reduced but absent in tested patients, which is the feature that names the disease.

neutrophil CL:0000775

neutrophil chemotaxis GO:0030593 ↓ DECREASED

Downstream

Myeloid Effector Dysfunction

Show evidence (1 reference)

PMID:31071452 SUPPORT Human Clinical

"Flow cytometric investigation of neutrophil migration demonstrated an absence of chemotaxis to fMLP."

The measured absence of chemotaxis in a patient.

Accelerated Lymphocyte and Neutrophil Apoptosis

Patient lymphocytes and neutrophils show augmented intracellular active caspase 3. This is the arm through which a cytoskeletal and oxidase lesion reaches a lymphoid phenotype, though the pathway from RAC2 signalling to thymic and marrow output remains partly inferred.

T cell CL:0000084 B cell CL:0000236

apoptotic process GO:0006915 ↑ INCREASED

Downstream

T and B Lymphopenia with Impaired Lymphocyte Output

Show evidence (2 references)

PMID:35596857 SUPPORT Human Clinical

"accelerated apoptosis with augmented intracellular active caspase 3"

The caspase-3 measurement behind this node.

PMID:11278678 SUPPORT INDIRECT In Vitro

"expansion of cells transduced with WT Rac2 and a dominant active mutant, Q61L, was associated with significantly increased proliferation"

An engineered dominant-active allele alters haematopoietic cell survival and proliferation, which supports RAC2 nucleotide state governing this axis. It is indirect because Q61L is a laboratory allele and the direction reported is increased proliferation rather than apoptosis.

T and B Lymphopenia with Impaired Lymphocyte Output

Low TREC and KREC numbers indicate reduced thymic and bone-marrow output rather than peripheral consumption alone, and memory B cells are severely reduced with absent isohaemagglutinins.

T cell CL:0000084 B cell CL:0000236

Animal models

Rac2 E62K heterozygous knock-in mouse Mouse recapitulates The knock-in reproduces the T- and B-cell lymphopenia seen in patients carrying the same allele.

Downstream

Hypogammaglobulinemia

Recurrent Viral Infection

Show evidence (2 references)

PMID:31071452 SUPPORT Human Clinical

"Immunologic investigation revealed low numbers of TRECs/KRECs, a severe reduction of memory B cells, absence of isohemagglutinins, and low IgG levels."

The laboratory signature of impaired lymphocyte output in a molecularly confirmed patient.

PMID:38194689 SUPPORT Human Clinical

"Significant T- and B-lymphopenia with low immunoglobulins were seen in most patients"

Confirms the finding is typical across the cohort rather than a single-case observation.

Myeloid Effector Dysfunction

The converged myeloid consequence, comprising neutropenia, altered oxidative burst, impaired migration and visible neutrophil macropinosomes. Notably the direction of the oxidase defect predicts the infection type, since it is the mutants unable to support superoxide formation that were associated with bacterial infection.

neutrophil CL:0000775

Downstream

Recurrent Respiratory Tract Infection

Bronchiectasis

Show evidence (2 references)

PMID:38194689 SUPPORT Human Clinical

"myeloid abnormalities included neutropenia, altered oxidative burst, impaired neutrophil migration, and visible neutrophil macropinosomes"

Enumerates the components of this node from the largest cohort.

PMID:38194689 SUPPORT Human Clinical

"Most mutants produced elevated superoxide; mutations unable to support superoxide formation were associated with bacterial infections."

Supports the description's claim that oxidase direction stratifies the infection phenotype.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

9

Blood 4

Decreased Total T Cell Count VERY_FREQUENT HP:0005403

Show evidence (1 reference)

PMID:38194689 SUPPORT Human Clinical

"Significant T- and B-lymphopenia with low immunoglobulins were seen in most patients"

Frequency statement for T lymphopenia across the cohort.

Decreased Total B Cell Count VERY_FREQUENT HP:0010976

Show evidence (2 references)

PMID:38194689 SUPPORT Human Clinical

"Significant T- and B-lymphopenia with low immunoglobulins were seen in most patients"

Frequency statement for B lymphopenia across the cohort.

PMID:31071452 SUPPORT Human Clinical

"a severe reduction of memory B cells, absence of isohemagglutinins"

Characterizes the B-cell compartment beyond the raw count.

Hypogammaglobulinemia VERY_FREQUENT Decreased circulating IgG concentration HP:0004315

Show evidence (1 reference)

PMID:35596857 SUPPORT Human Clinical

"lymphopenia, and low serum immunoglobulin G"

Low serum IgG measured in a molecularly confirmed patient.

Neutropenia Decreased total neutrophil count HP:0001875

Show evidence (1 reference)

PMID:38194689 SUPPORT Human Clinical

"myeloid abnormalities included neutropenia, altered oxidative burst, impaired neutrophil migration, and visible neutrophil macropinosomes"

Lists neutropenia among the myeloid abnormalities of the cohort.

Immune 4

Combined Immunodeficiency VERY_FREQUENT HP:0005387

Show evidence (1 reference)

PMID:31071452 SUPPORT Human Clinical

"Our findings broaden the clinical picture of RAC2 dysfunction, showing that some individuals can present with a combined immunodeficiency later in childhood rather than a congenital neutrophil disease."

States both the combined character and the later presentation that separates this arm.

Recurrent Respiratory Tract Infection VERY_FREQUENT Recurrent respiratory infections HP:0002205

Show evidence (1 reference)

PMID:38194689 SUPPORT Human Clinical

"Among 42 patients with CID with clinical data, upper and lower respiratory infections and viral infections were common."

Frequency statement from the 42 patients with combined immunodeficiency and clinical data.

Recurrent Viral Infection FREQUENT Recurrent viral infections HP:0004429

Show evidence (2 references)

PMID:41685306 SUPPORT Human Clinical

"She subsequently experienced severe, treatment-refractory cutaneous viral infections."

Documents refractory viral disease as a distinct problem from the bacterial respiratory infections.

PMID:41685306 SUPPORT Human Clinical

"Persistent viral disease with oncogenic complications, bronchiectasis, lymphoproliferation, or progressive organ involvement should prompt consideration of RAC2 testing even beyond infancy."

The authors' own summary of the viral phenotype and its oncogenic consequences.

Recurrent Skin Infection Recurrent skin infections HP:0001581

Show evidence (1 reference)

PMID:31071452 SUPPORT Human Clinical

"Here we describe a 10-year-old girl with combined immunodeficiency presenting as recurring chest infections, lung disease and herpetic skin infections."

Herpetic skin infection at presentation in a molecularly confirmed patient.

Respiratory 1

Bronchiectasis FREQUENT HP:0002110

Show evidence (2 references)

PMID:35596857 SUPPORT Human Clinical

"Here, we describe an 11-year-old girl with combined immunodeficiency presenting with recurrent respiratory infections and bronchiectasis."

Bronchiectasis at presentation in a molecularly confirmed dominant-activating case.

PMID:41685306 SUPPORT Human Clinical

"recurrent bacterial respiratory infections and early bronchiectasis that initially responded to immunoglobulin replacement therapy"

A second independent report of early bronchiectasis in this allele class.

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Genetic Associations

1

RAC2 (RAC2 encodes a haematopoietic-restricted Rho-family GTPase. Heterozygous dominant-activating missense variants cause IMD73B; other biochemical classes of RAC2 allele cause different diseases.)

Gene: RAC2 hgnc:9802 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:38194689 SUPPORT Human Clinical

"Disease correlated to RAC2 activity: constitutively active RAS-like mutations caused neonatal SCID, dominant-negative mutations caused LAD-like disease, whereas dominant-activating mutations caused CID."

The largest compiled cohort maps the dominant-activating allele class specifically onto combined immunodeficiency, which is this entry.

PMID:11278678 SUPPORT In Vitro

"The Rho GTPase, Rac2, is expressed only in hematopoietic cell lineages, suggesting a specific cellular function in these cells."

The haematopoietic-restricted expression is what confines the disease to the immune compartment and is the rationale for transplant being curative.

Variants (4)

RAC2 p.Glu62Lys (E62K) Pathogenic

The best-characterised dominant-activating allele. It retains intrinsic GTP hydrolysis but is not accelerated by GTPase-activating protein, so it dwells in the active GTP-bound state.

Show evidence (1 reference)

PMID:30723080 SUPPORT In Vitro

"retains intrinsic GTP hydrolysis; however, GTPase-activating protein failed to accelerate hydrolysis resulting in prolonged active GTP-bound RAC2."

Defines the biochemical lesion precisely, as failure of GAP-accelerated hydrolysis rather than loss of the intrinsic reaction.

RAC2 p.Asn92Thr (N92T) Pathogenic

A dominant-activating allele in a child who presented with combined immunodeficiency at 10 years rather than with a congenital neutrophil disease.

Show evidence (1 reference)

PMID:31071452 SUPPORT In Vitro

"displayed characteristics of active GTP-bound RAC2 including enhanced NADPH oxidase-derived superoxide production both at rest and in response to PMA."

Transfection assay showing the allele behaves as constitutively GTP-bound.

RAC2 p.Pro29Arg (P29R) Pathogenic

A de novo dominant-activating allele in the highly conserved Switch I domain, reported with raised ROS, elevated F-actin and increased RAC2 protein expression.

Show evidence (1 reference)

PMID:35596857 SUPPORT Human Clinical

"The mutation resulted in enhanced reactive oxygen species production, elevated F-actin content, and increased RAC2 protein expression in neutrophils, as well as increased cytokine production and a dysregulated phenotype in T lymphocytes."

The functional signature of a dominant-activating allele, measured in the patient's own neutrophils and T lymphocytes in a case report, which is why it is graded HUMAN_CLINICAL like every other result from this paper rather than as a cell-culture experiment.

RAC2 p.Arg68Trp (R68W), homozygous Pathogenic

A rare variant that produces the dominant-activating phenotype only in the homozygous state. Protein expression is markedly reduced yet effector signalling is increased, so expression level and functional direction point opposite ways in the same patient.

Show evidence (2 references)

PMID:41685306 SUPPORT Human Clinical

"Despite significantly reduced RAC2 protein expression, patient-derived cells exhibited increased effector signaling in the homozygous state, producing a phenotype that phenocopies dominant gain-of-function RAC2 variants."

Establishes that this allele reaches the same functional endpoint as the heterozygous dominant-activating alleles.

PMID:41685306 SUPPORT Human Clinical

"Functional hyperactivation was not observed in heterozygous cells, supporting a dosage-dependent mechanism."

The dose dependence is why this is a homozygous-only phenocopy rather than a further dominant allele.

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Medical Actions

3

Immunoglobulin Replacement Therapy

Action: Intravenous Immunoglobulin Therapy NCIT:C121331

Agent: human immunoglobulin G NCIT:C80829

Platform: Protein replacement

Replaces the missing humoral arm. It improves the bacterial respiratory infection burden but does not correct the cellular defect, and in the longest-followed patient the viral disease progressed despite it.

Mechanism Target:

Hypogammaglobulinemia — Substitutes for the immunoglobulin the failed B-cell compartment does not produce.

Show evidence (1 reference)

PMID:41685306 SUPPORT Human Clinical

"recurrent bacterial respiratory infections and early bronchiectasis that initially responded to immunoglobulin replacement therapy"

Documents the response, and by saying initially, also its limits.

Antimicrobial Prophylaxis

Action: Pharmacotherapy NCIT:C15986

Agent: cotrimoxazole NCIT:C909

Platform: Small molecule

Prophylactic antimicrobials, alongside immunoglobulin replacement, are the standing supportive measure while transplant is being considered or declined. In the largest cohort this is stated as part of how the immunodeficiency is treated, and one sibling pair gives the concrete case: both were placed on cotrimoxazole, and the younger, treated from ten months, did not go on to the recurrent pulmonary infections his brother had. That is a single uncontrolled comparison within one family, not an efficacy result.

Mechanism Target:

INHIBITS Recurrent Respiratory Tract Infection — Suppresses the bacterial respiratory burden that follows from the neutrophil defect, which is the infection type the cited prophylaxis addresses. It does not act on the RAC2 lesion, so the underlying susceptibility is unchanged.

Show evidence (2 references)

PMID:38194689 SUPPORT Human Clinical

"The older sibling, diagnosed at 7 years, had recurrent upper and lower respiratory tract infections and was placed on prophylactic cotrimoxazole, as was the younger after diagnosis at age 10 months."

Names the agent actually used, and dates it in each sibling, which is what makes the following sentence about the younger brother's course readable as a within-family comparison rather than a claim about the drug.

PMID:38194689 SUPPORT Human Clinical

"Three patients with CID with early diagnosis were treated prophylactically and, to date, remain clinically healthy."

The cohort-level outcome for early prophylaxis. Three patients with no comparator, so it supports the practice without establishing an effect size.

Allogeneic Hematopoietic Cell Transplantation

Action: Hematopoietic Cell Transplantation NCIT:C15431

Platform: Cell therapy

The only definitive therapy, and mechanistically rational because RAC2 is expressed only in haematopoietic cells, so replacing that compartment replaces the entire diseased tissue. It carries real transplant-related mortality in this disease.

