🏷

Classifications

Harrison's Part

IUIS Category

👪

Inheritance

2

Autosomal Recessive HP:0000007

Biallelic DOCK2 variants with complete penetrance. Reported genotypes include homozygous frameshift, homozygous missense, and compound heterozygous missense/nonsense combinations.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:26083206 SUPPORT Human Clinical

"Intra-familial segregation was consistent with autosomal recessive inheritance with complete penetrance"

Direct statement of the segregation pattern across the five index families.

Heterozygous Hypomorphic (ELMO1-Binding Domain) HP:0000006

A separately described form in which a single heterozygous variant in the DOCK2 region that binds and stabilizes ELMO1 reduces DOCK2 protein level and function. Six individuals from three unrelated families, aged 3 months to 50 years, presented with severe HPV, RSV or SARS-CoV-2 infection rather than with the infantile combined immunodeficiency of the recessive form.

Autosomal dominant inheritance

Show evidence (2 references)

PMID:41654261 SUPPORT Human Clinical

"Six individuals from 3 unrelated families, aged 3 months to 50 years, carried 1 of 3 heterozygous variants in DOCK2 and experienced severe infections with human papilloma virus, respiratory syncytial virus, or severe acute respiratory syndrome coronavirus 2."

Documents the heterozygous carriers and their virus-restricted clinical phenotype, the basis for a second, dominant inheritance mode.

PMID:41654261 SUPPORT In Vitro

"All variants reside within the DOCK2 domain that binds and stabilizes ELMO1. Each variant reduced DOCK2 protein expression, ELMO1 binding, and DOCK2 function, as shown by diminished Rac1 activation and selective defects in Toll-like receptor signaling."

Establishes the molecular mechanism of the heterozygous form: destabilization through loss of ELMO1 binding, converging on the same reduced RAC1 activation.

◆

Subtypes

2

Autosomal recessive DOCK2 deficiency (biallelic loss of function)

The classical form. Biallelic frameshift, nonsense, splice-site or missense variants abolishing or truncating DOCK2. Early-onset combined immunodeficiency with lymphopenia, invasive bacterial and viral infection, and a leaky SCID or Omenn presentation in some kindreds. Fatal without transplantation in a substantial proportion.

Heterozygous DOCK2 ELMO1-binding-domain variants (viral susceptibility)

Single heterozygous variants in the ELMO1-binding region. Reduced DOCK2 protein stability with preserved T-cell function, presenting across a wide age range as selective severe viral illness (HPV, RSV, SARS-CoV-2) rather than as combined immunodeficiency.

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Discussions and Knowledge Gaps

2

Does haematopoietic stem cell transplantation correct the non-haematopoietic, fibroblast-intrinsic antiviral defect in DOCK2 deficiency, and if not, what is the long-term viral risk in transplanted patients?

KNOWLEDGE GAP hsct_does_not_correct_stromal_defect

Attached to

pathophysiology#Increased Viral Replication in Non-Haematopoietic Cells treatments#Allogeneic Hematopoietic Stem Cell Transplantation

The index report establishes two separable arms: a haematopoietic defect that transplantation demonstrably corrects, and a cell-intrinsic antiviral defect in fibroblasts that transplantation has no obvious mechanism to touch, since the recipient's stromal cells remain DOCK2-deficient. Transplanted patients are reported as "alive and well", but the longest follow-up reported is 17.5 years in one patient and the others are measured in months, and no study has asked whether stromal viral susceptibility persists. If it does, the standard framing of HSCT as curative for this disorder is incomplete, and interferon alfa-2b - which corrects the fibroblast phenotype in vitro - would be worth evaluating as an adjunct rather than only as a mechanistic probe.

By what route does loss of DOCK2-dependent RAC1 activation reduce type I and type III interferon production?

KNOWLEDGE GAP rac1_to_interferon_link

Attached to

pathophysiology#Diminished Type I and Type III Interferon Production

The entry draws this edge as INDIRECT_UNKNOWN_INTERMEDIATES because no intermediate is established. RAC1 activation downstream of antigen and chemokine receptors is a cytoskeletal signal, and the canonical antiviral interferon induction pathways run through RIG-I/MDA5 and TLR sensing, not through DOCK2. Whether the interferon defect is a direct signalling consequence, a consequence of impaired endosomal trafficking of nucleic acid sensors, or simply a knock-on of the reduced and abnormal plasmacytoid dendritic cell compartment has not been resolved. The answer determines whether interferon supplementation is treating the lesion or bypassing it.

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Pathophysiology

9

DOCK2 Loss of Function

DOCK2 is an atypical guanine nucleotide exchange factor expressed almost exclusively in haematopoietic and lymphoid tissue. Its DHR2 domain is what catalyses nucleotide exchange on RAC. Disease alleles either abolish the protein - frameshift and nonsense variants leave absent or trace amounts on immunoblot - or truncate it short of DHR2, which removes the catalytic function while leaving a protein product. Missense alleles hit evolutionarily conserved residues.

Genetic context DOCK2 hgnc:2988 variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION

RAC guanine nucleotide exchange factor activity GO:0005085 ⇓ LOSS OF FUNCTION

Downstream

Failure of Receptor-Driven RAC1 Activation

Show evidence (2 references)

PMID:26083206 SUPPORT Human Clinical

"Immunoblot analysis revealed absent or trace amounts of DOCK2 protein expression in T cell lines from P1 and P2, respectively, and markedly reduced levels of protein were detected in P3 EBV-B cells"

Demonstrates loss of DOCK2 protein in patient cells across three genotypes.

PMID:26083206 SUPPORT In Vitro

"overexpression of Strep-HA-tagged DOCK2 bearing the p.F744Cfs*27 mutation (present in P4) shows expression of a truncated DOCK2 protein (Fig.S4B) which lacks the DHR2 domain critical for the DOCK2 GEF function"

Supports the second route stated in the description: a protein product is made but lacks the catalytic DHR2 domain.

Failure of Receptor-Driven RAC1 Activation

DOCK2 is the exchange factor that loads GTP onto RAC1 downstream of the T-cell receptor and of chemokine receptors. In patient T cells, engaging CD3 fails to produce GTP-bound RAC1 at all, while control cells and a heterozygous carrier parent's cells do. This is the single molecular switch from which every downstream defect in this entry follows.

RAC1 signalling downstream of antigen and chemokine receptors GO:0016601 ⇓ LOSS OF FUNCTION

Downstream

Defective Actin Polymerization and Leukocyte Chemotaxis

Impaired Neutrophil Respiratory Burst

Impaired NK Cell Degranulation

Diminished Type I and Type III Interferon Production

Show evidence (1 reference)

PMID:26083206 SUPPORT Human Clinical

"Upon activation of polyclonal human T-cell lines with anti-CD3 mAb, GTP-bound RAC1 was clearly detected in T cells from the healthy control and from P2's mother, but not from P1 and P2"

Direct measurement of the failed RAC1 activation step in patient T cells, with a carrier control that shows heterozygosity is sufficient.

Defective Actin Polymerization and Leukocyte Chemotaxis

Without RAC1 activation, chemokine receptors cannot drive actin polymerization, so lymphocytes fail to migrate. Both the stimulated and the resting cytoskeleton are affected: CXCL12-induced actin polymerization is impaired and delayed, and baseline F-actin is reduced even before stimulation. Neutrophils are affected too, which is why DOCK2 deficiency is classified as a combined immunodeficiency with neutrophil abnormalities rather than a purely lymphoid defect.

T cell CL:0000084 B cell CL:0000236 neutrophil CL:0000775

actin filament polymerization GO:0030041 ↓ DECREASED leukocyte chemotaxis GO:0030595 ↓ DECREASED

Downstream

T Cell Lymphopenia

Impaired T Cell Activation and Antibody Response

Chronic diarrhea and colitis The colitis biopsy shows a paucity of B and plasma cells in the lamina propria, which is the mucosal counterpart of the trafficking defect this node names. The route from failed chemotaxis to mucosal inflammation is not established in DOCK2 deficiency, so the edge is drawn with unknown intermediates rather than as a demonstrated mechanism.

Recurrent invasive bacterial infections

Show evidence (4 references)

PMID:26083206 SUPPORT Human Clinical

"Furthermore, CXCL12-induced actin polymerization in T and B lymphocytes from P1 and P2 was impaired and delayed"

Measures the chemokine-driven actin defect in patient T and B cells.

PMID:26083206 SUPPORT Human Clinical

"Interestingly, baseline levels of polymerized actin (F-actin) were also reduced in DOCK2-deficient lymphocytes from P1 and P2"

Supports the specific claim that the resting cytoskeleton, not only the stimulated response, is affected.

PMID:36947335 SUPPORT Human Clinical

"In addition, we noted neutrophil defects, the weakening of actin polymerization, and BCR internalization under TCR/BCR activation."

Extends the actin defect to neutrophils, supporting the combined-with-neutrophil -abnormalities framing.

+ 1 more reference

Impaired Neutrophil Respiratory Burst

Primary DOCK2-deficient neutrophils generate reactive oxygen species poorly. This is a separate arm from the cytoskeletal defect and is not a consequence of it: RAC is a required component of the phagocyte NADPH oxidase complex as well as a cytoskeletal regulator, so a failure of RAC activation removes both. The reported impairment is partial, which is consistent with the disorder not behaving as a chronic granulomatous disease phenocopy.

neutrophil CL:0000775

respiratory burst GO:0045730 ↓ DECREASED

Downstream

Recurrent invasive bacterial infections A partial respiratory-burst defect is one of several contributors to bacterial susceptibility here, alongside the T-cell and chemotaxis arms. No study apportions the contribution, so the edge is drawn with unknown intermediates.

Show evidence (1 reference)

PMID:30838481 SUPPORT Human Clinical

"Moreover, both cytoskeletal rearrangement and reactive oxygen species production are partially impaired in DOCK2-deficient neutrophils."

The direct measurement in primary human DOCK2-deficient neutrophils. The same sentence carries the cytoskeletal defect, which is curated on the chemotaxis node; this node takes the reactive-oxygen-species half.

Impaired NK Cell Degranulation

NK cells are present in normal numbers with a normal immunophenotype, but they do not degranulate on target engagement. The defect is receptor-general rather than adaptor-specific: it appears through CD16, NKp30, NKp46 (which signal via CD3-zeta and FcERI-gamma), NKp44 (DAP12) and NKG2D (DAP10) alike, which is what one expects if the shared downstream step - actin polymerization - is what is broken. Severity tracks residual DOCK2 protein.

natural killer cell CL:0000623

natural killer cell degranulation GO:0043320 ↓ DECREASED

Downstream

Recurrent invasive viral infections

Show evidence (2 references)

PMID:26083206 SUPPORT Human Clinical

"However, NK cells from P1 and P2 showed impaired degranulation upon stimulation with the human erythroleukemia cell line K562"

Measures the degranulation failure in patient NK cells despite normal NK numbers.

PMID:26083206 SUPPORT Human Clinical

"observed severely impaired degranulation in P1 (Fig.3B), and moderately impaired in P2, likely corresponding to residual amounts of DOCK2 protein in P2's hematopoietic cells"

Supports the genotype-severity relationship: degranulation loss scales with residual protein.

Diminished Type I and Type III Interferon Production

Peripheral blood mononuclear cells from DOCK2-deficient patients make less interferon-alpha and interferon-lambda after viral exposure. This is a separate antiviral arm from the NK-cell one, and together with the fibroblast defect below it explains why invasive viral disease - including disease from live attenuated vaccine strains - is so prominent in this disorder.

type I interferon production GO:0032606 ↓ DECREASED type III interferon production GO:0034343 ↓ DECREASED

Downstream

Increased Viral Replication in Non-Haematopoietic Cells

Recurrent invasive viral infections

Show evidence (1 reference)

PMID:26083206 SUPPORT Human Clinical

"Interferon-α and interferon-λ production by peripheral-blood mononuclear cells was diminished after viral infection."

States the interferon production defect in patient PBMCs.

Increased Viral Replication in Non-Haematopoietic Cells

The cell-intrinsic defect that takes DOCK2 deficiency outside the usual boundaries of a combined immunodeficiency. Patient fibroblasts - which are not haematopoietic and do not express the immune receptors above - support increased viral replication and die more readily on infection. Both abnormalities are corrected by interferon alfa-2b or by re-expressing wild-type DOCK2, which establishes them as consequences of the DOCK2 lesion rather than incidental. This node is the reason HSCT is not expected to fully correct the phenotype.

fibroblast CL:0000057

defense response to virus GO:0051607 ↓ DECREASED

Downstream

Recurrent invasive viral infections

Show evidence (1 reference)

PMID:26083206 SUPPORT In Vitro

"Moreover, in DOCK2-deficient fibroblasts, viral replication was increased and virus-induced cell death was enhanced; these conditions were normalized by treatment with interferon alfa-2b or after expression of wild-type DOCK2."

Establishes the non-haematopoietic antiviral defect and its rescue, which is what makes it attributable to DOCK2 rather than to the immunodeficiency.

T Cell Lymphopenia

A quantitative T-cell deficit present in every reported patient. The naive compartment is depleted and the effector-memory compartment expanded, and T-cell receptor excision circles - a marker of thymic output - are already low on newborn dried blood spots, so the deficit is developmental rather than purely a consequence of infection. B cells are variably reduced. This is a cell-count claim and is kept separate from the functional activation defect below, which is measured differently and is not simply its consequence.

T cell CL:0000084

Downstream

Decreased total T cell count

Combined immunodeficiency

Show evidence (2 references)

PMID:26083206 SUPPORT Human Clinical

"In all five patients, T-cell lymphopenia and impaired in vitro T-cell activation in response to PHA were documented"

Records the lymphopenia in the full index cohort. The same sentence carries the activation defect, which is curated on the separate node below.

PMID:26083206 SUPPORT Human Clinical

"levels of T-cell receptor excision circles (TRECs), a marker of active thymopoiesis, were markedly reduced in dried blood spots collected at birth in P2 and P4"

Supports the claim that thymic output is already reduced at birth, making the deficit developmental.

Impaired T Cell Activation and Antibody Response

A functional defect distinct from the cell count above: patient T cells proliferate poorly to phytohaemagglutinin, and antibody responses to T-dependent immunization antigens are defective even when total IgG and IgM are normal. Normal immunoglobulin levels with failed specific responses is the combination that makes a quantitative assay alone miss this disease.

