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Classifications

IUIS Category

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Inheritance

1

Autosomal recessive inheritance HP:0000007

Biallelic CD3G variants. Almost all reported patients are homozygous, and parental consanguinity is common; two siblings from one non-consanguineous Spanish family were compound heterozygous.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:42661620 SUPPORT Human Clinical

"CD3γ deficiency is an ultrarare autosomal recessive inborn error of immunity characterized by immune dysregulation and variable immunodeficiency."

States the autosomal recessive mode of inheritance and the defining combination of immune dysregulation with variable immunodeficiency.

PMID:42661620 SUPPORT Human Clinical

"Variants were homozygous in all but two reported cases"

Records that the biallelic variants are homozygous in nearly every reported family.

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Discussions and Knowledge Gaps

9

Which developmental and receptor-composition differences explain retained human T cells, and how faithfully do these systems reproduce human tolerance defects?

HUMAN MODEL MISMATCH OPEN mismatch_cd3g_mouse_vs_human

Attached to

pathophysiology#Distorted Thymic Selection and Self-Reactive Repertoire pathophysiology#Impaired TCR/CD3 Complex Assembly and Surface Expression

Cd3g-null mice retain only 2–5% of normal peripheral T cells. Human CD3delta rescues gamma-delta development in double-deficient mice, but this does not reconstruct the human alpha-beta/Treg pathway. Mature Jurkat knockdown and congenital patient-derived cells also differ; the immature-organ-culture perturbation in the 2021 study was CD3D. None of these observations proves that autoimmunity is absent from every model or that no model can study it.

Show evidence (2 references)

PMID:9524111 SUPPORT Model Organism

"Peripheral lymphoid organs are also practically devoid of T cells, with absolute numbers of peripheral T cells reduced to only 2-5% of those in normal mice."

The model retains a small peripheral population; the result must not be described as complete absence.

PMID:17923503 SUPPORT Model Organism

"A human, but not a mouse, CD3delta transgene rescues gammadelta T cell development in mice lacking both mouse CD3delta and CD3gamma chains."

The perturbation demonstrates lineage-specific structural compensation in a mouse model; it does not by itself resolve human alpha-beta/Treg biology.

Which modifiers account for different clinical courses among relatives sharing a CD3G variant?

KNOWLEDGE GAP OPEN gap_cd3g_genotype_phenotype

Attached to

genetic#CD3G pathophysiology#Multisystem Autoimmunity

Identical variants accompany divergent infection and autoimmune outcomes. Demonstrated protein loss for particular alleles shows that residual CD3gamma is not required for all retained human T-cell development; it does not exclude allele-specific effects across the whole spectrum. Preserved Taiwanese Treg function and variable age/stimulus-dependent proliferation are correlates, not validated prognostic rules.

Show evidence (2 references)

PMID:42661620 SUPPORT Human Clinical

"Notably, patients carrying identical deleterious variants exhibited substantial variability in clinical presentation and outcomes, indicating that no obvious genotype-phenotype correlation could be established based on the currently available data."

States the absence of a genotype-phenotype correlation.

PMID:31921117 SUPPORT In Vitro

"Treg cells isolated from the CD3 γ Del 213A T cells of the patient were able to suﬃciently suppress the proliferation of Teﬀ cells upon stimulation"

The Taiwanese adult retained suppression in the reported coculture conditions, qualifying universal Treg-dysfunction claims.

How should overlapping case counts and contradictions between primary reports and later summary tables be interpreted?

INTERPRETATION OPEN interpretation_cd3g_cohorts

Attached to

phenotypes#Autoimmune thyroiditis phenotypes#Decreased circulating immunoglobulin concentration phenotypes#Impaired PHA-induced T-cell proliferation

The 2026 18-patient aggregation overlaps the 2014 families, 2018 mechanistic cohort and detailed later case reports. It is not an independent prevalence sample. Its 9/18 antibody category combines hypo- and dysgammaglobulinemia, and its 11/11 mitogen category is not PHA-specific. The detailed 2021 child had homozygous c.1A>G and died after transplantation; the later table assigns a different variant/alive status to that report. Normal Taiwanese IgG measurements were during replacement. The earlier 2007 sibling VI3 was presumed affected rather than molecularly tested. Frequencies therefore retain reported-series scope and detailed primary narratives take precedence for patient facts.

Show evidence (2 references)

PMID:31921117 SUPPORT Human Clinical

"this was compatible with hypogammaglobulinemia, but normal PHA-lymphocyte proliferation."

The Taiwanese patient is an explicitly scoped exception to universal PHA impairment, not a disease-level absence annotation.

PMID:42661620 SUPPORT Human Clinical

"To date, only 16 predominantly pediatric cases have been reported. Here, we describe two additional adult patients with CD3γ deficiency and provide a comprehensive reevaluation of all previously published cases."

The authors give the literature count and two new cases; this provides no population denominator.

Which additional 2014 patient findings and proposed atopy mechanism can be encoded after the primary full text becomes available through the prescribed reference fetcher?

CURATION TODO OPEN access_cd3g_2014_fulltext

Attached to

phenotypes#Atopic dermatitis phenotypes#Increased circulating IgE concentration phenotypes#Asthma

The Wiley full text was readable for context but the prescribed full-page/PDF fetches returned access errors; the PMID cache contains the abstract. The authors propose immune dysregulation/Th2 involvement in atopy without assaying Th2 cells. That source-established provisional route is not called a biological gap merely because an exact cached quotation is unavailable. The primary abstract supports high IgE and eczema in 2/5. Additional body-only findings and table contradictions are recorded in notes pending cache access.

Show evidence (1 reference)

PMID:24910257 SUPPORT Human Clinical

"We found all five patients to display autoimmunity: autoimmune thyroiditis (n = 5), autoimmune haemolytic anaemia (n = 2), immune thrombocytopenia (n = 1), autoimmune hepatitis (n = 1), minimal change nephrotic syndrome (n = 1), vitiligo (n = 1) and positive antinuclear antibodies (n = 3) as..."

The frequency recorded here is the atopic-eczema count of 2 out of the 5 patients in the series.

What accounts for short stature in the reported autoimmune family?

KNOWLEDGE GAP OPEN gap_cd3g_growth

Attached to

phenotypes#Short stature

The case observation does not distinguish nutrition, thyroid disease, chronic inflammation or treatment effects. A specific CD3G-to-growth route is not established in the reviewed sources; this differs from the explicitly linked enteropathy-to-failure-to-thrive course.

Show evidence (1 reference)

PMID:42661620 SUPPORT Human Clinical

"8 F5-2/Turkey f 20 y NM_000073.3:c.80-1G>C (p.)? Hom Hashimoto thyroiditis, AIHA, short stature"

The 2026 case table explicitly lists short stature for F5-2; the observation does not establish a growth mechanism.

How are alopecia areata and psoriasis related to the measured tolerance defects in these particular patients?

KNOWLEDGE GAP OPEN gap_cd3g_skin

Attached to

phenotypes#Alopecia areata phenotypes#Psoriasis

The reports list these clinical diagnoses but do not establish their CD3G-specific effectors or directly attribute them to the studied Treg/repertoire changes. Their relation to atopy is also unresolved; these observations are retained without a fabricated causal edge.

Show evidence (2 references)

PMID:42661620 SUPPORT Human Clinical

"17 F12-1/Bulgaria f 50 y NM_000073.3:c.213dup (p. Trp72Metfs*6) Hom Hashimoto thyroiditis, lymphadenopathy, AIHA, ITP, alopecia areata/steroids, RTX, SCIG"

The visually verified P1 row lists alopecia areata; the patient identifier preserves the table attribution.

PMID:42661620 SUPPORT Human Clinical

"15 F10-1/Turkey m >30 y NM_000073.3:c.205A>T (p.Lys69Ter) Hom severe varicella infection, respiratory infections, psoriasis, asthma"

The visually verified F10-1 row records psoriasis separately from asthma and infection.

What drives the adult patient's reactive generalized lymphadenopathy?

KNOWLEDGE GAP OPEN gap_cd3g_reactive_nodes

Attached to

phenotypes#Lymphadenopathy

Repeated biopsies excluded malignancy and identified reactive hyperplasia. Infection, immune dysregulation and their interaction remain possible contributors; regression during immunoglobulin treatment does not isolate one mechanism.

Show evidence (1 reference)

PMID:42661620 SUPPORT Human Clinical

"Histopathological examination consistently demonstrated reactive lymphoid hyperpla- sia without evidence of lymphoma or other malignancy."

Repeated biopsies distinguished the nodal enlargement from lymphoma.

Is the suspected hepatic remodeling caused by CD3G-associated immune dysfunction, and what is its histological substrate?

KNOWLEDGE GAP OPEN gap_cd3g_hepatic_attribution

Attached to

pathophysiology#Suspected Nodular Regenerative Hepatic Remodeling

The local proposed hepatic-to-portal/splenic route is represented, but biopsy was declined and a steroid trial for possible autoimmune hepatitis failed. These facts do not establish a CD3G-to-NRH mechanism or confirm autoimmune hepatitis in the Taiwanese adult.

Show evidence (1 reference)

PMID:31921117 SUPPORT Human Clinical

"he was unwilling to undergo a liver biopsy for pathological proof."

The proposed hepatic substrate was not biopsy-confirmed.

Does CD3G deficiency contribute to gastric MALT lymphoma risk beyond the local H. pylori-associated process?

KNOWLEDGE GAP OPEN gap_cd3g_malt_attribution

Attached to

pathophysiology#Helicobacter pylori-Associated Gastric Disease phenotypes#Gastric MALT lymphoma

A single patient had an H. pylori-associated lymphoma that remitted after eradication. The local contribution is represented, but a syndrome-wide tumor predisposition or upstream CD3G effect is not established.

Show evidence (1 reference)

PMID:42661620 SUPPORT Human Clinical

"At 22 years of age, she was diagnosed with Helicobacter pylori -associated gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Eradication therapy resulted in complete remission."

The lymphoma and eradication response are patient observations; HPO gastric lymphoma is broader than the source's MALT subtype.

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Pathophysiology

15

Biallelic CD3G Loss-of-Function Variants

Biallelic CD3G variants impair the CD3gamma subunit of the TCR/CD3 complex. Complete transcript and protein loss was demonstrated for homozygous c.1A>G in cultured blasts from one child; PBMC protein loss was also shown in the two adults reported in 2026. These results establish that human T-cell development can persist without detectable CD3gamma; they do not establish identical residual function for every reported allele. The original Spanish siblings were compound heterozygotes, not homozygotes for the initiation-codon variant.

CD3G hgnc:1675

Downstream

Impaired TCR/CD3 Complex Assembly and Surface Expression Loss of CD3gamma compromises receptor assembly and surface abundance, with residual expression varying by cellular context.

Impaired T-Cell Help for Memory B-Cell Maturation The Taiwanese report attributes a diminished CD40L response and memory-B-cell defect to CD3G deficiency, but the intervening route is unresolved.

Show evidence (2 references)

PMID:42661620 SUPPORT Human Clinical

"Pathogenic variants included splice-site, nonsense, and frameshift mutations predicted to result in loss of function"

Describes the class of CD3G alleles reported across the literature.

PMID:33215322 SUPPORT In Vitro

"Together, these results demonstrate biallelic CD3G c.1 A > G mutation results in the complete loss of CD3G mRNA transcripts and CD3γ protein translation."

Establishes, in patient-derived T-cell blasts, that a reported allele is a true null rather than a hypomorph.

Impaired TCR/CD3 Complex Assembly and Surface Expression

CD3gamma deficiency lowers, without invariably abolishing, surface TCR/CD3 expression in human T cells. CD3G-knockdown Jurkat cells show unstable partial receptor ensembles, ER retention and deficient zeta-dimer incorporation, but their profound receptor loss does not quantitatively reproduce patient cells. Patient-cell reconstitution supports a role for CD3gamma in surface expression; the precise assembly/export constraints depend on the cellular system. Human gamma-delta receptors can incorporate CD3delta, providing a supported explanation for partial compensation in that lineage.

mature alpha-beta T cell CL:0000791

alpha-beta T cell receptor complex GO:0042105

Experimental models

CD3G-knockdown human Jurkat T cells and the CD3gamma-negative JGN line CELL LINE Jurkat knockdown measures receptor assembly, ER retention and low surface export. In JGN, the CD3gamma extracellular domain is required for rescue, whereas patient-derived T-cell rescue differs. Domain requirements are therefore interpreted within each cellular system.

Animal models

Cd3g-deficient mouse Mouse partially recapitulates The mouse does reproduce the receptor-expression defect: surface TCR and CD3epsilon are severely reduced on thymocytes and peripheral T cells.

Downstream

Attenuated T-Cell Receptor Signaling Reduced and altered receptor complexes change signaling strength; signaling is attenuated selectively rather than uniformly abolished.

Show evidence (2 references)

PMID:42661620 SUPPORT Human Clinical

"Western blot analysis of PBMC-derived protein demonstrated complete absence of CD3 g expression, while ﬂow cytometry revealed reduced expression of the TCR/CD3 complex, conﬁrming the diagnosis of CD3 g deﬁciency (Figures 1B– D)."

Patient P1 had absent protein and reduced receptor expression measured directly in PBMCs.

PMID:34249896 SUPPORT In Vitro

"However, both defective TCR ensembles were strongly retained in the ER, lacked ζζ/CD2472, and barely reached the T-cell surface (<11% of normal controls) in any of the CD3 KD cells."

The assembly/export defect was measured in engineered Jurkat knockdowns; the paper separately documents a milder defect in patient-derived cells.

Attenuated T-Cell Receptor Signaling

Reduced and structurally altered TCR/CD3 complexes change signaling in a response-dependent manner. Cultured patient-derived lines retain several proximal responses but have altered adhesion/polarization and increased activation-induced death. In reconstituted JGN cells, removal of the CD3gamma intracellular domain impaired IL-2/TNF-alpha production while preserving proximal phosphorylation and CD69 induction. These model findings do not establish global absence of T-cell activation in patients; PHA and anti-CD3/CD28 responses can be preserved in particular patients or assay conditions.

T cell receptor signaling pathway GO:0050852 ↓ DECREASED

Experimental models

CD3G-knockdown human Jurkat T cells and the CD3gamma-negative JGN line CELL LINE Reconstituting the CD3gamma-negative JGN line with chimeric CD3gamma/CD3delta constructs measures which signalling outputs require which CD3gamma domain.

Downstream

Distorted Thymic Selection and Self-Reactive Repertoire The proposed signaling-strength model alters thymic selection and CD4-cell fate.

Regulatory T-Cell Deficiency and Impaired Suppression TCR-dependent Treg development and maintenance provide a proposed route to reduced Treg number, diversity and function.

Impaired T-Cell Proliferative Response Altered TCR signaling contributes to stimulus-dependent impairment of cell division.

Reduced Thymic Output and Altered T-Cell Homeostasis The authors' signaling-strength model alters T-cell development and homeostasis, compatible with reduced output markers despite retained peripheral T cells.

Show evidence (2 references)

PMID:12407027 SUPPORT In Vitro

"In contrast, other physiological responses like the specific adhesion and concomitant cell polarization on ICAM-1-coated dishes were selectively defective, and activation-induced cell death was increased."

Patient-derived mature T-cell lines had selective functional defects, despite largely preserved proximal responses.

PMID:36119034 SUPPORT In Vitro

"In contrast to cytokine synthesis, CD69 expression and TCR internalization after TCR engagement were normal for all constructs including γγ-, which scored highest for CD69 induction, indicating that it was capable of some functional signal transduction."

The full Results qualify the abstract: the intracellular-domain-truncated construct retained CD69 induction; cytokine secretion and CD69 cannot be bundled as uniformly reduced.

Distorted Thymic Selection and Self-Reactive Repertoire

Reduced TCR signaling is proposed to alter thymic selection and the fate of self-reactive CD4 cells. Peripheral repertoire sequencing in six patients with autoimmunity found reduced Treg repertoire diversity and a hydrophobic CDR3 signature associated with self-reactivity in conventional CD4 cells. This is a molecular surrogate and a mechanistic interpretation, not direct observation of failed negative selection or demonstration of each clone's autoantigen specificity. The same self-reactivity signature was not found in CD8 cells.

thymocyte CL:0000893

thymic T cell selection GO:0045061 ↓ DECREASED

Animal models

Cd3g-deficient mouse Mouse fails to recapitulate The profound mouse developmental bottleneck does not reproduce the preserved, variably skewed peripheral repertoire studied in human autoimmune cohorts. The cited experiments do not directly establish fidelity for human Treg dysfunction or clinical autoimmunity.

Downstream

Multisystem Autoimmunity The inferred escape of self-reactive conventional CD4 cells can contribute to loss of tolerance; repertoire hydrophobicity is a surrogate, not direct antigen-specific proof.

Show evidence (1 reference)

PMID:29653965 SUPPORT Human Clinical

"The TRB repertoire of Tconv cells from patients with CD3G deficiency was enriched for hydrophobic amino acids at positions 6 and 7 of the CDR3, a biomarker of self-reactivity."

Peripheral repertoire sequencing found enrichment of hydrophobic CDR3 residues associated with self-reactivity; this surrogate does not directly demonstrate clone-specific autoantigen recognition or thymic negative-selection failure.