Mechanism Target:

RAC2 Dominant-Activating Missense Variant — Replacing the haematopoietic compartment removes the cells that carry and express the mutant allele, which is the whole of the diseased tissue.

Show evidence (1 reference)

PMID:11278678 SUPPORT INDIRECT In Vitro

"The Rho GTPase, Rac2, is expressed only in hematopoietic cell lineages, suggesting a specific cellular function in these cells."

The restricted expression is the reason a haematopoietic transplant can be curative. It is indirect because the paper establishes the expression pattern rather than testing transplant.

Show evidence (2 references)

PMID:41685306 SUPPORT Human Clinical

"Management included immunoglobulin therapy, and ultimately hematopoietic cell transplantation (HCT), after which he achieved sustained clinical improvement."

A documented sustained response to transplant in this allele class.

PMID:31071452 REFUTE Human Clinical

"The patient experienced two hematopoietic stem cell transplantations and despite full chimerism, she developed bone marrow aplasia due to adenovirus infection and died at post-transplant day 86."

A fatal outcome despite full chimerism, which refutes any reading of transplant as reliably curative here and is the reason the description names the mortality.

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Diagnosis

3

Targeted RAC2 signalling assays rather than protein expression alone

Variant interpretation in RAC2 disease cannot rest on expression level. The homozygous R68W patients had markedly reduced RAC2 protein yet increased effector signalling, so an expression-based read would have called the variant the wrong direction.

Show evidence (1 reference)

PMID:41685306 SUPPORT Human Clinical

"From a diagnostic standpoint, reliance on expression alone may be misleading; incorporating targeted signaling assays is essential for accurate variant interpretation."

The authors' explicit diagnostic recommendation, drawn from the discordance they measured.

Functional classification of the RAC2 allele

Because the allele class determines which disease the patient has, functional assessment is diagnostic rather than merely confirmatory. No single assay suffices, which is why panels combining superoxide, PAK1 binding, AKT activation and protein stability are used.

Show evidence (1 reference)

PMID:38194689 SUPPORT In Vitro

"All tested RAC2 mutant proteins exhibited aberrant function; no single assay was sufficient to determine functional consequence."

States directly that a single functional readout cannot classify a RAC2 variant.

Flow cytometric neutrophil chemotaxis to fMLP

The functional test that demonstrates the migration defect the disease is named for.

Show evidence (1 reference)

PMID:31071452 SUPPORT Human Clinical

"Flow cytometric investigation of neutrophil migration demonstrated an absence of chemotaxis to fMLP."

The assay and its result in a molecularly confirmed patient.

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Prevalence

1

Worldwide

Cases In Literature Ultra Rare

Fewer than 54 RAC2 patients from 37 families across all four allelic classes had been compiled worldwide by 2024, and only 44 of those were in the combined-immunodeficiency group that corresponds to this entry. No population prevalence or incidence estimate exists, and causal variants are private, so a rate cannot be normalized.

Show evidence (1 reference)

PMID:38194689 SUPPORT Human Clinical

"We investigated 54 patients (23 previously reported) from 37 families yielding 15 novel RAC2 missense mutations, including one present only in homozygosity."

The published denominator, which spans all allelic classes and therefore over-counts this entry.

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Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Immunodeficiency 73B:

Neutrophil Immunodeficiency Syndrome (RAC2 dominant-negative, IMD73A)

Overlapping Features Same gene, opposite biochemistry, different disease. The dominant-negative D57N allele gives a leukocyte-adhesion-deficiency mimic with neutrophilia and absent pus rather than a combined immunodeficiency with lymphopenia. The distinction is made functionally, not by gene panel.

Show evidence (1 reference)

PMID:38194689 SUPPORT Human Clinical

"constitutively active RAS-like mutations caused neonatal SCID, dominant-negative mutations caused LAD-like disease, whereas dominant-activating mutations caused CID"

The allele-class map that separates this entry from its two nearest neighbours in the same gene.

Common variable immunodeficiency

Overlapping Features The clinical route by which several of these patients were first labelled. Hypogammaglobulinaemia with recurrent sinopulmonary infection and bronchiectasis in an adult is treated as CVID until a RAC2 variant is found, and one reported patient carried that label for years.

Show evidence (1 reference)

PMID:41685306 SUPPORT Human Clinical

"She was treated with intravenous immunoglobulins for presumed common variable immunodeficiency (CVID)."

Documents the misattribution this differential exists to prevent.

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Animal Models

2

Rac2 E62K heterozygous knock-in mouse

An allele-matched heterozygous knock-in carrying the human dominant-activating E62K change. It reproduces the lymphoid and the myeloid halves of the human phenotype in one animal, which is unusual for this disease class.

Species

Mouse

Genotype

Rac2+/E62K

Publication

PMID:30723080

Pathograph links

T and B Lymphopenia with Impaired Lymphocyte Output recapitulates fidelity: high observes: organism The knock-in reproduces the T- and B-cell lymphopenia seen in patients carrying the same allele.

Limitations: The report establishes that the lymphopenia is reproduced but does not demonstrate the intervening mechanism, so the model shares the human entry's uncertainty about how RAC2 signalling reaches thymic and marrow output rather than resolving it.

Readouts

Peripheral T- and B-cell counts in Rac2+/E62K mice

Direction: DECREASED

Interpretation: The lymphoid arm of the human phenotype is allele-driven and reproducible in a mouse carrying only that change.

Show evidence (1 reference)

PMID:30723080 SUPPORT Model Organism

"Rac2+/E62K mice phenocopy the T- and B-cell lymphopenia, increased neutrophil F-actin, and excessive superoxide production seen in patients."

The lymphopenia readout in the knock-in.

Dysregulated F-Actin Assembly and Loss of Polarization recapitulates fidelity: high observes: cellular Neutrophil F-actin is increased in the knock-in, matching the patient finding.

Limitations: The mouse readout reported is F-actin content rather than polarization, so it supports the assembly half of this node more directly than the loss of polarity.

Readouts

Neutrophil F-actin content in Rac2+/E62K mice

Direction: INCREASED

Interpretation: Raised F-actin in the mouse matches the raised F-actin in patient neutrophils.

Show evidence (1 reference)

PMID:30723080 SUPPORT Model Organism

"increased neutrophil F-actin, and excessive superoxide production seen in patients"

The F-actin readout in the knock-in.

Show evidence (1 reference)

PMID:30723080 SUPPORT Model Organism

"Rac2+/E62K mice phenocopy the T- and B-cell lymphopenia, increased neutrophil F-actin, and excessive superoxide production seen in patients."

A same-allele knock-in that phenocopies three separate patient findings is strong grounds for treating this model as informative.

Rac2-null mouse

The loss-of-function counterpart. It is the model that established RAC2 as non-redundant with the ubiquitous RAC1 and that mapped the two effector arms, but it models the wrong direction of the human lesion.

Species

Mouse

Genotype

Rac2 knockout

Publication

PMID:15528331

Pathograph links

Constitutive GTP-Loading of RAC2 fails to recapitulate fidelity: low observes: cellular The null mouse cannot model constitutive activation, and is cited here for the separability of the two effector arms rather than for the disease state.

Limitations: The lesion is inverted. The human disease is constitutive activation and the model is absence of the protein, so any shared phenotype is convergent rather than mechanistically matched. What the model does establish is that the two outputs are separable and that neither is redundant with RAC1.

Show evidence (1 reference)

PMID:15814684 SUPPORT INDIRECT Model Organism

"These findings suggest that binding to any single effector is not sufficient to rescue the distinct cellular phenotypes of Rac2-/- PMN, implicating multiple, distinct, and potentially parallel effector pathways."

Effector-rescue experiments in null neutrophils establish the parallel-pathway architecture the human branch point depends on. It is indirect because it is a loss-of-function system reasoning about a gain-of-function disease.

Show evidence (1 reference)

PMID:15528331 SUPPORT Model Organism

"Mice deficient in hemopoietic-specific Rac2 exhibited agonist-specific defects in neutrophil functions including chemoattractant-stimulated filamentous actin polymerization and chemotaxis, and superoxide production elicited by phorbol ester, fMLP, or IgG-coated particles, despite expression of..."

Establishes the non-redundancy of RAC2 against RAC1, which is why a single RAC2 allele can produce disease at all.

{ }

Source YAML

click to show

name: Immunodeficiency 73B
creation_date: "2026-09-05T10:00:00Z"
category: Mendelian
synonyms:
- IMD73B
- immunodeficiency 73b with defective neutrophil chemotaxis and lymphopenia
- RAC2 dominant-activating combined immunodeficiency
- RAC2 gain-of-function combined immunodeficiency
description: >-
  Immunodeficiency 73B is the combined immunodeficiency produced by heterozygous
  dominant-activating missense variants in RAC2, a Rho-family GTPase expressed
  only in haematopoietic cells. Patients present later than in infancy with
  recurrent upper and lower respiratory infections, bronchiectasis, persistent
  viral disease, T- and B-cell lymphopenia and hypogammaglobulinaemia, together
  with a neutrophil compartment that cannot chemotax.

  The counterintuitive part is that a gain of GTPase activity produces a loss of
  coordinated cell function. RAC2 works as a switch that must cycle between a
  GDP-bound and a GTP-bound state, and its two principal outputs, NADPH-oxidase
  superoxide production and actin-cytoskeleton remodelling for migration, run
  through separable effector modules. An allele that holds the switch on
  therefore does not amplify both outputs usefully: superoxide rises at rest and
  on stimulation, while F-actin is assembled without polarity and directed
  migration fails outright.

  RAC2 disease is an allele-class spectrum in which biochemistry, not gene
  identity, predicts the syndrome. Constitutively active RAS-like alleles cause
  neonatal SCID, dominant-negative alleles cause a leukocyte-adhesion-deficiency
  mimic, biallelic null alleles cause CVID-like disease, and dominant-activating
  alleles cause the combined immunodeficiency catalogued here.