T cell CL:0000084 B cell CL:0000236

Animal models

DOCK2-deficient mouse (HSV-1 challenge) Mouse partially recapitulates Identifies a cell-intrinsic DOCK2 requirement for the initial expansion of antiviral CD8+ T cells, a step that is not visible in the human data because early activation markers look normal.

Downstream

Combined immunodeficiency

Recurrent invasive bacterial infections

Granulomatous inflammation Granulomatous lesions in this disorder are reported with mycobacteria in them, the organism class whose containment depends on T-cell help. The route is the general one for a T-cell defect rather than anything established in DOCK2 deficiency, so the edge is drawn with unknown intermediates.

Show evidence (2 references)

PMID:26083206 SUPPORT Human Clinical

"In all five patients, T-cell lymphopenia and impaired in vitro T-cell activation in response to PHA were documented"

Records the activation defect in the full index cohort. The same sentence carries the lymphopenia, which is curated on the separate node above.

PMID:26083206 SUPPORT Human Clinical

"Despite normal IgG and IgM serum levels, P2, P4 and P5 showed defective antibody production to T-dependent immunization antigens"

Supports the specific claim that functional antibody responses fail even with normal total immunoglobulin.

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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

8

Blood 2

Decreased total T cell count HP:0005403

Show evidence (2 references)

PMID:26083206 SUPPORT Human Clinical

"In all five patients, T-cell lymphopenia and impaired in vitro T-cell activation in response to PHA were documented"

Records T-cell lymphopenia in every patient of the index cohort.

PMID:34872585 SUPPORT Human Clinical

"Her immunological workup revealed persistent lymphopenia and low CD4 + T cell count along with elevated levels of CD19 +, CD20 +, CD16 +, and CD56 + cells."

An independent patient outside the index cohort with the same T-cell deficit, showing it is not confined to the original five families.

Elevated serum IgE Increased circulating IgE concentration HP:0003212

Show evidence (1 reference)

PMID:34872585 SUPPORT Human Clinical

"Furthermore, she had a high level of immunoglobulin (Ig) E and a slightly reduced IgM level with a non-protective antibody titer against diphtheria."

The single reported observation of raised IgE, quoted with the rest of the immunoglobulin picture so the reader can see it is one patient.

Digestive 1

Chronic diarrhea and colitis HP:0002028

Sequelae: Failure to thrive

Show evidence (1 reference)

PMID:26083206 SUPPORT Human Clinical

"colon histopathology revealed focal active colitis (Fig.1B), associated with paucity of B and plasma cells and to a lesser extent of T cells in the lamina propria of the gut"

Documents the colitis and the mucosal lymphocyte paucity underlying it.

Immune 4

Combined immunodeficiency HP:0005387

Show evidence (1 reference)

PMID:26083206 SUPPORT Human Clinical

"Autosomal recessive DOCK2 deficiency is a new mendelian disorder with pleiotropic defects of hematopoietic and nonhematopoietic immunity."

The paper's own conclusion classifying the disorder, including the non-haematopoietic component.

Recurrent invasive bacterial infections Recurrent bacterial infections HP:0002718

Show evidence (1 reference)

PMID:26083206 SUPPORT Human Clinical

"ultimately died at the age of 20 months due to Klebsiella pneumoniae sepsis"

Documents fatal invasive bacterial infection in an index patient.

Recurrent invasive viral infections Recurrent viral infections HP:0004429

Show evidence (2 references)

PMID:26083206 SUPPORT Human Clinical

"At 2.5 years of age, she developed vaccine strain-related varicella, with liver and lung involvement and multiple pulmonary infiltrates, requiring ventilatory support"

Documents invasive live-attenuated-vaccine-strain viral disease, the feature most specific to this disorder.

PMID:36947335 SUPPORT Human Clinical

"we report two patients harboring four novel DOCK2 mutations associated with recurrent infections including live attenuated vaccine-related infections"

Independent confirmation of vaccine-strain infection in further patients.

Granulomatous inflammation HP:0032252

Show evidence (1 reference)

PMID:26083206 SUPPORT Human Clinical

"A lung biopsy revealed granulomatous inflammation (Fig.S2B) with acid-fast bacilli."

Documents granulomatous inflammation with mycobacteria on biopsy.

Growth 1

Failure to thrive HP:0001508

Show evidence (1 reference)

PMID:26083206 SUPPORT Human Clinical

"growth failure (body weight: 4.5 kg, 3.5kg below third percentile; length: 64 cm, 9cm below third percentile)"

Quantifies the growth failure in an index patient.

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Genetic Associations

2

DOCK2 (Biallelic Loss-of-Function Variants)

Gene: DOCK2 hgnc:2988 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (1 reference)

PMID:26083206 SUPPORT Human Clinical

"Collectively, we identified seven distinct DOCK2 rare mutations in five patients of different ethnic origin, four of which lead to premature termination, and three of which were predicted deleterious missense mutations affecting conserved residues of DOCK2"

Documents the allelic spectrum stated in the notes.

DOCK2 (heterozygous ELMO1-binding-domain variants) (Heterozygous ELMO1-Binding-Domain Hypomorphic Variants)

Gene: DOCK2 hgnc:2988 relationship_type: SUSCEPTIBILITY variant_origin: GERMLINE

Show evidence (2 references)

PMID:41654261 SUPPORT In Vitro

"All variants reside within the DOCK2 domain that binds and stabilizes ELMO1. Each variant reduced DOCK2 protein expression, ELMO1 binding, and DOCK2 function, as shown by diminished Rac1 activation and selective defects in Toll-like receptor signaling."

Establishes the allelic class and its hypomorphic mechanism, which is what distinguishes this record from the biallelic loss-of-function one above.

PMID:38857861 SUPPORT INDIRECT BACKGROUND In Vitro

"Recent cryo-EM structures of the DOCK2/ELMO1 and DOCK2/ELMO1/Rac1 complexes have identified closed and open conformations that are key to understanding the autoinhibition mechanism."

Supplies the structural reason a variant in the ELMO1-binding region is pathogenic at all: ELMO1 binding is what releases DOCK2 autoinhibition. The sentence is this paper's framing of the DOCK2 structures rather than its own result, which is about DOCK5, hence quote_role BACKGROUND and directness INDIRECT.

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External Assertions

2

OMIM immunodeficiency 40 phenotype record

OMIM disease record OMIM:616433

The OMIM phenotype record for this disease, Immunodeficiency 40. Recorded here rather than under `mappings` because `DiseaseMappings` carries only ICD-10-CM, ICD-11, MONDO and NCIT slots and there is no `omim_mappings` slot in the schema; issue #9922 withdrew a proposal to add one. This is the identifier a reader coming from OMIM will be holding, and it is not the number that appears in the IUIS table quoted under `classifications`.

OMIM DOCK2 gene record

OMIM gene record OMIM:603122

The OMIM record for the DOCK2 gene. Recorded explicitly because 603122 is the number carried in the IUIS 2022 table row quoted in this entry, where the column is a gene MIM, and reading it as the disease MIM is the mistake this pair of records exists to prevent.

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Medical Actions

4

Allogeneic Hematopoietic Stem Cell Transplantation

Action: hematopoietic cell transplantation Ontology label: Hematopoietic Cell Transplantation NCIT:C15431

Platform: Cell therapy

The only curative treatment. Three of the five index patients were transplanted and had normalization of T-cell function and clinical improvement, one of them still well 17.5 years later. Transplantation replaces the haematopoietic compartment and therefore addresses the lymphocyte and NK arms; it does not obviously address the fibroblast-intrinsic antiviral defect, which is a reason to follow transplanted patients for viral disease rather than assume cure.

Mechanism Target:

T Cell Lymphopenia — Replaces the DOCK2-deficient haematopoietic compartment with donor cells that can activate RAC1 normally, restoring thymic output from a donor-derived progenitor pool.

Impaired T Cell Activation and Antibody Response — Donor lymphocytes activate RAC1 normally, so the proliferative and antibody responses that fail in patient cells are reconstituted.

Show evidence (2 references)

PMID:26083206 SUPPORT Human Clinical

"Two patients died early in childhood; after allogeneic hematopoietic stem-cell transplantation, the other three had normalization of T-cell function and clinical improvement."

Reports the outcome of transplantation in the index cohort, including the normalization of T-cell function.

PMID:40860338 SUPPORT Human Clinical

"Hematopoietic stem cell transplantation (HSCT) was conducted on 24.0% of patients, which significantly improved survival in patients with defects in WAS, DOCK8 and DOCK2."

A 503-patient multi-country registry reporting a survival benefit from transplantation that names DOCK2 specifically, which is the largest denominator behind the curative claim this treatment makes.

Interferon Alfa Therapy for Viral Complications

Action: Pharmacotherapy NCIT:C15986

Agent: interferon alfa NCIT:C225

Platform: Other

Interferon alfa is the one mechanistically grounded adjunct short of transplant. It corrects the fibroblast antiviral defect in vitro, and weekly interferon-alfa completely resolved refractory warts in one patient with a heterozygous ELMO1-binding-domain variant. The source says only "IFN-alpha" and does not name the product, so the bound agent is the general recombinant interferon alfa term; the modality is OTHER rather than PROTEIN_REPLACEMENT because this is an immunomodulatory cytokine given pharmacologically, not replacement of a protein the patient lacks. This is a single-patient observation in the hypomorphic form, not a trial and not evidence in the recessive form; it is curated here because it is the direct clinical counterpart of the in vitro rescue this entry already records.

Mechanism Target:

Increased Viral Replication in Non-Haematopoietic Cells — Supplies the interferon signal that DOCK2-deficient cells fail to produce, restoring the antiviral state in cells that remain genetically deficient.

Show evidence (1 reference)

PMID:41654261 SUPPORT Human Clinical

"Weekly IFN-α therapy led to complete resolution of refractory warts in 1 patient, highlighting a potential therapeutic approach for DOCK2-associated immunodeficiency."

The single clinical observation behind this treatment, quoted with its own hedging intact.

Immunoglobulin Replacement

Action: intravenous immunoglobulin therapy Ontology label: Intravenous Immunoglobulin Therapy NCIT:C121331

Platform: Protein replacement

Intravenous immunoglobulin while awaiting transplantation, or where transplantation is not undertaken. It supplies the specific antibody the T-dependent response fails to make; it does not touch the cellular arm, so it is partial and palliative.

Mechanism Target:

Impaired T Cell Activation and Antibody Response — Substitutes pooled donor antibody for the specific antibody response that fails in these patients despite normal total IgG and IgM.

Show evidence (1 reference)

PMID:36947335 SUPPORT Human Clinical

"The patient's condition was partially alleviated by symptomatic treatment or intravenous immunoglobulin."

Documents partial benefit from immunoglobulin, and its limits.

Anti-Infective Prophylaxis and Symptomatic Care

Action: Supportive Care NCIT:C15747

Platform: Small molecule

Antimicrobial prophylaxis and symptomatic treatment of intercurrent infection, alongside immunoglobulin, while awaiting transplantation. Split from the immunoglobulin record above because the two are different modalities and the combined record could not answer what kind of intervention it was.

Show evidence (1 reference)

PMID:36947335 SUPPORT Human Clinical

"The patient's condition was partially alleviated by symptomatic treatment or intravenous immunoglobulin."

Documents partial benefit from symptomatic treatment, and its limits.

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Diagnosis

1

Molecular and Functional Diagnosis of DOCK2 Deficiency

The diagnosis is genetic: biallelic DOCK2 variants on a primary-immunodeficiency panel or exome sequencing in a child with early-onset invasive infection and lymphopenia. Supporting functional assays, where available, are RAC1 activation after CD3 stimulation, chemokine-induced actin polymerization and chemotaxis, and NK-cell degranulation. Low TRECs on newborn screening can be the first signal.

The diagnosis is easy to miss. In one reported case it was made 18 years after the patient had already been transplanted for a presumed combined immunodeficiency of unknown cause, and in another the transplant was performed before the genetic diagnosis was available. Anyone transplanted for undefined CID is a candidate for retrospective genetic diagnosis, which matters because the non-haematopoietic arm of the disease is not corrected by the transplant.

Show evidence (4 references)

PMID:26083206 SUPPORT Human Clinical

"Children with clinical features of combined immunodeficiencies, especially with early-onset, invasive infections, may have this condition."

The authors' own statement of who should be tested.

PMID:35023658 SUPPORT Human Clinical

"He underwent HSCT without conditioning regimen before the genetic diagnosis"

Documents a case transplanted before the genetic diagnosis was made, supporting the retrospective-diagnosis point in the notes.

PMID:34418894 SUPPORT Human Clinical

"Very low to zero amounts of TREC and/or KREC were detected in 14 out of 23 cases of common variable immunodeficiency (CVID), 14 out of 17 cases of AT, 8 out of 20 cases of WAS, 6 out of 7 cases of DOCK8-deficiency patients, 4 out of 8 cases of HIES with unknown genetic defects and all patients..."

The measured basis for the TREC claim in the description. Note the DOCK2 arm of this series is a single patient, so it establishes that the assay is abnormal in DOCK2 deficiency rather than how sensitive it is.

+ 1 more reference

📊

Prevalence

1

Worldwide

Cases In Literature Ultra Rare

Sixteen patients reported in the literature as of the 2023 review, all with a severe early-onset phenotype. No prevalence estimate exists.

Show evidence (1 reference)

PMID:36947335 SUPPORT BACKGROUND Human Clinical

"Until recently, only 16 DOCK2-deficient patients have been reported in the literature, and all had a severe phenotype characterized by early-onset of recurrent, invasive viral, and bacterial infections associated with T and B cell lymphopenia"

Gives an explicit worldwide case count. Graded HUMAN_CLINICAL for the clinical picture it describes, with quote_role BACKGROUND because the sentence sits in this paper's introduction summarizing others' cases rather than reporting its own.

🐁

Animal Models

1

DOCK2-deficient mouse (HSV-1 challenge)

A mouse model developed specifically to separate DOCK2's own contribution to antiviral immunity from the treatments and comorbid infections that confound interpretation in patients.

Species

Mouse

Genotype

Dock2-deficient

Publication

PMID:38366567

Pathograph links

Impaired T Cell Activation and Antibody Response partially recapitulates fidelity: moderate observes: cellular Identifies a cell-intrinsic DOCK2 requirement for the initial expansion of antiviral CD8+ T cells, a step that is not visible in the human data because early activation markers look normal.