Regulatory T-Cell Deficiency and Impaired Suppression

In the 2018 autoimmune cohort, circulating Treg proportions and repertoire diversity were reduced; suppression was tested in four patients and was impaired. Reduced TCR signaling may affect Treg selection, maintenance and suppressive function, but the relative contribution of these processes remains unresolved. A Taiwanese adult had preserved Treg proportion and suppressive activity with no recognized autoimmunity. Treg deficiency is therefore an important variable mechanism, not a universal requirement for CD3G-associated disease.

regulatory T cell CL:0000815

regulatory T cell differentiation GO:0045066 ↓ DECREASED

Downstream

Multisystem Autoimmunity Reduced Treg diversity and suppressive control can permit autoreactive-cell expansion in the affected autoimmune cohorts.

Show evidence (3 references)

url:https://www.ucm.es/data/cont/docs/1572-2019-04-22-Blood%202018.pdf SUPPORT Human Clinical

"Among CD41 Tc e l l s ,t h e proportion of CD25hi FOXP31 Treg cells was signiﬁcantly lower in CD3G-mutated patients than in con trols."

Direct flow-cytometric observation in the 2018 cohort selected for CD3G mutations and autoimmunity.

url:https://www.ucm.es/data/cont/docs/1572-2019-04-22-Blood%202018.pdf SUPPORT In Vitro

"By contrast, T reg cells from CD3G-mutated patients completely failed to suppress proliferation of control Teff cells up to a 1:2 Treg: Teff cell ratio; reduced suppressive activity was also detected at a 1:1 Treg:Tconv ratio (Figure 4B-C)."

Suppression cocultures used Tregs from four patients P2–P5; the assay does not imply that all six patients underwent functional testing.

PMID:31921117 SUPPORT In Vitro

"Treg cells isolated from the CD3 γ Del 213A T cells of the patient were able to suﬃciently suppress the proliferation of Teﬀ cells upon stimulation"

The Taiwanese adult retained suppression in the reported coculture conditions, qualifying universal Treg-dysfunction claims.

Impaired T-Cell Proliferative Response

Mitogen-driven T-cell division is impaired in several CD3G cohorts, consistent with altered receptor signaling. The response depends on stimulus, cell subset, age and assay: anti-CD3 plus CD28 restored near-control responses in the 2018 study, and the Taiwanese patient had normal PHA responses despite reduced ConA incorporation. The 2026 count of 11/11 abnormal responses to at least one mitogen does not establish universal impairment of PHA-induced transformation or predict clinical severity.

T cell proliferation GO:0042098 ↓ DECREASED

Downstream

Defective Adaptive Host Defense Deficient cellular immune responses can compromise pathogen control, while assay and patient heterogeneity preclude a deterministic severity rule.

Show evidence (2 references)

url:https://www.ucm.es/data/cont/docs/1572-2019-04-22-Blood%202018.pdf SUPPORT In Vitro

"When stimulated with phytohema gglutinin (PHA), both CD4 1 and CD81 T cells in CD3g-deﬁcient patients demonstrated reduced cellular division (as shown by CFSE dilution);"

The six-patient study measured reduced division after PHA stimulation.

url:https://www.ucm.es/data/cont/docs/1572-2019-04-22-Blood%202018.pdf SUPPORT In Vitro

"Stimulation with both anti-CD3 and anti-CD28 resulted in overall equivalent activation, proliferation, and cell division in both CD4 1 and CD81 T cells from patients and controls (Figure 2A-D)."

Costimulation preserved responses in the tested patients; this constrains a global proliferation-failure model.

Humoral Immune Failure

Humoral impairment ranges from profound low immunoglobulins and deficient vaccine responses to normal or elevated concentrations. Reduced switched-memory B cells and diminished CD40L induction in a Taiwanese patient suggest impaired T-cell help as one contributor; intrinsic B-cell dysfunction was not demonstrated by rescue or Tfh/B-cell coculture. Nephrotic protein loss, glucocorticoids and immunoglobulin replacement can also influence measured concentrations. The 2026 9/18 hypo-/dysgammaglobulinemia aggregate cannot be assigned to low total IgG alone.

immunoglobulin production GO:0002377 ↓ DECREASED

Downstream

Defective Adaptive Host Defense Insufficient antibody-mediated protection contributes to bacterial respiratory infection in patients with hypogammaglobulinemia, including the Taiwanese adult with preserved PHA responses.

Show evidence (2 references)

PMID:33215322 SUPPORT Human Clinical

"Reduced numbers of switched and unswitched memory B cells, hypogammaglobulinemia (IgG 338 mg/dL), and impaired vaccination response to Haemophilus influenzae type B and Pneumococcus were also present (Table 1)."

The child had several directly documented humoral defects before replacement therapy.

PMID:31921117 SUPPORT INDIRECT Other

"This may have been associated with insuﬃcient CD40L expression, which has been reported in some patients with CVID and hyper IgM"

The authors propose insufficient T-cell help as a contributor to the Taiwanese patient's memory-B-cell abnormality; they did not establish an intrinsic B-cell lesion.

Multisystem Autoimmunity

Defective central and peripheral tolerance can permit autoreactive T-cell activity and autoantibody-associated tissue injury. The 2018 repertoire/suppression study proposes this mechanism for the patients' autoimmunity, rather than directly demonstrating every organ-specific effector pathway. Thyroid disease, autoimmune cytopenias, enteropathy, hepatitis, vitiligo and a lupus-like presentation occur variably. The absence of autoimmunity in a patient with preserved Treg function is a scope constraint, not evidence that autoimmunity is absent from the disorder.

Downstream

Immune-Mediated Gastrointestinal Mucosal Injury Loss of immune tolerance can mediate intestinal injury in the patient with biopsy-supported autoimmune enteropathy.

Autoimmune thyroiditis Impaired tolerance permits autoimmune thyroid inflammation in selected patients. Antithyroid antibodies and variable thyroid functional states support an organ-specific autoimmune process; the precise T-cell/B-cell effectors are not resolved.

Autoimmune hemolytic anemia Loss of immune tolerance contributes to antibody-associated erythrocyte destruction in reported AIHA cases. Rituximab-responsive Evans syndrome supports a B-cell contribution, without identifying the initiating autoreactive clone.

Autoimmune thrombocytopenia Tolerance failure permits immune-mediated platelet loss in reported ITP/Evans syndrome. The receptor/Treg model is an upstream explanation; the relative platelet-clearance and production mechanisms were not established.

Autoimmune hepatitis The tolerance-defect model provides a qualified contribution to the explicitly diagnosed autoimmune hepatitis in the Turkish series. This is separate from the unconfirmed hepatic diagnosis in the Taiwanese adult.

Vitiligo Defective immune tolerance offers a proposed contribution to the reported autoimmune depigmentation. The CD3G studies do not directly measure melanocyte-specific effector cells or explain why only some patients develop vitiligo.

Minimal change glomerulonephritis The primary authors classify the single minimal-change nephrotic presentation among autoimmune manifestations. The tolerance model is a qualified upstream contribution; no particular podocyte-targeting antibody or T-cell mediator was established.

Lupus-like systemic autoimmunity The 2024 authors attribute a lupus-like syndrome meeting SLICC criteria to CD3G deficiency. The tolerance model provides an indirect explanation, while organ-specific immune mechanisms remain unresolved.

Hypothyroidism Autoimmune thyroid disease can produce hypothyroidism in the reported patients; euthyroid thyroiditis and the opposite functional state also occur.

Hyperthyroidism Autoimmune thyroid disease can produce hyperthyroidism in the reported patients; euthyroid thyroiditis and the opposite functional state also occur.

Interstitial lung disease Immune dysregulation contributed to the 2021 child's interstitial lung disease as suggested by partial improvement during immunosuppression. EBER-positive infiltrates and bacterial infection make this a mixed, incompletely resolved attribution.

Show evidence (1 reference)

url:https://www.ucm.es/data/cont/docs/1572-2019-04-22-Blood%202018.pdf SUPPORT INDIRECT Other

"Ultimately, this results in enrichment for self-reactive speciﬁ cities within CD4 1 Tconv cells, which may undergo peripheral activation and expansion because of the reduced number and impaired function of T reg cells. Alto- gether, these abnormalities create an environment that promotes the..."

The authors' integrated model links altered selection and Treg control to autoimmunity; organ-specific effectors and penetrance remain incompletely resolved.

Defective Adaptive Host Defense

Impaired T-cell effector responses and, in some patients, antibody deficiency reduce adaptive control of infection. Clinical expression ranges from recurrent sinopulmonary bacterial infections to severe viral, fungal and intestinal infections. Preserved PHA responses and Treg function in the Taiwanese adult coexist with humoral failure and recurrent respiratory infection. Neither a single proliferation assay nor surface receptor intensity is a validated predictor of infection severity.

Downstream

Chronic Infection-Associated Airway Injury Repeated respiratory infection contributes to structural airway injury in reported patients.

Recurrent respiratory infections Deficient adaptive pathogen control contributes to recurrent respiratory infections in the reported infection-prone patients; exposure, treatment and residual function modify the outcome.

Recurrent oral thrush Deficient adaptive pathogen control contributes to recurrent oral thrush in the reported infection-prone patients; exposure, treatment and residual function modify the outcome.

Severe Epstein-Barr virus infection Deficient adaptive pathogen control contributes to severe epstein-barr virus infection in the reported infection-prone patients; exposure, treatment and residual function modify the outcome.

Mastoiditis Recurrent sinopulmonary infection led to mastoiditis in the Taiwanese adult, representing a local infectious complication.

Pleural effusion Recurrent sinopulmonary infection led to pleural effusion in the Taiwanese adult, representing a local infectious complication.

Severe varicella infection Impaired cellular host defense provides a qualified contribution to severe varicella in the reported patients; viral exposure and residual function are not resolved by the clinical table.

Show evidence (2 references)

PMID:31921117 SUPPORT INDIRECT Other

"Patients with opportunistic infections, including parainﬂuenza pneumonia, Candida albicans , Giardia intestinalis, and severe EBV infection, reﬂect profoundly impaired lymphocyte proliferation"

The authors relate opportunistic infection to impaired cellular immunity, based on reported cases rather than a prospective causal experiment.

PMID:39094808 SUPPORT INDIRECT Other

"CD3G gene encodes one of the CD3 subunits named CD3γ, and its deficiency can cause autoimmune disorders, immunodeficiency and recurrent infections."

The clinical report summarizes the causal association between CD3G deficiency and impaired host defense.

Chronic Infection-Associated Airway Injury

Repeated sinopulmonary infection can produce structural airway damage and bronchiectasis. The Taiwanese case explicitly describes bronchiectasis as a complication of recurrent infections and later links worsening bronchiectasis to increased pulmonary artery pressure and cor pulmonale. The route is supported within that longitudinal case and is not a claim that every patient develops permanent lung disease.

Downstream

Bronchiectasis Cumulative infection-associated airway injury produces permanent airway dilatation in the reported respiratory disease cases.

Finger clubbing The Taiwanese authors attribute finger clubbing to chronic endobronchial disease. This case-level causal interpretation is not extrapolated to all patients.

Obstructive sleep apnea The Taiwanese authors attribute obstructive sleep apnea to chronic endobronchial disease. This case-level causal interpretation is not extrapolated to all patients.

Exertional tachypnea The Taiwanese authors attribute exertional tachypnea to chronic endobronchial disease. This case-level causal interpretation is not extrapolated to all patients.

Pulmonary hypertension Worsening bronchiectasis was reported to raise pulmonary artery pressure and progress to cor pulmonale in the Taiwanese patient; this is a case-specific sequence.

Cor pulmonale Worsening bronchiectasis was reported to raise pulmonary artery pressure and progress to cor pulmonale in the Taiwanese patient; this is a case-specific sequence.

Show evidence (1 reference)

PMID:31921117 SUPPORT Human Clinical

"He experienced recurrent sinopulmonary infections that were complicated by mastoiditis, pleural eﬀusion, and bronchiecta sis (Supplemental Figure 1A) and required hospitalization from the age of 14-years."

The longitudinal case attributes these pulmonary/ENT complications to recurrent infection.

Impaired T-Cell Help for Memory B-Cell Maturation

In the Taiwanese adult, stimulated CD4 cells expressed about half the control CD40L level and class-switched memory B cells were reduced. The authors propose insufficient CD40L-dependent help as a contributor to B-cell maturation failure. CD40L was measured after PMA/ionomycin, not direct TCR triggering; the CD3G-to-CD40L route and its prevalence remain unresolved, and the proposed Tfh/B-cell coculture was not performed.

Downstream

Humoral Immune Failure Reduced CD40L-dependent T-cell help is a proposed contributor to deficient memory-B-cell maturation and humoral responses in the Taiwanese patient.

Show evidence (1 reference)

PMID:31921117 SUPPORT In Vitro

"The CD40L expression of activated CD4 + in the patient was around half that of the healthy control, while CD69 expression was used as an a ctivation marker after stimulation with 10 ng/mL PMA and 1 ug/m L ionomycin for 5 h. T wo duplicates were performed."

Stimulated patient-cell measurement; it does not directly test TCR-dependent induction or rescue of B-cell maturation.

Immune-Mediated Gastrointestinal Mucosal Injury

Autoimmune enteropathy with anti-enterocyte reactivity was demonstrated in the 2021 child, together with chronic active gastritis and colitis. Persistent gastrointestinal mucosal injury can account for diarrhea and nutritional failure; improvement during immunosuppression and in another patient after HSCT supports an immune contribution. The gastric contribution is inferred from the overall inflammatory presentation rather than a demonstrated stomach-specific effector. This mechanism is not assigned to every infectious or unclassified episode of diarrhea.

Downstream

Protracted diarrhea Biopsy-supported autoimmune enteropathy provides a local cause of persistent diarrhea in the 2021 child, with improvement during combined immunosuppression; infection-associated diarrhea in other cases is not assigned this route.

Failure to thrive The 2021 clinical course explicitly links worsening gastrointestinal disease to growth failure and parenteral nutrition; improvement of diarrhea and weight during immunosuppression supports this case-scoped sequence.

Chronic colitis Anti-enterocyte reactivity and autoimmune enteropathy provide an immune explanation for the associated chronic active colitis in the 2021 child. They do not identify a single pathogenic autoantibody as the proven effector.

Anoperineal fistula The transplant report attributes fistula improvement to improving inflammatory bowel disease, supporting a qualified local inflammatory contribution in that infant.

Chronic gastritis The biopsy-supported autoimmune gastrointestinal presentation provides a qualified immune contribution to accompanying chronic active gastritis; a stomach-specific effector was not isolated.

Show evidence (1 reference)

PMID:33215322 SUPPORT Human Clinical

"Upper and lower endoscopy showed chronic active gastritis and colitis, and biopsies of small intestine and colon were consistent with autoimmune enteropathy. Linear staining along the periapical border of the enterocytes was positive for anti-enterocyte auto-antibodies."

Clinical pathology supports immune-mediated intestinal injury in this child; antibody positivity alone does not establish the entire effector pathway.

Suspected Nodular Regenerative Hepatic Remodeling

The Taiwanese adult had imaging and clinical findings interpreted as nodular regenerative hyperplasia. Liver biopsy was declined. The authors favored a slowly progressive portal-hypertensive pattern after an unsuccessful steroid trial for possible autoimmune hepatitis. The upstream relation to CD3G/humoral deficiency is not established; the local hepatic-to-portal/splenic interpretation remains provisional.

Downstream

Portal hypertension The authors' suspected NRH pattern provides a qualified local explanation for portal hypertension. Unconfirmed histology and unresolved upstream genetic attribution limit this route.

Splenomegaly The authors' suspected NRH pattern provides a qualified local explanation for splenomegaly. Unconfirmed histology and unresolved upstream genetic attribution limit this route.

Show evidence (2 references)

PMID:31921117 SUPPORT INDIRECT Other

"V ascular engorgement of the portal vein, uneven liver surfac e, tortuous splenic artery, splenomegaly, and poor response to steroids were characteristic of NRH classiﬁcation II in our patient with the CD3 γ Del 213A mutation"

The authors interpret a constellation of clinical/imaging findings as a portal-hypertensive NRH pattern, without histological confirmation.

PMID:31921117 SUPPORT Human Clinical

"he was unwilling to undergo a liver biopsy for pathological proof."

The proposed hepatic substrate was not biopsy-confirmed.

Reduced Thymic Output and Altered T-Cell Homeostasis

Human CD3G case studies infer reduced thymic output from low TRECs and naive-cell numbers despite preservation or later accumulation of peripheral polyclonal memory T cells. Absolute CD4/CD8 counts vary, and TCR/CD3-dependent gating can underestimate cells. The relative effects of production, selection, peripheral survival and treatment cannot be separated in every patient.

Show evidence (1 reference)

PMID:17277165 SUPPORT INDIRECT Other

"Thus, the peripheral T lymphocyte pool was comparatively well preserved in human CD3gamma deficiencies despite poor thymus output or clinical outcome."

The human series distinguishes reduced output from a complete developmental block.