  SCOPE. This entry covers the dominant-activating (CID) arm only. The
  dominant-negative arm is curated separately as Neutrophil Immunodeficiency
  Syndrome (IMD73A, MONDO:0011988), whose own scope note names the
  dominant-activating alleles as a different disease with a different graph. The
  neonatal-SCID and recessive loss-of-function arms are not curated here either.
disease_term:
  preferred_term: immunodeficiency 73B with defective neutrophil chemotaxis and lymphopenia
  term:
    id: MONDO:0033554
    label: immunodeficiency 73b with defective neutrophil chemotaxis and lymphopenia
parents:
- Inborn Error of Immunity
- Combined immunodeficiency
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    A single heterozygous dominant-activating RAC2 allele is sufficient.
    Reported variants are private missense changes, frequently de novo, and
    vertical transmission from an affected parent has been documented.
  de_novo_rate: Frequently de novo; vertical transmission also documented
  evidence:
  - reference: PMID:30723080
    reference_title: "Dominant activating RAC2 mutation with lymphopenia, immunodeficiency, and cytoskeletal defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mutations resulting in severe T- and B-cell lymphopenia, myeloid dysfunction, and recurrent respiratory infections"
    explanation: Three unrelated de novo heterozygous cases establish the dominant, single-allele mechanism.
genetic:
- name: RAC2
  gene_term:
    preferred_term: RAC2
    term:
      id: hgnc:9802
      label: RAC2
  association: >-
    RAC2 encodes a haematopoietic-restricted Rho-family GTPase. Heterozygous
    dominant-activating missense variants cause IMD73B; other biochemical
    classes of RAC2 allele cause different diseases.
  relationship_type: CAUSATIVE
  evidence:
  - reference: PMID:38194689
    reference_title: "Clinical and functional spectrum of RAC2-related immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Disease correlated to RAC2 activity: constitutively active RAS-like mutations caused neonatal SCID, dominant-negative mutations caused LAD-like disease, whereas dominant-activating mutations caused CID."
    explanation: The largest compiled cohort maps the dominant-activating allele class specifically onto combined immunodeficiency, which is this entry.
  - reference: PMID:11278678
    reference_title: "Biochemical and biological characterization of a human Rac2 GTPase mutant associated with phagocytic immunodeficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The Rho GTPase, Rac2, is expressed only in hematopoietic cell lineages, suggesting a specific cellular function in these cells."
    explanation: The haematopoietic-restricted expression is what confines the disease to the immune compartment and is the rationale for transplant being curative.
  variants:
  - name: RAC2 p.Glu62Lys (E62K)
    description: >-
      The best-characterised dominant-activating allele. It retains intrinsic
      GTP hydrolysis but is not accelerated by GTPase-activating protein, so it
      dwells in the active GTP-bound state.
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:30723080
      reference_title: "Dominant activating RAC2 mutation with lymphopenia, immunodeficiency, and cytoskeletal defects."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "retains intrinsic GTP hydrolysis; however, GTPase-activating protein failed to accelerate hydrolysis resulting in prolonged active GTP-bound RAC2."
      explanation: Defines the biochemical lesion precisely, as failure of GAP-accelerated hydrolysis rather than loss of the intrinsic reaction.
  - name: RAC2 p.Asn92Thr (N92T)
    description: >-
      A dominant-activating allele in a child who presented with combined
      immunodeficiency at 10 years rather than with a congenital neutrophil
      disease.
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:31071452
      reference_title: "Heterozygous activating mutation in RAC2 causes infantile-onset combined immunodeficiency with susceptibility to viral infections."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "displayed characteristics of active GTP-bound RAC2 including enhanced NADPH oxidase-derived superoxide production both at rest and in response to PMA."
      explanation: Transfection assay showing the allele behaves as constitutively GTP-bound.
  - name: RAC2 p.Pro29Arg (P29R)
    description: >-
      A de novo dominant-activating allele in the highly conserved Switch I
      domain, reported with raised ROS, elevated F-actin and increased RAC2
      protein expression.
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:35596857
      reference_title: "Combined Immunodeficiency Caused by a Novel De Novo Gain-of-Function RAC2 Mutation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The mutation resulted in enhanced reactive oxygen species production, elevated F-actin content, and increased RAC2 protein expression in neutrophils, as well as increased cytokine production and a dysregulated phenotype in T lymphocytes."
      explanation: >-
        The functional signature of a dominant-activating allele, measured in
        the patient's own neutrophils and T lymphocytes in a case report, which
        is why it is graded HUMAN_CLINICAL like every other result from this
        paper rather than as a cell-culture experiment.
  - name: RAC2 p.Arg68Trp (R68W), homozygous
    description: >-
      A rare variant that produces the dominant-activating phenotype only in the
      homozygous state. Protein expression is markedly reduced yet effector
      signalling is increased, so expression level and functional direction
      point opposite ways in the same patient.
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:41685306
      reference_title: "Case Report: Characterization of a RAC2 R68W homozygous activating mutation causing combined immune deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Despite significantly reduced RAC2 protein expression, patient-derived cells exhibited increased effector signaling in the homozygous state, producing a phenotype that phenocopies dominant gain-of-function RAC2 variants."
      explanation: Establishes that this allele reaches the same functional endpoint as the heterozygous dominant-activating alleles.
    - reference: PMID:41685306
      reference_title: "Case Report: Characterization of a RAC2 R68W homozygous activating mutation causing combined immune deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Functional hyperactivation was not observed in heterozygous cells, supporting a dosage-dependent mechanism."
      explanation: The dose dependence is why this is a homozygous-only phenocopy rather than a further dominant allele.
pathophysiology:
- name: RAC2 Dominant-Activating Missense Variant
  biological_scale: MOLECULAR
  description: >-
    A heterozygous germline missense change, typically in a switch region or the
    nucleotide-binding pocket, that shifts RAC2 toward its active state. For
    E62K the defect is specific and measurable, in that intrinsic hydrolysis is
    preserved but GTPase-activating protein no longer accelerates it.
  gene:
    preferred_term: RAC2
    modifier: GAIN_OF_FUNCTION
    term:
      id: hgnc:9802
      label: RAC2
  molecular_functions:
  - preferred_term: GTPase activity
    modifier: DECREASED
    term:
      id: GO:0003924
      label: GTPase activity
  evidence:
  - reference: PMID:30723080
    reference_title: "Dominant activating RAC2 mutation with lymphopenia, immunodeficiency, and cytoskeletal defects."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "retains intrinsic GTP hydrolysis; however, GTPase-activating protein failed to accelerate hydrolysis resulting in prolonged active GTP-bound RAC2."
    explanation: The measured biochemical lesion behind this node.
  downstream:
  - target: Constitutive GTP-Loading of RAC2
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31071452
      reference_title: "Heterozygous activating mutation in RAC2 causes infantile-onset combined immunodeficiency with susceptibility to viral infections."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "displayed characteristics of active GTP-bound RAC2 including enhanced NADPH oxidase-derived superoxide production both at rest and in response to PMA."
      explanation: Expressing the patient allele is sufficient to produce the active GTP-bound state, which is the step this edge asserts.
- name: Constitutive GTP-Loading of RAC2
  biological_scale: MOLECULAR
  description: >-
    RAC2 is a molecular switch whose function depends on cycling, not on being
    on. Holding it in the GTP-bound state engages its effector modules at rest.
    Because superoxide production and chemotaxis run through separable effector
    pathways, the lesion branches here rather than producing a single graded
    output.
  molecular_functions:
  - preferred_term: GTP-bound occupancy of RAC2
    modifier: INCREASED
    term:
      id: GO:0005525
      label: GTP binding
  evidence:
  - reference: PMID:35596857
    reference_title: "Combined Immunodeficiency Caused by a Novel De Novo Gain-of-Function RAC2 Mutation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "RAC2 undergoes a tightly regulated GTP-binding/GTP-hydrolysis cycle, enabling it to function as a molecular switch."
    explanation: >-
      States the switch behaviour that constitutive GTP-loading subverts. Graded
      OTHER because the sentence is the paper's background statement of
      established RAC2 biochemistry rather than a result of the case it reports.
  - reference: PMID:15814684
    reference_title: "Rac2 regulates neutrophil chemotaxis, superoxide production, and myeloid colony formation through multiple distinct effector pathways."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In this study, we demonstrate that Rac2 controls chemotaxis and superoxide production via distinct pathways and is critical for development of myeloid colonies in vitro."
    explanation: The separability of the two effector arms is what makes this node a branch point rather than a single downstream chain.
  downstream:
  - target: Excessive NADPH Oxidase Superoxide Production
    causal_link_type: DIRECT
    description: >-
      The oxidase arm, engaged through p67phox.
    evidence:
    - reference: PMID:30723080
      reference_title: "Dominant activating RAC2 mutation with lymphopenia, immunodeficiency, and cytoskeletal defects."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "patients exhibited excessive superoxide production, impaired fMLF-directed chemotaxis, and abnormal macropinocytosis"
      explanation: Patient neutrophils show the raised superoxide this edge asserts.
  - target: Dysregulated F-Actin Assembly and Loss of Polarization
    causal_link_type: DIRECT
    description: >-
      The cytoskeletal arm, engaged through PAK1 and POR1/Arfaptin 2.
    evidence:
    - reference: PMID:35596857
      reference_title: "Combined Immunodeficiency Caused by a Novel De Novo Gain-of-Function RAC2 Mutation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "the dominant activating RAC2 mutation led to accelerated apoptosis with augmented intracellular active caspase 3, impaired actin polarization in lymphocytes and neutrophils, and diminished RAC2 polarization in neutrophils"
      explanation: Patient cells show loss of actin polarization, which is the cytoskeletal consequence this edge asserts.
  - target: Accelerated Lymphocyte and Neutrophil Apoptosis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:35596857
      reference_title: "Combined Immunodeficiency Caused by a Novel De Novo Gain-of-Function RAC2 Mutation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "accelerated apoptosis with augmented intracellular active caspase 3"
      explanation: Directly attributes the accelerated apoptosis to the dominant-activating allele.
- name: Excessive NADPH Oxidase Superoxide Production
  biological_scale: CELLULAR
  description: >-
    Superoxide is elevated both at rest and on stimulation. The clinically
    relevant defect is dysregulation rather than excess as such, since an
    oxidative burst that cannot be timed is not an effective one.
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  biological_processes:
  - preferred_term: superoxide anion generation
    modifier: INCREASED
    term:
      id: GO:0042554
      label: superoxide anion generation
  evidence:
  - reference: PMID:31071452
    reference_title: "Heterozygous activating mutation in RAC2 causes infantile-onset combined immunodeficiency with susceptibility to viral infections."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "enhanced NADPH oxidase-derived superoxide production both at rest and in response to PMA"
    explanation: Records that the elevation is present at rest as well as on stimulation.
  downstream:
  - target: Myeloid Effector Dysfunction
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38194689
      reference_title: "Clinical and functional spectrum of RAC2-related immunodeficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "myeloid abnormalities included neutropenia, altered oxidative burst, impaired neutrophil migration, and visible neutrophil macropinosomes"
      explanation: The cohort places altered oxidative burst inside the myeloid dysfunction syndrome this node feeds.
- name: Dysregulated F-Actin Assembly and Loss of Polarization
  biological_scale: CELLULAR
  description: >-
    F-actin content rises while polarization is lost. This is the step at which
    a gain of GTPase activity becomes a functional loss, because directed
    migration requires an asymmetric, dynamically remodelled cytoskeleton rather
    than more polymer.
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  biological_processes:
  - preferred_term: regulation of actin cytoskeleton organization
    modifier: ABNORMAL
    term:
      id: GO:0032956
      label: regulation of actin cytoskeleton organization
  evidence:
  - reference: PMID:35596857
    reference_title: "Combined Immunodeficiency Caused by a Novel De Novo Gain-of-Function RAC2 Mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "elevated F-actin content, and increased RAC2 protein expression in neutrophils"
    explanation: The raised F-actin content this node asserts, measured in patient neutrophils.
  downstream:
  - target: Absent Neutrophil Chemotaxis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30723080
      reference_title: "Dominant activating RAC2 mutation with lymphopenia, immunodeficiency, and cytoskeletal defects."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "patients exhibited excessive superoxide production, impaired fMLF-directed chemotaxis, and abnormal macropinocytosis"
      explanation: Links the cytoskeletal abnormality to impaired directed migration in the same patient cells.
- name: Absent Neutrophil Chemotaxis
  biological_scale: CELLULAR
  description: >-
    Directed migration toward fMLP is not merely reduced but absent in tested
    patients, which is the feature that names the disease.
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  biological_processes:
  - preferred_term: neutrophil chemotaxis
    modifier: DECREASED
    term:
      id: GO:0030593
      label: neutrophil chemotaxis
  evidence:
  - reference: PMID:31071452
    reference_title: "Heterozygous activating mutation in RAC2 causes infantile-onset combined immunodeficiency with susceptibility to viral infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Flow cytometric investigation of neutrophil migration demonstrated an absence of chemotaxis to fMLP."
    explanation: The measured absence of chemotaxis in a patient.
  downstream:
  - target: Myeloid Effector Dysfunction
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38194689
      reference_title: "Clinical and functional spectrum of RAC2-related immunodeficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "myeloid abnormalities included neutropenia, altered oxidative burst, impaired neutrophil migration, and visible neutrophil macropinosomes"
      explanation: Impaired neutrophil migration is one of the components of the myeloid dysfunction this node feeds.
- name: Accelerated Lymphocyte and Neutrophil Apoptosis
  biological_scale: CELLULAR
  description: >-
    Patient lymphocytes and neutrophils show augmented intracellular active
    caspase 3. This is the arm through which a cytoskeletal and oxidase lesion
    reaches a lymphoid phenotype, though the pathway from RAC2 signalling to
    thymic and marrow output remains partly inferred.
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  biological_processes:
  - preferred_term: apoptotic process
    modifier: INCREASED
    term:
      id: GO:0006915
      label: apoptotic process
  evidence:
  - reference: PMID:35596857
    reference_title: "Combined Immunodeficiency Caused by a Novel De Novo Gain-of-Function RAC2 Mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "accelerated apoptosis with augmented intracellular active caspase 3"
    explanation: The caspase-3 measurement behind this node.
  - reference: PMID:11278678
    reference_title: "Biochemical and biological characterization of a human Rac2 GTPase mutant associated with phagocytic immunodeficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "expansion of cells transduced with WT Rac2 and a dominant active mutant, Q61L, was associated with significantly increased proliferation"