Limitations: The human node covers failed proliferation to mitogen and defective T-dependent antibody responses; the mouse result speaks only to antigen-specific CD8+ expansion after priming. The mouse also shows that DOCK2-deficient CD8+ cells are protective once primed in vitro, a rescue with no human counterpart, so the model bears on the mechanism of the T-cell defect rather than on its clinical severity.

Readouts

Antiviral CD8+ T-cell expansion after HSV-1 priming

Direction: DECREASED

Interpretation: The expansion deficit is the functional correlate of the human T-cell activation defect.

Show evidence (1 reference)

PMID:38366567 SUPPORT Model Organism

"We also uncovered a critical, cell-intrinsic role of DOCK2 in the priming of antiviral CD8+ T cells and in particular their initial expansion, despite apparently normal early activation of these cells."

Reports the measured expansion defect and its cell-intrinsic nature.

Show evidence (1 reference)

PMID:38366567 SUPPORT Model Organism

"These results shed light on a cellular deficiency that is likely to impact antiviral immunity in DOCK2-deficient patients."

The authors' own statement of the model's intended relevance to the human disease.

{ }

Source YAML

click to show

name: DOCK2 Deficiency
creation_date: "2026-09-16T21:25:00Z"
description: >
  DOCK2 deficiency is an autosomal recessive combined immunodeficiency caused by
  biallelic loss-of-function variants in DOCK2, which encodes a haematopoietic
  atypical guanine nucleotide exchange factor for the small GTPase RAC1. Without
  DOCK2, antigen and chemokine receptors can no longer activate RAC1, so the actin
  polymerization that every downstream response depends on fails: T, B and NK
  cells cannot migrate towards chemokine, cannot build the cytoskeletal structures
  that receptor engagement requires, and NK cells cannot degranulate. The result
  is early-onset, invasive bacterial and viral infection with lymphopenia and
  defective T-, B- and NK-cell function. What makes the disorder mechanistically
  distinctive among the combined immunodeficiencies is that it is not confined to
  haematopoietic cells: DOCK2-deficient patients also have diminished type I and
  type III interferon production, and DOCK2-deficient fibroblasts support
  increased viral replication and enhanced virus-induced cell death - a
  cell-intrinsic, non-haematopoietic antiviral defect that is corrected by
  interferon alfa-2b. Allogeneic haematopoietic stem-cell transplantation
  normalizes T-cell function and is the only curative treatment, but it addresses
  only the haematopoietic half of the defect. The disease is no longer purely
  recessive: heterozygous variants in the ELMO1-binding region destabilize DOCK2
  and produce a milder, later-onset, virus-selective susceptibility in otherwise
  healthy people, so DOCK2-related immunodeficiency is better read as a
  dose-dependent continuum than a binary recessive condition.
category: Mendelian
disease_term:
  preferred_term: DOCK2 deficiency
  term:
    id: MONDO:0014637
    label: DOCK2 deficiency
synonyms:
- DOCK2 immunodeficiency
- combined immunodeficiency due to DOCK2 deficiency
- immunodeficiency 40
- IMD40
- dedicator of cytokinesis 2 deficiency
parents:
- Combined Immunodeficiency
- Inborn Error of Immunity
classifications:
  harrisons_chapter:
  - classification_value: IMMUNE_RHEUMATOLOGIC
  - classification_value: INFECTIOUS_DISEASES
  iuis_category:
    classification_value: combined immunodeficiency
    notes: >-
      IUIS 2022 phenotypic classification (Tangye et al., PMID:35748970) lists
      DOCK2 deficiency among the immunodeficiencies affecting cellular and humoral
      immunity, with autosomal recessive inheritance. The 603122 in the quoted row
      is the IUIS table's gene-MIM column, so it is the MIM for the DOCK2 gene, not
      for the disease. The disease MIM is 616433, Immunodeficiency 40; both are
      recorded in `external_assertions`.
    evidence:
    - reference: PMID:35748970
      reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "DOCK2 deficiency DOCK2 AR 603122"
      explanation: >-
        The IUIS table row placing DOCK2 deficiency in the combined immunodeficiency
        classification, with its inheritance and OMIM number.
inheritance:
- name: Autosomal Recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Biallelic DOCK2 variants with complete penetrance. Reported genotypes include
    homozygous frameshift, homozygous missense, and compound heterozygous
    missense/nonsense combinations.
  evidence:
  - reference: PMID:26083206
    reference_title: "Inherited DOCK2 Deficiency in Patients with Early-Onset Invasive Infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Intra-familial segregation was consistent with autosomal recessive
      inheritance with complete penetrance
    explanation: >-
      Direct statement of the segregation pattern across the five index families.
- name: Heterozygous Hypomorphic (ELMO1-Binding Domain)
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    A separately described form in which a single heterozygous variant in the
    DOCK2 region that binds and stabilizes ELMO1 reduces DOCK2 protein level and
    function. Six individuals from three unrelated families, aged 3 months to 50
    years, presented with severe HPV, RSV or SARS-CoV-2 infection rather than with
    the infantile combined immunodeficiency of the recessive form.
  evidence:
  - reference: PMID:41654261
    reference_title: "Heterozygous variants in DOCK2 leading to susceptibility to viral illnesses."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Six individuals from 3 unrelated families, aged 3 months to 50 years, carried
      1 of 3 heterozygous variants in DOCK2 and experienced severe infections with
      human papilloma virus, respiratory syncytial virus, or severe acute
      respiratory syndrome coronavirus 2.
    explanation: >-
      Documents the heterozygous carriers and their virus-restricted clinical
      phenotype, the basis for a second, dominant inheritance mode.
  - reference: PMID:41654261
    reference_title: "Heterozygous variants in DOCK2 leading to susceptibility to viral illnesses."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      All variants reside within the DOCK2 domain that binds and stabilizes ELMO1.
      Each variant reduced DOCK2 protein expression, ELMO1 binding, and DOCK2
      function, as shown by diminished Rac1 activation and selective defects in
      Toll-like receptor signaling.
    explanation: >-
      Establishes the molecular mechanism of the heterozygous form: destabilization
      through loss of ELMO1 binding, converging on the same reduced RAC1 activation.
has_subtypes:
- name: AR DOCK2 deficiency
  display_name: Autosomal recessive DOCK2 deficiency (biallelic loss of function)
  description: >-
    The classical form. Biallelic frameshift, nonsense, splice-site or missense
    variants abolishing or truncating DOCK2. Early-onset combined immunodeficiency
    with lymphopenia, invasive bacterial and viral infection, and a leaky SCID or
    Omenn presentation in some kindreds. Fatal without transplantation in a
    substantial proportion.
- name: Heterozygous DOCK2-ELMO1 hypomorph
  display_name: Heterozygous DOCK2 ELMO1-binding-domain variants (viral susceptibility)
  description: >-
    Single heterozygous variants in the ELMO1-binding region. Reduced DOCK2 protein
    stability with preserved T-cell function, presenting across a wide age range as
    selective severe viral illness (HPV, RSV, SARS-CoV-2) rather than as combined
    immunodeficiency.
pathophysiology:
- name: DOCK2 Loss of Function
  biological_scale: MOLECULAR
  description: >-
    DOCK2 is an atypical guanine nucleotide exchange factor expressed almost
    exclusively in haematopoietic and lymphoid tissue. Its DHR2 domain is what
    catalyses nucleotide exchange on RAC. Disease alleles either abolish the
    protein - frameshift and nonsense variants leave absent or trace amounts on
    immunoblot - or truncate it short of DHR2, which removes the catalytic function
    while leaving a protein product. Missense alleles hit evolutionarily conserved
    residues.
  genetic_context:
    gene:
      preferred_term: DOCK2
      term:
        id: hgnc:2988
        label: DOCK2
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
  molecular_functions:
  - preferred_term: RAC guanine nucleotide exchange factor activity
    modifier: LOSS_OF_FUNCTION
    term:
      id: GO:0005085
      label: guanyl-nucleotide exchange factor activity
  downstream:
  - target: Failure of Receptor-Driven RAC1 Activation
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:26083206
    reference_title: "Inherited DOCK2 Deficiency in Patients with Early-Onset Invasive Infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Immunoblot analysis revealed absent or trace amounts of DOCK2 protein
      expression in T cell lines from P1 and P2, respectively, and markedly reduced
      levels of protein were detected in P3 EBV-B cells
    explanation: >-
      Demonstrates loss of DOCK2 protein in patient cells across three genotypes.
  - reference: PMID:26083206
    reference_title: "Inherited DOCK2 Deficiency in Patients with Early-Onset Invasive Infections."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      overexpression of Strep-HA-tagged DOCK2 bearing the p.F744Cfs*27 mutation
      (present in P4) shows expression of a truncated DOCK2 protein (Fig.S4B) which
      lacks the DHR2 domain critical for the DOCK2 GEF function
    explanation: >-
      Supports the second route stated in the description: a protein product is made
      but lacks the catalytic DHR2 domain.
- name: Failure of Receptor-Driven RAC1 Activation
  biological_scale: MOLECULAR
  description: >-
    DOCK2 is the exchange factor that loads GTP onto RAC1 downstream of the T-cell
    receptor and of chemokine receptors. In patient T cells, engaging CD3 fails to
    produce GTP-bound RAC1 at all, while control cells and a heterozygous carrier
    parent's cells do. This is the single molecular switch from which every
    downstream defect in this entry follows.
  biological_processes:
  - preferred_term: RAC1 signalling downstream of antigen and chemokine receptors
    modifier: LOSS_OF_FUNCTION
    term:
      id: GO:0016601
      label: Rac protein signal transduction
  downstream:
  - target: Defective Actin Polymerization and Leukocyte Chemotaxis
    causal_link_type: DIRECT
  - target: Impaired Neutrophil Respiratory Burst
    causal_link_type: DIRECT
  - target: Impaired NK Cell Degranulation
    causal_link_type: DIRECT
  - target: Diminished Type I and Type III Interferon Production
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:26083206
    reference_title: "Inherited DOCK2 Deficiency in Patients with Early-Onset Invasive Infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Upon activation of polyclonal human T-cell lines with anti-CD3 mAb, GTP-bound
      RAC1 was clearly detected in T cells from the healthy control and from P2's
      mother, but not from P1 and P2
    explanation: >-
      Direct measurement of the failed RAC1 activation step in patient T cells, with
      a carrier control that shows heterozygosity is sufficient.
- name: Defective Actin Polymerization and Leukocyte Chemotaxis
  biological_scale: CELLULAR
  description: >-
    Without RAC1 activation, chemokine receptors cannot drive actin polymerization,
    so lymphocytes fail to migrate. Both the stimulated and the resting cytoskeleton
    are affected: CXCL12-induced actin polymerization is impaired and delayed, and
    baseline F-actin is reduced even before stimulation. Neutrophils are affected
    too, which is why DOCK2 deficiency is classified as a combined immunodeficiency
    with neutrophil abnormalities rather than a purely lymphoid defect.
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  biological_processes:
  - preferred_term: actin filament polymerization
    modifier: DECREASED
    term:
      id: GO:0030041
      label: actin filament polymerization
  - preferred_term: leukocyte chemotaxis
    modifier: DECREASED
    term:
      id: GO:0030595
      label: leukocyte chemotaxis
  downstream:
  - target: T Cell Lymphopenia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Impaired T Cell Activation and Antibody Response
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Chronic diarrhea and colitis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The colitis biopsy shows a paucity of B and plasma cells in the lamina
      propria, which is the mucosal counterpart of the trafficking defect this node
      names. The route from failed chemotaxis to mucosal inflammation is not
      established in DOCK2 deficiency, so the edge is drawn with unknown
      intermediates rather than as a demonstrated mechanism.
  - target: Recurrent invasive bacterial infections
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:26083206
    reference_title: "Inherited DOCK2 Deficiency in Patients with Early-Onset Invasive Infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Furthermore, CXCL12-induced actin polymerization in T and B lymphocytes from
      P1 and P2 was impaired and delayed
    explanation: >-
      Measures the chemokine-driven actin defect in patient T and B cells.
  - reference: PMID:26083206
    reference_title: "Inherited DOCK2 Deficiency in Patients with Early-Onset Invasive Infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Interestingly, baseline levels of polymerized actin (F-actin) were also
      reduced in DOCK2-deficient lymphocytes from P1 and P2
    explanation: >-
      Supports the specific claim that the resting cytoskeleton, not only the
      stimulated response, is affected.
  - reference: PMID:36947335
    reference_title: "Multiple Immune Defects in Two Patients with Novel DOCK2 Mutations Result in Recurrent Multiple Infection Including Live Attenuated Virus Vaccine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition, we noted neutrophil defects, the weakening of actin
      polymerization, and BCR internalization under TCR/BCR activation.
    explanation: >-
      Extends the actin defect to neutrophils, supporting the combined-with-neutrophil
      -abnormalities framing.
  - reference: PMID:30838481
    reference_title: "Human DOCK2 Deficiency: Report of a Novel Mutation and Evidence for Neutrophil Dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Moreover, both cytoskeletal rearrangement and reactive oxygen species
      production are partially impaired in DOCK2-deficient neutrophils.
    explanation: >-
      First direct assessment of primary human DOCK2-deficient neutrophils,
      establishing both the cytoskeletal and the respiratory-burst defect.
- name: Impaired Neutrophil Respiratory Burst
  biological_scale: CELLULAR
  description: >-
    Primary DOCK2-deficient neutrophils generate reactive oxygen species poorly.
    This is a separate arm from the cytoskeletal defect and is not a consequence of
    it: RAC is a required component of the phagocyte NADPH oxidase complex as well
    as a cytoskeletal regulator, so a failure of RAC activation removes both. The
    reported impairment is partial, which is consistent with the disorder not
    behaving as a chronic granulomatous disease phenocopy.
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  biological_processes:
  - preferred_term: respiratory burst
    modifier: DECREASED
    term:
      id: GO:0045730
      label: respiratory burst
  downstream:
  - target: Recurrent invasive bacterial infections
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      A partial respiratory-burst defect is one of several contributors to bacterial
      susceptibility here, alongside the T-cell and chemotaxis arms. No study
      apportions the contribution, so the edge is drawn with unknown intermediates.
  evidence:
  - reference: PMID:30838481
    reference_title: "Human DOCK2 Deficiency: Report of a Novel Mutation and Evidence for Neutrophil Dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Moreover, both cytoskeletal rearrangement and reactive oxygen species
      production are partially impaired in DOCK2-deficient neutrophils.
    explanation: >-
      The direct measurement in primary human DOCK2-deficient neutrophils. The same
      sentence carries the cytoskeletal defect, which is curated on the chemotaxis
      node; this node takes the reactive-oxygen-species half.
- name: Impaired NK Cell Degranulation
  biological_scale: CELLULAR
  description: >-
    NK cells are present in normal numbers with a normal immunophenotype, but they
    do not degranulate on target engagement. The defect is receptor-general rather
    than adaptor-specific: it appears through CD16, NKp30, NKp46 (which signal via
    CD3-zeta and FcERI-gamma), NKp44 (DAP12) and NKG2D (DAP10) alike, which is what
    one expects if the shared downstream step - actin polymerization - is what is
    broken. Severity tracks residual DOCK2 protein.
  cell_types:
  - preferred_term: natural killer cell
    term:
      id: CL:0000623
      label: natural killer cell
  biological_processes:
  - preferred_term: natural killer cell degranulation
    modifier: DECREASED
    term:
      id: GO:0043320
      label: natural killer cell degranulation
  downstream:
  - target: Recurrent invasive viral infections
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:26083206
    reference_title: "Inherited DOCK2 Deficiency in Patients with Early-Onset Invasive Infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, NK cells from P1 and P2 showed impaired degranulation upon
      stimulation with the human erythroleukemia cell line K562
    explanation: >-
      Measures the degranulation failure in patient NK cells despite normal NK
      numbers.
  - reference: PMID:26083206
    reference_title: "Inherited DOCK2 Deficiency in Patients with Early-Onset Invasive Infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      observed severely impaired degranulation in P1 (Fig.3B), and moderately
      impaired in P2, likely corresponding to residual amounts of DOCK2 protein in
      P2's hematopoietic cells
    explanation: >-
      Supports the genotype-severity relationship: degranulation loss scales with
      residual protein.
- name: Diminished Type I and Type III Interferon Production