Helicobacter pylori-Associated Gastric Disease

Adult P2 developed H. pylori-associated gastric MALT lymphoma, which entered remission after eradication. This treatment response supports a local infectious contribution to the lymphoma; the report does not establish that CD3G deficiency caused the infection or conferred a general lymphoma predisposition.

Downstream

Gastric MALT lymphoma The reported H. pylori association and complete remission following eradication support a case-scoped infectious contribution to gastric MALT lymphoma. The intervening cellular mechanism and upstream CD3G attribution were not demonstrated.

Show evidence (1 reference)

PMID:42661620 SUPPORT Human Clinical

"At 22 years of age, she was diagnosed with Helicobacter pylori -associated gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Eradication therapy resulted in complete remission."

The lymphoma and eradication response are patient observations; HPO gastric lymphoma is broader than the source's MALT subtype.

⬡

Pathograph

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

●

Phenotypes

48

Blood 12

Reduced surface TCR/CD3 expression Abnormal T cell physiology HP:0011840

Show evidence (1 reference)

url:https://www.ucm.es/data/cont/docs/1572-2019-04-22-Blood%202018.pdf SUPPORT Human Clinical

"expression of both CD3 (as indicated by staining with a monoclonal antibody speciﬁcf o rt h eC D 3e chain) and TCRab was markedly reduced in each of these subsets in all patients with CD3G mutations (Figure 1)."

Surface CD3/TCR was assessed in five patients P1–P5 across conventional CD4, regulatory CD4 and CD8 subsets. Normal total T-cell counts are not part of this phenotype definition.

Impaired PHA-induced T-cell proliferation Impaired phytohemagglutinin-induced T lymphocyte transformation HP:0025834

Show evidence (2 references)

url:https://www.ucm.es/data/cont/docs/1572-2019-04-22-Blood%202018.pdf SUPPORT In Vitro

"When stimulated with phytohema gglutinin (PHA), both CD4 1 and CD81 T cells in CD3g-deﬁcient patients demonstrated reduced cellular division (as shown by CFSE dilution);"

The six-patient study measured reduced division after PHA stimulation.

PMID:31921117 SUPPORT Human Clinical

"this was compatible with hypogammaglobulinemia, but normal PHA-lymphocyte proliferation."

The Taiwanese patient is an explicitly scoped exception to universal PHA impairment, not a disease-level absence annotation.

Autoimmune hemolytic anemia 7/18 in the 2026 reported-case aggregation HP:0001890

Show evidence (1 reference)

PMID:42661620 SUPPORT Human Clinical

"The most frequently reported autoimmune manifestations included autoimmune thyroiditis (7/18, 38.9%), AIHA (7/18, 38.9%), and ITP (4/18, 22.2%)"

The frequency recorded here is the 7/18 figure quoted.

Autoimmune thrombocytopenia 4/18 in the 2026 reported-case aggregation HP:0001973

Show evidence (2 references)

PMID:42661620 SUPPORT Human Clinical

"The most frequently reported autoimmune manifestations included autoimmune thyroiditis (7/18, 38.9%), AIHA (7/18, 38.9%), and ITP (4/18, 22.2%)"

The frequency recorded here is the 4/18 figure quoted.

PMID:42661620 SUPPORT Human Clinical

"Both patients presented with humoral immunodeficiency and Evans syndrome responsive to rituximab therapy."

Documents the pairing of immune thrombocytopenia with haemolytic anaemia as Evans syndrome.

Decreased circulating immunoglobulin concentration HP:0004313

Show evidence (2 references)

PMID:33215322 SUPPORT Human Clinical

"Reduced numbers of switched and unswitched memory B cells, hypogammaglobulinemia (IgG 338 mg/dL), and impaired vaccination response to Haemophilus influenzae type B and Pneumococcus were also present (Table 1)."

The child had several directly documented humoral defects before replacement therapy.

PMID:42661620 SUPPORT Human Clinical

"Immunological assessment demonstrated mark- edly reduced serum IgG levels, while IgA and IgM were initially normal (Table 1)."

Adult P1 had a selective initial IgG deficit; other isotypes declined later during glucocorticoid treatment.

Decreased regulatory T cell proportion HP:0020113

Show evidence (1 reference)

PMID:33215322 SUPPORT Human Clinical

"Immunological evaluations revealed a combined immunodeficiency with normal absolute CD3+ T cell numbers, CD4+ T cell lymphopenia (627 cells/μl) with a reduced proportion of naïve T cells and T regulatory cells, increased frequency of memory CD4+, CD8+ cells, and CD45RA+CCR7− CD8+ T cells (TEMRA)."

Records the reduced regulatory T-cell proportion alongside the normal absolute T-cell count.

Increased circulating IgE concentration 2/5 in the 2014 two-family series HP:0003212

Show evidence (1 reference)

PMID:24910257 SUPPORT Human Clinical

"We found all five patients to display autoimmunity: autoimmune thyroiditis (n = 5), autoimmune haemolytic anaemia (n = 2), immune thrombocytopenia (n = 1), autoimmune hepatitis (n = 1), minimal change nephrotic syndrome (n = 1), vitiligo (n = 1) and positive antinuclear antibodies (n = 3) as..."

The frequency recorded here is the high-IgE count of 2 out of the 5 patients in the series.

Decreased CD4 T-cell count Decreased total CD4+ T cell count HP:5210418

Show evidence (1 reference)

url:https://www.ucm.es/data/cont/docs/1572-2019-04-22-Blood%202018.pdf SUPPORT Human Clinical

"a low CD4 1 cell count was observed in P4, and decreased CD8 1 cell counts were detected in P2, P4, and P6."

The six-patient study distinguishes absolute CD4 and CD8 count deficits by patient.

Decreased CD8 T-cell count Decreased total CD8+ T cell count HP:5210426

Show evidence (1 reference)

url:https://www.ucm.es/data/cont/docs/1572-2019-04-22-Blood%202018.pdf SUPPORT Human Clinical

"a low CD4 1 cell count was observed in P4, and decreased CD8 1 cell counts were detected in P2, P4, and P6."

Three specified patients had low absolute CD8 counts, unlike the separate CD4 finding.

Decreased naive CD4 T-cell proportion HP:0410378

Show evidence (2 references)

url:https://www.ucm.es/data/cont/docs/1572-2019-04-22-Blood%202018.pdf SUPPORT Human Clinical

"All patients had a reduced proportion of na ¨ıve T cells and increased percentage of memory CD41 and CD81 cells,"

The six-patient study reported altered naive/memory balance; CD4-specific scope is corroborated in the Taiwanese report.

PMID:31921117 SUPPORT Human Clinical

"a mild decrease in naïve T cells (CD4+CD45RA+ or CD4 +CD45RO-CCR7+; Table 1 and Supplemental Figure 2)."

The explicit CD4 phenotype avoids transferring a mixed T-cell count to a specific subset.

Decreased class-switched memory B-cell proportion HP:0030388

Show evidence (1 reference)

PMID:31921117 SUPPORT Human Clinical

"His CD27 + memory B cells were obviously decreased (6.8%), predominantly in switched CD27 + memory B cells"

The patient's memory-B-cell reduction was predominantly in the switched compartment.

Gastric MALT lymphoma Gastric lymphoma HP:0045038

Show evidence (1 reference)

PMID:42661620 SUPPORT Human Clinical

"At 22 years of age, she was diagnosed with Helicobacter pylori -associated gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Eradication therapy resulted in complete remission."

The lymphoma and eradication response are patient observations; HPO gastric lymphoma is broader than the source's MALT subtype.

Cardiovascular 5

Lymphadenopathy HP:0002716

Show evidence (2 references)

PMID:42661620 SUPPORT Human Clinical

"At 37 years of age, she developed generalized lymphadenopathy accompanied by mild pan- cytopenia."

Generalized nodal enlargement is a direct clinical observation in adult P1.

PMID:42661620 SUPPORT Human Clinical

"Histopathological examination consistently demonstrated reactive lymphoid hyperpla- sia without evidence of lymphoma or other malignancy."

Repeated biopsies distinguished the nodal enlargement from lymphoma.

Portal hypertension HP:0001409

Show evidence (1 reference)

PMID:31921117 SUPPORT Human Clinical

"He was given steroid treatment (1 mg/kg/day) for 2 months in an attempt to alleviate portal vein hypertension, which may hav e been caused by autoimmune hepatitis, but the treatment failed ."

The clinical report documents portal hypertension and an unsuccessful therapeutic hypothesis; it does not confirm autoimmune hepatitis.

Splenomegaly HP:0001744

Show evidence (1 reference)

PMID:31921117 SUPPORT Human Clinical

"an engorged portal vein, splenomegaly, splenic artery, and coarse liver su rface gradually developed"

Imaging and examination showed progressive splenic enlargement in the reported hepatic course.

Pulmonary hypertension Pulmonary arterial hypertension HP:0002092

Show evidence (1 reference)

PMID:31921117 SUPPORT Human Clinical

"Exacerbation of his bronchiectasis increased his pulmonary artery pressure, reopened a closed atrial septal defect, and gradually progressed to cor pulmonale."

The Taiwanese report explicitly describes a longitudinal airway-to-pulmonary-pressure-to-right-heart sequence; this is one clinical attribution.

Cor pulmonale HP:0001648

Show evidence (1 reference)

PMID:31921117 SUPPORT Human Clinical

"Exacerbation of his bronchiectasis increased his pulmonary artery pressure, reopened a closed atrial septal defect, and gradually progressed to cor pulmonale."

The Taiwanese report explicitly describes a longitudinal airway-to-pulmonary-pressure-to-right-heart sequence; this is one clinical attribution.

Digestive 5

Protracted diarrhea HP:0004385

Show evidence (1 reference)

PMID:18482219 SUPPORT Human Clinical

"The patient had suffered from intractable diarrhea, recurrent pulmonary infections and oral moniliasis since two months of age."

Documents intractable diarrhoea from early infancy in a CD3gamma-deficient patient.

Autoimmune hepatitis HP:5210421

Show evidence (1 reference)

PMID:24910257 SUPPORT Human Clinical

"We found all five patients to display autoimmunity: autoimmune thyroiditis (n = 5), autoimmune haemolytic anaemia (n = 2), immune thrombocytopenia (n = 1), autoimmune hepatitis (n = 1), minimal change nephrotic syndrome (n = 1), vitiligo (n = 1) and positive antinuclear antibodies (n = 3) as..."

The primary series assigns autoimmune hepatitis to one of five patients, not both siblings collectively.

Chronic colitis HP:0100281

Show evidence (1 reference)

PMID:33215322 SUPPORT Human Clinical

"Upper and lower endoscopy showed chronic active gastritis and colitis, and biopsies of small intestine and colon were consistent with autoimmune enteropathy."

The detailed patient report directly documents chronic colitis and the broader autoimmune enteropathy.

Anoperineal fistula HP:0005218

Show evidence (1 reference)

PMID:18482219 SUPPORT Human Clinical

"A significant improvement in diarrhea, perianal lesions, and rectal fistula was observed suggesting an improvement in inflammatory bowel disease."

The transplant report links improvement of the fistula to improvement of inflammatory bowel disease.

Chronic gastritis HP:0005231

Show evidence (1 reference)

PMID:33215322 SUPPORT Human Clinical

"Upper and lower endoscopy showed chronic active gastritis and colitis, and biopsies of small intestine and colon were consistent with autoimmune enteropathy."

The detailed patient report directly documents chronic active gastritis at endoscopy, alongside colitis and biopsy-supported autoimmune enteropathy.

Endocrine 3

Autoimmune thyroiditis 7/18 in the 2026 reported-case aggregation HP:0100646

Show evidence (2 references)

PMID:42661620 SUPPORT Human Clinical

"The most frequently reported autoimmune manifestations included autoimmune thyroiditis (7/18, 38.9%), AIHA (7/18, 38.9%), and ITP (4/18, 22.2%)"

The published aggregate covers autoimmune thyroiditis broadly, rather than a Hashimoto-only numerator; these are selected reported cases.

PMID:24910257 SUPPORT Human Clinical

"We found all five patients to display autoimmunity: autoimmune thyroiditis (n = 5), autoimmune haemolytic anaemia (n = 2), immune thrombocytopenia (n = 1), autoimmune hepatitis (n = 1), minimal change nephrotic syndrome (n = 1), vitiligo (n = 1) and positive antinuclear antibodies (n = 3) as..."

Autoimmune thyroiditis in all five patients of a two-family series.

Hypothyroidism HP:0000821

Show evidence (1 reference)

PMID:42661620 SUPPORT Human Clinical

"Until the age of 37 years, her medical history was unremarkable except for hypothy- roidism secondary to Hashimoto thyroiditis."

Adult P1's hypothyroidism is explicitly attributed to Hashimoto disease.

Hyperthyroidism HP:0000836

Show evidence (1 reference)

PMID:42661620 SUPPORT Human Clinical

"lupus-like disease, thyroiditis (hyperthyroidism), cytopenias, infections/ steroids, high dose IVIG"

The 2026 table reports hyperthyroidism in the Chinese child; this is a subtype of thyroid dysfunction, not all autoimmune thyroiditis.

Genitourinary 1

Minimal change glomerulonephritis HP:0012579

Show evidence (1 reference)

PMID:24910257 SUPPORT Human Clinical

"We found all five patients to display autoimmunity: autoimmune thyroiditis (n = 5), autoimmune haemolytic anaemia (n = 2), immune thrombocytopenia (n = 1), autoimmune hepatitis (n = 1), minimal change nephrotic syndrome (n = 1), vitiligo (n = 1) and positive antinuclear antibodies (n = 3) as..."

The explicit minimal-change diagnosis supports the more specific renal binding; this is one affected patient.

Head and Neck 2

Recurrent oral thrush Chronic oral candidiasis HP:0009098

Show evidence (1 reference)

PMID:18482219 SUPPORT Human Clinical

"The patient had suffered from intractable diarrhea, recurrent pulmonary infections and oral moniliasis since two months of age."

Oral moniliasis was part of the infant's early recurring infectious phenotype.

Mastoiditis HP:0000265

Show evidence (1 reference)

PMID:31921117 SUPPORT Human Clinical

"He experienced recurrent sinopulmonary infections that were complicated by mastoiditis, pleural eﬀusion, and bronchiecta sis (Supplemental Figure 1A) and required hospitalization from the age of 14-years."

The longitudinal case attributes these pulmonary/ENT complications to recurrent infection.

Immune 10

Combined immunodeficiency HP:0005387

Show evidence (1 reference)

PMID:40147628 SUPPORT Human Clinical

"In contrast, patients with CD3γ deficiency may either show an SCID phenotype or a milder, less severe CID phenotype."

The 2025 analysis distinguishes severe clinical presentations from milder CID within CD3G deficiency; CD3D/E/Z cases are not pooled into this phenotype.

Recurrent respiratory infections HP:0002205

Show evidence (1 reference)

PMID:31921117 SUPPORT Human Clinical

"we report the case of a 36-year-old male who presented with recurrent sinopulmonary infections without opportunistic infections; this was compatible with hypogammaglobulinemia, but normal PHA-lymphocyte proliferation."

Documents recurrent sinopulmonary infection as a presenting feature.

Atopic dermatitis 2/5 in the 2014 two-family series HP:0001047

Show evidence (1 reference)

PMID:24910257 SUPPORT Human Clinical

"We found all five patients to display autoimmunity: autoimmune thyroiditis (n = 5), autoimmune haemolytic anaemia (n = 2), immune thrombocytopenia (n = 1), autoimmune hepatitis (n = 1), minimal change nephrotic syndrome (n = 1), vitiligo (n = 1) and positive antinuclear antibodies (n = 3) as..."

The frequency recorded here is the atopic-eczema count of 2 out of the 5 patients in the series.

Impaired specific antibody response to vaccination Decreased specific antibody response to vaccination HP:0032140

Show evidence (1 reference)

PMID:33215322 SUPPORT Human Clinical

"Reduced numbers of switched and unswitched memory B cells, hypogammaglobulinemia (IgG 338 mg/dL), and impaired vaccination response to Haemophilus influenzae type B and Pneumococcus were also present (Table 1)."

The child had several directly documented humoral defects before replacement therapy.

Severe Epstein-Barr virus infection HP:0031693

Show evidence (1 reference)

PMID:33215322 SUPPORT Human Clinical

"EBV viremia (102,000 copies/mL) was documented. Bronchoalveolar lavage (BAL) showed neutrophilia and led to isolation of Klebsiella pneumoniae. Lung biopsy was significant for interstitial lymphoplasmacytic infiltrate with positive in situ hybridization for Epstein-Barr encoding region (EBER)."

The pre-transplant clinical episode combined EBV viremia and EBV-positive lung pathology, with concomitant bacterial infection.

Antinuclear antibody positivity HP:0003493

Show evidence (1 reference)

PMID:24910257 SUPPORT Human Clinical

"We found all five patients to display autoimmunity: autoimmune thyroiditis (n = 5), autoimmune haemolytic anaemia (n = 2), immune thrombocytopenia (n = 1), autoimmune hepatitis (n = 1), minimal change nephrotic syndrome (n = 1), vitiligo (n = 1) and positive antinuclear antibodies (n = 3) as..."

The five-person series explicitly reports ANA positivity in three patients; it does not diagnose lupus in those three individuals.