    explanation: An engineered dominant-active allele alters haematopoietic cell survival and proliferation, which supports RAC2 nucleotide state governing this axis. It is indirect because Q61L is a laboratory allele and the direction reported is increased proliferation rather than apoptosis.
  downstream:
  - target: T and B Lymphopenia with Impaired Lymphocyte Output
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:30723080
      reference_title: "Dominant activating RAC2 mutation with lymphopenia, immunodeficiency, and cytoskeletal defects."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "mutations resulting in severe T- and B-cell lymphopenia, myeloid dysfunction, and recurrent respiratory infections"
      explanation: Establishes that the allele produces severe lymphopenia; the intervening steps between altered RAC2 signalling and reduced thymic and marrow output are not demonstrated in patient tissue.
- name: T and B Lymphopenia with Impaired Lymphocyte Output
  biological_scale: ORGANISM
  description: >-
    Low TREC and KREC numbers indicate reduced thymic and bone-marrow output
    rather than peripheral consumption alone, and memory B cells are severely
    reduced with absent isohaemagglutinins.
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  evidence:
  - reference: PMID:31071452
    reference_title: "Heterozygous activating mutation in RAC2 causes infantile-onset combined immunodeficiency with susceptibility to viral infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immunologic investigation revealed low numbers of TRECs/KRECs, a severe reduction of memory B cells, absence of isohemagglutinins, and low IgG levels."
    explanation: The laboratory signature of impaired lymphocyte output in a molecularly confirmed patient.
  - reference: PMID:38194689
    reference_title: "Clinical and functional spectrum of RAC2-related immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Significant T- and B-lymphopenia with low immunoglobulins were seen in most patients"
    explanation: Confirms the finding is typical across the cohort rather than a single-case observation.
  downstream:
  - target: Hypogammaglobulinemia
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:35596857
      reference_title: "Combined Immunodeficiency Caused by a Novel De Novo Gain-of-Function RAC2 Mutation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Immunological investigations revealed low T-cell receptor excision circle/K-deleting recombination excision circles numbers, lymphopenia, and low serum immunoglobulin G."
      explanation: Couples the reduced lymphocyte output to the low serum IgG in the same patient.
  - target: Recurrent Viral Infection
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38194689
      reference_title: "Clinical and functional spectrum of RAC2-related immunodeficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Among 42 patients with CID with clinical data, upper and lower respiratory infections and viral infections were common."
      explanation: The lymphoid arm is the conventional route to viral susceptibility, and the cohort documents that susceptibility in the CID group.
- name: Myeloid Effector Dysfunction
  biological_scale: ORGANISM
  description: >-
    The converged myeloid consequence, comprising neutropenia, altered
    oxidative burst, impaired migration and visible neutrophil macropinosomes.
    Notably the direction of the oxidase defect predicts the infection type,
    since it is the mutants unable to support superoxide formation that were
    associated with bacterial infection.
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  evidence:
  - reference: PMID:38194689
    reference_title: "Clinical and functional spectrum of RAC2-related immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "myeloid abnormalities included neutropenia, altered oxidative burst, impaired neutrophil migration, and visible neutrophil macropinosomes"
    explanation: Enumerates the components of this node from the largest cohort.
  - reference: PMID:38194689
    reference_title: "Clinical and functional spectrum of RAC2-related immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most mutants produced elevated superoxide; mutations unable to support superoxide formation were associated with bacterial infections."
    explanation: Supports the description's claim that oxidase direction stratifies the infection phenotype.
  downstream:
  - target: Recurrent Respiratory Tract Infection
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30723080
      reference_title: "Dominant activating RAC2 mutation with lymphopenia, immunodeficiency, and cytoskeletal defects."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "resulting in severe T- and B-cell lymphopenia, myeloid dysfunction, and recurrent respiratory infections"
      explanation: States the myeloid dysfunction and the respiratory infection phenotype as consequences of the same allele.
  - target: Bronchiectasis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:41685306
      reference_title: "Case Report: Characterization of a RAC2 R68W homozygous activating mutation causing combined immune deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The first patient developed recurrent bacterial respiratory infections and early bronchiectasis that initially responded to immunoglobulin replacement therapy."
      explanation: Names recurrent bacterial respiratory infection as the intermediate between the immune defect and the structural airway damage.
phenotypes:
- name: Combined Immunodeficiency
  category: Immunological
  description: >-
    The defining laboratory picture, with both lymphoid and myeloid compartments
    affected. In several reported patients it presented in later childhood
    rather than as a congenital neutrophil disease, which is what distinguishes
    this arm clinically from the dominant-negative one.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Combined immunodeficiency
    term:
      id: HP:0005387
      label: Combined immunodeficiency
  evidence:
  - reference: PMID:31071452
    reference_title: "Heterozygous activating mutation in RAC2 causes infantile-onset combined immunodeficiency with susceptibility to viral infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our findings broaden the clinical picture of RAC2 dysfunction, showing that some individuals can present with a combined immunodeficiency later in childhood rather than a congenital neutrophil disease."
    explanation: States both the combined character and the later presentation that separates this arm.
- name: Recurrent Respiratory Tract Infection
  category: Immunological
  description: >-
    Recurrent upper and lower respiratory tract infection is the commonest
    presenting problem across the CID group.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Recurrent respiratory infections
    term:
      id: HP:0002205
      label: Recurrent respiratory infections
  evidence:
  - reference: PMID:38194689
    reference_title: "Clinical and functional spectrum of RAC2-related immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among 42 patients with CID with clinical data, upper and lower respiratory infections and viral infections were common."
    explanation: Frequency statement from the 42 patients with combined immunodeficiency and clinical data.
- name: Bronchiectasis
  category: Respiratory
  description: >-
    Structural airway damage following recurrent bacterial respiratory
    infection, reported early in some patients and progressing to lobar collapse
    and pneumonectomy in one.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Bronchiectasis
    term:
      id: HP:0002110
      label: Bronchiectasis
  evidence:
  - reference: PMID:35596857
    reference_title: "Combined Immunodeficiency Caused by a Novel De Novo Gain-of-Function RAC2 Mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we describe an 11-year-old girl with combined immunodeficiency presenting with recurrent respiratory infections and bronchiectasis."
    explanation: Bronchiectasis at presentation in a molecularly confirmed dominant-activating case.
  - reference: PMID:41685306
    reference_title: "Case Report: Characterization of a RAC2 R68W homozygous activating mutation causing combined immune deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "recurrent bacterial respiratory infections and early bronchiectasis that initially responded to immunoglobulin replacement therapy"
    explanation: A second independent report of early bronchiectasis in this allele class.
- name: Recurrent Viral Infection
  category: Immunological
  description: >-
    Persistent and treatment-refractory viral disease, particularly HPV, EBV and
    herpetic skin infection. In the longest-followed patient it progressed to
    HPV-associated gynaecological and anal neoplasia.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Recurrent viral infections
    term:
      id: HP:0004429
      label: Recurrent viral infections
  evidence:
  - reference: PMID:41685306
    reference_title: "Case Report: Characterization of a RAC2 R68W homozygous activating mutation causing combined immune deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She subsequently experienced severe, treatment-refractory cutaneous viral infections."
    explanation: Documents refractory viral disease as a distinct problem from the bacterial respiratory infections.
  - reference: PMID:41685306
    reference_title: "Case Report: Characterization of a RAC2 R68W homozygous activating mutation causing combined immune deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Persistent viral disease with oncogenic complications, bronchiectasis, lymphoproliferation, or progressive organ involvement should prompt consideration of RAC2 testing even beyond infancy."
    explanation: The authors' own summary of the viral phenotype and its oncogenic consequences.
- name: Recurrent Skin Infection
  category: Dermatological
  description: >-
    Herpetic skin infection and persistent warts, reported in several patients.
  phenotype_term:
    preferred_term: Recurrent skin infections
    term:
      id: HP:0001581
      label: Recurrent skin infections
  evidence:
  - reference: PMID:31071452
    reference_title: "Heterozygous activating mutation in RAC2 causes infantile-onset combined immunodeficiency with susceptibility to viral infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we describe a 10-year-old girl with combined immunodeficiency presenting as recurring chest infections, lung disease and herpetic skin infections."
    explanation: Herpetic skin infection at presentation in a molecularly confirmed patient.
- name: Decreased Total T Cell Count
  category: Immunological
  frequency: VERY_FREQUENT
  description: >-
    T lymphopenia is present in most patients across the RAC2 cohort.
  phenotype_term:
    preferred_term: T lymphopenia
    term:
      id: HP:0005403
      label: Decreased total T cell count
  evidence:
  - reference: PMID:38194689
    reference_title: "Clinical and functional spectrum of RAC2-related immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Significant T- and B-lymphopenia with low immunoglobulins were seen in most patients"
    explanation: Frequency statement for T lymphopenia across the cohort.
- name: Decreased Total B Cell Count
  category: Immunological
  frequency: VERY_FREQUENT
  description: >-
    B lymphopenia accompanies the T-cell defect, with severe reduction of memory
    B cells and absent isohaemagglutinins.
  phenotype_term:
    preferred_term: B lymphopenia
    term:
      id: HP:0010976
      label: Decreased total B cell count
  evidence:
  - reference: PMID:38194689
    reference_title: "Clinical and functional spectrum of RAC2-related immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Significant T- and B-lymphopenia with low immunoglobulins were seen in most patients"
    explanation: Frequency statement for B lymphopenia across the cohort.
  - reference: PMID:31071452
    reference_title: "Heterozygous activating mutation in RAC2 causes infantile-onset combined immunodeficiency with susceptibility to viral infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a severe reduction of memory B cells, absence of isohemagglutinins"
    explanation: Characterizes the B-cell compartment beyond the raw count.
- name: Hypogammaglobulinemia
  category: Immunological
  frequency: VERY_FREQUENT
  description: >-
    Low serum IgG is the usual accompaniment of the B-cell defect and is what
    immunoglobulin replacement addresses.
  phenotype_term:
    preferred_term: Decreased circulating IgG
    term:
      id: HP:0004315
      label: Decreased circulating IgG concentration
  evidence:
  - reference: PMID:35596857
    reference_title: "Combined Immunodeficiency Caused by a Novel De Novo Gain-of-Function RAC2 Mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "lymphopenia, and low serum immunoglobulin G"
    explanation: Low serum IgG measured in a molecularly confirmed patient.
- name: Neutropenia
  category: Hematological
  description: >-
    Neutropenia is one of the reported myeloid abnormalities, which is worth
    noting because the disease is otherwise a functional rather than a numerical
    neutrophil defect.
  phenotype_term:
    preferred_term: Neutropenia
    term:
      id: HP:0001875
      label: Decreased total neutrophil count
  evidence:
  - reference: PMID:38194689
    reference_title: "Clinical and functional spectrum of RAC2-related immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "myeloid abnormalities included neutropenia, altered oxidative burst, impaired neutrophil migration, and visible neutrophil macropinosomes"
    explanation: Lists neutropenia among the myeloid abnormalities of the cohort.
animal_models:
- name: Rac2 E62K heterozygous knock-in mouse
  species: Mouse
  genotype: Rac2+/E62K
  publication: PMID:30723080
  description: >-
    An allele-matched heterozygous knock-in carrying the human dominant-activating
    E62K change. It reproduces the lymphoid and the myeloid halves of the human
    phenotype in one animal, which is unusual for this disease class.
  modeled_mechanisms:
  - target: T and B Lymphopenia with Impaired Lymphocyte Output
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: ORGANISM
    description: >-
      The knock-in reproduces the T- and B-cell lymphopenia seen in patients
      carrying the same allele.
    limitations: >-
      The report establishes that the lymphopenia is reproduced but does not
      demonstrate the intervening mechanism, so the model shares the human
      entry's uncertainty about how RAC2 signalling reaches thymic and marrow
      output rather than resolving it.
    readouts:
    - name: Peripheral T- and B-cell counts in Rac2+/E62K mice
      target: T and B Lymphopenia with Impaired Lymphocyte Output
      direction: DECREASED
      interpretation: >-
        The lymphoid arm of the human phenotype is allele-driven and reproducible
        in a mouse carrying only that change.
      evidence:
      - reference: PMID:30723080
        reference_title: "Dominant activating RAC2 mutation with lymphopenia, immunodeficiency, and cytoskeletal defects."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Rac2+/E62K mice phenocopy the T- and B-cell lymphopenia, increased neutrophil F-actin, and excessive superoxide production seen in patients."
        explanation: The lymphopenia readout in the knock-in.
  - target: Dysregulated F-Actin Assembly and Loss of Polarization
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: CELLULAR
    description: >-
      Neutrophil F-actin is increased in the knock-in, matching the patient
      finding.
    limitations: >-
      The mouse readout reported is F-actin content rather than polarization, so
      it supports the assembly half of this node more directly than the loss of
      polarity.
    readouts:
    - name: Neutrophil F-actin content in Rac2+/E62K mice
      target: Dysregulated F-Actin Assembly and Loss of Polarization
      direction: INCREASED
      interpretation: >-
        Raised F-actin in the mouse matches the raised F-actin in patient
        neutrophils.
      evidence:
      - reference: PMID:30723080
        reference_title: "Dominant activating RAC2 mutation with lymphopenia, immunodeficiency, and cytoskeletal defects."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "increased neutrophil F-actin, and excessive superoxide production seen in patients"
        explanation: The F-actin readout in the knock-in.
  evidence:
  - reference: PMID:30723080
    reference_title: "Dominant activating RAC2 mutation with lymphopenia, immunodeficiency, and cytoskeletal defects."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Rac2+/E62K mice phenocopy the T- and B-cell lymphopenia, increased neutrophil F-actin, and excessive superoxide production seen in patients."
    explanation: A same-allele knock-in that phenocopies three separate patient findings is strong grounds for treating this model as informative.
- name: Rac2-null mouse
  species: Mouse
  genotype: Rac2 knockout
  publication: PMID:15528331
  description: >-
    The loss-of-function counterpart. It is the model that established RAC2 as
    non-redundant with the ubiquitous RAC1 and that mapped the two effector arms,