  biological_scale: CELLULAR
  description: >-
    Peripheral blood mononuclear cells from DOCK2-deficient patients make less
    interferon-alpha and interferon-lambda after viral exposure. This is a separate
    antiviral arm from the NK-cell one, and together with the fibroblast defect
    below it explains why invasive viral disease - including disease from live
    attenuated vaccine strains - is so prominent in this disorder.
  biological_processes:
  - preferred_term: type I interferon production
    modifier: DECREASED
    term:
      id: GO:0032606
      label: type I interferon production
  - preferred_term: type III interferon production
    modifier: DECREASED
    term:
      id: GO:0034343
      label: type III interferon production
  downstream:
  - target: Increased Viral Replication in Non-Haematopoietic Cells
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Recurrent invasive viral infections
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:26083206
    reference_title: "Inherited DOCK2 Deficiency in Patients with Early-Onset Invasive Infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Interferon-α and interferon-λ production by peripheral-blood mononuclear cells
      was diminished after viral infection.
    explanation: >-
      States the interferon production defect in patient PBMCs.
- name: Increased Viral Replication in Non-Haematopoietic Cells
  biological_scale: CELLULAR
  description: >-
    The cell-intrinsic defect that takes DOCK2 deficiency outside the usual
    boundaries of a combined immunodeficiency. Patient fibroblasts - which are not
    haematopoietic and do not express the immune receptors above - support increased
    viral replication and die more readily on infection. Both abnormalities are
    corrected by interferon alfa-2b or by re-expressing wild-type DOCK2, which
    establishes them as consequences of the DOCK2 lesion rather than incidental.
    This node is the reason HSCT is not expected to fully correct the phenotype.
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: defense response to virus
    modifier: DECREASED
    term:
      id: GO:0051607
      label: defense response to virus
  downstream:
  - target: Recurrent invasive viral infections
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:26083206
    reference_title: "Inherited DOCK2 Deficiency in Patients with Early-Onset Invasive Infections."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Moreover, in DOCK2-deficient fibroblasts, viral replication was increased and
      virus-induced cell death was enhanced; these conditions were normalized by
      treatment with interferon alfa-2b or after expression of wild-type DOCK2.
    explanation: >-
      Establishes the non-haematopoietic antiviral defect and its rescue, which is
      what makes it attributable to DOCK2 rather than to the immunodeficiency.
- name: T Cell Lymphopenia
  biological_scale: ORGANISM
  description: >-
    A quantitative T-cell deficit present in every reported patient. The naive
    compartment is depleted and the effector-memory compartment expanded, and
    T-cell receptor excision circles - a marker of thymic output - are already low
    on newborn dried blood spots, so the deficit is developmental rather than
    purely a consequence of infection. B cells are variably reduced. This is a
    cell-count claim and is kept separate from the functional activation defect
    below, which is measured differently and is not simply its consequence.
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  downstream:
  - target: Decreased total T cell count
    causal_link_type: DIRECT
  - target: Combined immunodeficiency
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:26083206
    reference_title: "Inherited DOCK2 Deficiency in Patients with Early-Onset Invasive Infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In all five patients, T-cell lymphopenia and impaired in vitro T-cell
      activation in response to PHA were documented
    explanation: >-
      Records the lymphopenia in the full index cohort. The same sentence carries
      the activation defect, which is curated on the separate node below.
  - reference: PMID:26083206
    reference_title: "Inherited DOCK2 Deficiency in Patients with Early-Onset Invasive Infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      levels of T-cell receptor excision circles (TRECs), a marker of active
      thymopoiesis, were markedly reduced in dried blood spots collected at birth in
      P2 and P4
    explanation: >-
      Supports the claim that thymic output is already reduced at birth, making the
      deficit developmental.
- name: Impaired T Cell Activation and Antibody Response
  biological_scale: CELLULAR
  description: >-
    A functional defect distinct from the cell count above: patient T cells
    proliferate poorly to phytohaemagglutinin, and antibody responses to
    T-dependent immunization antigens are defective even when total IgG and IgM are
    normal. Normal immunoglobulin levels with failed specific responses is the
    combination that makes a quantitative assay alone miss this disease.
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  downstream:
  - target: Combined immunodeficiency
    causal_link_type: DIRECT
  - target: Recurrent invasive bacterial infections
    causal_link_type: DIRECT
  - target: Granulomatous inflammation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Granulomatous lesions in this disorder are reported with mycobacteria in
      them, the organism class whose containment depends on T-cell help. The route
      is the general one for a T-cell defect rather than anything established in
      DOCK2 deficiency, so the edge is drawn with unknown intermediates.
  evidence:
  - reference: PMID:26083206
    reference_title: "Inherited DOCK2 Deficiency in Patients with Early-Onset Invasive Infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In all five patients, T-cell lymphopenia and impaired in vitro T-cell
      activation in response to PHA were documented
    explanation: >-
      Records the activation defect in the full index cohort. The same sentence
      carries the lymphopenia, which is curated on the separate node above.
  - reference: PMID:26083206
    reference_title: "Inherited DOCK2 Deficiency in Patients with Early-Onset Invasive Infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Despite normal IgG and IgM serum levels, P2, P4 and P5 showed defective
      antibody production to T-dependent immunization antigens
    explanation: >-
      Supports the specific claim that functional antibody responses fail even with
      normal total immunoglobulin.
phenotypes:
- category: Immunological
  name: Decreased total T cell count
  description: >-
    T-cell lymphopenia, documented in every patient of the index cohort and
    described as near-universal in the reported series since. Low T-cell receptor
    excision circles on the newborn blood spot show the deficit is present at
    birth.
  phenotype_term:
    preferred_term: T-cell lymphopenia
    term:
      id: HP:0005403
      label: Decreased total T cell count
  diagnostic: true
  evidence:
  - reference: PMID:26083206
    reference_title: "Inherited DOCK2 Deficiency in Patients with Early-Onset Invasive Infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In all five patients, T-cell lymphopenia and impaired in vitro T-cell
      activation in response to PHA were documented
    explanation: >-
      Records T-cell lymphopenia in every patient of the index cohort.
  - reference: PMID:34872585
    reference_title: "First patient in the Iranian Registry with novel DOCK2 gene mutation, presenting with skeletal tuberculosis, and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Her immunological workup revealed persistent lymphopenia and low CD4 + T cell
      count along with elevated levels of CD19 +, CD20 +, CD16 +, and CD56 + cells.
    explanation: >-
      An independent patient outside the index cohort with the same T-cell
      deficit, showing it is not confined to the original five families.
- category: Laboratory
  name: Elevated serum IgE
  description: >-
    Raised serum IgE has been reported. It is not universal and is recorded here
    from a single patient, but it matters clinically because it is the finding that
    can push the differential towards a hyper-IgE syndrome and away from DOCK2.
  phenotype_term:
    preferred_term: Elevated serum IgE
    term:
      id: HP:0003212
      label: Increased circulating IgE concentration
  evidence:
  - reference: PMID:34872585
    reference_title: "First patient in the Iranian Registry with novel DOCK2 gene mutation, presenting with skeletal tuberculosis, and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Furthermore, she had a high level of immunoglobulin (Ig) E and a slightly
      reduced IgM level with a non-protective antibody titer against diphtheria.
    explanation: >-
      The single reported observation of raised IgE, quoted with the rest of the
      immunoglobulin picture so the reader can see it is one patient.
- category: Immunological
  name: Combined immunodeficiency
  description: >-
    Quantitative and functional defects of T cells with associated B- and NK-cell
    impairment, presenting in infancy.
  phenotype_term:
    preferred_term: Combined immunodeficiency
    term:
      id: HP:0005387
      label: Combined immunodeficiency
  evidence:
  - reference: PMID:26083206
    reference_title: "Inherited DOCK2 Deficiency in Patients with Early-Onset Invasive Infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Autosomal recessive DOCK2 deficiency is a new mendelian disorder with
      pleiotropic defects of hematopoietic and nonhematopoietic immunity.
    explanation: >-
      The paper's own conclusion classifying the disorder, including the
      non-haematopoietic component.
- category: Infectious
  name: Recurrent invasive bacterial infections
  description: >-
    Severe, invasive bacterial infection from the first months of life: recurrent
    pneumonia, otitis media, and in one index patient fatal Klebsiella pneumoniae
    sepsis. Mycobacterial disease occurs, including BCG-site reaction and
    Mycobacterium avium.
  phenotype_term:
    preferred_term: Recurrent bacterial infections
    term:
      id: HP:0002718
      label: Recurrent bacterial infections
  evidence:
  - reference: PMID:26083206
    reference_title: "Inherited DOCK2 Deficiency in Patients with Early-Onset Invasive Infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ultimately died at the age of 20 months due to Klebsiella pneumoniae sepsis
    explanation: >-
      Documents fatal invasive bacterial infection in an index patient.
- category: Infectious
  name: Recurrent invasive viral infections
  description: >-
    Invasive viral disease is the most characteristic feature, and includes disease
    caused by live attenuated vaccine strains: vaccine-strain varicella with liver
    and lung involvement, and fatal chickenpox with alveolar infiltrates. Herpes
    viruses, mumps meningoencephalitis, parainfluenza, adenovirus and CMV
    reactivation are all reported.
  phenotype_term:
    preferred_term: Recurrent viral infections
    term:
      id: HP:0004429
      label: Recurrent viral infections
  diagnostic: true
  evidence:
  - reference: PMID:26083206
    reference_title: "Inherited DOCK2 Deficiency in Patients with Early-Onset Invasive Infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At 2.5 years of age, she developed vaccine strain-related varicella, with
      liver and lung involvement and multiple pulmonary infiltrates, requiring
      ventilatory support
    explanation: >-
      Documents invasive live-attenuated-vaccine-strain viral disease, the feature
      most specific to this disorder.
  - reference: PMID:36947335
    reference_title: "Multiple Immune Defects in Two Patients with Novel DOCK2 Mutations Result in Recurrent Multiple Infection Including Live Attenuated Virus Vaccine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we report two patients harboring four novel DOCK2 mutations associated with
      recurrent infections including live attenuated vaccine-related infections
    explanation: >-
      Independent confirmation of vaccine-strain infection in further patients.
- category: Gastrointestinal
  name: Chronic diarrhea and colitis
  description: >-
    Neonatal-onset chronic mucous diarrhoea with focal active colitis and a marked
    paucity of B and plasma cells in the lamina propria.
  phenotype_term:
    preferred_term: Chronic diarrhea
    term:
      id: HP:0002028
      label: Chronic diarrhea
  sequelae:
  - target: Failure to thrive
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Neonatal-onset chronic diarrhoea and the growth failure below are reported in
      the same index patient. Enteric loss is the obvious route and recurrent
      invasive infection is a second one; neither is separated out in the source, so
      the edge is drawn with unknown intermediates rather than as a demonstrated
      cause.
  evidence:
  - reference: PMID:26083206
    reference_title: "Inherited DOCK2 Deficiency in Patients with Early-Onset Invasive Infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      colon histopathology revealed focal active colitis (Fig.1B), associated with
      paucity of B and plasma cells and to a lesser extent of T cells in the lamina
      propria of the gut
    explanation: >-
      Documents the colitis and the mucosal lymphocyte paucity underlying it.
- category: Growth
  name: Failure to thrive
  description: >-
    Severe growth failure, in one index patient 3.5 kg below the third percentile
    for weight at one year.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:26083206
    reference_title: "Inherited DOCK2 Deficiency in Patients with Early-Onset Invasive Infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      growth failure (body weight: 4.5 kg, 3.5kg below third percentile; length: 64
      cm, 9cm below third percentile)
    explanation: >-
      Quantifies the growth failure in an index patient.
- category: Immunological
  name: Granulomatous inflammation
  description: >-
    Granulomatous lesions reported in lung (with acid-fast bacilli and cultured
    Mycobacterium avium) and in liver as non-necrotic eosinophilic granuloma-like
    lesions.
  phenotype_term:
    preferred_term: Granuloma
    term:
      id: HP:0032252
      label: Granuloma
  evidence:
  - reference: PMID:26083206
    reference_title: "Inherited DOCK2 Deficiency in Patients with Early-Onset Invasive Infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A lung biopsy revealed granulomatous inflammation (Fig.S2B) with acid-fast
      bacilli.
    explanation: >-
      Documents granulomatous inflammation with mycobacteria on biopsy.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Sixteen patients reported in the literature as of the 2023 review, all with a
    severe early-onset phenotype. No prevalence estimate exists.
  evidence:
  - reference: PMID:36947335
    reference_title: "Multiple Immune Defects in Two Patients with Novel DOCK2 Mutations Result in Recurrent Multiple Infection Including Live Attenuated Virus Vaccine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Until recently, only 16 DOCK2-deficient patients have been reported in the
      literature, and all had a severe phenotype characterized by early-onset of
      recurrent, invasive viral, and bacterial infections associated with T and B
      cell lymphopenia
    explanation: >-
      Gives an explicit worldwide case count. Graded HUMAN_CLINICAL for the
      clinical picture it describes, with quote_role BACKGROUND because the sentence
      sits in this paper's introduction summarizing others' cases rather than
      reporting its own.
genetic:
- name: DOCK2
  gene_term:
    preferred_term: DOCK2
    term:
      id: hgnc:2988
      label: DOCK2
  presence: Positive
  association: Biallelic Loss-of-Function Variants
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    Seven distinct rare DOCK2 variants were identified in the five index patients -
    four leading to premature termination and three predicted-deleterious missense
    changes at conserved residues. Further novel alleles have been reported since.
    Genotypes include homozygous dinucleotide insertions causing frameshift,
    homozygous missense, and compound heterozygous missense/nonsense.
  evidence:
  - reference: PMID:26083206
    reference_title: "Inherited DOCK2 Deficiency in Patients with Early-Onset Invasive Infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Collectively, we identified seven distinct DOCK2 rare mutations in five
      patients of different ethnic origin, four of which lead to premature
      termination, and three of which were predicted deleterious missense mutations
      affecting conserved residues of DOCK2
    explanation: >-
      Documents the allelic spectrum stated in the notes.
- name: DOCK2 (heterozygous ELMO1-binding-domain variants)
  subtype: Heterozygous DOCK2-ELMO1 hypomorph
  gene_term:
    preferred_term: DOCK2
    term:
      id: hgnc:2988
      label: DOCK2
  presence: Positive
  association: Heterozygous ELMO1-Binding-Domain Hypomorphic Variants
  relationship_type: SUSCEPTIBILITY
  variant_origin: GERMLINE
  notes: >-
    Three distinct heterozygous variants, all inside the DOCK2 region that binds and
    stabilizes ELMO1, carried by six individuals from three unrelated families.
    Each reduces DOCK2 protein level, ELMO1 binding and RAC1 activation, so the
    mechanism is hypomorphic destabilization rather than the null or truncating
    alleles of the recessive form, and it converges on the same RAC1 step.
    relationship_type is SUSCEPTIBILITY because the phenotype is severe illness on
    encountering particular viruses rather than a constitutive immunodeficiency.
    Note that the enum's own description for that value is written for polygenic
    GWAS loci; this is a monogenic susceptibility trait, and the value is used for
    its plain meaning. CAUSATIVE would assert a constitutive disease these carriers
    do not have.
  evidence:
  - reference: PMID:41654261
    reference_title: "Heterozygous variants in DOCK2 leading to susceptibility to viral illnesses."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      All variants reside within the DOCK2 domain that binds and stabilizes ELMO1.