Asthma HP:0002099

Show evidence (1 reference)

PMID:39094808 SUPPORT Human Clinical

"We report a 10-year-old Chinese boy presented with lupus-like disease in addition to autoimmune thyroiditis, asthma, immunodeficiency and recurrent infection."

Asthma is explicitly reported in the genetically confirmed child; no disease-wide frequency follows.

Lupus-like systemic autoimmunity Systemic lupus erythematosus HP:0002725

Show evidence (1 reference)

PMID:39094808 SUPPORT Human Clinical

"This is the first patient who met the diagnostic criteria for systemic lupus erythematosus by the Systemic Lupus International Collaborating Clinics (SLICC) group."

The authors explicitly report fulfillment of lupus criteria; the preferred wording preserves their lupus-like terminology.

Psoriasis Psoriasiform dermatitis HP:0003765

Show evidence (1 reference)

PMID:42661620 SUPPORT Human Clinical

"15 F10-1/Turkey m >30 y NM_000073.3:c.205A>T (p.Lys69Ter) Hom severe varicella infection, respiratory infections, psoriasis, asthma"

The visually verified F10-1 row records psoriasis separately from asthma and infection.

Severe varicella infection Severe chickenpox infection HP:5210299

Show evidence (1 reference)

PMID:42661620 SUPPORT Human Clinical

"15 F10-1/Turkey m >30 y NM_000073.3:c.205A>T (p.Lys69Ter) Hom severe varicella infection, respiratory infections, psoriasis, asthma"

The patient-specific row records severe varicella; the table was visually checked for column identity.

Integument 2

Vitiligo HP:0001045

Show evidence (1 reference)

PMID:24910257 SUPPORT Human Clinical

"We found all five patients to display autoimmunity: autoimmune thyroiditis (n = 5), autoimmune haemolytic anaemia (n = 2), immune thrombocytopenia (n = 1), autoimmune hepatitis (n = 1), minimal change nephrotic syndrome (n = 1), vitiligo (n = 1) and positive antinuclear antibodies (n = 3) as..."

Records vitiligo among the autoimmune manifestations of the series.

Alopecia areata Patchy alopecia HP:0002232

Show evidence (1 reference)

PMID:42661620 SUPPORT Human Clinical

"17 F12-1/Bulgaria f 50 y NM_000073.3:c.213dup (p. Trp72Metfs*6) Hom Hashimoto thyroiditis, lymphadenopathy, AIHA, ITP, alopecia areata/steroids, RTX, SCIG"

The visually verified P1 row lists alopecia areata; the patient identifier preserves the table attribution.

Limbs 1

Finger clubbing Clubbing of fingers HP:0100759

Show evidence (1 reference)

PMID:31921117 SUPPORT Human Clinical

"Atrophic endobronchial mucosa caused exercise tachypnea, clubbing of the ﬁngers, and obstructive sleep apnea."

The authors attribute these findings to the patient's chronic airway disease; the report does not establish this as a universal route in CD3G deficiency.

Metabolism 1

Pleural effusion HP:0002202

Show evidence (1 reference)

PMID:31921117 SUPPORT Human Clinical

"He experienced recurrent sinopulmonary infections that were complicated by mastoiditis, pleural eﬀusion, and bronchiecta sis (Supplemental Figure 1A) and required hospitalization from the age of 14-years."

The longitudinal case attributes these pulmonary/ENT complications to recurrent infection.

Nervous System 1

Obstructive sleep apnea HP:0002870

Show evidence (1 reference)

PMID:31921117 SUPPORT Human Clinical

"Atrophic endobronchial mucosa caused exercise tachypnea, clubbing of the ﬁngers, and obstructive sleep apnea."

The authors attribute these findings to the patient's chronic airway disease; the report does not establish this as a universal route in CD3G deficiency.

Respiratory 3

Bronchiectasis 4/5 with recurrent sinopulmonary infection in the 2019 review HP:0002110

Show evidence (1 reference)

PMID:31921117 SUPPORT Human Clinical

"Four of the ﬁve patients with recurrent sinopulmonary infections developed bronchiectasis."

The frequency recorded here is the 4/5 figure quoted.

Interstitial lung disease Abnormal pulmonary interstitial morphology HP:0006530

Show evidence (2 references)

PMID:33215322 SUPPORT Human Clinical

"EBV viremia (102,000 copies/mL) was documented. Bronchoalveolar lavage (BAL) showed neutrophilia and led to isolation of Klebsiella pneumoniae. Lung biopsy was significant for interstitial lymphoplasmacytic infiltrate with positive in situ hybridization for Epstein-Barr encoding region (EBER)."

The pre-transplant clinical episode combined EBV viremia and EBV-positive lung pathology, with concomitant bacterial infection.

PMID:33215322 SUPPORT Human Clinical

"The patient responded to the immunosuppressant therapy with significant improvement of the diarrhea (weight: 20th percentile), of the AIHA (Hb11.1 g/dL), and partial improvement of the chronic lung disease by chest CT up to transplant."

Clinical response supports an immune contribution but was incomplete and occurred with infection-directed treatment.

Exertional tachypnea HP:0002789

Show evidence (1 reference)

PMID:31921117 SUPPORT Human Clinical

"Atrophic endobronchial mucosa caused exercise tachypnea, clubbing of the ﬁngers, and obstructive sleep apnea."

The authors attribute these findings to the patient's chronic airway disease; the report does not establish this as a universal route in CD3G deficiency.

Growth 2

Failure to thrive HP:0001508

Show evidence (1 reference)

PMID:33215322 SUPPORT Human Clinical

"the patient continued to suffer from progressively worsening GI manifestations for the first 2 years of life with consequent failure to thrive (weight below third percentile) and TPN requirement at 22 months of age for 3 months."

Documents growth failure driven by the enteropathy in a severely affected infant.

Short stature HP:0004322

Show evidence (1 reference)

PMID:42661620 SUPPORT Human Clinical

"8 F5-2/Turkey f 20 y NM_000073.3:c.80-1G>C (p.)? Hom Hashimoto thyroiditis, AIHA, short stature"

The 2026 case table explicitly lists short stature for F5-2; the observation does not establish a growth mechanism.

🧬

Genetic Associations

1

CD3G (Causal biallelic variant)

Gene: CD3G hgnc:1675

Show evidence (2 references)

PMID:42661620 SUPPORT Human Clinical

"Notably, patients carrying identical deleterious variants exhibited substantial variability in clinical presentation and outcomes, indicating that no obvious genotype-phenotype correlation could be established based on the currently available data."

States the absence of a genotype-phenotype correlation.

PMID:24910257 SUPPORT Human Clinical

"We report three new CD3gamma-deficient siblings from a consanguineous family with a combined T-B+NK+ immunodeficiency and their variable clinical and cellular phenotypes despite the same homozygous mutation of the CD3G gene (c.80-1G>C)."

Documents variable phenotype within a single family sharing one homozygous allele.

💊

Medical Actions

5

Immunoglobulin replacement therapy

Action: Pharmacotherapy NCIT:C15986

Agent: therapeutic immune globulin NCIT:C2701

Platform: Protein replacement

Regular immunoglobulin infusion for the hypogammaglobulinaemia and impaired vaccine responses. One patient received it for over twenty years before the genetic diagnosis was made.

Mechanism Target:

BYPASSES Humoral Immune Failure — Replacement immunoglobulin supplies antibody-mediated protection without correcting the cellular immune lesion. Long-term use does not prove prevention of every infectious or hepatic complication.

Show evidence (1 reference)

PMID:31921117 SUPPORT Human Clinical

"This patient had the common variable immunodeficiency (CVID) phenotype and received regular immunoglobulin infusions over 20-years; he gradually developed nodular regenerative hyperplasia over a 5-year period."

Documents long-term immunoglobulin replacement given for the humoral defect, and that it did not prevent later complications.

Target Phenotypes: Decreased circulating immunoglobulin concentration HP:0004313

Show evidence (1 reference)

PMID:33215322 SUPPORT Human Clinical

"The child was started on immunoglobulin replacement and antimicrobial therapy, but she continued to have frequent respiratory tract infections over the first year of life."

Documents the indication and the incomplete response in a severely affected infant.

Rituximab for autoimmune cytopenias

Action: Pharmacotherapy NCIT:C15986

Agent: rituximab NCIT:C1702

Platform: Monoclonal antibody

B-cell depletion for autoimmune haemolytic anaemia and immune thrombocytopenia. Both adults in the 2026 series had Evans syndrome that responded to it.

Mechanism Target:

INHIBITS Multisystem Autoimmunity — B-cell depletion suppressed the autoimmune-cytopenia component of immune dysregulation in the two adults. Their clinical response does not establish efficacy against every organ manifestation or restoration of Treg function.

Show evidence (1 reference)

PMID:42661620 SUPPORT Human Clinical

"Both patients presented with humoral immunodeficiency and Evans syndrome responsive to rituximab therapy."

Records the response of the autoimmune cytopenias to B-cell depletion.

Target Phenotypes: Autoimmune hemolytic anemia HP:0001890 Autoimmune thrombocytopenia HP:0001973

Show evidence (1 reference)

PMID:42661620 SUPPORT Human Clinical

"Both patients presented with humoral immunodeficiency and Evans syndrome responsive to rituximab therapy."

Documents the indication and the observed response.

Glucocorticoids and other immunosuppression for autoimmune manifestations

Action: Pharmacotherapy NCIT:C15986

Agent: glucocorticoid CHEBI:24261 sirolimus NCIT:C1212

Platform: Small molecule

Steroids and other immunosuppressants were used for autoimmune cytopenias and enteropathy. A child improved on combined rituximab, sirolimus and steroids, with partial lung improvement; the individual drug contributions cannot be isolated. In the adult report, immunological deterioration during glucocorticoid exposure and later tapering after rituximab support caution. The authors propose additional suppression of already impaired TCR signaling, rather than demonstrating that mechanism experimentally in these patients.

Mechanism Target:

INHIBITS Multisystem Autoimmunity — Combined immunosuppression improved the child's diarrhea and AIHA and partially improved lung disease. This observed response supports suppression of an immune-mediated component but cannot separate steroid, sirolimus and rituximab effects.

Show evidence (1 reference)

PMID:33215322 SUPPORT Human Clinical

"The patient responded to the immunosuppressant therapy with significant improvement of the diarrhea (weight: 20th percentile), of the AIHA (Hb11.1 g/dL), and partial improvement of the chronic lung disease by chest CT up to transplant."

Clinical response supports an immune contribution but was incomplete and occurred with infection-directed treatment.

MODULATES Attenuated T-Cell Receptor Signaling — The authors propose that glucocorticoid inhibition of TCR signaling could worsen host defense in CD3G deficiency. MODULATES records this proposed downward signaling effect; it is not a directly measured disease-specific pharmacodynamic result.

Show evidence (2 references)

PMID:42661620 SUPPORT INDIRECT Other

"Glucocorticoids are known to suppress TCR signaling at multiple levels, including modulation of downstream signaling kinases and inhibition of TCR-activated transcription factors (20)."

This is cited background pharmacology used in the authors' proposed disease-specific interpretation.

PMID:42661620 SUPPORT INDIRECT Other

"In the context of an already impaired TCR/CD3 signaling pathway, these effects may further compromise host defense"

The authors' statement of the direction of the effect in this specific disorder, hedged as a proposal.

Target Phenotypes: Autoimmune hemolytic anemia HP:0001890 Autoimmune thrombocytopenia HP:0001973

Show evidence (1 reference)

PMID:33215322 SUPPORT Human Clinical

"The patient responded to the immunosuppressant therapy with significant improvement of the diarrhea (weight: 20th percentile), of the AIHA (Hb11.1 g/dL), and partial improvement of the chronic lung disease by chest CT up to transplant."

Clinical response supports an immune contribution but was incomplete and occurred with infection-directed treatment.

Antimicrobial therapy and prophylaxis

Action: antibiotic therapy Ontology label: Antibiotic Therapy NCIT:C15620

Platform: Small molecule

Antimicrobials were used to treat infection and as prophylaxis in reported patients. Breakthrough infections occurred despite treatment and immunoglobulin replacement. The cases do not establish one regimen or indefinite prophylaxis for every patient.

Mechanism Target:

BYPASSES Defective Adaptive Host Defense — Pathogen-directed drugs bypass deficient host control while leaving the CD3G lesion intact; treatment in the reported child did not eliminate respiratory infections.

Show evidence (1 reference)

PMID:33215322 SUPPORT Human Clinical

"The child was started on immunoglobulin replacement and antimicrobial therapy, but she continued to have frequent respiratory tract infections over the first year of life."

Documents antimicrobial therapy given for the infection susceptibility, and that it did not abolish it.

Target Phenotypes: Recurrent respiratory infections HP:0002205 Bronchiectasis HP:0002110

Show evidence (1 reference)

PMID:33215322 SUPPORT Human Clinical

"The child was started on immunoglobulin replacement and antimicrobial therapy, but she continued to have frequent respiratory tract infections over the first year of life."

Documents antimicrobial therapy given for the infection susceptibility, and that it did not abolish it.

Hematopoietic stem cell transplantation

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

Platform: Cell therapy

Allogeneic HSCT has been used in severe infantile disease. One infant showed donor chimerism, increased surface TCR expression and improved intestinal disease before dying on day 50 from infection. Other reports also describe transplant-associated deaths. These small, selected cases support possible immune restoration but do not establish a comparative survival benefit or a universal indication.

Mechanism Target:

RESTORES Impaired TCR/CD3 Complex Assembly and Surface Expression — Donor-derived T cells carry an intact CD3G gene, restoring surface TCR/CD3 expression; in one transplanted infant TCR alpha/beta expression rose to 66% with full donor chimerism.

Show evidence (1 reference)

PMID:18482219 SUPPORT Human Clinical

"On day +19 after second transplantation, the CD3 TCR alpha/beta chain expression increased to 66% with development of full donor chimerism (98.6%)."

Direct measurement of restored surface receptor expression after engraftment.

Target Phenotypes: Combined immunodeficiency HP:0005387 Protracted diarrhea HP:0004385

Show evidence (3 references)

PMID:18482219 SUPPORT Human Clinical

"The case was interesting being the first reported case with SCID and inflammatory bowel disease who responded very well to HSCT by full recovery of intractable diarrhea, failure to thrive, laboratory findings, and improvement of fistula formation."

The infant improved in intestinal disease and laboratory measures after transplantation but died on day 50; clinical response and survival are distinct outcomes.

PMID:42661620 SUPPORT Human Clinical

"Reevaluation of all reported cases demonstrated marked phenotypic heterogeneity, ranging from isolated autoimmune manifestations to severe early-onset combined immunodeficiency requiring hematopoietic stem cell transplantation."

Records that the severe end of the clinical range is what brings patients to transplant.

PMID:31921117 SUPPORT Human Clinical

"Three patients died, one from a severe infection at 31 months, one from post-transplant respiratory failure due to viral pneumonia at 17 months, and one from graft-vs.-host disease at 47 months."

Records the transplant-related deaths behind the statement that outcomes have been poor.

🔬

Biochemical Markers

2

Serum IgG (Decreased)

Context: Low IgG is variable: the detailed child had IgG 338 mg/dL and impaired vaccine responses, and the Taiwanese adult had profound deficiency before replacement. The 9/18 aggregate combines hypo- and dysgammaglobulinemia and is not an IgG-specific frequency.

Show evidence (1 reference)

PMID:33215322 SUPPORT Human Clinical

"Reduced numbers of switched and unswitched memory B cells, hypogammaglobulinemia (IgG 338 mg/dL), and impaired vaccination response to Haemophilus influenzae type B and Pneumococcus were also present (Table 1)."

The child had several directly documented humoral defects before replacement therapy.

CD4+ T-lymphocyte count (Decreased)

Context: Absolute CD4 counts can be low despite preserved total T-cell counts; other patients have normal counts. The 2021 report calls 627 cells/μl lymphopenic, whereas the earlier cohort table used a different reference interval. Age, laboratory ranges and receptor-dependent gating require attention.

Show evidence (1 reference)

PMID:33215322 SUPPORT Human Clinical

"Immunological evaluations revealed a combined immunodeficiency with normal absolute CD3+ T cell numbers, CD4+ T cell lymphopenia (627 cells/μl) with a reduced proportion of naïve T cells and T regulatory cells, increased frequency of memory CD4+, CD8+ cells, and CD45RA+CCR7− CD8+ T cells (TEMRA)."

This report labels the child's measured CD4 count as low; it does not establish universal lymphopenia or universal normal total T-cell numbers.

🔬

Diagnosis

2

Lymphocyte immunophenotyping with surface TCR/CD3 quantitation

Flow cytometry assesses surface TCR/CD3 abundance alongside absolute total and subset T-cell counts. Reduced receptor expression can be informative even with preserved counts, but normal counts and impaired PHA responses are not obligatory findings.

flow cytometry NCIT:C16585

Results: Reduced surface receptor expression with variable absolute T-cell and subset counts; naive and regulatory proportions may be reduced.