    but it models the wrong direction of the human lesion.
  modeled_mechanisms:
  - target: Constitutive GTP-Loading of RAC2
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    model_scale: CELLULAR
    description: >-
      The null mouse cannot model constitutive activation, and is cited here for
      the separability of the two effector arms rather than for the disease
      state.
    limitations: >-
      The lesion is inverted. The human disease is constitutive activation and
      the model is absence of the protein, so any shared phenotype is convergent
      rather than mechanistically matched. What the model does establish is that
      the two outputs are separable and that neither is redundant with RAC1.
    evidence:
    - reference: PMID:15814684
      reference_title: "Rac2 regulates neutrophil chemotaxis, superoxide production, and myeloid colony formation through multiple distinct effector pathways."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: "These findings suggest that binding to any single effector is not sufficient to rescue the distinct cellular phenotypes of Rac2-/- PMN, implicating multiple, distinct, and potentially parallel effector pathways."
      explanation: Effector-rescue experiments in null neutrophils establish the parallel-pathway architecture the human branch point depends on. It is indirect because it is a loss-of-function system reasoning about a gain-of-function disease.
  evidence:
  - reference: PMID:15528331
    reference_title: "Rac2-deficient murine macrophages have selective defects in superoxide production and phagocytosis of opsonized particles."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Mice deficient in hemopoietic-specific Rac2 exhibited agonist-specific defects in neutrophil functions including chemoattractant-stimulated filamentous actin polymerization and chemotaxis, and superoxide production elicited by phorbol ester, fMLP, or IgG-coated particles, despite expression of the highly homologous Rac1 isoform."
    explanation: Establishes the non-redundancy of RAC2 against RAC1, which is why a single RAC2 allele can produce disease at all.
treatments:
- name: Immunoglobulin Replacement Therapy
  description: >-
    Replaces the missing humoral arm. It improves the bacterial respiratory
    infection burden but does not correct the cellular defect, and in the
    longest-followed patient the viral disease progressed despite it.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: Intravenous Immunoglobulin Therapy
    term:
      id: NCIT:C121331
      label: Intravenous Immunoglobulin Therapy
    therapeutic_agent:
    - preferred_term: human immunoglobulin G
      term:
        id: NCIT:C80829
        label: Human Immunoglobulin G
  evidence:
  - reference: PMID:41685306
    reference_title: "Case Report: Characterization of a RAC2 R68W homozygous activating mutation causing combined immune deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "recurrent bacterial respiratory infections and early bronchiectasis that initially responded to immunoglobulin replacement therapy"
    explanation: Documents the response, and by saying initially, also its limits.
  target_mechanisms:
  - target: Hypogammaglobulinemia
    description: >-
      Substitutes for the immunoglobulin the failed B-cell compartment does not
      produce.
- name: Antimicrobial Prophylaxis
  description: >-
    Prophylactic antimicrobials, alongside immunoglobulin replacement, are the
    standing supportive measure while transplant is being considered or
    declined. In the largest cohort this is stated as part of how the
    immunodeficiency is treated, and one sibling pair gives the concrete case:
    both were placed on cotrimoxazole, and the younger, treated from ten months,
    did not go on to the recurrent pulmonary infections his brother had. That is
    a single uncontrolled comparison within one family, not an efficacy result.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: cotrimoxazole
      term:
        id: NCIT:C909
        label: Trimethoprim-Sulfamethoxazole
  evidence:
  - reference: PMID:38194689
    reference_title: "Clinical and functional spectrum of RAC2-related immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The older sibling, diagnosed at 7 years, had recurrent upper and lower respiratory tract infections and was placed on prophylactic cotrimoxazole, as was the younger after diagnosis at age 10 months."
    explanation: >-
      Names the agent actually used, and dates it in each sibling, which is what
      makes the following sentence about the younger brother's course readable
      as a within-family comparison rather than a claim about the drug.
  - reference: PMID:38194689
    reference_title: "Clinical and functional spectrum of RAC2-related immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three patients with CID with early diagnosis were treated prophylactically and, to date, remain clinically healthy."
    explanation: >-
      The cohort-level outcome for early prophylaxis. Three patients with no
      comparator, so it supports the practice without establishing an effect
      size.
  target_mechanisms:
  - target: Recurrent Respiratory Tract Infection
    treatment_effect: INHIBITS
    description: >-
      Suppresses the bacterial respiratory burden that follows from the
      neutrophil defect, which is the infection type the cited prophylaxis
      addresses. It does not act on the RAC2 lesion, so the underlying
      susceptibility is unchanged.
- name: Allogeneic Hematopoietic Cell Transplantation
  description: >-
    The only definitive therapy, and mechanistically rational because RAC2 is
    expressed only in haematopoietic cells, so replacing that compartment
    replaces the entire diseased tissue. It carries real transplant-related
    mortality in this disease.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: Hematopoietic Cell Transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  evidence:
  - reference: PMID:41685306
    reference_title: "Case Report: Characterization of a RAC2 R68W homozygous activating mutation causing combined immune deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Management included immunoglobulin therapy, and ultimately hematopoietic cell transplantation (HCT), after which he achieved sustained clinical improvement."
    explanation: A documented sustained response to transplant in this allele class.
  - reference: PMID:31071452
    reference_title: "Heterozygous activating mutation in RAC2 causes infantile-onset combined immunodeficiency with susceptibility to viral infections."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient experienced two hematopoietic stem cell transplantations and despite full chimerism, she developed bone marrow aplasia due to adenovirus infection and died at post-transplant day 86."
    explanation: A fatal outcome despite full chimerism, which refutes any reading of transplant as reliably curative here and is the reason the description names the mortality.
  target_mechanisms:
  - target: RAC2 Dominant-Activating Missense Variant
    description: >-
      Replacing the haematopoietic compartment removes the cells that carry and
      express the mutant allele, which is the whole of the diseased tissue.
    evidence:
    - reference: PMID:11278678
      reference_title: "Biochemical and biological characterization of a human Rac2 GTPase mutant associated with phagocytic immunodeficiency."
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      snippet: "The Rho GTPase, Rac2, is expressed only in hematopoietic cell lineages, suggesting a specific cellular function in these cells."
      explanation: The restricted expression is the reason a haematopoietic transplant can be curative. It is indirect because the paper establishes the expression pattern rather than testing transplant.
diagnosis:
- name: Targeted RAC2 signalling assays rather than protein expression alone
  description: >-
    Variant interpretation in RAC2 disease cannot rest on expression level. The
    homozygous R68W patients had markedly reduced RAC2 protein yet increased
    effector signalling, so an expression-based read would have called the
    variant the wrong direction.
  evidence:
  - reference: PMID:41685306
    reference_title: "Case Report: Characterization of a RAC2 R68W homozygous activating mutation causing combined immune deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "From a diagnostic standpoint, reliance on expression alone may be misleading; incorporating targeted signaling assays is essential for accurate variant interpretation."
    explanation: The authors' explicit diagnostic recommendation, drawn from the discordance they measured.
- name: Functional classification of the RAC2 allele
  description: >-
    Because the allele class determines which disease the patient has, functional
    assessment is diagnostic rather than merely confirmatory. No single assay
    suffices, which is why panels combining superoxide, PAK1 binding, AKT
    activation and protein stability are used.
  evidence:
  - reference: PMID:38194689
    reference_title: "Clinical and functional spectrum of RAC2-related immunodeficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "All tested RAC2 mutant proteins exhibited aberrant function; no single assay was sufficient to determine functional consequence."
    explanation: States directly that a single functional readout cannot classify a RAC2 variant.
- name: Flow cytometric neutrophil chemotaxis to fMLP
  description: >-
    The functional test that demonstrates the migration defect the disease is
    named for.
  evidence:
  - reference: PMID:31071452
    reference_title: "Heterozygous activating mutation in RAC2 causes infantile-onset combined immunodeficiency with susceptibility to viral infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Flow cytometric investigation of neutrophil migration demonstrated an absence of chemotaxis to fMLP."
    explanation: The assay and its result in a molecularly confirmed patient.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Fewer than 54 RAC2 patients from 37 families across all four allelic classes
    had been compiled worldwide by 2024, and only 44 of those were in the
    combined-immunodeficiency group that corresponds to this entry. No
    population prevalence or incidence estimate exists, and causal variants are
    private, so a rate cannot be normalized.
  evidence:
  - reference: PMID:38194689
    reference_title: "Clinical and functional spectrum of RAC2-related immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We investigated 54 patients (23 previously reported) from 37 families yielding 15 novel RAC2 missense mutations, including one present only in homozygosity."
    explanation: The published denominator, which spans all allelic classes and therefore over-counts this entry.
differential_diagnoses:
- name: Neutrophil Immunodeficiency Syndrome (RAC2 dominant-negative, IMD73A)
  description: >-
    Same gene, opposite biochemistry, different disease. The dominant-negative
    D57N allele gives a leukocyte-adhesion-deficiency mimic with neutrophilia and
    absent pus rather than a combined immunodeficiency with lymphopenia. The
    distinction is made functionally, not by gene panel.
  evidence:
  - reference: PMID:38194689
    reference_title: "Clinical and functional spectrum of RAC2-related immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "constitutively active RAS-like mutations caused neonatal SCID, dominant-negative mutations caused LAD-like disease, whereas dominant-activating mutations caused CID"
    explanation: The allele-class map that separates this entry from its two nearest neighbours in the same gene.
- name: Common variable immunodeficiency
  description: >-
    The clinical route by which several of these patients were first labelled.
    Hypogammaglobulinaemia with recurrent sinopulmonary infection and
    bronchiectasis in an adult is treated as CVID until a RAC2 variant is found,
    and one reported patient carried that label for years.
  evidence:
  - reference: PMID:41685306
    reference_title: "Case Report: Characterization of a RAC2 R68W homozygous activating mutation causing combined immune deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She was treated with intravenous immunoglobulins for presumed common variable immunodeficiency (CVID)."
    explanation: Documents the misattribution this differential exists to prevent.
discussions:
- discussion_id: imd73b_lymphopenia_mechanism
  kind: KNOWLEDGE_GAP
  prompt: >-
    By what route does constitutive RAC2 activation in the cytoskeletal and
    oxidase arms produce reduced thymic and bone-marrow lymphocyte output?
  attaches_to:
  - pathophysiology#T and B Lymphopenia with Impaired Lymphocyte Output
  rationale: >-
    Low TRECs and KRECs establish that output is reduced rather than that
    peripheral cells are being consumed, and accelerated caspase-3-positive
    apoptosis is measured in patient lymphocytes. What is missing is the step
    between them, since no patient thymus or marrow study demonstrates where in
    development the loss occurs. This entry therefore types the edge from
    apoptosis to lymphopenia as having unknown intermediates rather than
    asserting a pathway.
  evidence:
  - reference: PMID:31071452
    reference_title: "Heterozygous activating mutation in RAC2 causes infantile-onset combined immunodeficiency with susceptibility to viral infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immunologic investigation revealed low numbers of TRECs/KRECs, a severe reduction of memory B cells, absence of isohemagglutinins, and low IgG levels."
    explanation: Establishes that output is reduced, which is the observation the missing mechanism has to explain.
- discussion_id: imd73b_allele_class_boundary
  kind: KNOWLEDGE_GAP
  prompt: >-
    Where exactly is the boundary between the dominant-activating alleles that
    cause IMD73B and the constitutively active RAS-like alleles that cause
    neonatal SCID?
  attaches_to:
  - genetic#RAC2
  rationale: >-
    The cohort framework treats activity level as a continuum that maps onto
    discrete syndromes, but individual reports do not always sort cleanly. The
    G12R allele is described biochemically as gain of function while its three
    reported newborns presented with profound leukopenia and a severe
    autosomal-dominant SCID picture rather than the later-onset combined
    immunodeficiency of this entry. Until functional thresholds are standardized,
    assigning a new activating allele to IMD73B rather than to the SCID arm is a
    clinical judgement, not a measurement.
  evidence:
  - reference: PMID:31919089
    reference_title: "A gain-of-function RAC2 mutation is associated with bone-marrow hypoplasia and an autosomal dominant form of severe combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In three newborns presenting with frequent infections and profound leukopenia, we identified a private, heterozygous mutation in the RAC2 gene (p.G12R)."
    explanation: A gain-of-function allele presenting at the SCID end rather than as later-onset CID, which is the boundary problem this gap records.
  - reference: PMID:38194689
    reference_title: "Clinical and functional spectrum of RAC2-related immunodeficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "All tested RAC2 mutant proteins exhibited aberrant function; no single assay was sufficient to determine functional consequence."
    explanation: Confirms that no single functional measurement settles the class of a new allele.
references:
- reference: PMID:38194689
  title: "Clinical and functional spectrum of RAC2-related immunodeficiency."
- reference: PMID:30723080
  title: "Dominant activating RAC2 mutation with lymphopenia, immunodeficiency, and cytoskeletal defects."
- reference: PMID:31071452
  title: "Heterozygous activating mutation in RAC2 causes infantile-onset combined immunodeficiency with susceptibility to viral infections."
- reference: PMID:35596857
  title: "Combined Immunodeficiency Caused by a Novel De Novo Gain-of-Function RAC2 Mutation."
- reference: PMID:41685306
  title: "Case Report: Characterization of a RAC2 R68W homozygous activating mutation causing combined immune deficiency."
- reference: PMID:31919089
  title: "A gain-of-function RAC2 mutation is associated with bone-marrow hypoplasia and an autosomal dominant form of severe combined immunodeficiency."
- reference: PMID:15814684
  title: "Rac2 regulates neutrophil chemotaxis, superoxide production, and myeloid colony formation through multiple distinct effector pathways."
- reference: PMID:15528331
  title: "Rac2-deficient murine macrophages have selective defects in superoxide production and phagocytosis of opsonized particles."
- reference: PMID:11278678
  title: "Biochemical and biological characterization of a human Rac2 GTPase mutant associated with phagocytic immunodeficiency."
- reference: PMID:31382036
  title: "A dominant activating RAC2 variant associated with immunodeficiency and pulmonary disease."
notes: >-
  Deep-research provenance and two corrections. This entry was curated against an
  OpenScientist report (research/Immunodeficiency_73B-deep-research-openscientist.md).
  Two of its claims were not carried across.