      Each variant reduced DOCK2 protein expression, ELMO1 binding, and DOCK2
      function, as shown by diminished Rac1 activation and selective defects in
      Toll-like receptor signaling.
    explanation: >-
      Establishes the allelic class and its hypomorphic mechanism, which is what
      distinguishes this record from the biallelic loss-of-function one above.
  - reference: PMID:38857861
    reference_title: "RhoG facilitates a conformational transition in the guanine nucleotide exchange factor complex DOCK5/ELMO1 to an open state."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: >-
      Recent cryo-EM structures of the DOCK2/ELMO1 and DOCK2/ELMO1/Rac1 complexes
      have identified closed and open conformations that are key to understanding
      the autoinhibition mechanism.
    explanation: >-
      Supplies the structural reason a variant in the ELMO1-binding region is
      pathogenic at all: ELMO1 binding is what releases DOCK2 autoinhibition. The
      sentence is this paper's framing of the DOCK2 structures rather than its own
      result, which is about DOCK5, hence quote_role BACKGROUND and directness
      INDIRECT.
diagnosis:
- name: Molecular and Functional Diagnosis of DOCK2 Deficiency
  description: >-
    The diagnosis is genetic: biallelic DOCK2 variants on a primary-immunodeficiency
    panel or exome sequencing in a child with early-onset invasive infection and
    lymphopenia. Supporting functional assays, where available, are RAC1 activation
    after CD3 stimulation, chemokine-induced actin polymerization and chemotaxis,
    and NK-cell degranulation. Low TRECs on newborn screening can be the first
    signal.
  notes: >-
    The diagnosis is easy to miss. In one reported case it was made 18 years after
    the patient had already been transplanted for a presumed combined
    immunodeficiency of unknown cause, and in another the transplant was performed
    before the genetic diagnosis was available. Anyone transplanted for undefined
    CID is a candidate for retrospective genetic diagnosis, which matters because
    the non-haematopoietic arm of the disease is not corrected by the transplant.
  evidence:
  - reference: PMID:26083206
    reference_title: "Inherited DOCK2 Deficiency in Patients with Early-Onset Invasive Infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Children with clinical features of combined immunodeficiencies, especially
      with early-onset, invasive infections, may have this condition.
    explanation: >-
      The authors' own statement of who should be tested.
  - reference: PMID:35023658
    reference_title: "Hematopoietic stem cell transplantation complicated with EBV associated hemophagocytic lymphohistiocytosis in a patient with DOCK2 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He underwent HSCT without conditioning regimen before the genetic diagnosis
    explanation: >-
      Documents a case transplanted before the genetic diagnosis was made,
      supporting the retrospective-diagnosis point in the notes.
  - reference: PMID:34418894
    reference_title: "Investigating the Variation of TREC/KREC in Combined Immunodeficiencies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Very low to zero amounts of TREC and/or KREC were detected in 14 out of 23
      cases of common variable immunodeficiency (CVID), 14 out of 17 cases of AT, 8
      out of 20 cases of WAS, 6 out of 7 cases of DOCK8-deficiency patients, 4 out
      of 8 cases of HIES with unknown genetic defects and all patients with defects
      in DOCK2, PNP, and RAG1.
    explanation: >-
      The measured basis for the TREC claim in the description. Note the DOCK2 arm
      of this series is a single patient, so it establishes that the assay is
      abnormal in DOCK2 deficiency rather than how sensitive it is.
  - reference: PMID:34872585
    reference_title: "First patient in the Iranian Registry with novel DOCK2 gene mutation, presenting with skeletal tuberculosis, and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We also recommended that DOCK2-deficient patients might benefit from T-cell
      receptor excision circle (TREC) assay as part of the routine newborn
      screening program.
    explanation: >-
      The authors' own recommendation that newborn TREC screening should pick these
      patients up, which is the clinical claim the description makes.
treatments:
- name: Allogeneic Hematopoietic Stem Cell Transplantation
  description: >-
    The only curative treatment. Three of the five index patients were transplanted
    and had normalization of T-cell function and clinical improvement, one of them
    still well 17.5 years later. Transplantation replaces the haematopoietic
    compartment and therefore addresses the lymphocyte and NK arms; it does not
    obviously address the fibroblast-intrinsic antiviral defect, which is a reason
    to follow transplanted patients for viral disease rather than assume cure.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: hematopoietic cell transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  target_mechanisms:
  - target: T Cell Lymphopenia
    description: >-
      Replaces the DOCK2-deficient haematopoietic compartment with donor cells that
      can activate RAC1 normally, restoring thymic output from a donor-derived
      progenitor pool.
  - target: Impaired T Cell Activation and Antibody Response
    description: >-
      Donor lymphocytes activate RAC1 normally, so the proliferative and antibody
      responses that fail in patient cells are reconstituted.
  evidence:
  - reference: PMID:26083206
    reference_title: "Inherited DOCK2 Deficiency in Patients with Early-Onset Invasive Infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two patients died early in childhood; after allogeneic hematopoietic
      stem-cell transplantation, the other three had normalization of T-cell
      function and clinical improvement.
    explanation: >-
      Reports the outcome of transplantation in the index cohort, including the
      normalization of T-cell function.
  - reference: PMID:40860338
    reference_title: "Clinical and molecular findings in actin-related inborn errors of immunity: the middle East and North Africa registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hematopoietic stem cell transplantation (HSCT) was conducted on 24.0% of
      patients, which significantly improved survival in patients with defects in
      WAS, DOCK8 and DOCK2.
    explanation: >-
      A 503-patient multi-country registry reporting a survival benefit from
      transplantation that names DOCK2 specifically, which is the largest denominator
      behind the curative claim this treatment makes.
  notes: >-
    Transplant complications are reported: EBV-associated haemophagocytic
    lymphohistiocytosis after HSCT performed without a conditioning regimen.
- name: Interferon Alfa Therapy for Viral Complications
  description: >-
    Interferon alfa is the one mechanistically grounded adjunct short of transplant.
    It corrects the fibroblast antiviral defect in vitro, and weekly interferon-alfa
    completely resolved refractory warts in one patient with a heterozygous
    ELMO1-binding-domain variant. The source says only "IFN-alpha" and does not name
    the product, so the bound agent is the general recombinant interferon alfa term;
    the modality is OTHER rather than PROTEIN_REPLACEMENT because this is an
    immunomodulatory cytokine given pharmacologically, not replacement of a protein
    the patient lacks. This is a single-patient observation in the
    hypomorphic form, not a trial and not evidence in the recessive form; it is
    curated here because it is the direct clinical counterpart of the in vitro
    rescue this entry already records.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: interferon alfa
      term:
        id: NCIT:C225
        label: Recombinant Interferon Alfa
  target_mechanisms:
  - target: Increased Viral Replication in Non-Haematopoietic Cells
    description: >-
      Supplies the interferon signal that DOCK2-deficient cells fail to produce,
      restoring the antiviral state in cells that remain genetically deficient.
  evidence:
  - reference: PMID:41654261
    reference_title: "Heterozygous variants in DOCK2 leading to susceptibility to viral illnesses."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Weekly IFN-α therapy led to complete resolution of refractory warts in 1
      patient, highlighting a potential therapeutic approach for DOCK2-associated
      immunodeficiency.
    explanation: >-
      The single clinical observation behind this treatment, quoted with its own
      hedging intact.
- name: Immunoglobulin Replacement
  description: >-
    Intravenous immunoglobulin while awaiting transplantation, or where
    transplantation is not undertaken. It supplies the specific antibody the
    T-dependent response fails to make; it does not touch the cellular arm, so it
    is partial and palliative.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: intravenous immunoglobulin therapy
    term:
      id: NCIT:C121331
      label: Intravenous Immunoglobulin Therapy
  target_mechanisms:
  - target: Impaired T Cell Activation and Antibody Response
    description: >-
      Substitutes pooled donor antibody for the specific antibody response that
      fails in these patients despite normal total IgG and IgM.
  evidence:
  - reference: PMID:36947335
    reference_title: "Multiple Immune Defects in Two Patients with Novel DOCK2 Mutations Result in Recurrent Multiple Infection Including Live Attenuated Virus Vaccine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient's condition was partially alleviated by symptomatic treatment or
      intravenous immunoglobulin.
    explanation: >-
      Documents partial benefit from immunoglobulin, and its limits.
- name: Anti-Infective Prophylaxis and Symptomatic Care
  description: >-
    Antimicrobial prophylaxis and symptomatic treatment of intercurrent infection,
    alongside immunoglobulin, while awaiting transplantation. Split from the
    immunoglobulin record above because the two are different modalities and the
    combined record could not answer what kind of intervention it was.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  notes: >-
    No source cited here names a specific prophylactic agent or regimen in a DOCK2
    patient, so no `therapeutic_agent` is bound. The quoted evidence covers
    symptomatic treatment generically.
  evidence:
  - reference: PMID:36947335
    reference_title: "Multiple Immune Defects in Two Patients with Novel DOCK2 Mutations Result in Recurrent Multiple Infection Including Live Attenuated Virus Vaccine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient's condition was partially alleviated by symptomatic treatment or
      intravenous immunoglobulin.
    explanation: >-
      Documents partial benefit from symptomatic treatment, and its limits.
animal_models:
- name: DOCK2-deficient mouse (HSV-1 challenge)
  species: Mouse
  genotype: Dock2-deficient
  publication: PMID:38366567
  description: >-
    A mouse model developed specifically to separate DOCK2's own contribution to
    antiviral immunity from the treatments and comorbid infections that confound
    interpretation in patients.
  modeled_mechanisms:
  - target: Impaired T Cell Activation and Antibody Response
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Identifies a cell-intrinsic DOCK2 requirement for the initial expansion of
      antiviral CD8+ T cells, a step that is not visible in the human data because
      early activation markers look normal.
    limitations: >-
      The human node covers failed proliferation to mitogen and defective
      T-dependent antibody responses; the mouse result speaks only to
      antigen-specific CD8+ expansion after priming. The mouse also shows that DOCK2-deficient CD8+
      cells are protective once primed in vitro, a rescue with no human counterpart,
      so the model bears on the mechanism of the T-cell defect rather than on its
      clinical severity.
    readouts:
    - name: Antiviral CD8+ T-cell expansion after HSV-1 priming
      target: Impaired T Cell Activation and Antibody Response
      direction: DECREASED
      interpretation: >-
        The expansion deficit is the functional correlate of the human T-cell
        activation defect.
      evidence:
      - reference: PMID:38366567
        reference_title: "DOCK2 Deficiency Causes Defects in Antiviral T-Cell Responses and Impaired Control of Herpes Simplex Virus Infection."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          We also uncovered a critical, cell-intrinsic role of DOCK2 in the priming
          of antiviral CD8+ T cells and in particular their initial expansion,
          despite apparently normal early activation of these cells.
        explanation: >-
          Reports the measured expansion defect and its cell-intrinsic nature.
    evidence:
    - reference: PMID:38366567
      reference_title: "DOCK2 Deficiency Causes Defects in Antiviral T-Cell Responses and Impaired Control of Herpes Simplex Virus Infection."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        These results shed light on a cellular deficiency that is likely to impact
        antiviral immunity in DOCK2-deficient patients.
      explanation: >-
        The authors' own statement of the model's intended relevance to the human
        disease.
  - target: Recurrent invasive viral infections
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Delayed clearance of herpes simplex virus type 1, an organism-level antiviral
      phenotype matching the herpesvirus susceptibility seen in patients.
    limitations: >-
      Delayed clearance of a single experimentally administered virus is a much
      milder phenotype than the fatal disseminated varicella and vaccine-strain
      disease reported in patients, so the model reproduces the direction of the
      defect but not its clinical magnitude.
    evidence:
    - reference: PMID:38366567
      reference_title: "DOCK2 Deficiency Causes Defects in Antiviral T-Cell Responses and Impaired Control of Herpes Simplex Virus Infection."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We developed a mouse model of DOCK2 immunodeficiency and herein demonstrate
        that these mice have delayed clearance of herpes simplex virus type 1
        (HSV-1) infections.
      explanation: >-
        Reports the organism-level viral clearance defect in the model.
external_assertions:
- name: OMIM immunodeficiency 40 phenotype record
  source: OMIM
  assertion_type: disease_record
  external_id: OMIM:616433
  url: https://omim.org/entry/616433
  description: >-
    The OMIM phenotype record for this disease, Immunodeficiency 40. Recorded here
    rather than under `mappings` because `DiseaseMappings` carries only ICD-10-CM,
    ICD-11, MONDO and NCIT slots and there is no `omim_mappings` slot in the schema;
    issue #9922 withdrew a proposal to add one. This is the identifier a reader
    coming from OMIM will be holding, and it is not the number that appears in the
    IUIS table quoted under `classifications`.
- name: OMIM DOCK2 gene record
  source: OMIM
  assertion_type: gene_record
  external_id: OMIM:603122
  url: https://omim.org/entry/603122
  description: >-
    The OMIM record for the DOCK2 gene. Recorded explicitly because 603122 is the
    number carried in the IUIS 2022 table row quoted in this entry, where the column
    is a gene MIM, and reading it as the disease MIM is the mistake this pair of
    records exists to prevent.
discussions:
- discussion_id: hsct_does_not_correct_stromal_defect
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Increased Viral Replication in Non-Haematopoietic Cells
  - treatments#Allogeneic Hematopoietic Stem Cell Transplantation
  prompt: >-
    Does haematopoietic stem cell transplantation correct the non-haematopoietic,
    fibroblast-intrinsic antiviral defect in DOCK2 deficiency, and if not, what is
    the long-term viral risk in transplanted patients?
  rationale: >-
    The index report establishes two separable arms: a haematopoietic defect that
    transplantation demonstrably corrects, and a cell-intrinsic antiviral defect in
    fibroblasts that transplantation has no obvious mechanism to touch, since the
    recipient's stromal cells remain DOCK2-deficient. Transplanted patients are
    reported as "alive and well", but the longest follow-up reported is 17.5 years
    in one patient and the others are measured in months, and no study has asked
    whether stromal viral susceptibility persists. If it does, the standard framing
    of HSCT as curative for this disorder is incomplete, and interferon alfa-2b -
    which corrects the fibroblast phenotype in vitro - would be worth evaluating as
    an adjunct rather than only as a mechanistic probe.
- discussion_id: rac1_to_interferon_link
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Diminished Type I and Type III Interferon Production
  prompt: >-
    By what route does loss of DOCK2-dependent RAC1 activation reduce type I and
    type III interferon production?
  rationale: >-
    The entry draws this edge as INDIRECT_UNKNOWN_INTERMEDIATES because no
    intermediate is established. RAC1 activation downstream of antigen and chemokine
    receptors is a cytoskeletal signal, and the canonical antiviral interferon
    induction pathways run through RIG-I/MDA5 and TLR sensing, not through DOCK2.
    Whether the interferon defect is a direct signalling consequence, a consequence
    of impaired endosomal trafficking of nucleic acid sensors, or simply a knock-on
    of the reduced and abnormal plasmacytoid dendritic cell compartment has not been
    resolved. The answer determines whether interferon supplementation is treating
    the lesion or bypassing it.
notes: >-
  Not curated: the detailed NK receptor-by-receptor degranulation data (CD16,
  NKp30, NKp44, NKp46, NKG2D) and the MEK/ERK phosphorylation findings from
  PMID:26083206. They are real and support the "shared downstream step" argument in
  the NK node, but curating each receptor as its own node would multiply the
  pathograph without adding a distinct mechanistic claim.