Show evidence (1 reference)

PMID:42661620 SUPPORT Other

"that assessment of abTCR and CD3 z surface expression may represent a useful diagnostic marker in patients with suspected CD3g"

The authors propose surface expression as a diagnostic marker; this is interpretive guidance, not a validated sensitivity/specificity estimate.

CD3G sequencing

Molecular confirmation by gene panel, exome or genome sequencing. Because the phenotype ranges from a CVID-like adult presentation to infantile SCID-like disease, the gene is reached by different panels in different patients.

genetic testing NCIT:C15709

Results: Biallelic loss-of-function CD3G variants.

Show evidence (1 reference)

PMID:42661620 SUPPORT Human Clinical

"Whole-genome sequencing was used to identify pathogenic CD3G variants, and protein expression was assessed by Western blot analysis."

Documents the sequencing route to diagnosis.

📊

Prevalence

1

Worldwide

Cases In Literature Ultra Rare

The 2026 paper aggregates 16 previously reported patients and two new adults. This is a published-case count, not population prevalence or an independent cohort. Its assertion of universal genetic confirmation is limited by the earlier report of one clinically presumed, untested affected sibling, and several table entries conflict with the detailed primary reports.

Show evidence (1 reference)

PMID:42661620 SUPPORT Human Clinical

"To date, only 16 predominantly pediatric cases have been reported. Here, we describe two additional adult patients with CD3γ deficiency and provide a comprehensive reevaluation of all previously published cases."

The authors give the literature count and two new cases; this provides no population denominator.

🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Combined immunodeficiency due to CD3gamma deficiency:

CD3delta, CD3epsilon and CD3zeta deficiencies MONDO:0015974

Overlapping Features CD3D, CD3E and CD247/CD3zeta deficiencies typically present with classical SCID and profound T-cell developmental impairment. CD3G deficiency more often retains peripheral T cells, but severe clinical SCID-like CD3G presentations also occur; gene and allele-specific evaluation is required.

Distinguishing Features

Typical profound T-cell depletion in other CD3-chain defects
Variable retained T-cell numbers and autoimmunity in CD3G deficiency
Gene-specific molecular diagnosis rather than clinical severity alone

Show evidence (1 reference)

PMID:40147628 SUPPORT Human Clinical

"Our results show that patients with CD3δ, CD3ε, and CD3ζ deficiencies typically present with a classic SCID phenotype. In contrast, patients with CD3γ deficiency may either show an SCID phenotype or a milder, less severe CID phenotype."

The comparative CD3-subunit analysis supports a typical rather than absolute distinction; its mixed 49-patient denominator is not assigned to CD3G alone.

Common variable immunodeficiency MONDO:0015517

Overlapping Features Adult patients with CD3G deficiency have been managed as CVID because of antibody deficiency and low memory B cells. Reduced surface TCR/CD3 and biallelic CD3G variants identify the cellular lesion; a normal PHA response, as in the Taiwanese patient, does not exclude it.

Distinguishing Features

Reduced surface TCRalphabeta and CD3 expression
Variable proliferative defects; normal PHA does not exclude CD3G deficiency
Biallelic CD3G variants on sequencing

Show evidence (1 reference)

PMID:31921117 SUPPORT Human Clinical

"This patient had the common variable immunodeficiency (CVID) phenotype and received regular immunoglobulin infusions over 20-years; he gradually developed nodular regenerative hyperplasia over a 5-year period."

A CD3gamma-deficient adult managed for two decades as common variable immunodeficiency.

🧫

Experimental Models

1

CD3G-knockdown human Jurkat T cells and the CD3gamma-negative JGN line CELL_LINE

Human T-cell lines in which CD3gamma is absent or knocked down: the JGN variant of Jurkat, which lacks CD3gamma and has no surface TCR, and stable short-hairpin knockdowns of CD3G in Jurkat E6-1. They are the systems in which the assembly and signalling roles of individual CD3gamma domains have been dissected, using domain-swap chimeras with CD3delta.

Organism

human NCBITaxon:9606

Cell source

Immortalized human T-cell leukaemia lines (Jurkat E6-1, JGN)

Culture

Two-dimensional suspension culture with lentiviral shRNA knockdown or retroviral domain-swap reconstitution

Publication

PMID:34249896

Pathograph links

Impaired TCR/CD3 Complex Assembly and Surface Expression partially recapitulates fidelity: moderate Jurkat knockdown measures receptor assembly, ER retention and low surface export. In JGN, the CD3gamma extracellular domain is required for rescue, whereas patient-derived T-cell rescue differs. Domain requirements are therefore interpreted within each cellular system.

Limitations: Knockdown lines have less than 11% surface expression, compared with greater than 30% in congenital patient-derived cells. Developmental adaptation is proposed, but the immature thymic-organ-culture perturbation used shCD3D, not shCD3G. JGN may carry additional mutations; patient-cell limitations restricted biochemical/nanocluster analyses to JGN.

Readouts

Surface TCR expression in CD3G-knockdown Jurkat cells

Direction: DECREASED

Interpretation: Confirms that CD3gamma loss impairs receptor export in a purely human system, while showing the magnitude is model-dependent.

Show evidence (1 reference)

PMID:34249896 SUPPORT In Vitro

"However, both defective TCR ensembles were strongly retained in the ER, lacked ζζ/CD2472, and barely reached the T-cell surface (<11% of normal controls) in any of the CD3 KD cells."

The measurement of residual surface receptor in the knockdown lines.

Show evidence (1 reference)

PMID:34249896 SUPPORT In Vitro

"However, both defective TCR ensembles were strongly retained in the ER, lacked ζζ/CD2472, and barely reached the T-cell surface (<11% of normal controls) in any of the CD3 KD cells."

The assembly/export defect was measured in engineered Jurkat knockdowns; the paper separately documents a milder defect in patient-derived cells.

Attenuated T-Cell Receptor Signaling measures fidelity: moderate Reconstituting the CD3gamma-negative JGN line with chimeric CD3gamma/CD3delta constructs measures which signalling outputs require which CD3gamma domain.

Limitations: JGN is a mutagenized leukemia-derived line with possible additional defects. Cytokine/nanocluster experiments were limited to JGN; proximal signaling and CD69 can remain intact despite impaired cytokine production, and these results are not clinical cytokine measurements.

Readouts

TCR-induced IL-2 and TNF-alpha production

Direction: DECREASED

Interpretation: The intracellular-domain-truncated construct had reduced cytokine production, while CD69 induction was normal/highest. The two response classes are not a single uniformly reduced activation readout.

Show evidence (2 references)

PMID:36119034 SUPPORT In Vitro

"Quantification of IL-2 and TNF-α showed differences among the constructs, with γγ- inducing a very poor response compared to γγγ, γγδ or γδδ."

The Results specifically support reduced cytokine output by the truncated construct.

+ 1 more reference

Show evidence (1 reference)

PMID:36119034 SUPPORT In Vitro

"In contrast to cytokine synthesis, CD69 expression and TCR internalization after TCR engagement were normal for all constructs including γγ-, which scored highest for CD69 induction, indicating that it was capable of some functional signal transduction."

The full Results qualify the abstract: the intracellular-domain-truncated construct retained CD69 induction; cytokine secretion and CD69 cannot be bundled as uniformly reduced.

🐁

Animal Models

1

Cd3g-deficient mouse

Cd3g-null mice have thymic cellularity below 1% and peripheral T-cell numbers at 2–5% of normal, with severe impairment of both TCR lineages. This differs from the substantial peripheral T-cell compartment retained by many human patients, although human clinical disease can also be severe. Residual mouse cells are not described as wholly absent.

Species

Mouse

Genotype

Cd3g null (selective loss of CD3gamma expression)

Publication

PMID:9524111

Pathograph links

Impaired TCR/CD3 Complex Assembly and Surface Expression partially recapitulates fidelity: moderate The mouse does reproduce the receptor-expression defect: surface TCR and CD3epsilon are severely reduced on thymocytes and peripheral T cells.

Limitations: The developmental and quantitative receptor deficits are more severe than in typical human cases. This limits direct translation to mature patient T cells, without proving that no mature-cell question can be studied in the model.

Readouts

Surface TCR and CD3epsilon expression on thymocytes and peripheral T cells

Direction: DECREASED

Interpretation: The receptor-expression component of the human lesion is present in the mouse.

Show evidence (1 reference)

PMID:9524111 SUPPORT Model Organism

"Furthermore, absence of CD3gamma results in a severe reduction in the level of TCR and CD3epsilon expression at the cell surface of thymocytes and peripheral T cells."

Direct measurement of the surface receptor deficit in the model.

Show evidence (1 reference)

PMID:9524111 SUPPORT Model Organism

"We generated mice selectively lacking expression of CD3gamma, in which expression of CD3delta, CD3epsilon, CD3zeta, pTalpha and TCRbeta remained undisturbed."

Establishes that the model isolates loss of CD3gamma, the same lesion as in patients.

Distorted Thymic Selection and Self-Reactive Repertoire fails to recapitulate fidelity: low The profound mouse developmental bottleneck does not reproduce the preserved, variably skewed peripheral repertoire studied in human autoimmune cohorts. The cited experiments do not directly establish fidelity for human Treg dysfunction or clinical autoimmunity.

Limitations: Peripheral mouse T cells are reduced to 2–5%, not absent. Human CD3delta rescues gamma-delta development in double-deficient mice, explaining a lineage-specific compensation mechanism; this does not fully explain preserved human alpha-beta development or establish all autoimmune outcomes in the model.

Show evidence (3 references)

PMID:9524111 SUPPORT Model Organism

"The number of cells in the thymus is reduced to <1% of that in normal mice, and the large majority of thymocytes lack CD4 and CD8 and are arrested at the CD44-CD25+ double negative (DN) stage of development."

The mouse developmental bottleneck is much more profound than that in human cohorts retaining peripheral T cells.

+ 2 more references

Show evidence (2 references)

PMID:9524111 SUPPORT Model Organism

"Peripheral lymphoid organs are also practically devoid of T cells, with absolute numbers of peripheral T cells reduced to only 2-5% of those in normal mice."

The model retains a small peripheral population; the result must not be described as complete absence.

PMID:17923503 SUPPORT Model Organism

"A human, but not a mouse, CD3delta transgene rescues gammadelta T cell development in mice lacking both mouse CD3delta and CD3gamma chains."

The perturbation demonstrates lineage-specific structural compensation in a mouse model; it does not by itself resolve human alpha-beta/Treg biology.