  First, the report lists the G15D allele (PMID:36459342) among the
  dominant-activating variants. The paper itself classifies it as
  loss-of-function inactivating and says so in terms, describing it as the first
  LoF-I RAC2 mutation affecting lymphocyte function. It causes a combined
  immunodeficiency but through the opposite biochemical direction, so it is not
  curated as an IMD73B allele here.

  Second, the report's limitations section states that no knock-in mouse carries
  a human dominant-activating allele. One does: the Rac2+/E62K heterozygous
  knock-in reported in PMID:30723080, which is curated above as the entry's
  primary animal model.

  Reference validation. The report's validator listed PMID:15814684 as
  unresolved with a confabulation rate of 0.083. That identifier was re-checked
  directly against NCBI during curation and resolves to Carstanjen et al. 2005 in
  J Immunol, with the title the report attributed to it, so the failure was in
  the lookup rather than in the citation. It is cached and cited here on that
  basis.

  PMID:31382036 has no abstract available in PubMed, so it carries no evidence
  item and appears in the reference block only.

  PMID:40860338 is deliberately not used. The report cites it as a MENA
  actinopathy registry describing late-onset presentation with higher EBV and
  HPV rates, autoimmune cytopenia and lymphoproliferation. Its scope is the
  broader RAC2-pathway actinopathies rather than dominant-activating RAC2
  itself, so curating its phenotype rates against this entry would attribute a
  mixed cohort's findings to one allele class. That is the same
  named-entity problem the report's own coherence section describes as
  "variable expressivity within the broader RAC2-regulator spectrum". It is not
  cached and not cited.

  Classifications. No IUIS category is asserted here. RAC2 appears in three
  tables of the IUIS 2022 classification and the KB's IUIS campaign
  (monarch-initiative/dismech#10106, #10477) is assigning those systematically;
  both of those pull requests deliberately left the RAC2 entry unclassified for
  the same reason. Adding a category here would pre-empt that work.

📚

References & Deep Research

References

10

PMID:38194689

Clinical and functional spectrum of RAC2-related immunodeficiency.

No top-level findings curated for this source.

PMID:30723080

Dominant activating RAC2 mutation with lymphopenia, immunodeficiency, and cytoskeletal defects.

No top-level findings curated for this source.

PMID:31071452

Heterozygous activating mutation in RAC2 causes infantile-onset combined immunodeficiency with susceptibility to viral infections.

No top-level findings curated for this source.

PMID:35596857

Combined Immunodeficiency Caused by a Novel De Novo Gain-of-Function RAC2 Mutation.

No top-level findings curated for this source.

PMID:41685306

Case Report: Characterization of a RAC2 R68W homozygous activating mutation causing combined immune deficiency.

No top-level findings curated for this source.

PMID:31919089

A gain-of-function RAC2 mutation is associated with bone-marrow hypoplasia and an autosomal dominant form of severe combined immunodeficiency.

No top-level findings curated for this source.

PMID:15814684

Rac2 regulates neutrophil chemotaxis, superoxide production, and myeloid colony formation through multiple distinct effector pathways.

No top-level findings curated for this source.

PMID:15528331

Rac2-deficient murine macrophages have selective defects in superoxide production and phagocytosis of opsonized particles.

No top-level findings curated for this source.

PMID:11278678

Biochemical and biological characterization of a human Rac2 GTPase mutant associated with phagocytic immunodeficiency.

No top-level findings curated for this source.

PMID:31382036

A dominant activating RAC2 variant associated with immunodeficiency and pulmonary disease.

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 (2)

Record notes

Deep-research provenance and two corrections. This entry was curated against an OpenScientist report (research/Immunodeficiency_73B-deep-research-openscientist.md). Two of its claims were not carried across. First, the report lists the G15D allele (PMID:36459342) among the dominant-activating variants. The paper itself classifies it as loss-of-function inactivating and says so in terms, describing it as the first LoF-I RAC2 mutation affecting lymphocyte function. It causes a combined immunodeficiency but through the opposite biochemical direction, so it is not curated as an IMD73B allele here. Second, the report's limitations section states that no knock-in mouse carries a human dominant-activating allele. One does: the Rac2+/E62K heterozygous knock-in reported in PMID:30723080, which is curated above as the entry's primary animal model. Reference validation. The report's validator listed PMID:15814684 as unresolved with a confabulation rate of 0.083. That identifier was re-checked directly against NCBI during curation and resolves to Carstanjen et al. 2005 in J Immunol, with the title the report attributed to it, so the failure was in the lookup rather than in the citation. It is cached and cited here on that basis. PMID:31382036 has no abstract available in PubMed, so it carries no evidence item and appears in the reference block only. PMID:40860338 is deliberately not used. The report cites it as a MENA actinopathy registry describing late-onset presentation with higher EBV and HPV rates, autoimmune cytopenia and lymphoproliferation. Its scope is the broader RAC2-pathway actinopathies rather than dominant-activating RAC2 itself, so curating its phenotype rates against this entry would attribute a mixed cohort's findings to one allele class. That is the same named-entity problem the report's own coherence section describes as "variable expressivity within the broader RAC2-regulator spectrum". It is not cached and not cited. Classifications. No IUIS category is asserted here. RAC2 appears in three tables of the IUIS 2022 classification and the KB's IUIS campaign (monarch-initiative/dismech#10106, #10477) is assigning those systematically; both of those pull requests deliberately left the RAC2 entry unclassified for the same reason. Adding a category here would pre-empt that work.

Create: Immunodeficiency 73B (RAC2 dominant-activating combined immunodeficiency) · 2026-09-05T14:54:58Z · View source

New kb/disorders entry for IMD73B (MONDO:0033554), claimed via issue #11107. Curated as the dominant-activating arm of the RAC2 allele-class spectrum, which the existing Neutrophil_Immunodeficiency_Syndrome entry (IMD73A, dominant-negative) explicitly scopes out of itself. Pathograph branches at constitutive GTP-loading into the NADPH-oxidase arm, the actin arm and an apoptosis arm, converging on myeloid effector dysfunction and on T/B lymphopenia with impaired output. Nine HPO-bound phenotypes, four variants with functional evidence, two mouse models (the allele-matched Rac2+/E62K knock-in as RECAPITULATES, the Rac2 null as FAILS_TO_RECAPITULATE with an inverted-lesion limitation), and two KNOWLEDGE_GAP discussions. Deep research: OpenScientist report committed. Two of its claims were rejected and the rejections recorded in entry notes. First, it listed the G15D allele (PMID:36459342) as dominant-activating; the paper classifies it as loss-of-function inactivating, so it is excluded. Second, it states no knock-in mouse exists for a human dominant-activating allele; PMID:30723080 reports Rac2+/E62K, which is curated as the primary model. Reference validation: the report flagged PMID:15814684 as unresolved (confabulation_rate 0.083). I re-checked that identifier directly against NCBI esummary during curation; it resolves to Carstanjen et al. 2005 J Immunol with the title the report attributed to it, so the failure was in the lookup rather than the citation, and it is cached and cited on that basis. PMID:31382036 has no PubMed abstract (content_type unavailable) so it carries no evidence item and appears in the reference block only. Four snippets had to be requoted around square-bracketed allele designations (RAC2[E62K], RAC2 [N92 T]) that the reference validator strips; commented on issue #10192 with this as a new sub-form no proposed keep-pattern reaches. No iuis_category asserted, to avoid pre-empting the IUIS campaign in PRs #10106 and #10477, both of which deliberately left RAC2 unclassified. Validation: schema pass, term validation pass, 62/62 snippets verified, check-entity-refs / check-causal-targets / check-duplicate-keys / check-enum-values clean.

OpenScientist ▸

Immunodeficiency 73B (RAC2 Gain-of-Function Combined Immunodeficiency) — Comprehensive Disease Report

openscientist-autonomous 12 citations 2026-09-05T14:25:42.113196

Immunodeficiency 73B (RAC2 Gain-of-Function Combined Immunodeficiency) — Comprehensive Disease Report

Disease: Immunodeficiency 73B (IMD73B), with defective neutrophil chemotaxis and lymphopenia MONDO ID: MONDO:0033554 | OMIM phenotype: #618986 | Gene: RAC2 (OMIM 602049; HGNC:9802; NCBI Gene 5880; UniProt P15153) | Locus: 22q13.1 Category: Mendelian, autosomal dominant

Summary

Immunodeficiency 73B (IMD73B) is an ultra-rare, autosomal dominant combined immunodeficiency (CID) caused by heterozygous, dominant-activating (gain-of-function, GOF) missense mutations in RAC2, a Rho-family small GTPase expressed exclusively in hematopoietic cells. RAC2 normally functions as a molecular switch, cycling between an inactive GDP-bound and an active GTP-bound state to control two parallel effector arms critical to immune-cell function: (1) NADPH-oxidase–driven superoxide production (via p67phox) and (2) actin-cytoskeleton remodeling for cell migration (via PAK1 and POR1/Arfaptin2). In IMD73B, the mutant protein is locked in, or biased toward, the constitutively active GTP-bound state, dysregulating both effector arms simultaneously.

The clinical consequence is a combined immune defect that spans the myeloid and lymphoid lineages: patients develop T- and B-cell lymphopenia, hypogammaglobulinemia, defective neutrophil chemotaxis, and dysregulated oxidative burst, presenting with recurrent respiratory infections, bronchiectasis, and heightened susceptibility to viral pathogens (HPV, EBV, herpesviruses). IMD73B sits within a broader RAC2-related immunodeficiency spectrum in which the biochemical class of the mutation predicts the clinical phenotype — constitutively active "RAS-like" alleles produce neonatal SCID, dominant-negative alleles produce a leukocyte-adhesion-deficiency (LAD)-like disease, and dominant-activating alleles produce the CID category corresponding to IMD73B.

Management combines supportive care (immunoglobulin replacement, antimicrobial prophylaxis) with allogeneic hematopoietic cell transplantation (HCT) as the only definitive, curative therapy — rational because RAC2 is expressed solely in hematopoietic cells, so replacing that compartment corrects the defect. Transplant carries substantial risk, however, with reported transplant-related mortality. IMD73B is genetically ultra-rare: fewer than ~54 RAC2 patients from 37 families (across all allelic classes) had been compiled worldwide by 2024, and causal variants are private, frequently de novo germline missense changes with apparently complete penetrance.

Key Findings

Finding 1 — IMD73B is caused by dominant-activating (gain-of-function) heterozygous RAC2 mutations producing combined immunodeficiency with lymphopenia

RAC2-related immunodeficiency demonstrates a striking genotype–function–phenotype correlation. In the largest compiled cohort to date — 54 patients from 37 families — the biochemical activity of the mutant RAC2 protein predicts the clinical syndrome. As Donkó et al. state directly: "Disease correlated to RAC2 activity: constitutively active RAS-like mutations caused neonatal SCID, dominant-negative mutations caused LAD-like disease, whereas dominant-activating mutations caused CID" (PMID: 38194689). The combined immune deficiency (CID) produced by dominant-activating alleles is the entity catalogued as IMD73B (OMIM #618986).

Reported dominant-activating variants include E62K (PMID: 30723080), G12R (PMID: 31919089), N92T (PMID: 31071452), and P29R (PMID: 35596857). The gain-of-function mechanism is directly demonstrated at the biochemical level: cell lines transfected with the N92T variant "displayed characteristics of active GTP-bound RAC2 including enhanced NADPH oxidase-derived superoxide production both at rest and in response to PMA" (PMID: 31071452). The heterozygous, dominant nature of the G12R allele — "we identified a private, heterozygous mutation in the RAC2 gene (p.G12R)" — confirms the autosomal dominant, single-allele mechanism (PMID: 31919089). Patients uniformly show significant T- and B-lymphopenia with low immunoglobulins.