  PMID:33928462 ("DOCK2 Deficiency Diagnosed 18 Years After Hematopoietic Stem Cell
  Transplantation") is cited nowhere in this entry although it is directly relevant
  to the late-diagnosis point in `diagnosis.notes`. The reference fetcher returns
  content type "unavailable" for it - neither abstract nor full text is
  retrievable - so there is no quotable text, and this repository does not permit
  hand-writing a cache file. The late-diagnosis claim is instead supported from
  PMID:35023658, which is cached and makes the weaker but quotable version of the
  same point.

📚

References & Deep Research

Deep Research

1

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

Evaluations and curation notes (1)

Create: DOCK2 Deficiency · 2026-09-16T21:07:01Z · View source

Created kb/disorders/DOCK2_Deficiency.yaml from claim issue #11962. Deep research: openscientist (research/DOCK2_Deficiency-deep-research-openscientist.md, 19 citations, 19/19 resolved, 0 unresolved, 0 off topic; 12 of 19 weighed on topic, 7 undecided for lack of an abstract). The run's own term-validation step aborted on an EBI network timeout, so the report was written with no reference_validation or term_validation frontmatter; the ## Reference Validation section was added afterwards with just validate-research-reference. Pathograph: 7 nodes from the SCARB2-independent single lesion (DOCK2 LOF) through failed RAC1 activation to four functional branches - lymphocyte actin/chemotaxis, NK degranulation, interferon production, and a non-haematopoietic fibroblast antiviral defect. The deep-research report changed the entry's framing: it surfaced PMID:41654261 (2026), a heterozygous ELMO1-binding-domain hypomorphic form, so the entry now carries two has_subtypes and a second (dominant) inheritance block rather than describing a purely recessive disease. It also supplied PMID:30838481 (primary human neutrophil ROS/cytoskeleton defect) and PMID:38366567 (mouse HSV-1 model). Two ontology CURIEs written from memory were caught and corrected during curation elsewhere in this run; every CURIE here was read from cache/ or OAK. Validation: just validate passes (schema, terms, 35/35 snippets verified); check-duplicate-keys, check-entity-refs, check-causal-targets, check-qualifier-terms, check-enum-values all clean. PMID:33928462 is deliberately not cited - the fetcher returns content type unavailable for it, so there is no quotable text; recorded in the entry notes.

OpenScientist ▸

DOCK2 Deficiency — Comprehensive Disease Characterization

openscientist-autonomous 19 citations 2026-09-16T21:00:00.250198

DOCK2 Deficiency — Comprehensive Disease Characterization

Disease: DOCK2 Deficiency MONDO ID: MONDO:0014637 OMIM: 616433 (Immunodeficiency 40, phenotype); 603122 (DOCK2 gene) Orphanet: ORPHA:317425 (Combined immunodeficiency due to DOCK2 deficiency) Category: Mendelian, autosomal recessive combined immunodeficiency Report type: Aggregated disease-level synthesis of primary literature (25 papers reviewed, 14 findings confirmed)

Summary

DOCK2 (Dedicator of Cytokinesis 2) deficiency is an ultra-rare, early-onset autosomal recessive combined immunodeficiency (CID) caused by biallelic loss-of-function mutations in the DOCK2 gene. DOCK2 is a hematopoietic-restricted, atypical guanine-nucleotide exchange factor (GEF) that activates the small Rho-family GTPases Rac1 and Rac2. Because Rac-driven actin polymerization underlies leukocyte migration, immune-synapse formation, phagocyte oxidative burst, and cytoskeleton-dependent signaling, loss of DOCK2 produces a broad, multilineage immune failure. Affected children typically present in the first two years of life with invasive bacterial and viral infections (especially herpesviruses and other DNA/RNA viruses), T-cell lymphopenia with low CD4⁺ counts, defective T-, B-, and NK-cell function, and frequently elevated serum IgE. The clinical spectrum ranges from leaky SCID to Omenn syndrome. The landmark description of the disease was the 2015 New England Journal of Medicine report of five unrelated children (Dobbs et al., PMID: 26083206).

Mechanistically, the disease is a member of the "actinopathies" — inborn errors of immunity that disrupt actin-cytoskeleton regulation. Beyond the classic hematopoietic migration defect, DOCK2 has a non-hematopoietic, interferon-dependent antiviral role: DOCK2-deficient fibroblasts show increased viral replication and enhanced virus-induced cell death, both correctable by interferon alfa-2b. This connects a cell-autonomous cytoskeletal GEF to type I/III interferon antiviral immunity and provides a direct mechanism-to-therapy link — IFN-α as a targeted adjunct. The only curative treatment is allogeneic hematopoietic stem-cell transplantation (HSCT), which is most effective when performed early, motivating detection through newborn TREC screening.

The disease is enriched in consanguineous populations (particularly the Middle East and North Africa) and remains ultra-rare, with only a few dozen patients reported worldwide since 2015. A newly recognized (2026) hypomorphic heterozygous form — variants clustering in the ELMO1-binding region — causes a milder, later-onset susceptibility to specific viral illnesses (HPV, RSV, SARS-CoV-2), broadening the phenotypic spectrum from a purely recessive severe CID to a graded, dose-dependent immune defect.

Section 1 — Disease Information

Overview. DOCK2 deficiency is a Mendelian combined immunodeficiency in which biallelic loss-of-function mutations abolish DOCK2, a Rac-specific GEF essential for leukocyte cytoskeletal dynamics. The result is defective migration, activation, and function across T, B, NK, dendritic, and neutrophil lineages, plus a cell-intrinsic antiviral defect in non-hematopoietic cells.

Key identifiers.

Resource	Identifier
MONDO	MONDO:0014637
OMIM (phenotype)	616433 (Immunodeficiency 40)
OMIM (gene)	603122
Orphanet	ORPHA:317425
Gene (HGNC)	DOCK2, HGNC:2988
Gene locus	5q35.1
UniProt (protein)	Q92608 (DOCK2_HUMAN)
MeSH	Severe Combined Immunodeficiency (closest); DOCK2 (protein)

Synonyms / alternative names. Immunodeficiency 40 (IMD40); Combined immunodeficiency due to DOCK2 deficiency; DOCK2-related combined immunodeficiency; DOCK2 actinopathy.

Information source. The knowledge here is aggregated disease-level synthesis from primary case reports, small cohorts, structural biology, and mouse-model studies — not derived from a single EHR dataset. Given rarity (a few dozen patients), evidence is dominated by individual patient reports and mechanistic model-organism/in-vitro work.

Section 2 — Etiology

Primary cause — genetic. DOCK2 deficiency is monogenic and autosomal recessive, caused by biallelic loss-of-function DOCK2 variants. Dobbs et al. identified biallelic mutations in five unrelated children (Finding F001): "We identified biallelic mutations in the dedicator of cytokinesis 2 gene (DOCK2) in these five patients. RAC1 activation was impaired in the T cells" (PMID: 26083206).

Genetic risk factors. The causal variants are the disease. There are no separate common susceptibility loci; the principal population-level risk factor is consanguinity/founder effects (Finding F013). A newly recognized heterozygous, partial-loss-of-function mechanism (variants in the ELMO1-binding domain) confers milder viral susceptibility (Finding F005).

Environmental risk factors. None cause the disease; however, infectious exposures (herpesviruses, HPV, RSV, SARS-CoV-2, live attenuated vaccines) are the environmental triggers that unmask and drive morbidity. Live attenuated virus vaccines can cause vaccine-strain infection in DOCK2-deficient patients (PMID: 36947335).

Protective factors. No genetic or dietary protective factors are established. The functionally relevant "protective" intervention is exogenous interferon-α, which corrects the antiviral defect in vitro and clinically (Findings F002, F014).

Gene–environment interaction. The genotype (biallelic vs. hypomorphic heterozygous DOCK2) sets a threshold of immune competence; the environmental pathogen load determines clinical expression. Severe biallelic LOF → early invasive infection; hypomorphic heterozygous → later-onset, pathogen-specific viral disease.

Section 3 — Phenotypes

DOCK2 deficiency is a combined immunodeficiency affecting cellular and humoral arms. Onset is typically neonatal-to-early-childhood (<2 years); severity ranges mild→severe; course is progressive without HSCT.

Phenotype	Type	HPO term (suggested)	Onset / severity / frequency
Recurrent/invasive bacterial infections	Clinical sign	HP:0002718 (Recurrent bacterial infections)	Infancy; severe; most patients
Severe viral infections (HHV/HSV, EBV, HPV, RSV, SARS-CoV-2)	Clinical sign	HP:0004429 (Recurrent viral infections)	Infancy–adult; severe; characteristic
T-cell lymphopenia / low CD4⁺	Lab abnormality	HP:0005403 (Decreased circulating T-cell count)	Congenital/infancy; persistent; near-universal
Elevated serum IgE	Lab abnormality	HP:0003212 (Increased serum IgE)	Childhood; frequent
Defective NK function / cytopenia	Lab abnormality	HP:0040218 (Reduced NK cell count)	Infancy; common
Neutrophil dysfunction (impaired ROS, chemotaxis)	Lab abnormality	HP:0001878 (neutrophil abnormalities)	Infancy; partial
Failure to thrive / recurrent pneumonia	Clinical sign	HP:0006532 (Recurrent pneumonia)	Infancy; common
Autoimmune cytopenia / lymphoproliferation	Clinical sign	HP:0001973; HP:0002733	Variable/later; RAC-pathway class
Omenn / leaky SCID presentation	Clinical picture	HP:0004430 (Severe combined immunodeficiency)	Neonatal; severe

Representative case: a 27-month-old with recurrent pneumonia and skeletal tuberculosis had "persistent lymphopenia and low CD4 + T cell count... she had a high level of immunoglobulin (Ig) E" (Finding F008; PMID: 34872585). A literature review found "14 DOCK2-deficient patients suffering from both cellular and humoral immune defects leading to early-onset infections, particularly human herpesvirus (HHV) infection."