{ }

Source YAML

click to show

name: Combined immunodeficiency due to CD3gamma deficiency
creation_date: "2026-08-28T00:00:00Z"
category: Mendelian
synonyms:
- CD3gamma deficiency
- CD3-gamma deficiency
- CD3 deficiency
- immunodeficiency 17
- immunodeficiency type 17
- IMD17
- immunodeficiency 17, CD3 gamma deficient
- SCID-like immunodeficiency, T cell-partial, B cell-positive, NK cell-positive
description: >-
  Autosomal recessive CD3G deficiency is a variable combined immunodeficiency caused by biallelic variants
  affecting the CD3gamma chain of the TCR/CD3 complex. Human patients retain variable numbers of T cells
  with reduced surface receptor expression, unlike the profound developmental block typical of several
  other CD3-chain deficiencies. Clinical presentations range from severe infantile infection and enteropathy
  to predominantly autoimmune disease or adult-recognized antibody deficiency. Autoimmune thyroid disease,
  cytopenias and other organ manifestations are frequent in published cohorts but are not universal. Altered
  TCR signaling, Treg number/function and repertoire selection provide a qualified immune-dysregulation
  model; normal Treg function and selected normal mitogen responses in some patients constrain universal
  claims.
disease_term:
  preferred_term: combined immunodeficiency due to CD3gamma deficiency
  term:
    id: MONDO:0014276
    label: combined immunodeficiency due to CD3gamma deficiency
parents:
- Combined immunodeficiency
- Inborn error of immunity
references:
- reference: PMID:42661620
  title: "Expanding the clinical spectrum of CD3γ deficiency: comprehensive characterization of adult-onset
    disease and integrated reevaluation of all reported patients."
- reference: PMID:33215322
  title: Complete Absence of CD3γ Protein Expression Is Responsible for Combined Immunodeficiency
    with Autoimmunity Rather than SCID.
- reference: PMID:29653965
  title: "Patients with CD3G mutations reveal a role for human CD3γ in T(reg) diversity and suppressive
    function."
- reference: PMID:24910257
  title: CD3G gene defects in familial autoimmune thyroiditis.
- reference: PMID:23590417
  title: "Variable presentation of primary immune deficiency: two cases with CD3 gamma deficiency presenting
    with only autoimmunity."
- reference: PMID:31921117
  title: "A Novel CD3G Mutation in a Taiwanese Patient With Normal T Regulatory Function Presenting With
    the CVID Phenotype Free of Autoimmunity-Analysis of all Genotypes and Phenotypes."
- reference: PMID:18482219
  title: Hematopoietic stem cell transplantation in a CD3 gamma-deficient infant with inflammatory
    bowel disease.
- reference: PMID:16264327
  title: CD3 deficiencies.
- reference: PMID:34249896
  title: "CD3G or CD3D Knockdown in Mature, but Not Immature, T Lymphocytes Similarly Cripples the Human
    TCRαβ Complex."
- reference: PMID:17923503
  title: Different composition of the human and the mouse gammadelta T cell receptor explains
    different phenotypes of CD3gamma and CD3delta immunodeficiencies.
- reference: PMID:9524111
  title: The CD3gamma chain is essential for development of both the TCRalphabeta and TCRgammadelta
    lineages.
- reference: PMID:35748970
  title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union
    of Immunological Societies Expert Committee."
- reference: PMID:12407027
  title: Contribution of CD3 gamma to TCR regulation and signaling in human mature T lymphocytes.
- reference: PMID:17277165
  title: Differential biological role of CD3 chains revealed by human immunodeficiencies.
- reference: PMID:36119034
  title: The role of the different CD3γ domains in TCR expression and signaling.
- reference: PMID:39094808
  title: A CD3G homozygous pathogenic variant in a Chinese child with lupus-like disease, autoimmune
    thyroiditis and immunodeficiency.
- reference: PMID:40147628
  title: Five Patients With Two Novel Homozygous Variants in CD3 Subunits and Comprehensive Review
    of the Literature.
- reference: url:https://www.ucm.es/data/cont/docs/1572-2019-04-22-Blood%202018.pdf
  title: https://www.ucm.es/data/cont/docs/1572-2019-04-22-Blood%202018.pdf
classifications:
  iuis_category:
    classification_value: combined immunodeficiency
    notes: >-
      IUIS 2022 places CD3G deficiency among defects affecting cellular and humoral immunity. Its normal-T-cell-number/low-TCR-expression
      row describes a characteristic pattern, not an invariant diagnostic requirement; clinical reports
      include absolute subset lymphopenia and severe SCID-like presentations.
    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
      snippet: >-
        CD3  deficiency CD3G AR 186740 Normal number, but low TCR expression Normal Normal Immune deficiency
        and autoimmunity of variable severity
      explanation: >-
        The IUIS classification table row for CD3G, which places the disorder in
        the combined-immunodeficiency table and records the normal T-cell number
        with low TCR expression and the variable-severity phenotype.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Biallelic CD3G variants. Almost all reported patients are homozygous, and
    parental consanguinity is common; two siblings from one non-consanguineous
    Spanish family were compound heterozygous.
  evidence:
  - reference: PMID:42661620
    reference_title: "Expanding the clinical spectrum of CD3γ deficiency: comprehensive characterization
      of adult-onset disease and integrated reevaluation of all reported patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CD3γ deficiency is an ultrarare autosomal recessive inborn error of immunity characterized by immune
      dysregulation and variable immunodeficiency.
    explanation: >-
      States the autosomal recessive mode of inheritance and the defining
      combination of immune dysregulation with variable immunodeficiency.
  - reference: PMID:42661620
    reference_title: "Expanding the clinical spectrum of CD3γ deficiency: comprehensive characterization
      of adult-onset disease and integrated reevaluation of all reported patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Variants were homozygous in all but two reported cases
    explanation: >-
      Records that the biallelic variants are homozygous in nearly every
      reported family.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    The 2026 paper aggregates 16 previously reported patients and two new adults. This is a published-case
    count, not population prevalence or an independent cohort. Its assertion of universal genetic confirmation
    is limited by the earlier report of one clinically presumed, untested affected sibling, and several
    table entries conflict with the detailed primary reports.
  evidence:
  - reference: PMID:42661620
    reference_title: "Expanding the clinical spectrum of CD3γ deficiency: comprehensive characterization
      of adult-onset disease and integrated reevaluation of all reported patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To date, only 16 predominantly pediatric cases have been reported. Here, we describe two additional
      adult patients with CD3γ deficiency and provide a comprehensive reevaluation of all previously published
      cases.
    explanation: >-
      The authors give the literature count and two new cases; this provides no population denominator.
pathophysiology:
- name: Biallelic CD3G Loss-of-Function Variants
  biological_scale: MOLECULAR
  description: >-
    Biallelic CD3G variants impair the CD3gamma subunit of the TCR/CD3 complex. Complete transcript and
    protein loss was demonstrated for homozygous c.1A>G in cultured blasts from one child; PBMC protein
    loss was also shown in the two adults reported in 2026. These results establish that human T-cell
    development can persist without detectable CD3gamma; they do not establish identical residual function
    for every reported allele. The original Spanish siblings were compound heterozygotes, not homozygotes
    for the initiation-codon variant.
  genes:
  - preferred_term: CD3G
    term:
      id: hgnc:1675
      label: CD3G
  evidence:
  - reference: PMID:42661620
    reference_title: "Expanding the clinical spectrum of CD3γ deficiency: comprehensive characterization
      of adult-onset disease and integrated reevaluation of all reported patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pathogenic variants included splice-site, nonsense, and frameshift mutations predicted to result
      in loss of function
    explanation: >-
      Describes the class of CD3G alleles reported across the literature.
  - reference: PMID:33215322
    reference_title: Complete Absence of CD3γ Protein Expression Is Responsible for Combined
      Immunodeficiency with Autoimmunity Rather than SCID.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Together, these results demonstrate biallelic CD3G c.1 A > G mutation results in the complete loss
      of CD3G mRNA transcripts and CD3γ protein translation.
    explanation: >-
      Establishes, in patient-derived T-cell blasts, that a reported allele is a
      true null rather than a hypomorph.
  downstream:
  - target: Impaired TCR/CD3 Complex Assembly and Surface Expression
    description: >-
      Loss of CD3gamma compromises receptor assembly and surface abundance, with residual expression varying
      by cellular context.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:42661620
      reference_title: 'Expanding the clinical spectrum of CD3γ deficiency: comprehensive characterization
        of adult-onset disease and integrated reevaluation of all reported patients.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        Western blot analysis of PBMC-derived protein
        demonstrated complete absence of CD3 g expression, while ﬂow
        cytometry revealed reduced expression of the TCR/CD3 complex,
        conﬁrming the diagnosis of CD3 g deﬁciency (Figures 1B– D).
      explanation: >-
        Patient P1 had absent protein and reduced receptor expression measured directly in PBMCs.
  - target: Impaired T-Cell Help for Memory B-Cell Maturation
    description: >-
      The Taiwanese report attributes a diminished CD40L response and memory-B-cell defect to CD3G deficiency,
      but the intervening route is unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31921117
      reference_title: A Novel CD3G Mutation in a Taiwanese Patient With Normal T Regulatory
        Function Presenting With the CVID Phenotype Free of Autoimmunity-Analysis of all Genotypes
        and Phenotypes.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: |-
        the novel CD3G deletion (c.del213A) in our patient caused an obvious decrease in switched memory B cells and diminished CD40L expression.
      explanation: >-
        The authors attribute these patient-cell findings to the variant; the graph retains this as a
        case-scoped indirect relation rather than an established signaling cascade.
      directness: INDIRECT
- name: Impaired TCR/CD3 Complex Assembly and Surface Expression
  biological_scale: MOLECULAR
  description: >-
    CD3gamma deficiency lowers, without invariably abolishing, surface TCR/CD3 expression in human T cells.
    CD3G-knockdown Jurkat cells show unstable partial receptor ensembles, ER retention and deficient zeta-dimer
    incorporation, but their profound receptor loss does not quantitatively reproduce patient cells. Patient-cell
    reconstitution supports a role for CD3gamma in surface expression; the precise assembly/export constraints
    depend on the cellular system. Human gamma-delta receptors can incorporate CD3delta, providing a supported
    explanation for partial compensation in that lineage.
  protein_complexes:
  - preferred_term: alpha-beta T cell receptor complex
    modifier: DECREASED
    term:
      id: GO:0042105
      label: alpha-beta T cell receptor complex
  cell_types:
  - preferred_term: mature alpha-beta T cell
    term:
      id: CL:0000791
      label: mature alpha-beta T cell
  evidence:
  - reference: PMID:42661620
    reference_title: 'Expanding the clinical spectrum of CD3γ deficiency: comprehensive characterization
      of adult-onset disease and integrated reevaluation of all reported patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Western blot analysis of PBMC-derived protein
      demonstrated complete absence of CD3 g expression, while ﬂow
      cytometry revealed reduced expression of the TCR/CD3 complex,
      conﬁrming the diagnosis of CD3 g deﬁciency (Figures 1B– D).
    explanation: >-
      Patient P1 had absent protein and reduced receptor expression measured directly in PBMCs.
  - reference: PMID:34249896
    reference_title: CD3G or CD3D Knockdown in Mature, but Not Immature, T Lymphocytes Similarly
      Cripples the Human TCRαβ Complex.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: |-
      However, both defective TCR ensembles were strongly retained in the ER, lacked ζζ/CD2472, and barely reached the T-cell surface (<11% of normal controls) in any of the CD3 KD cells.
    explanation: >-
      The assembly/export defect was measured in engineered Jurkat knockdowns; the paper separately documents
      a milder defect in patient-derived cells.
  downstream:
  - target: Attenuated T-Cell Receptor Signaling
    description: >-
      Reduced and altered receptor complexes change signaling strength; signaling is attenuated selectively
      rather than uniformly abolished.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33215322
      reference_title: Complete Absence of CD3γ Protein Expression Is Responsible for Combined
        Immunodeficiency with Autoimmunity Rather than SCID.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: |-
        recent data from our group suggest a model where human CD3γ deficiency alters but does not abrogate surface expression of CD3 and TCR molecules, reducing TCR signaling strength and thereby affecting T cell development, thymus selection, and fate [8].
      explanation: >-
        This is the authors' proposed mechanistic model, informed by patient repertoire and functional
        experiments.
      directness: INDIRECT
- name: Attenuated T-Cell Receptor Signaling
  biological_scale: CELLULAR
  description: >-
    Reduced and structurally altered TCR/CD3 complexes change signaling in a response-dependent manner.
    Cultured patient-derived lines retain several proximal responses but have altered adhesion/polarization
    and increased activation-induced death. In reconstituted JGN cells, removal of the CD3gamma intracellular
    domain impaired IL-2/TNF-alpha production while preserving proximal phosphorylation and CD69 induction.
    These model findings do not establish global absence of T-cell activation in patients; PHA and anti-CD3/CD28
    responses can be preserved in particular patients or assay conditions.
  biological_processes:
  - preferred_term: T cell receptor signaling pathway
    modifier: DECREASED
    term:
      id: GO:0050852
      label: T cell receptor signaling pathway
  evidence:
  - reference: PMID:12407027
    reference_title: Contribution of CD3 gamma to TCR regulation and signaling in human mature T
      lymphocytes.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: |-
      In contrast, other physiological responses like the specific adhesion and concomitant cell polarization on ICAM-1-coated dishes were selectively defective, and activation-induced cell death was increased.
    explanation: >-
      Patient-derived mature T-cell lines had selective functional defects, despite largely preserved
      proximal responses.
  - reference: PMID:36119034
    reference_title: The role of the different CD3γ domains in TCR expression and signaling.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: |-
      In contrast to cytokine synthesis, CD69 expression and TCR internalization after TCR engagement were normal for all constructs including γγ-, which scored highest for CD69 induction, indicating that it was capable of some functional signal transduction.
    explanation: >-
      The full Results qualify the abstract: the intracellular-domain-truncated construct retained CD69
      induction; cytokine secretion and CD69 cannot be bundled as uniformly reduced.
  downstream:
  - target: Distorted Thymic Selection and Self-Reactive Repertoire
    description: >-
      The proposed signaling-strength model alters thymic selection and CD4-cell fate.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33215322
      reference_title: Complete Absence of CD3γ Protein Expression Is Responsible for Combined
        Immunodeficiency with Autoimmunity Rather than SCID.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: |-
        recent data from our group suggest a model where human CD3γ deficiency alters but does not abrogate surface expression of CD3 and TCR molecules, reducing TCR signaling strength and thereby affecting T cell development, thymus selection, and fate [8].
      explanation: >-
        This is the authors' proposed mechanistic model, informed by patient repertoire and functional
        experiments.
      directness: INDIRECT
  - target: Regulatory T-Cell Deficiency and Impaired Suppression
    description: >-
      TCR-dependent Treg development and maintenance provide a proposed route to reduced Treg number,
      diversity and function.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ucm.es/data/cont/docs/1572-2019-04-22-Blood%202018.pdf
      reference_title: https://www.ucm.es/data/cont/docs/1572-2019-04-22-Blood%202018.pdf
      supports: SUPPORT
      evidence_source: OTHER
      snippet: |-
        Treg cells are dependent on TCR signaling for their development
        and suppressive function.
      explanation: >-
        Background biology used by the authors to interpret the patient findings; the relative developmental
        and peripheral contributions are unresolved.
      directness: INDIRECT
  - target: Impaired T-Cell Proliferative Response
    description: >-
      Altered TCR signaling contributes to stimulus-dependent impairment of cell division.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:42661620
      reference_title: 'Expanding the clinical spectrum of CD3γ deficiency: comprehensive characterization
        of adult-onset disease and integrated reevaluation of all reported patients.'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: |-
        reduced proliferation is likely a direct
        consequence of impaired TCR/CD3-mediated signaling resulting
        from defective CD3 g expression
      explanation: >-
        The 2026 authors infer a signaling-to-proliferation relation; preserved responses under other
        conditions limit its scope.
      directness: INDIRECT
  - target: Reduced Thymic Output and Altered T-Cell Homeostasis
    description: >-
      The authors' signaling-strength model alters T-cell development and homeostasis, compatible with
      reduced output markers despite retained peripheral T cells.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33215322
      reference_title: Complete Absence of CD3γ Protein Expression Is Responsible for Combined
        Immunodeficiency with Autoimmunity Rather than SCID.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: |-
        recent data from our group suggest a model where human CD3γ deficiency alters but does not abrogate surface expression of CD3 and TCR molecules, reducing TCR signaling strength and thereby affecting T cell development, thymus selection, and fate [8].
      explanation: >-
        This is the authors' proposed mechanistic model, informed by patient repertoire and functional
        experiments.
      directness: INDIRECT
- name: Distorted Thymic Selection and Self-Reactive Repertoire
  biological_scale: CELLULAR
  description: >-
    Reduced TCR signaling is proposed to alter thymic selection and the fate of self-reactive CD4 cells.
    Peripheral repertoire sequencing in six patients with autoimmunity found reduced Treg repertoire diversity
    and a hydrophobic CDR3 signature associated with self-reactivity in conventional CD4 cells. This is
    a molecular surrogate and a mechanistic interpretation, not direct observation of failed negative
    selection or demonstration of each clone's autoantigen specificity. The same self-reactivity signature
    was not found in CD8 cells.
  biological_processes:
  - preferred_term: thymic T cell selection
    modifier: DECREASED
    term:
      id: GO:0045061
      label: thymic T cell selection
  cell_types:
  - preferred_term: thymocyte
    term:
      id: CL:0000893
      label: thymocyte
  evidence:
  - reference: PMID:29653965
    reference_title: "Patients with CD3G mutations reveal a role for human CD3γ in T(reg) diversity and
      suppressive function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The TRB repertoire of Tconv cells from patients with CD3G deficiency was enriched for hydrophobic
      amino acids at positions 6 and 7 of the CDR3, a biomarker of self-reactivity.
    explanation: >-
      Peripheral repertoire sequencing found enrichment of hydrophobic CDR3 residues associated with self-reactivity;
      this surrogate does not directly demonstrate clone-specific autoantigen recognition or thymic negative-selection
      failure.
  downstream:
  - target: Multisystem Autoimmunity
    description: >-
      The inferred escape of self-reactive conventional CD4 cells can contribute to loss of tolerance;
      repertoire hydrophobicity is a surrogate, not direct antigen-specific proof.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ucm.es/data/cont/docs/1572-2019-04-22-Blood%202018.pdf
      reference_title: https://www.ucm.es/data/cont/docs/1572-2019-04-22-Blood%202018.pdf
      supports: SUPPORT
      evidence_source: OTHER
      snippet: |-
        Ultimately, this results in
        enrichment for self-reactive speciﬁ cities within CD4
        1 Tconv cells,
        which may undergo peripheral activation and expansion because
        of the reduced number and impaired function of T
        reg cells. Alto-
        gether, these abnormalities create an environment that promotes
        the development of autoimmunity in this condition.
      explanation: >-
        The authors' integrated model links altered selection and Treg control to autoimmunity; organ-specific
        effectors and penetrance remain incompletely resolved.
      directness: INDIRECT
- name: Regulatory T-Cell Deficiency and Impaired Suppression
  biological_scale: CELLULAR
  description: >-
    In the 2018 autoimmune cohort, circulating Treg proportions and repertoire diversity were reduced;
    suppression was tested in four patients and was impaired. Reduced TCR signaling may affect Treg selection,
    maintenance and suppressive function, but the relative contribution of these processes remains unresolved.