Finding 2 — Clinical phenotype: recurrent respiratory/viral infections, T/B lymphopenia, hypogammaglobulinemia, and defective neutrophil chemotaxis

Across dominant-activating RAC2 CID patients, the recurring clinical picture combines lymphoid and myeloid dysfunction. Common features include recurrent upper and lower respiratory tract infections, susceptibility to viral infections (HPV, EBV, herpetic skin infections), and a characteristic combined-immunodeficiency laboratory profile. Sharapova et al. document: "Immunologic investigation revealed low numbers of TRECs/KRECs, a severe reduction of memory B cells, absence of isohemagglutinins, and low IgG levels" (PMID: 31071452) — reflecting impaired thymic/bone-marrow output and defective humoral immunity.

The defining neutrophil migration defect — which gives the disease its "defective neutrophil chemotaxis" character — is captured directly: "Flow cytometric investigation of neutrophil migration demonstrated an absence of chemotaxis to fMLP" (PMID: 31071452). Myeloid abnormalities are broad; the cohort study summarizes that "myeloid abnormalities included neutropenia, altered oxidative burst, impaired neutrophil migration, and visible neutrophil macropinosomes" (PMID: 38194689). Bronchiectasis and chronic pulmonary disease are frequently reported (PMID: 31382036; PMID: 35596857). The P29R report additionally describes "increased cytokine production and a dysregulated phenotype in T lymphocytes" and "accelerated apoptosis with augmented intracellular active caspase 3" (PMID: 35596857).

Suggested HPO terms: Recurrent respiratory infections (HP:0002205); Bronchiectasis (HP:0002110); Recurrent viral infections (HP:0004429); T lymphocytopenia (HP:0005403); B lymphocytopenia (HP:0010976); Decreased circulating IgG (HP:0004315); Neutropenia (HP:0001875); Recurrent bacterial infections (HP:0002718); Lymphopenia (HP:0001888).

Finding 3 — Mechanism: RAC2 signals through p67phox, PAK1, and POR1/Arfaptin2 to control superoxide production and chemotaxis via distinct effector pathways

RAC2 is a hematopoietic-restricted Rho GTPase that cycles between a GTP-bound (active) and GDP-bound (inactive) state. Murine loss-of-function studies established its non-redundant role despite the presence of the homologous RAC1: "Mice deficient in hemopoietic-specific Rac2 exhibited agonist-specific defects in neutrophil functions including chemoattractant-stimulated filamentous actin polymerization and chemotaxis, and superoxide production elicited by phorbol ester, fMLP, or IgG-coated particles, despite expression of the highly homologous Rac1 isoform" (PMID: 15528331).

Critically, the two principal RAC2 outputs are separable and run through distinct effector modules: "Rac2 controls chemotaxis and superoxide production via distinct pathways" (PMID: 15814684) — the NADPH-oxidase superoxide arm via p67phox, and cytoskeletal/migration control via PAK1 and POR1/Arfaptin2. The consequences of altered nucleotide-state balance were shown with engineered mutants: the dominant-active Q61L mutant increased hematopoietic proliferation, whereas the dominant-negative D57N sequestered guanine-nucleotide exchange factors (GEFs), reduced GTP binding to ~10%, and increased apoptosis — "expansion of cells transduced with WT Rac2 and a dominant active mutant, Q61L, was associated with significantly increased proliferation" (PMID: 11278678). In IMD73B patient cells, the constitutively GTP-bound mutant produces elevated resting and stimulated superoxide, increased F-actin content, and increased RAC2 protein expression (PMID: 31071452; PMID: 35596857).

Suggested GO terms: neutrophil chemotaxis (GO:0030593); superoxide anion generation (GO:0042554); respiratory burst (GO:0045730); regulation of actin cytoskeleton organization (GO:0032956); GTPase activity (GO:0003924); apoptotic process (GO:0006915).

Finding 4 — Model organisms: Rac2-null and mutant mice recapitulate neutrophil migration/oxidase defects; RAC2 is highly conserved

Rac2 knockout mice (Mus musculus, NCBI Taxon 10090; ortholog gene Rac2) reproduce the core cellular pathology, showing non-redundant defects in neutrophil chemotaxis, L-selectin capture/rolling, F-actin polymerization, and superoxide production, plus impaired myeloid colony formation — "is critical for development of myeloid colonies in vitro" (PMID: 15814684; see also PMID: 11278678; PMID: 15528331). Bone-marrow transduction/transplantation systems expressing human RAC2 mutants (D57N dominant-negative, Q61L dominant-active) in murine hematopoietic cells reproduce mutation-specific phenotypes — "Transplantation of transduced bone marrow cells into lethally irradiated rec[ipients]" (PMID: 11278678). Heterologous expression systems are used to classify patient variants by superoxide, PAK1 binding, and F-actin readouts (PMID: 38194689). These are chiefly loss-of-function/knockout and mutant-overexpression models; a dedicated knock-in mouse carrying a specific human dominant-activating IMD73B allele would be the ideal next-generation model.

Finding 5 — Treatment: immunoglobulin replacement and anti-infective supportive care, with allogeneic HCT as the definitive/curative therapy

Management combines supportive care (immunoglobulin replacement therapy, antimicrobial prophylaxis/treatment) with allogeneic hematopoietic stem cell/cell transplantation (HSCT/HCT) as the only curative option. Because RAC2 is expressed only in hematopoietic cells, replacing that compartment corrects the underlying defect. An index G12R patient was "cured by hematopoietic stem cell transplantation" (PMID: 31919089); a homozygous R68W patient managed with "immunoglobulin therapy, and ultimately hematopoietic cell transplantation (HCT), after which he achieved sustained clinical improvement" (PMID: 41685306).

Transplant is high-risk, however: an N92T patient "experienced two hematopoietic stem cell transplantations and despite full chimerism, she developed bone marrow aplasia due to adenovirus infection and died at post-transplant day 86" (PMID: 31071452), underscoring substantial transplant-related mortality risk.

Suggested NCIT terms: Hematopoietic Cell Transplantation (NCIT:C15431); Immunoglobulin Therapy (NCIT:C593); Bone Marrow Transplantation (NCIT:C15265).

Finding 6 — Genetics/epidemiology: ultra-rare autosomal dominant disorder; de novo or dominantly inherited germline missense variants with complete penetrance

RAC2 maps to chromosome 22q13.1 (HGNC:9802; NCBI Gene 5880; UniProt P15153; gene OMIM 602049). IMD73B (phenotype OMIM #618986; MONDO:0033554) is inherited in an autosomal dominant manner; causal variants are heterozygous germline missense mutations that are frequently de novo. Duan et al. describe a de novo variant: "Exome sequencing identified a de novo RAC2 mutation (c.44G > A/p.G15D) that was co-segregated with the disease in the family" (PMID: 36459342); and Lagresle-Peyrou et al. document both a de novo origin and subsequent vertical transmission: "This mutation was de novo in the index case, who had been cured by hematopoietic stem cell transplantation but had transmitted the mutation to her sick daughter" (PMID: 31919089) — establishing new-mutation origin plus autosomal dominant transmission with apparent complete penetrance.

The disease is ultra-rare: "We investigated 54 patients (23 previously reported) from 37 families yielding 15 novel RAC2 missense mutations, including one present only in homozygosity" (PMID: 38194689) — and this total spans all three allelic classes, so the dominant-activating IMD73B subset is smaller still. No population prevalence or incidence estimate is established. Pathogenic activating variants are private and absent/vanishingly rare in gnomAD. A homozygous activating variant (R68W) that phenocopies the dominant GOF state has also been described (PMID: 41685306).

Finding 7 — Anatomical/cellular targets and ontology mapping

RAC2 is expressed exclusively in hematopoietic cells, so the primary affected system is the hematopoietic/immune system (UBERON:0002390), with the bone marrow (UBERON:0002371) and circulating leukocytes as the disease compartment. The cohort description that "Mutations in the small Rho-family guanosine triphosphate hydrolase RAC2, [are] critical for actin cytoskeleton remodeling and intracellular signal transduction" (PMID: 38194689) supports the cellular and subcellular mapping.

Level	Structures / terms
Organ/system	Hematopoietic/immune system (UBERON:0002390); bone marrow (UBERON:0002371); secondary lung/bronchi (UBERON:0002048 / UBERON:0002185, bronchiectasis); skin/mucosa (HPV lesions); lymph nodes/spleen (lymphoproliferation); rarely kidney (light-chain deposition)
Cell types	Neutrophil (CL:0000775); T cell (CL:0000084); B cell (CL:0000236); monocyte/macrophage (CL:0000235); hematopoietic stem/progenitor cell (CL:0000037)
Subcellular	Cytosol (GO:0005829); plasma membrane/leading edge/lamellipodium (GO:0030027); actin cytoskeleton (GO:0015629); NADPH oxidase complex

Mechanistic Model / Interpretation

Ordered causal chain (initiating lesion → clinical manifestation)

A heterozygous, dominant-activating missense mutation arises in RAC2 (22q13.1) — de novo or inherited (e.g., G12R, E62K, N92T, P29R, G15D). (demonstrated)
The mutation, often in the Switch I/Switch II region or nucleotide-binding pocket, biases RAC2 toward the constitutively GTP-bound active state (reduced GTP hydrolysis and/or spontaneous nucleotide exchange). (demonstrated for N92T in vitro — enhanced GTP-bound characteristics) → leads to
Constitutive activation of RAC2 effector arms even at rest. Because chemotaxis and superoxide are controlled through distinct effectors, the lesion branches: → results in

Branch A — NADPH oxidase (p67phox): constitutive and hyper-inducible superoxide/ROS production (elevated resting and PMA-stimulated superoxide). → contributes to oxidative dysregulation and myeloid dysfunction.

Branch B — actin cytoskeleton (PAK1, POR1/Arfaptin2): dysregulated, non-polarized F-actin assembly (increased F-actin content, impaired polarization) that paradoxically impairs directed migration despite an "active" GTPase. → leads to absent neutrophil chemotaxis to fMLP.

Branch C — cell survival/proliferation: altered RAC2 signaling drives accelerated apoptosis (augmented active caspase-3) in lymphocytes and neutrophils, and lymphocyte dysregulation. → leads to T/B lymphopenia. 4. Combined myeloid (defective chemotaxis, altered oxidative burst, neutropenia, macropinosomes) and lymphoid (T/B lymphopenia, reduced memory B cells, low TRECs/KRECs, hypogammaglobulinemia) failure. (demonstrated) → results in 5. Combined immunodeficiency (IMD73B): recurrent bacterial respiratory infections, bronchiectasis, and susceptibility to viral pathogens (HPV, EBV, herpesviruses). (demonstrated)

   RAC2 dominant-activating missense mutation (heterozygous, germline)
        │
constitutive GTP-bound (active) RAC2
        │
┌───────────────┼────────────────────┐
▼               ▼                     ▼
  p67phox/NADPH    PAK1 + POR1/         apoptosis / survival
   oxidase          Arfaptin2            dysregulation
│            (actin)                  │
   ↑ superoxide   dysregulated F-actin   ↑ caspase-3
   (rest + PMA)   → impaired polarization  → T/B lymphopenia,
│              │                    low memory B cells
└──────┬───────┘                        │
       ▼                                ▼
    absent neutrophil chemotaxis      hypogammaglobulinemia
    + altered oxidative burst          low TRECs/KRECs
       └──────────────┬─────────────────┘
              ▼
     COMBINED IMMUNODEFICIENCY (IMD73B)
   recurrent respiratory + viral infection, bronchiectasis

Upstream vs downstream: The mutation and its biochemical effect (constitutive GTP loading) are the most upstream events. The parallel effector arms are intermediate. Lymphopenia, hypogammaglobulinemia, and neutrophil dysfunction are downstream cellular readouts, and the infection phenotype is the terminal clinical manifestation. A key conceptual point is that a gain of GTPase activity produces a loss of coordinated cell function — because directed migration and regulated oxidative burst require dynamic cycling, not constitutive activation.

Genotype–phenotype axis across the RAC2 allelic series

Biochemical class	Example alleles	Phenotype	Relation to IMD73B
Constitutively active ("RAS-like")	(high-activity alleles)	Neonatal SCID	Severe end of spectrum
Dominant-activating (GOF)	E62K, G12R, N92T, P29R	Combined immunodeficiency (CID)	= IMD73B (OMIM #618986)
Dominant-negative	D57N	LAD-like phagocyte defect	Distinct entity
Autosomal-recessive loss-of-function	(biallelic LOF)	CVID-like / other	Distinct entity

Source: PMID: 38194689; PMID: 35596857.

Section-by-Section Report Content

1. Disease Information

IMD73B is an autosomal dominant combined immunodeficiency caused by gain-of-function RAC2 variants. Identifiers: OMIM #618986; MONDO:0033554; gene RAC2 (OMIM 602049). MeSH-level indexing falls under "Severe Combined Immunodeficiency"/"Primary Immunodeficiency Diseases"; ICD-10 maps broadly to D81 (combined immunodeficiencies). Synonyms/related names: RAC2-related immunodeficiency (dominant-activating type); RAC2 gain-of-function combined immunodeficiency; combined immunodeficiency due to activating RAC2 mutation. Information is derived from aggregated disease-level resources and published individual case reports/case series, not EHR data.