Quality-of-life impact. Untreated disease is life-threatening in early childhood with recurrent hospitalizations, invasive infections, and organ damage; disease-specific QoL instruments have not been reported. Successful HSCT can normalize immune function and dramatically improve outlook (Finding F004).

Section 4 — Genetic / Molecular Information

Causal gene. DOCK2 (HGNC:2988; OMIM gene 603122), 5q35.1, encodes an ~1830-residue atypical Rac-GEF (UniProt Q92608). Disease = Immunodeficiency 40 (OMIM 616433).

Pathogenic variant spectrum. Reported biallelic variants are predominantly loss-of-function: frameshift, nonsense, and splice-site alleles, plus some missense/hypomorphic alleles. Documented examples:

Variant (nucleotide)	Protein consequence	Type	Zygosity	Reference
c.2704-2 A>C	splice-site; complete loss of DOCK2 protein	splice	homozygous	PMID: 30838481
c.1512delG	p.I505Sfs*28	frameshift	homozygous	PMID: 34872585
c.3624+5G>A	exon 35 skipping, p.L1157Ifs*12 (predicted)	splice	homozygous	PMID: 40153067
ELMO1-binding-domain variants	reduced DOCK2 expression + ELMO1 binding	missense (hypomorphic)	heterozygous	PMID: 41654261

Variant classification (ACMG/AMP). LOF variants (frameshift/nonsense/canonical splice) are classified pathogenic/likely pathogenic given that LOF is an established disease mechanism. The heterozygous hypomorphic missense variants (2026 report) are supported by functional evidence of reduced protein and Rac1 activation.

Allele frequency. Pathogenic DOCK2 alleles are extremely rare/private in gnomAD, consistent with an ultra-rare recessive disease; several are founder/consanguineous-family alleles.

Somatic vs germline. All disease variants are germline.

Functional consequence. Loss of function — abolished or reduced Rac-GEF activity (Finding F001). The heterozygous ELMO1-binding variants act by destabilizing DOCK2 and impairing ELMO1 binding, reducing Rac1 activation (partial LOF; Finding F005): "Each variant reduced DOCK2 protein expression, ELMO1 binding, and DOCK2 function, as shown by diminished Rac1 activation and selective defects in Toll-like receptor signaling" (PMID: 41654261).

Modifier genes. ELMO1 is a functional partner that stabilizes DOCK2; its binding region is the hotspot for hypomorphic variants. RAC1/RAC2 are downstream effectors. No formal disease-severity modifier genes are established.

Epigenetics / chromosomal abnormalities. No specific epigenetic signatures or large-scale chromosomal abnormalities are described for DOCK2 deficiency; the disease arises from point/indel/splice mutations, not structural variants.

Section 5 — Environmental Information

Environmental/toxic factors: none causal.
Lifestyle factors: none causal.
Infectious agents (triggers/manifestations): herpesviruses (HSV-1, EBV, other HHV), human papillomavirus (HPV), respiratory syncytial virus (RSV), SARS-CoV-2, and live attenuated vaccine strains. These are the disease's defining clinical challenges (Findings F005, F006, F008; PMID: 36947335, PMID: 40153067). EBV is notably associated with hemophagocytic lymphohistiocytosis (HLH) as a post-HSCT complication (PMID: 35023658).

Section 6 — Mechanism / Pathophysiology

Ordered causal chain

Biallelic LOF mutation in DOCK2 → loss (or severe reduction) of DOCK2 protein in hematopoietic cells (demonstrated; F001, F003).
Loss of DOCK2 → loss of Rac1/Rac2 GEF activity (DOCK2 exchanges GDP→GTP on Rac via its DHR-2 domain) → failure to generate active GTP-bound Rac at the plasma membrane (demonstrated; F001, F007).
In wild-type cells, chemoattractant stimulation → PIP3-dependent DOCK2 recruitment to the plasma membrane → phospholipase-D–generated phosphatidic acid stabilizes DOCK2 at the leading edge via its C-terminal polybasic cluster → local, polarized Rac activation (demonstrated in neutrophils; F007). Without DOCK2 this spatial Rac activation is abolished.
Loss of polarized Rac-GTP → failure of leading-edge actin polymerization and cell polarization → defective chemotaxis / leukocyte migration, defective immune-synapse formation, impaired integrin activation (cell-type-specific, prominent in B cells; F007, F010).
Branch A (adaptive immunity): defective migration/synapse → impaired T-, B-, NK-cell homing, activation, and clonal expansion → T-cell lymphopenia, low CD4⁺, poor antibody responses, impaired NK cytotoxicity → recurrent/invasive infection (demonstrated; F001, F006, F008, F011).
Branch B (innate/phagocyte): loss of Rac2-dependent NADPH-oxidase assembly and cytoskeletal rearrangement → impaired neutrophil ROS production and chemotaxis → defective bacterial/fungal killing (demonstrated; F003).
Branch C (antiviral, partly non-hematopoietic): loss of DOCK2 → diminished type I/III interferon (IFN-α, IFN-λ) production and impaired cell-intrinsic antiviral defense → increased viral replication and virus-induced cell death (demonstrated in fibroblasts; corrected by IFN-α or WT DOCK2 re-expression; F002, F014). In hypomorphic heterozygotes, an additional selective Toll-like-receptor signaling defect contributes (F005).
Branch D (antiviral T cells): DOCK2 is required cell-intrinsically for the initial clonal expansion of antiviral CD8⁺ T cells → delayed viral (HSV-1) clearance (demonstrated in mouse model; F006, F010).
Net clinical manifestation → early-onset combined immunodeficiency with severe bacterial and viral disease, ranging from leaky SCID to Omenn syndrome, and (in the RAC-pathway class) autoimmune/lymphoproliferative features.

Molecular / cellular detail

Molecular pathway: DOCK2 → Rac1/Rac2 GTPase activation → actin cytoskeleton remodeling (Rho-GTPase signaling; not the canonical Dbl-homology GEF family — DOCK proteins use a DHR-2 catalytic domain).
Regulation: DOCK2 forms an autoinhibited DOCK2/ELMO1 complex. Cryo-EM structures reveal closed (autoinhibited) and open (active) conformations; RhoG facilitates the closed-to-open transition, and PIP3-membrane binding enhances GEF activity (Finding F012; PMID: 38857861): "Recent cryo-EM structures of the DOCK2/ELMO1 and DOCK2/ELMO1/Rac1 complexes have identified closed and open conformations that are key to understanding the autoinhibition mechanism." ELMO1 binding stabilizes DOCK2; the hypomorphic heterozygous variants map to this ELMO1-binding region.
Protein dysfunction: loss of function via absent protein (LOF alleles) or reduced stability/ELMO1 binding (hypomorphic alleles).
Cellular processes: cell migration/chemotaxis (GO:0006935), actin filament polymerization (GO:0030041), Rac protein signal transduction (GO:0016601), leukocyte chemotaxis (GO:0030595), immunological synapse formation, respiratory burst (GO:0045730), and defense response to virus (GO:0051607).
Cell types involved (CL): T cell (CL:0000084), B cell (CL:0000236), natural killer cell (CL:0000623), NKT cell, neutrophil (CL:0000775), macrophage (CL:0000235), plasmacytoid dendritic cell (CL:0000784), plus non-hematopoietic fibroblast (CL:0000057) for the interferon-dependent antiviral role.
Immune involvement: combined immunodeficiency (cellular + humoral + innate), with a distinctive antiviral/interferon deficit.

DOCK2 is hematopoietic-restricted, predominantly expressed in peripheral blood, spleen, and thymus (lymphocytes and macrophages), and is "essential for lymphocyte migration and activation as well as neutrophil chemotaxis... also regulates the differentiation of natural killer T cells, type 2 T helper cells, and plasmacytoid dendritic cells" (Finding F011; PMID: 27504608).

  DOCK2 biallelic LOF
│
▼
  No Rac1/Rac2 GEF activity ──(PIP3 + PA localization lost)──► no leading-edge actin
│
   ┌────┼─────────────┬──────────────────┬───────────────────┐
   ▼    ▼             ▼                  ▼                   ▼
 T/B/NK  Neutrophil   pDC/IFN-α,λ        Fibroblast          CD8 T-cell
 migration ROS burst  production down    antiviral defense   clonal expansion
 & synapse  down       ▼                  down (correctable   down (mouse)
   ▼        ▼        impaired viral        by IFN-α)            ▼
 lymphopenia poor    sensing               ▼                delayed HSV-1
 low CD4    bacterial ▼                  ↑viral replication  clearance
 poor Ab    killing  severe viral        + cell death
   └────────┴──────────┴── EARLY-ONSET COMBINED IMMUNODEFICIENCY ──┴────────┘

Section 7 — Anatomical Structures Affected

Primary system: the hematopoietic/immune system (UBERON:0002390 hematopoietic system; UBERON:0000178 blood).
Organs/tissues: thymus (UBERON:0002370), spleen (UBERON:0002106), lymph nodes (UBERON:0000029), bone marrow (UBERON:0002371) — with severe atrophy of secondary lymphoid tissues (Finding F011; PMID: 35023658).
Secondary organ involvement: lungs (recurrent pneumonia), skin/mucosa (warts, viral lesions), and any site of invasive infection; skeletal involvement (tuberculosis) reported.
Cell populations: T, B, NK, NKT, Th2 lymphocytes; neutrophils; macrophages; plasmacytoid dendritic cells (CL terms as in Section 6); plus non-hematopoietic fibroblasts for the antiviral defect.
Subcellular compartments (GO Cellular Component): plasma membrane / leading edge (GO:0031252 cell leading edge), actin cytoskeleton (GO:0015629), lamellipodium (GO:0030027), cytosol.
Lateralization: not applicable (systemic immune disorder).

Section 8 — Temporal Development

Onset: typically congenital/infantile, usually <2 years; presentations from neonatal leaky SCID/Omenn syndrome to early childhood invasive infection. The hypomorphic heterozygous form can present much later (reported ages 3 months to 50 years; PMID: 41654261).
Onset pattern: subacute-to-chronic with acute infectious crises.
Progression: progressive and life-threatening without HSCT; two of five patients in the original cohort died in early childhood (PMID: 26083206).
Disease course: chronic/lifelong absent curative transplant; recurrent infectious episodes.
Remission: achievable only through treatment-induced immune reconstitution after HSCT; no spontaneous remission.
Critical period: the window before irreversible infectious organ damage — early diagnosis (e.g., newborn TREC screening) enabling HSCT "soon after diagnosis" is the key intervention opportunity (Finding F004).

Section 9 — Inheritance and Population

Inheritance: autosomal recessive (biallelic homozygous or compound heterozygous LOF). A distinct hypomorphic heterozygous partial-penetrance form also exists (F005).
Penetrance/expressivity: biallelic LOF is highly penetrant with variable expressivity (leaky SCID ↔ Omenn); heterozygous hypomorphic variants show incomplete penetrance and milder, pathogen-selective disease.
Epidemiology: ultra-rare — only a few dozen patients reported worldwide since 2015; precise prevalence/incidence not established.
Founder effects / consanguinity: strong — almost all biallelic cases arise in consanguineous or founder families. DOCK2 deficiency is one of ~15 monogenic actinopathies with high prevalence in the Middle East and North Africa (MENA) (Finding F013; PMID: 40860338): "The majority of monogenic inborn errors of immunity presenting as actinopathies were reported originally from the Middle East and North Africa (MENA) countries indicating a high prevalence of these entities in the region."
Carrier frequency: not established; expected very low outside founder populations.
Sex ratio: no strong sex bias reported (autosomal).
Class-level demographics: within the RAC2-associated actinopathy subgroup, patients tend to have "late-onset symptoms... higher rate of EBV and HPV infections, autoimmune cytopenia, asthma, and lymphoproliferation" (PMID: 40860338).

Section 10 — Diagnostics

Molecular diagnosis is definitive.

Genetic testing: whole-exome sequencing (WES) or targeted primary-immunodeficiency NGS panels identify biallelic DOCK2 variants; single-gene/Sanger confirmation and segregation in family. WGS can resolve non-coding/splice variants. Karyotype/CMA/FISH are not indicated (no structural mechanism).
Newborn screening: DOCK2-deficient patients show very low to zero T-cell receptor excision circles (TREC) and sometimes low KREC. In a combined-immunodeficiency series, "Very low to zero amounts of TREC and/or KREC were detected in 14 out of 23 cases" (PMID: 34418894); TREC-based newborn screening is recommended for early DOCK2 detection (Finding F009; PMID: 34872585).
Laboratory immunophenotyping: T-cell lymphopenia, low CD4⁺, abnormal/absent proliferative responses, decreased/dysfunctional NK cells, dysregulated immunoglobulins (often elevated IgE; sometimes low IgM), non-protective vaccine antibody titers.
Functional assays: impaired chemokine-induced migration and actin polymerization (T, B, NK cells); reduced RAC1 activation; impaired neutrophil ROS/oxidative burst and cytoskeletal rearrangement; diminished IFN-α/IFN-λ production; in fibroblasts, increased viral replication.
Protein testing: absent/reduced DOCK2 by immunoblot for LOF/hypomorphic alleles.
Clinical criteria: meets ESID definitions for SCID/CID; classify per IUIS inborn-errors-of-immunity framework (combined immunodeficiency with actin-cytoskeleton/RAC-pathway involvement).
Differential diagnosis: other SCID/CID genes and actinopathies — DOCK8 deficiency (CDC42 axis, hyper-IgE/atopy), DOCK11 deficiency (X-linked actinopathy with autoimmunity; PMID: 36952639), RAC2 defects (PMID: 32636302), and GATA2 haploinsufficiency (can overlap in severe viral/COVID-19 pneumonia; PMID: 40153067).