    A Taiwanese adult had preserved Treg proportion and suppressive activity with no recognized autoimmunity.
    Treg deficiency is therefore an important variable mechanism, not a universal requirement for CD3G-associated
    disease.
  biological_processes:
  - preferred_term: regulatory T cell differentiation
    modifier: DECREASED
    term:
      id: GO:0045066
      label: regulatory T cell differentiation
  cell_types:
  - preferred_term: regulatory T cell
    term:
      id: CL:0000815
      label: regulatory T cell
  evidence:
  - reference: url:https://www.ucm.es/data/cont/docs/1572-2019-04-22-Blood%202018.pdf
    reference_title: https://www.ucm.es/data/cont/docs/1572-2019-04-22-Blood%202018.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Among CD41 Tc e l l s ,t h e
      proportion of CD25hi FOXP31 Treg cells was signiﬁcantly lower in
      CD3G-mutated patients than in con trols.
    explanation: >-
      Direct flow-cytometric observation in the 2018 cohort selected for CD3G mutations and autoimmunity.
  - reference: url:https://www.ucm.es/data/cont/docs/1572-2019-04-22-Blood%202018.pdf
    reference_title: https://www.ucm.es/data/cont/docs/1572-2019-04-22-Blood%202018.pdf
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: |-
      By contrast, T reg cells from CD3G-mutated patients completely
      failed to suppress proliferation of control Teff cells up to a 1:2 Treg:
      Teff cell ratio; reduced suppressive activity was also detected at a
      1:1 Treg:Tconv ratio (Figure 4B-C).
    explanation: >-
      Suppression cocultures used Tregs from four patients P2–P5; the assay does not imply that all six
      patients underwent functional testing.
  - reference: PMID:31921117
    reference_title: A Novel CD3G Mutation in a Taiwanese Patient With Normal T Regulatory Function
      Presenting With the CVID Phenotype Free of Autoimmunity-Analysis of all Genotypes and
      Phenotypes.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: |-
      Treg cells isolated from the CD3 γ Del 213A T cells of the patient
      were able to suﬃciently suppress the proliferation of Teﬀ cells
      upon stimulation
    explanation: >-
      The Taiwanese adult retained suppression in the reported coculture conditions, qualifying universal
      Treg-dysfunction claims.
  downstream:
  - target: Multisystem Autoimmunity
    description: >-
      Reduced Treg diversity and suppressive control can permit autoreactive-cell expansion in the affected
      autoimmune cohorts.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ucm.es/data/cont/docs/1572-2019-04-22-Blood%202018.pdf
      reference_title: https://www.ucm.es/data/cont/docs/1572-2019-04-22-Blood%202018.pdf
      supports: SUPPORT
      evidence_source: OTHER
      snippet: |-
        Ultimately, this results in
        enrichment for self-reactive speciﬁ cities within CD4
        1 Tconv cells,
        which may undergo peripheral activation and expansion because
        of the reduced number and impaired function of T
        reg cells. Alto-
        gether, these abnormalities create an environment that promotes
        the development of autoimmunity in this condition.
      explanation: >-
        The authors' integrated model links altered selection and Treg control to autoimmunity; organ-specific
        effectors and penetrance remain incompletely resolved.
      directness: INDIRECT
- name: Impaired T-Cell Proliferative Response
  biological_scale: CELLULAR
  description: >-
    Mitogen-driven T-cell division is impaired in several CD3G cohorts, consistent with altered receptor
    signaling. The response depends on stimulus, cell subset, age and assay: anti-CD3 plus CD28 restored
    near-control responses in the 2018 study, and the Taiwanese patient had normal PHA responses despite
    reduced ConA incorporation. The 2026 count of 11/11 abnormal responses to at least one mitogen does
    not establish universal impairment of PHA-induced transformation or predict clinical severity.
  biological_processes:
  - preferred_term: T cell proliferation
    modifier: DECREASED
    term:
      id: GO:0042098
      label: T cell proliferation
  evidence:
  - reference: url:https://www.ucm.es/data/cont/docs/1572-2019-04-22-Blood%202018.pdf
    reference_title: https://www.ucm.es/data/cont/docs/1572-2019-04-22-Blood%202018.pdf
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: |-
      When
      stimulated with phytohema gglutinin (PHA), both CD4 1 and
      CD81 T cells in CD3g-deﬁcient patients demonstrated reduced
      cellular division (as shown by CFSE dilution);
    explanation: >-
      The six-patient study measured reduced division after PHA stimulation.
  - reference: url:https://www.ucm.es/data/cont/docs/1572-2019-04-22-Blood%202018.pdf
    reference_title: https://www.ucm.es/data/cont/docs/1572-2019-04-22-Blood%202018.pdf
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: |-
      Stimulation with
      both anti-CD3 and anti-CD28 resulted in overall equivalent
      activation, proliferation, and cell division in both CD4
      1 and
      CD81 T cells from patients and controls (Figure 2A-D).
    explanation: >-
      Costimulation preserved responses in the tested patients; this constrains a global proliferation-failure
      model.
  downstream:
  - target: Defective Adaptive Host Defense
    description: >-
      Deficient cellular immune responses can compromise pathogen control, while assay and patient heterogeneity
      preclude a deterministic severity rule.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31921117
      reference_title: A Novel CD3G Mutation in a Taiwanese Patient With Normal T Regulatory
        Function Presenting With the CVID Phenotype Free of Autoimmunity-Analysis of all Genotypes
        and Phenotypes.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: |-
        Patients with opportunistic infections,
        including parainﬂuenza pneumonia, Candida albicans , Giardia
        intestinalis, and severe EBV infection, reﬂect profoundly
        impaired lymphocyte proliferation
      explanation: >-
        The authors relate opportunistic infection to impaired cellular immunity, based on reported cases
        rather than a prospective causal experiment.
      directness: INDIRECT
- name: Humoral Immune Failure
  biological_scale: ORGANISM
  description: >-
    Humoral impairment ranges from profound low immunoglobulins and deficient vaccine responses to normal
    or elevated concentrations. Reduced switched-memory B cells and diminished CD40L induction in a Taiwanese
    patient suggest impaired T-cell help as one contributor; intrinsic B-cell dysfunction was not demonstrated
    by rescue or Tfh/B-cell coculture. Nephrotic protein loss, glucocorticoids and immunoglobulin replacement
    can also influence measured concentrations. The 2026 9/18 hypo-/dysgammaglobulinemia aggregate cannot
    be assigned to low total IgG alone.
  biological_processes:
  - preferred_term: immunoglobulin production
    modifier: DECREASED
    term:
      id: GO:0002377
      label: immunoglobulin production
  evidence:
  - reference: PMID:33215322
    reference_title: Complete Absence of CD3γ Protein Expression Is Responsible for Combined
      Immunodeficiency with Autoimmunity Rather than SCID.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Reduced numbers of switched and unswitched memory B cells, hypogammaglobulinemia (IgG 338 mg/dL), and impaired vaccination response to Haemophilus influenzae type B and Pneumococcus were also present (Table 1).
    explanation: >-
      The child had several directly documented humoral defects before replacement therapy.
  - reference: PMID:31921117
    reference_title: A Novel CD3G Mutation in a Taiwanese Patient With Normal T Regulatory Function
      Presenting With the CVID Phenotype Free of Autoimmunity-Analysis of all Genotypes and
      Phenotypes.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: |-
      This may have been
      associated with insuﬃcient CD40L expression, which has been
      reported in some patients with CVID and hyper IgM
    explanation: >-
      The authors propose insufficient T-cell help as a contributor to the Taiwanese patient's memory-B-cell
      abnormality; they did not establish an intrinsic B-cell lesion.
    directness: INDIRECT
  downstream:
  - target: Defective Adaptive Host Defense
    description: >-
      Insufficient antibody-mediated protection contributes to bacterial respiratory infection in patients
      with hypogammaglobulinemia, including the Taiwanese adult with preserved PHA responses.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31921117
      reference_title: A Novel CD3G Mutation in a Taiwanese Patient With Normal T Regulatory
        Function Presenting With the CVID Phenotype Free of Autoimmunity-Analysis of all Genotypes
        and Phenotypes.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        we report the case of a 36-year-old male who presented with recurrent sinopulmonary infections without opportunistic infections; this was compatible with hypogammaglobulinemia, but normal PHA-lymphocyte proliferation.
      explanation: >-
        Clinical concordance supports a humoral contribution in this patient; it does not exclude all
        cellular defects.
      directness: INDIRECT
- name: Multisystem Autoimmunity
  biological_scale: ORGANISM
  description: >-
    Defective central and peripheral tolerance can permit autoreactive T-cell activity and autoantibody-associated
    tissue injury. The 2018 repertoire/suppression study proposes this mechanism for the patients' autoimmunity,
    rather than directly demonstrating every organ-specific effector pathway. Thyroid disease, autoimmune
    cytopenias, enteropathy, hepatitis, vitiligo and a lupus-like presentation occur variably. The absence
    of autoimmunity in a patient with preserved Treg function is a scope constraint, not evidence that
    autoimmunity is absent from the disorder.
  evidence:
  - reference: url:https://www.ucm.es/data/cont/docs/1572-2019-04-22-Blood%202018.pdf
    reference_title: https://www.ucm.es/data/cont/docs/1572-2019-04-22-Blood%202018.pdf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: |-
      Ultimately, this results in
      enrichment for self-reactive speciﬁ cities within CD4
      1 Tconv cells,
      which may undergo peripheral activation and expansion because
      of the reduced number and impaired function of T
      reg cells. Alto-
      gether, these abnormalities create an environment that promotes
      the development of autoimmunity in this condition.
    explanation: >-
      The authors' integrated model links altered selection and Treg control to autoimmunity; organ-specific
      effectors and penetrance remain incompletely resolved.
    directness: INDIRECT
  downstream:
  - target: Immune-Mediated Gastrointestinal Mucosal Injury
    description: >-
      Loss of immune tolerance can mediate intestinal injury in the patient with biopsy-supported autoimmune
      enteropathy.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33215322
      reference_title: Complete Absence of CD3γ Protein Expression Is Responsible for Combined
        Immunodeficiency with Autoimmunity Rather than SCID.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        Upper and lower endoscopy showed chronic active gastritis and colitis, and biopsies of small intestine and colon were consistent with autoimmune enteropathy. Linear staining along the periapical border of the enterocytes was positive for anti-enterocyte auto-antibodies.
      explanation: >-
        Clinical pathology supports immune-mediated intestinal injury in this child; antibody positivity
        alone does not establish the entire effector pathway.
  - target: Autoimmune thyroiditis
    description: >-
      Impaired tolerance permits autoimmune thyroid inflammation in selected patients. Antithyroid antibodies
      and variable thyroid functional states support an organ-specific autoimmune process; the precise
      T-cell/B-cell effectors are not resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ucm.es/data/cont/docs/1572-2019-04-22-Blood%202018.pdf
      reference_title: https://www.ucm.es/data/cont/docs/1572-2019-04-22-Blood%202018.pdf
      supports: SUPPORT
      evidence_source: OTHER
      snippet: |-
        Ultimately, this results in
        enrichment for self-reactive speciﬁ cities within CD4
        1 Tconv cells,
        which may undergo peripheral activation and expansion because
        of the reduced number and impaired function of T
        reg cells. Alto-
        gether, these abnormalities create an environment that promotes
        the development of autoimmunity in this condition.
      explanation: >-
        The authors' integrated model links altered selection and Treg control to autoimmunity; organ-specific
        effectors and penetrance remain incompletely resolved.
      directness: INDIRECT
    - reference: PMID:42661620
      reference_title: "Expanding the clinical spectrum of CD3γ deficiency: comprehensive characterization
        of adult-onset disease and integrated reevaluation of all reported patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The most frequently reported autoimmune manifestations included autoimmune thyroiditis (7/18,
        38.9%), AIHA (7/18, 38.9%), and ITP (4/18, 22.2%)
      explanation: >-
        The published aggregate covers autoimmune thyroiditis broadly, rather than a Hashimoto-only numerator;
        these are selected reported cases.
  - target: Autoimmune hemolytic anemia
    description: >-
      Loss of immune tolerance contributes to antibody-associated erythrocyte destruction in reported
      AIHA cases. Rituximab-responsive Evans syndrome supports a B-cell contribution, without identifying
      the initiating autoreactive clone.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ucm.es/data/cont/docs/1572-2019-04-22-Blood%202018.pdf
      reference_title: https://www.ucm.es/data/cont/docs/1572-2019-04-22-Blood%202018.pdf
      supports: SUPPORT
      evidence_source: OTHER
      snippet: |-
        Ultimately, this results in
        enrichment for self-reactive speciﬁ cities within CD4
        1 Tconv cells,
        which may undergo peripheral activation and expansion because
        of the reduced number and impaired function of T
        reg cells. Alto-
        gether, these abnormalities create an environment that promotes
        the development of autoimmunity in this condition.
      explanation: >-
        The authors' integrated model links altered selection and Treg control to autoimmunity; organ-specific
        effectors and penetrance remain incompletely resolved.
      directness: INDIRECT
    - reference: PMID:42661620
      reference_title: "Expanding the clinical spectrum of CD3γ deficiency: comprehensive characterization
        of adult-onset disease and integrated reevaluation of all reported patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The most frequently reported autoimmune manifestations included autoimmune thyroiditis (7/18,
        38.9%), AIHA (7/18, 38.9%), and ITP (4/18, 22.2%)
      explanation: >-
        The frequency recorded here is the 7/18 figure quoted.
  - target: Autoimmune thrombocytopenia
    description: >-
      Tolerance failure permits immune-mediated platelet loss in reported ITP/Evans syndrome. The receptor/Treg
      model is an upstream explanation; the relative platelet-clearance and production mechanisms were
      not established.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ucm.es/data/cont/docs/1572-2019-04-22-Blood%202018.pdf
      reference_title: https://www.ucm.es/data/cont/docs/1572-2019-04-22-Blood%202018.pdf
      supports: SUPPORT
      evidence_source: OTHER
      snippet: |-
        Ultimately, this results in
        enrichment for self-reactive speciﬁ cities within CD4
        1 Tconv cells,
        which may undergo peripheral activation and expansion because
        of the reduced number and impaired function of T
        reg cells. Alto-
        gether, these abnormalities create an environment that promotes
        the development of autoimmunity in this condition.
      explanation: >-
        The authors' integrated model links altered selection and Treg control to autoimmunity; organ-specific
        effectors and penetrance remain incompletely resolved.
      directness: INDIRECT
    - reference: PMID:42661620
      reference_title: "Expanding the clinical spectrum of CD3γ deficiency: comprehensive characterization
        of adult-onset disease and integrated reevaluation of all reported patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The most frequently reported autoimmune manifestations included autoimmune thyroiditis (7/18,
        38.9%), AIHA (7/18, 38.9%), and ITP (4/18, 22.2%)
      explanation: >-
        The frequency recorded here is the 4/18 figure quoted.
  - target: Autoimmune hepatitis
    description: >-
      The tolerance-defect model provides a qualified contribution to the explicitly diagnosed autoimmune
      hepatitis in the Turkish series. This is separate from the unconfirmed hepatic diagnosis in the
      Taiwanese adult.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ucm.es/data/cont/docs/1572-2019-04-22-Blood%202018.pdf
      reference_title: https://www.ucm.es/data/cont/docs/1572-2019-04-22-Blood%202018.pdf
      supports: SUPPORT
      evidence_source: OTHER
      snippet: |-
        Ultimately, this results in
        enrichment for self-reactive speciﬁ cities within CD4
        1 Tconv cells,
        which may undergo peripheral activation and expansion because
        of the reduced number and impaired function of T
        reg cells. Alto-
        gether, these abnormalities create an environment that promotes
        the development of autoimmunity in this condition.
      explanation: >-
        The authors' integrated model links altered selection and Treg control to autoimmunity; organ-specific
        effectors and penetrance remain incompletely resolved.
      directness: INDIRECT
    - reference: PMID:24910257
      reference_title: CD3G gene defects in familial autoimmune thyroiditis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        We found all five patients to display autoimmunity: autoimmune thyroiditis (n = 5), autoimmune haemolytic anaemia (n = 2), immune thrombocytopenia (n = 1), autoimmune hepatitis (n = 1), minimal change nephrotic syndrome (n = 1), vitiligo (n = 1) and positive antinuclear antibodies (n = 3) as well as high IgE (n = 2) and atopic eczema (n = 2).
      explanation: >-
        The primary series assigns autoimmune hepatitis to one of five patients, not both siblings collectively.
  - target: Vitiligo
    description: >-
      Defective immune tolerance offers a proposed contribution to the reported autoimmune depigmentation.
      The CD3G studies do not directly measure melanocyte-specific effector cells or explain why only
      some patients develop vitiligo.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ucm.es/data/cont/docs/1572-2019-04-22-Blood%202018.pdf
      reference_title: https://www.ucm.es/data/cont/docs/1572-2019-04-22-Blood%202018.pdf
      supports: SUPPORT
      evidence_source: OTHER
      snippet: |-
        Ultimately, this results in
        enrichment for self-reactive speciﬁ cities within CD4
        1 Tconv cells,
        which may undergo peripheral activation and expansion because
        of the reduced number and impaired function of T
        reg cells. Alto-
        gether, these abnormalities create an environment that promotes
        the development of autoimmunity in this condition.
      explanation: >-
        The authors' integrated model links altered selection and Treg control to autoimmunity; organ-specific
        effectors and penetrance remain incompletely resolved.
      directness: INDIRECT
    - reference: PMID:24910257
      reference_title: CD3G gene defects in familial autoimmune thyroiditis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We found all five patients to display autoimmunity: autoimmune thyroiditis (n = 5), autoimmune
        haemolytic anaemia (n = 2), immune thrombocytopenia (n = 1), autoimmune hepatitis (n = 1), minimal
        change nephrotic syndrome (n = 1), vitiligo (n = 1) and positive antinuclear antibodies (n = 3)
        as well as high IgE (n = 2) and atopic eczema (n = 2).
      explanation: >-
        Records vitiligo among the autoimmune manifestations of the series.
  - target: Minimal change glomerulonephritis
    description: >-
      The primary authors classify the single minimal-change nephrotic presentation among autoimmune manifestations.
      The tolerance model is a qualified upstream contribution; no particular podocyte-targeting antibody
      or T-cell mediator was established.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ucm.es/data/cont/docs/1572-2019-04-22-Blood%202018.pdf
      reference_title: https://www.ucm.es/data/cont/docs/1572-2019-04-22-Blood%202018.pdf
      supports: SUPPORT
      evidence_source: OTHER
      snippet: |-
        Ultimately, this results in
        enrichment for self-reactive speciﬁ cities within CD4
        1 Tconv cells,
        which may undergo peripheral activation and expansion because
        of the reduced number and impaired function of T
        reg cells. Alto-
        gether, these abnormalities create an environment that promotes
        the development of autoimmunity in this condition.
      explanation: >-
        The authors' integrated model links altered selection and Treg control to autoimmunity; organ-specific
        effectors and penetrance remain incompletely resolved.
      directness: INDIRECT
    - reference: PMID:24910257
      reference_title: CD3G gene defects in familial autoimmune thyroiditis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        We found all five patients to display autoimmunity: autoimmune thyroiditis (n = 5), autoimmune haemolytic anaemia (n = 2), immune thrombocytopenia (n = 1), autoimmune hepatitis (n = 1), minimal change nephrotic syndrome (n = 1), vitiligo (n = 1) and positive antinuclear antibodies (n = 3) as well as high IgE (n = 2) and atopic eczema (n = 2).
      explanation: >-
        The explicit minimal-change diagnosis supports the more specific renal binding; this is one affected
        patient.
  - target: Lupus-like systemic autoimmunity
    description: >-
      The 2024 authors attribute a lupus-like syndrome meeting SLICC criteria to CD3G deficiency. The
      tolerance model provides an indirect explanation, while organ-specific immune mechanisms remain
      unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ucm.es/data/cont/docs/1572-2019-04-22-Blood%202018.pdf
      reference_title: https://www.ucm.es/data/cont/docs/1572-2019-04-22-Blood%202018.pdf