2. Etiology

Causal factor: monogenic — heterozygous dominant-activating germline missense mutation in RAC2. Genetic risk: the causal variant is itself the disease determinant (Mendelian, high penetrance); no separate susceptibility loci or modifier genes are established. Environmental risk/protective/gene–environment factors: none established; the disease is genetically determined. Environmental exposures (e.g., viral pathogens such as adenovirus post-transplant) act as precipitants of complications rather than disease causes.

3. Phenotypes

See Finding 2 and the HPO list above. Phenotype onset is typically infantile/childhood; severity moderate-to-severe and variable; course chronic/progressive with recurrent infections and structural lung damage (bronchiectasis). Laboratory abnormalities (LOINC-type analytes): low IgG, low T/B cell counts, low TRECs/KRECs, abnormal neutrophil oxidative burst and chemotaxis. Quality-of-life impact is substantial due to chronic infection burden, need for immunoglobulin therapy, and transplant-related morbidity; disease-specific QoL instruments have not been reported for this ultra-rare entity.

4. Genetic / Molecular Information

Causal gene RAC2 (HGNC:9802). Pathogenic variants are missense (e.g., G12R, G15D, P29R, E62K, R68W [homozygous], N92T), classified pathogenic/likely pathogenic per ACMG/AMP with functional evidence (PS3: abnormal superoxide/F-actin/PAK1 assays). Variants are private, de novo or dominantly transmitted germline changes; allele frequency in gnomAD is absent/vanishingly rare. Functional consequence: gain-of-function/dominant-activating (constitutively GTP-bound). No modifier genes, epigenetic mechanisms, or chromosomal abnormalities are established for this disorder.

5. Environmental Information

No environmental, lifestyle, or infectious causal agents. Infectious agents (HPV, EBV, herpesviruses, and post-transplant adenovirus) are consequences of the immunodeficiency, not causes.

6. Mechanism / Pathophysiology

See the ordered causal chain and diagram above. Molecular pathway: Rho-GTPase (RAC2) signaling → NADPH oxidase (p67phox) and actin-regulatory (PAK1, POR1/Arfaptin2) effectors. Cellular processes: dysregulated chemotaxis, respiratory burst, apoptosis, actin remodeling. Immune involvement: primary immunodeficiency affecting both myeloid and lymphoid compartments.

7. Anatomical Structures Affected

See Finding 7 table.

8. Temporal Development

Onset: typically infantile-to-childhood (e.g., infantile-onset CID; an 11-year-old presentation for P29R). Progression: chronic, lifelong, progressive with cumulative pulmonary damage (bronchiectasis). Course: recurrent-infection pattern; not self-limited. Critical intervention window: early diagnosis and HCT before irreversible organ (lung) damage or fatal infection.

9. Inheritance and Population

Autosomal dominant, frequently de novo, with vertical transmission documented; apparent complete penetrance; expressivity variable. Ultra-rare — <54 RAC2 patients from 37 families worldwide (all allelic classes) as of 2024; no prevalence/incidence figure established. No founder effect, established consanguinity role (except the rare homozygous R68W case), or sex bias is documented for the dominant-activating class.

10. Diagnostics

Genetic testing is definitive: WES/WGS or targeted immunodeficiency gene panels including RAC2; single-gene testing to confirm. Functional confirmation assays: neutrophil superoxide/oxidative burst, F-actin content, chemotaxis to fMLP, PAK1-binding. Immunophenotyping: T/B lymphopenia, low memory B cells, low TRECs/KRECs, low IgG, absent isohemagglutinins. Newborn screening: low TRECs on SCID newborn screening may flag severe cases. Differential diagnosis: SCID, other actinopathies (CDC42, ARPC1B, WAS/WIP, DOCK8/DOCK2), LAD, CVID, chronic granulomatous disease.

11. Outcome / Prognosis

Guarded without curative therapy; chronic infections and bronchiectasis cause progressive morbidity. HCT can be curative with sustained improvement, but carries significant transplant-related mortality (documented death from adenovirus-driven marrow aplasia at day 86). Prognostic factors: mutation severity/biochemical class, degree of lymphopenia, pre-transplant infection/organ damage, and transplant course.

12. Treatment

See Finding 5. Supportive: immunoglobulin replacement (NCIT:C593), antimicrobial prophylaxis/treatment, antiviral therapy. Definitive: allogeneic HCT (NCIT:C15431) / bone marrow transplantation (NCIT:C15265). No approved gene therapy or targeted RAC2 inhibitor exists, though RAC-pathway inhibition is a plausible future strategy given the GOF mechanism.

13. Prevention

No primary prevention (monogenic). Secondary: early genetic diagnosis via newborn SCID screening and prompt HCT. Genetic counseling for autosomal dominant transmission risk (50% to offspring); prenatal/preimplantation genetic testing possible for known familial variants. Tertiary: immunoglobulin replacement, antimicrobial prophylaxis, and infection surveillance to prevent complications.

14. Other Species / Natural Disease

RAC2 is highly conserved; the mouse ortholog is Rac2 (Mus musculus, NCBI Taxon 10090). No naturally occurring animal disease is catalogued for RAC2 GOF; comparative biology is based on engineered/knockout mouse models. No zoonotic relevance.

15. Model Organisms

Mouse (Mus musculus): Rac2 knockout and human-RAC2-mutant bone-marrow transduction/transplant models recapitulate neutrophil chemotaxis, F-actin, superoxide, and myeloid-colony defects. In-vitro heterologous expression systems classify patient variants. Limitation: existing models are largely loss-of-function/overexpression; a knock-in mouse for a specific human dominant-activating IMD73B allele would better model the lymphoid CID phenotype. Databases: MGI, IMPC/KOMP, Alliance of Genome Resources.

Evidence Base

PMID	Study (abbrev.)	Contribution	Evidence type
38194689	Donkó 2024 — Clinical and functional spectrum of RAC2-related immunodeficiency	Defines genotype–function–phenotype axis (active→SCID, dominant-negative→LAD-like, dominant-activating→CID); 54 patients/37 families; myeloid abnormality summary	Human clinical + in vitro
31071452	Sharapova 2019 — N92T	GOF biochemistry (GTP-bound, enhanced superoxide); CID labs; absent chemotaxis; fatal post-HSCT course	Human clinical + in vitro
35596857	Zhang 2022 — P29R	Novel de novo GOF variant; ↑ROS, ↑F-actin, ↑RAC2 expression; apoptosis and T-cell dysregulation	Human clinical + in vitro
31919089	Lagresle-Peyrou 2021 — G12R	Private heterozygous GOF; de novo then vertical transmission; HSCT curative; bone-marrow hypoplasia/AD-SCID	Human clinical
30723080	Hsu 2019 — E62K	Dominant activating variant with lymphopenia, immunodeficiency, cytoskeletal defects	Human clinical + in vitro
36459342	Duan 2023 — G15D	De novo variant identified by exome sequencing, co-segregating	Human clinical
41685306	Desjardins 2026 — R68W (homozygous)	Homozygous activating variant phenocopying GOF; Ig therapy + HCT with sustained improvement	Human clinical
31382036	Smits 2020	Dominant activating RAC2 variant with immunodeficiency and pulmonary disease	Human clinical
40860338	MENA actinopathy registry	RAC2-pathway actinopathies: late-onset, higher EBV/HPV, autoimmune cytopenia, lymphoproliferation; HSCT prioritization	Human clinical registry
15528331	Yamauchi 2004	Non-redundant Rac2 role in neutrophil actin polymerization, chemotaxis, superoxide	Model organism (mouse)
15814684	Carstanjen 2005	Chemotaxis vs superoxide via distinct effectors (p67phox, PAK1, POR1); myeloid colony development	Model organism (mouse)
11278678	Gu 2001	Q61L active/D57N dominant-negative biochemistry; BM transduction/transplant model	In vitro + model organism

Coherence: The human case reports (dominant-activating alleles) and the murine mechanistic studies converge — the GOF alleles constitutively activate the same p67phox and actin effector arms that mouse loss-of-function studies proved are non-redundantly RAC2-dependent. No paper in the reviewed set contradicts the core model. The MENA registry (PMID: 40860338) adds a note of phenotypic breadth (some RAC2-pathway patients present late with relatively normal immune profiles but higher EBV/HPV/autoimmune-cytopenia rates), indicating variable expressivity within the broader RAC2-regulator spectrum.

Limitations and Knowledge Gaps

Ultra-rare N. The entire RAC2 literature comprises fewer than ~54 patients across all allelic classes; the dominant-activating IMD73B subset is smaller, limiting robust genotype–phenotype and outcome statistics.
No population epidemiology. Prevalence/incidence, carrier frequency, sex ratio, and geographic distribution are unestablished (private de novo variants).
Mechanistic detail of lymphopenia. The precise pathway by which cytoskeletal/oxidase dysregulation produces T/B lymphopenia and impaired thymic output is partly inferred (apoptosis, impaired migration/development) rather than fully demonstrated in patient thymus/marrow.
Model gap. No knock-in mouse carrying a specific human dominant-activating IMD73B allele; existing models are knockout/overexpression, which capture myeloid but not fully the lymphoid CID phenotype.
Therapeutics. No targeted RAC2 inhibitor or gene therapy exists; HCT outcome data are anecdotal (individual cases, including one death), with no cohort-level transplant survival statistics.
Variant classification. Some RAC2 missense changes remain functionally ambiguous; standardized functional assay thresholds for GOF vs dominant-negative classification are still being refined.

Proposed Follow-up Experiments / Actions

Generate a conditional knock-in mouse for a canonical dominant-activating allele (e.g., E62K or P29R) to model the combined lymphoid+myeloid phenotype and test therapeutics in vivo.
Single-cell transcriptomics/CITE-seq of patient bone marrow and blood to map cell-type-specific effects on hematopoietic stem/progenitor, T, B, and neutrophil compartments and clarify the lymphopenia mechanism.
Systematic functional variant classification pipeline (superoxide, F-actin, PAK1-binding, GTP-loading) with defined GOF/DN thresholds, deposited to ClinVar/ClinGen, to resolve VUS.
Multi-center natural history and transplant-outcome registry for RAC2 immunodeficiency to establish prevalence, penetrance/expressivity, and HCT survival/optimal timing and conditioning.
Preclinical evaluation of RAC-pathway inhibition (e.g., small-molecule RAC/PAK1 inhibitors) as a mechanism-matched therapy or bridge-to-transplant, given the gain-of-function basis.
Prospective HCT protocol optimization including antiviral prophylaxis strategy, informed by the documented adenovirus-driven marrow aplasia mortality.

Report compiled from 5 iterations, 7 confirmed findings, and 12 reviewed papers. Evidence types span human clinical case reports/series, murine model-organism studies, and in-vitro functional assays. All mechanistic and clinical claims are cited to primary literature by PMID.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	12
Resolved	11
Unresolved (possible confabulation)	1
Unverifiable	0
References weighed for topical relevance	11
On topic	9
Off topic	0

Unresolved references

These identifiers did not resolve to a record and may be fabricated. A lookup that failed for transport reasons is indistinguishable from one that failed because the record does not exist, so spot-check before acting on them:

PMID:15814684 (6 mentions) - Identifier did not resolve to a record

Term Validation

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

Outcome	Count
Terms checked	32
Resolved	31
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	1
Terms whose name was checked	2
Terms named correctly	1
Terms named as a different term	0
Terms whose name is worth a second look	1

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The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

UBERON:0002390 (2 mentions) - the report calls it "hematopoietic/immune system"; UBERON calls it hematopoietic system

31 of 32 terms resolved to a current term; the rest could not be looked up either way.

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Immunodeficiency 73B (RAC2 Gain-of-Function Combined Immunodeficiency) — Comprehensive Disease Report

Summary

Key Findings

Finding 1 — IMD73B is caused by dominant-activating (gain-of-function) heterozygous RAC2 mutations producing combined immunodeficiency with lymphopenia

Finding 2 — Clinical phenotype: recurrent respiratory/viral infections, T/B lymphopenia, hypogammaglobulinemia, and defective neutrophil chemotaxis

Finding 3 — Mechanism: RAC2 signals through p67phox, PAK1, and POR1/Arfaptin2 to control superoxide production and chemotaxis via distinct effector pathways

Finding 4 — Model organisms: Rac2-null and mutant mice recapitulate neutrophil migration/oxidase defects; RAC2 is highly conserved

Finding 5 — Treatment: immunoglobulin replacement and anti-infective supportive care, with allogeneic HCT as the definitive/curative therapy

Finding 6 — Genetics/epidemiology: ultra-rare autosomal dominant disorder; de novo or dominantly inherited germline missense variants with complete penetrance

Finding 7 — Anatomical/cellular targets and ontology mapping

Mechanistic Model / Interpretation

Ordered causal chain (initiating lesion → clinical manifestation)

Genotype–phenotype axis across the RAC2 allelic series

Section-by-Section Report Content

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Evidence Base

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Artifacts

Reference Validation

Unresolved references

Term Validation

Terms whose name is worth a second look