Section 11 — Outcome / Prognosis

Untreated: poor — life-threatening invasive infections in early childhood; 2 of 5 patients in the original cohort died young (PMID: 26083206).
With HSCT: potentially curative; the surviving three original patients had normalization of T-cell function and clinical improvement after allogeneic HSCT (Finding F004). Outcome is best with early transplant.
Complications: invasive bacterial/viral infections, organ damage; post-HSCT EBV-associated hemophagocytic lymphohistiocytosis (HLH) is a recognized serious complication (PMID: 35023658); autoimmune cytopenia, lymphoproliferation, and atopy in the RAC-pathway class.
Prognostic factors: time to diagnosis and transplant, infectious burden at transplant, donor match, and residual protein/function (hypomorphic > null). A patient diagnosed 18 years after HSCT illustrates that early transplant (even before molecular diagnosis) can be durable (PMID: 33928462).
QoL measures: no disease-specific instruments reported.

Section 12 — Treatment

Curative therapy. - Allogeneic hematopoietic stem-cell transplantation (HSCT) — the only cure and standard of care; "The curative treatment should be HSCT soon after diagnosis" (Finding F004; PMID: 35023658). NCIT: Hematopoietic Cell Transplantation (NCIT:C15431).

Targeted / disease-modifying adjuncts. - Interferon-α (IFN-α / interferon alfa-2b) — mechanistically justified: DOCK2-deficient fibroblasts' increased viral replication/cell death are "normalized by treatment with interferon alfa-2b or after expression of wild-type DOCK2" (Finding F002/F014; PMID: 26083206); clinically, "Weekly IFN-α therapy led to complete resolution of refractory warts in 1 patient" (PMID: 41654261). NCIT: Interferon Alfa (NCIT:C583).

Supportive / prophylactic. - Immunoglobulin replacement (IVIG) and antimicrobial/antiviral prophylaxis; partial symptomatic benefit reported (PMID: 36947335). NCIT: Intravenous Immunoglobulin Therapy (NCIT:C603). - Avoid live attenuated vaccines (risk of vaccine-strain disease).

Pharmacogenomics / experimental. - No DOCK2-specific pharmacogenomic guidance. - Gene therapy / gene correction: conceptually supported (WT DOCK2 re-expression rescues antiviral defect in vitro) but not yet trialed in patients (Finding F014).

Section 13 — Prevention

Primary prevention: not possible for a germline recessive disease; genetic counseling and carrier/cascade testing in affected families (especially consanguineous kindreds) reduce recurrence. Preimplantation/prenatal genetic testing is feasible where the familial variant is known.
Secondary prevention: newborn TREC screening enables presymptomatic detection and early HSCT (Finding F009).
Tertiary prevention: antimicrobial/antiviral prophylaxis, IVIG, avoidance of live vaccines, and prompt treatment of infections to limit organ damage before/after transplant; IFN-α for refractory viral complications.
Public-health note: in high-consanguinity (MENA) populations, community genetic-counseling programs are the most impactful preventive lever.

Section 14 — Other Species / Natural Disease

Orthologs & conservation: DOCK2 is deeply conserved — a mammalian homolog of C. elegans CED-5 and Drosophila Myoblast City (Mbc) (Finding F010), reflecting an ancient role in Rac-dependent cytoskeletal/engulfment processes. Mouse ortholog Dock2 (NCBI Gene 94176).
Naturally occurring disease in other species: no well-characterized spontaneous animal disease reported (no OMIA entry emphasized in the reviewed literature); disease knowledge derives from engineered mouse models.
Zoonotic potential: none (host genetic disorder).

Section 15 — Model Organisms

Principal model: Dock2-knockout (Dock2⁻/⁻) mouse (mammalian, in vivo). It recapitulates the immunodeficiency and reveals cell-type-specific defects: "an unexpected defect in integrin activation in DOCK2-/- B cells, whereas lack of DOCK2 did not affect chemokine-triggered integrin activation in T cells" (Finding F010; PMID: 15357953). DOCK2 mediates lymphocyte migration largely PI3K-independently.
Antiviral model: a Dock2 immunodeficiency mouse shows delayed HSV-1 clearance due to a "critical, cell-intrinsic role of DOCK2 in the priming of antiviral CD8+ T cells and in particular their initial expansion" (Finding F006; PMID: 38366567).
Infection model: Dock2 studied in macrophage migration during Citrobacter rodentium infection (PMID: 33662140).
In vitro / structural models: patient fibroblasts (antiviral assays), neutrophils (chemotaxis/Rac imaging; PMID: 16943182, PMID: 19325080), and cryo-EM structures of DOCK2/ELMO1(±Rac1) (PMID: 38857861).
Phenotype recapitulation: mouse models faithfully reproduce migration, chemotaxis, and antiviral CD8⁺ T-cell defects. Limitation: murine models may not fully capture the human non-hematopoietic interferon-dependent antiviral phenotype or the full spectrum of human clinical severity.

Key Findings (Expanded)

F001 — Genetic basis. Biallelic LOF DOCK2 mutations cause an autosomal recessive combined immunodeficiency. The defining evidence: five unrelated children with early-onset invasive bacterial/viral infections, lymphopenia, and defective T/B/NK responses, all carrying biallelic DOCK2 mutations with impaired RAC1 activation and defective chemokine-induced migration and actin polymerization (PMID: 26083206).

F002 & F014 — Interferon-correctable antiviral defect. DOCK2 has a non-hematopoietic antiviral role: deficient fibroblasts show increased viral replication and virus-induced death, normalized by interferon alfa-2b or WT DOCK2 re-expression. This is the mechanistic rationale for IFN-α therapy — clinically validated by resolution of refractory warts on weekly IFN-α (PMID: 26083206, PMID: 41654261).

F003 — Neutrophil dysfunction. A four-sibling kindred (homozygous splice c.2704-2 A>C, complete protein loss; leaky SCID/Omenn) demonstrated partially impaired neutrophil cytoskeletal rearrangement and ROS production — extending the defect to innate phagocytes (PMID: 30838481).

F004 — HSCT curative. Allogeneic HSCT normalized T-cell function in the original cohort's survivors and is confirmed curative across reports, best performed early (PMID: 26083206, PMID: 35023658).

F005 — Heterozygous hypomorphic form. Six individuals from three families with heterozygous ELMO1-binding-domain variants had severe HPV/RSV/SARS-CoV-2 disease; variants reduced DOCK2 expression, ELMO1 binding, Rac1 activation, and selective TLR signaling — defining a dose-dependent, later-onset phenotype (PMID: 41654261).

F006 — Severe viral disease. Two siblings homozygous for DOCK2 c.3624+5G>A had critical COVID-19 with decreased CD4 counts, impaired lymphocyte transformation, and elevated IgG/IgA/IgE; a mouse model shows delayed HSV-1 clearance from a cell-intrinsic CD8⁺ T-cell expansion defect (PMID: 40153067, PMID: 38366567).

F007 — Spatial Rac activation. DOCK2 localizes Rac activation at the leading edge via sequential PIP3-dependent recruitment and phosphatidic-acid-dependent stabilization; its loss abolishes polarized F-actin/PIP3 and Rac1/Rac2 activation in neutrophils (PMID: 19325080, PMID: 16943182).

F012 — Structural regulation. Cryo-EM defines an autoinhibited DOCK2/ELMO1 complex with closed/open conformations; RhoG and PIP3 drive activation (PMID: 38857861).

F013 — Actinopathy class / consanguinity. DOCK2 belongs to the RAC-pathway "actinopathy" class, enriched in MENA consanguineous populations, with class-level EBV/HPV, autoimmune-cytopenia, asthma, and lymphoproliferation associations (PMID: 40860338).

Mechanistic Model / Interpretation

DOCK2 sits at a single molecular node — Rac GDP→GTP exchange — from which the entire disease radiates. Its function is fundamentally spatial: it does not merely activate Rac, it activates Rac at the right place and time, using PIP3 for initial membrane recruitment and phospholipase-D-derived phosphatidic acid for leading-edge stabilization. This explains why so many immune functions collapse together — chemotaxis, immune-synapse assembly, integrin activation, phagocyte respiratory burst, and antiviral T-cell expansion are all Rac/actin-dependent processes that require polarized Rac signaling.

The pathophysiology therefore branches from one lesion into four functional failures: (A) adaptive-lymphocyte migration/activation → lymphopenia and poor antigen responses; (B) neutrophil oxidative burst → impaired bacterial killing; (C) interferon-dependent, partly non-hematopoietic antiviral defense → uncontrolled viral replication; and (D) cell-intrinsic CD8⁺ T-cell clonal expansion → failed viral clearance. Because branch C is at least partly interferon-dependent and cell-autonomous, it is pharmacologically rescuable with IFN-α, providing a rare instance where a monogenic immunodeficiency has a mechanistically grounded targeted adjunct short of transplant.

The 2026 recognition of a hypomorphic heterozygous form reframes DOCK2 deficiency as a dose-dependent continuum rather than a binary recessive disease: complete biallelic loss → severe infantile CID; partial loss (ELMO1-binding destabilization) → milder, later-onset, virus-selective disease. This gradient tracks residual Rac1 activation and DOCK2 protein stability, unifying the genotype–phenotype spectrum.

Evidence Base

PMID	Title (abbrev.)	Contribution
26083206	Inherited DOCK2 deficiency (Dobbs 2015, NEJM)	Landmark: causal gene, biallelic LOF, Rac/actin/migration mechanism, IFN-correctable antiviral defect, HSCT
30838481	Novel mutation + neutrophil dysfunction	Innate/phagocyte ROS + cytoskeleton defect
41654261	Heterozygous DOCK2 variants (2026)	Hypomorphic heterozygous form, ELMO1 domain, IFN-α efficacy
40153067	DOCK2 + GATA2 in critical COVID-19	Severe viral disease incl. COVID-19; differential (GATA2)
38366567	DOCK2 antiviral T-cell defects (mouse)	Cell-intrinsic CD8⁺ priming; HSV-1 clearance
35023658	HSCT complicated by EBV-HLH	HSCT curative; EBV-HLH complication; multilineage cytopenia
34872585	Iranian registry case + review	Lab phenotype; frameshift variant; TREC screening; 14-patient review
34418894	TREC/KREC in CID	Very-low/zero TREC/KREC diagnostic pattern
27504608	DOCK2 review	Lineage dependence (T/B/NK/NKT/Th2/pDC/neutrophil)
15357953	DOCK2 vs PI3Kγ in homing	Mouse model; cell-type-specific integrin defect
19325080	Two-phospholipid regulation	PIP3 + phosphatidic acid leading-edge localization
16943182	DOCK2 Rac activator in neutrophils	Rac1/Rac2 activation; polarized F-actin/PIP3
38857861	RhoG/DOCK5-ELMO1 open state	Autoinhibition, closed/open, RhoG activation
40860338	MENA actinopathy registry	Consanguinity enrichment; RAC-pathway phenotype class
36947335	Two patients, novel mutations	Live-vaccine infection; expanded phenotype
33928462	Diagnosed 18 yr post-HSCT	Durability of early HSCT
36952639	DOCK11 X-linked actinopathy	Differential diagnosis within DOCK/actinopathy family
32636302	RAC2 E62K hyperactivation	Differential; RAC-pathway biology

Evidence source types: human clinical (case reports/cohorts/registries), model organism (Dock2⁻/⁻ mouse), in vitro (patient fibroblasts, neutrophils), and computational/structural (cryo-EM, molecular dynamics).

Limitations and Knowledge Gaps

Rarity: only a few dozen patients worldwide; no robust prevalence/incidence, penetrance, or natural-history statistics. Evidence is dominated by individual case reports (low on the evidence hierarchy).
Quantitative phenotype frequencies (percentages per HPO term) are not firmly established due to small N.
Heterozygous hypomorphic form is newly described (2026); its full penetrance, spectrum, and population frequency are unknown.
Genotype–phenotype correlation (null vs. hypomorphic) is suggested but not systematically quantified.
No approved DOCK2-directed therapy beyond HSCT and off-label IFN-α; gene therapy is untested in humans.
Non-hematopoietic (fibroblast/interferon) contribution to human disease severity vs. hematopoietic defects is not fully partitioned.
Epidemiology outside MENA/founder populations is essentially uncharacterized.

Proposed Follow-up Experiments / Actions

International DOCK2 registry to quantify prevalence, phenotype frequencies, genotype–phenotype correlations, and HSCT outcomes with standardized HPO annotation.
Prospective IFN-α adjunct trial for viral complications (warts, herpesvirus, respiratory viruses), building on the fibroblast-rescue mechanism and the single-patient wart resolution.
Gene-correction proof-of-concept: autologous HSC lentiviral/CRISPR correction of DOCK2, leveraging demonstrated WT re-expression rescue in vitro.
Systematic functional classification of DOCK2 VUS (protein expression, ELMO1 binding, Rac1-GTP, TLR signaling) to support ACMG interpretation, especially for heterozygous ELMO1-domain variants.
Newborn TREC-screening follow-through: define the DOCK2 detection rate and time-to-HSCT benefit within existing SCID screening programs.
Structure-guided small molecules that stabilize the DOCK2/ELMO1 open (active) conformation for hypomorphic alleles — an alternative to transplant.
Cell-type dissection (conditional Dock2 knockouts; patient iPSC-derived fibroblasts/immune cells) to quantify hematopoietic vs. non-hematopoietic interferon contributions to antiviral defense.

Report compiled from 14 confirmed findings and 25 reviewed papers across 5 investigation iterations. All mechanistic and clinical claims are cited to primary literature (PMID). Ontology suggestions (HPO, GO, CL, UBERON, NCIT, MONDO, OMIM, HGNC, UniProt) are provided throughout for knowledge-base ingestion.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	19
Resolved	19
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	19
On topic	12
Off topic	0

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Classifications

Inheritance

Subtypes

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

External Assertions

Medical Actions

Diagnosis

Prevalence

Animal Models

Source YAML

References & Deep Research

Deep Research

DOCK2 Deficiency — Comprehensive Disease Characterization

Summary

Section 1 — Disease Information

Section 2 — Etiology

Section 3 — Phenotypes

Section 4 — Genetic / Molecular Information

Section 5 — Environmental Information

Section 6 — Mechanism / Pathophysiology

Ordered causal chain

Molecular / cellular detail

Section 7 — Anatomical Structures Affected

Section 8 — Temporal Development

Section 9 — Inheritance and Population

Section 10 — Diagnostics

Section 11 — Outcome / Prognosis

Section 12 — Treatment

Section 13 — Prevention

Section 14 — Other Species / Natural Disease

Section 15 — Model Organisms

Key Findings (Expanded)

Mechanistic Model / Interpretation

Evidence Base

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Artifacts

Reference Validation