      supports: SUPPORT
      evidence_source: OTHER
      snippet: |-
        Ultimately, this results in
        enrichment for self-reactive speciﬁ cities within CD4
        1 Tconv cells,
        which may undergo peripheral activation and expansion because
        of the reduced number and impaired function of T
        reg cells. Alto-
        gether, these abnormalities create an environment that promotes
        the development of autoimmunity in this condition.
      explanation: >-
        The authors' integrated model links altered selection and Treg control to autoimmunity; organ-specific
        effectors and penetrance remain incompletely resolved.
      directness: INDIRECT
    - reference: PMID:39094808
      reference_title: A CD3G homozygous pathogenic variant in a Chinese child with lupus-like
        disease, autoimmune thyroiditis and immunodeficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        This is the first patient who met the diagnostic criteria for systemic lupus erythematosus by the Systemic Lupus International Collaborating Clinics (SLICC) group.
      explanation: >-
        The authors explicitly report fulfillment of lupus criteria; the preferred wording preserves their
        lupus-like terminology.
  - target: Hypothyroidism
    description: >-
      Autoimmune thyroid disease can produce hypothyroidism in the reported patients; euthyroid thyroiditis
      and the opposite functional state also occur.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:42661620
      reference_title: 'Expanding the clinical spectrum of CD3γ deficiency: comprehensive characterization
        of adult-onset disease and integrated reevaluation of all reported patients.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        Until the age of
        37 years, her medical history was unremarkable except for hypothy-
        roidism secondary to Hashimoto thyroiditis.
      explanation: >-
        Adult P1's hypothyroidism is explicitly attributed to Hashimoto disease.
  - target: Hyperthyroidism
    description: >-
      Autoimmune thyroid disease can produce hyperthyroidism in the reported patients; euthyroid thyroiditis
      and the opposite functional state also occur.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:42661620
      reference_title: 'Expanding the clinical spectrum of CD3γ deficiency: comprehensive characterization
        of adult-onset disease and integrated reevaluation of all reported patients.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        lupus-like disease, thyroiditis
        (hyperthyroidism), cytopenias, infections/
        steroids, high dose IVIG
      explanation: >-
        The 2026 table reports hyperthyroidism in the Chinese child; this is a subtype of thyroid dysfunction,
        not all autoimmune thyroiditis.
  - target: Interstitial lung disease
    description: >-
      Immune dysregulation contributed to the 2021 child's interstitial lung disease as suggested by partial
      improvement during immunosuppression. EBER-positive infiltrates and bacterial infection make this
      a mixed, incompletely resolved attribution.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33215322
      reference_title: Complete Absence of CD3γ Protein Expression Is Responsible for Combined
        Immunodeficiency with Autoimmunity Rather than SCID.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        The patient responded to the immunosuppressant therapy with significant improvement of the diarrhea (weight: 20th percentile), of the AIHA (Hb11.1 g/dL), and partial improvement of the chronic lung disease by chest CT up to transplant.
      explanation: >-
        Clinical response supports an immune contribution but was incomplete and occurred with infection-directed
        treatment.
- name: Defective Adaptive Host Defense
  biological_scale: ORGANISM
  downstream:
  - target: Chronic Infection-Associated Airway Injury
    description: >-
      Repeated respiratory infection contributes to structural airway injury in reported patients.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31921117
      reference_title: A Novel CD3G Mutation in a Taiwanese Patient With Normal T Regulatory
        Function Presenting With the CVID Phenotype Free of Autoimmunity-Analysis of all Genotypes
        and Phenotypes.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        He
        experienced recurrent sinopulmonary infections that were
        complicated by mastoiditis, pleural eﬀusion, and bronchiecta sis
        (Supplemental Figure 1A) and required hospitalization from
        the age of 14-years.
      explanation: >-
        The longitudinal case attributes these pulmonary/ENT complications to recurrent infection.
  - target: Recurrent respiratory infections
    description: >-
      Deficient adaptive pathogen control contributes to recurrent respiratory infections in the reported
      infection-prone patients; exposure, treatment and residual function modify the outcome.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31921117
      reference_title: A Novel CD3G Mutation in a Taiwanese Patient With Normal T Regulatory
        Function Presenting With the CVID Phenotype Free of Autoimmunity-Analysis of all Genotypes
        and Phenotypes.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: |-
        Patients with opportunistic infections,
        including parainﬂuenza pneumonia, Candida albicans , Giardia
        intestinalis, and severe EBV infection, reﬂect profoundly
        impaired lymphocyte proliferation
      explanation: >-
        The authors relate opportunistic infection to impaired cellular immunity, based on reported cases
        rather than a prospective causal experiment.
      directness: INDIRECT
    - reference: PMID:31921117
      reference_title: "A Novel CD3G Mutation in a Taiwanese Patient With Normal T Regulatory Function
        Presenting With the CVID Phenotype Free of Autoimmunity-Analysis of all Genotypes and Phenotypes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        we report the case of a 36-year-old male who presented with recurrent sinopulmonary infections
        without opportunistic infections; this was compatible with hypogammaglobulinemia, but normal PHA-lymphocyte
        proliferation.
      explanation: >-
        Documents recurrent sinopulmonary infection as a presenting feature.
  - target: Recurrent oral thrush
    description: >-
      Deficient adaptive pathogen control contributes to recurrent oral thrush in the reported infection-prone
      patients; exposure, treatment and residual function modify the outcome.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31921117
      reference_title: A Novel CD3G Mutation in a Taiwanese Patient With Normal T Regulatory
        Function Presenting With the CVID Phenotype Free of Autoimmunity-Analysis of all Genotypes
        and Phenotypes.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: |-
        Patients with opportunistic infections,
        including parainﬂuenza pneumonia, Candida albicans , Giardia
        intestinalis, and severe EBV infection, reﬂect profoundly
        impaired lymphocyte proliferation
      explanation: >-
        The authors relate opportunistic infection to impaired cellular immunity, based on reported cases
        rather than a prospective causal experiment.
      directness: INDIRECT
    - reference: PMID:18482219
      reference_title: Hematopoietic stem cell transplantation in a CD3 gamma-deficient infant with
        inflammatory bowel disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        The patient had suffered from intractable diarrhea, recurrent pulmonary infections and oral moniliasis since two months of age.
      explanation: >-
        Oral moniliasis was part of the infant's early recurring infectious phenotype.
  - target: Severe Epstein-Barr virus infection
    description: >-
      Deficient adaptive pathogen control contributes to severe epstein-barr virus infection in the reported
      infection-prone patients; exposure, treatment and residual function modify the outcome.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31921117
      reference_title: A Novel CD3G Mutation in a Taiwanese Patient With Normal T Regulatory
        Function Presenting With the CVID Phenotype Free of Autoimmunity-Analysis of all Genotypes
        and Phenotypes.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: |-
        Patients with opportunistic infections,
        including parainﬂuenza pneumonia, Candida albicans , Giardia
        intestinalis, and severe EBV infection, reﬂect profoundly
        impaired lymphocyte proliferation
      explanation: >-
        The authors relate opportunistic infection to impaired cellular immunity, based on reported cases
        rather than a prospective causal experiment.
      directness: INDIRECT
    - reference: PMID:33215322
      reference_title: Complete Absence of CD3γ Protein Expression Is Responsible for Combined
        Immunodeficiency with Autoimmunity Rather than SCID.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        EBV viremia (102,000 copies/mL) was documented. Bronchoalveolar lavage (BAL) showed neutrophilia and led to isolation of Klebsiella pneumoniae. Lung biopsy was significant for interstitial lymphoplasmacytic infiltrate with positive in situ hybridization for Epstein-Barr encoding region (EBER).
      explanation: >-
        The pre-transplant clinical episode combined EBV viremia and EBV-positive lung pathology, with
        concomitant bacterial infection.
  - target: Mastoiditis
    description: >-
      Recurrent sinopulmonary infection led to mastoiditis in the Taiwanese adult, representing a local
      infectious complication.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31921117
      reference_title: A Novel CD3G Mutation in a Taiwanese Patient With Normal T Regulatory
        Function Presenting With the CVID Phenotype Free of Autoimmunity-Analysis of all Genotypes
        and Phenotypes.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        He
        experienced recurrent sinopulmonary infections that were
        complicated by mastoiditis, pleural eﬀusion, and bronchiecta sis
        (Supplemental Figure 1A) and required hospitalization from
        the age of 14-years.
      explanation: >-
        The longitudinal case attributes these pulmonary/ENT complications to recurrent infection.
  - target: Pleural effusion
    description: >-
      Recurrent sinopulmonary infection led to pleural effusion in the Taiwanese adult, representing a
      local infectious complication.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31921117
      reference_title: A Novel CD3G Mutation in a Taiwanese Patient With Normal T Regulatory
        Function Presenting With the CVID Phenotype Free of Autoimmunity-Analysis of all Genotypes
        and Phenotypes.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        He
        experienced recurrent sinopulmonary infections that were
        complicated by mastoiditis, pleural eﬀusion, and bronchiecta sis
        (Supplemental Figure 1A) and required hospitalization from
        the age of 14-years.
      explanation: >-
        The longitudinal case attributes these pulmonary/ENT complications to recurrent infection.
  - target: Severe varicella infection
    description: >-
      Impaired cellular host defense provides a qualified contribution to severe varicella in the reported
      patients; viral exposure and residual function are not resolved by the clinical table.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31921117
      reference_title: A Novel CD3G Mutation in a Taiwanese Patient With Normal T Regulatory
        Function Presenting With the CVID Phenotype Free of Autoimmunity-Analysis of all Genotypes
        and Phenotypes.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: |-
        Patients with opportunistic infections,
        including parainﬂuenza pneumonia, Candida albicans , Giardia
        intestinalis, and severe EBV infection, reﬂect profoundly
        impaired lymphocyte proliferation
      explanation: >-
        The authors relate opportunistic infection to impaired cellular immunity, based on reported cases
        rather than a prospective causal experiment.
      directness: INDIRECT
    - reference: PMID:42661620
      reference_title: 'Expanding the clinical spectrum of CD3γ deficiency: comprehensive characterization
        of adult-onset disease and integrated reevaluation of all reported patients.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        15 F10-1/Turkey m >30 y NM_000073.3:c.205A>T
        (p.Lys69Ter)
        Hom severe varicella infection, respiratory infections,
        psoriasis, asthma
      explanation: >-
        The patient-specific row records severe varicella; the table was visually checked for column identity.
  description: >-
    Impaired T-cell effector responses and, in some patients, antibody deficiency reduce adaptive control
    of infection. Clinical expression ranges from recurrent sinopulmonary bacterial infections to severe
    viral, fungal and intestinal infections. Preserved PHA responses and Treg function in the Taiwanese
    adult coexist with humoral failure and recurrent respiratory infection. Neither a single proliferation
    assay nor surface receptor intensity is a validated predictor of infection severity.
  evidence:
  - reference: PMID:31921117
    reference_title: A Novel CD3G Mutation in a Taiwanese Patient With Normal T Regulatory Function
      Presenting With the CVID Phenotype Free of Autoimmunity-Analysis of all Genotypes and
      Phenotypes.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: |-
      Patients with opportunistic infections,
      including parainﬂuenza pneumonia, Candida albicans , Giardia
      intestinalis, and severe EBV infection, reﬂect profoundly
      impaired lymphocyte proliferation
    explanation: >-
      The authors relate opportunistic infection to impaired cellular immunity, based on reported cases
      rather than a prospective causal experiment.
    directness: INDIRECT
  - reference: PMID:39094808
    reference_title: A CD3G homozygous pathogenic variant in a Chinese child with lupus-like
      disease, autoimmune thyroiditis and immunodeficiency.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: |-
      CD3G gene encodes one of the CD3 subunits named CD3γ, and its deficiency can cause autoimmune disorders, immunodeficiency and recurrent infections.
    explanation: >-
      The clinical report summarizes the causal association between CD3G deficiency and impaired host
      defense.
    directness: INDIRECT
- name: Chronic Infection-Associated Airway Injury
  biological_scale: TISSUE
  description: >-
    Repeated sinopulmonary infection can produce structural airway damage and bronchiectasis. The Taiwanese
    case explicitly describes bronchiectasis as a complication of recurrent infections and later links
    worsening bronchiectasis to increased pulmonary artery pressure and cor pulmonale. The route is supported
    within that longitudinal case and is not a claim that every patient develops permanent lung disease.
  evidence:
  - reference: PMID:31921117
    reference_title: A Novel CD3G Mutation in a Taiwanese Patient With Normal T Regulatory Function
      Presenting With the CVID Phenotype Free of Autoimmunity-Analysis of all Genotypes and
      Phenotypes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      He
      experienced recurrent sinopulmonary infections that were
      complicated by mastoiditis, pleural eﬀusion, and bronchiecta sis
      (Supplemental Figure 1A) and required hospitalization from
      the age of 14-years.
    explanation: >-
      The longitudinal case attributes these pulmonary/ENT complications to recurrent infection.
  downstream:
  - target: Bronchiectasis
    description: >-
      Cumulative infection-associated airway injury produces permanent airway dilatation in the reported
      respiratory disease cases.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31921117
      reference_title: A Novel CD3G Mutation in a Taiwanese Patient With Normal T Regulatory
        Function Presenting With the CVID Phenotype Free of Autoimmunity-Analysis of all Genotypes
        and Phenotypes.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        He
        experienced recurrent sinopulmonary infections that were
        complicated by mastoiditis, pleural eﬀusion, and bronchiecta sis
        (Supplemental Figure 1A) and required hospitalization from
        the age of 14-years.
      explanation: >-
        The longitudinal case attributes these pulmonary/ENT complications to recurrent infection.
  - target: Finger clubbing
    description: >-
      The Taiwanese authors attribute finger clubbing to chronic endobronchial disease. This case-level
      causal interpretation is not extrapolated to all patients.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31921117
      reference_title: A Novel CD3G Mutation in a Taiwanese Patient With Normal T Regulatory
        Function Presenting With the CVID Phenotype Free of Autoimmunity-Analysis of all Genotypes
        and Phenotypes.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        Atrophic endobronchial mucosa caused
        exercise tachypnea, clubbing of the ﬁngers, and obstructive sleep
        apnea.
      explanation: >-
        The authors attribute these findings to the patient's chronic airway disease; the report does
        not establish this as a universal route in CD3G deficiency.
  - target: Obstructive sleep apnea
    description: >-
      The Taiwanese authors attribute obstructive sleep apnea to chronic endobronchial disease. This case-level
      causal interpretation is not extrapolated to all patients.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31921117
      reference_title: A Novel CD3G Mutation in a Taiwanese Patient With Normal T Regulatory
        Function Presenting With the CVID Phenotype Free of Autoimmunity-Analysis of all Genotypes
        and Phenotypes.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        Atrophic endobronchial mucosa caused
        exercise tachypnea, clubbing of the ﬁngers, and obstructive sleep
        apnea.
      explanation: >-
        The authors attribute these findings to the patient's chronic airway disease; the report does
        not establish this as a universal route in CD3G deficiency.
  - target: Exertional tachypnea
    description: >-
      The Taiwanese authors attribute exertional tachypnea to chronic endobronchial disease. This case-level
      causal interpretation is not extrapolated to all patients.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31921117
      reference_title: A Novel CD3G Mutation in a Taiwanese Patient With Normal T Regulatory
        Function Presenting With the CVID Phenotype Free of Autoimmunity-Analysis of all Genotypes
        and Phenotypes.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        Atrophic endobronchial mucosa caused
        exercise tachypnea, clubbing of the ﬁngers, and obstructive sleep
        apnea.
      explanation: >-
        The authors attribute these findings to the patient's chronic airway disease; the report does
        not establish this as a universal route in CD3G deficiency.
  - target: Pulmonary hypertension
    description: >-
      Worsening bronchiectasis was reported to raise pulmonary artery pressure and progress to cor pulmonale
      in the Taiwanese patient; this is a case-specific sequence.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31921117
      reference_title: A Novel CD3G Mutation in a Taiwanese Patient With Normal T Regulatory
        Function Presenting With the CVID Phenotype Free of Autoimmunity-Analysis of all Genotypes
        and Phenotypes.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        Exacerbation of his bronchiectasis increased his pulmonary
        artery pressure, reopened a closed atrial septal defect, and
        gradually progressed to cor pulmonale.
      explanation: >-
        The Taiwanese report explicitly describes a longitudinal airway-to-pulmonary-pressure-to-right-heart
        sequence; this is one clinical attribution.
  - target: Cor pulmonale
    description: >-
      Worsening bronchiectasis was reported to raise pulmonary artery pressure and progress to cor pulmonale
      in the Taiwanese patient; this is a case-specific sequence.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31921117
      reference_title: A Novel CD3G Mutation in a Taiwanese Patient With Normal T Regulatory
        Function Presenting With the CVID Phenotype Free of Autoimmunity-Analysis of all Genotypes
        and Phenotypes.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        Exacerbation of his bronchiectasis increased his pulmonary
        artery pressure, reopened a closed atrial septal defect, and
        gradually progressed to cor pulmonale.
      explanation: >-
        The Taiwanese report explicitly describes a longitudinal airway-to-pulmonary-pressure-to-right-heart
        sequence; this is one clinical attribution.
- name: Impaired T-Cell Help for Memory B-Cell Maturation
  biological_scale: CELLULAR
  description: >-
    In the Taiwanese adult, stimulated CD4 cells expressed about half the control CD40L level and class-switched
    memory B cells were reduced. The authors propose insufficient CD40L-dependent help as a contributor
    to B-cell maturation failure. CD40L was measured after PMA/ionomycin, not direct TCR triggering; the
    CD3G-to-CD40L route and its prevalence remain unresolved, and the proposed Tfh/B-cell coculture was
    not performed.
  evidence:
  - reference: PMID:31921117
    reference_title: A Novel CD3G Mutation in a Taiwanese Patient With Normal T Regulatory Function
      Presenting With the CVID Phenotype Free of Autoimmunity-Analysis of all Genotypes and
      Phenotypes.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: |-
      The CD40L expression of activated CD4 + in the patient was around half that
      of the healthy control, while CD69 expression was used as an a ctivation marker after stimulation with 10 ng/mL PMA and 1 ug/m L ionomycin for 5 h. T wo duplicates
      were performed.
    explanation: >-
      Stimulated patient-cell measurement; it does not directly test TCR-dependent induction or rescue
      of B-cell maturation.
  downstream:
  - target: Humoral Immune Failure
    description: >-
      Reduced CD40L-dependent T-cell help is a proposed contributor to deficient memory-B-cell maturation
      and humoral responses in the Taiwanese patient.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31921117
      reference_title: A Novel CD3G Mutation in a Taiwanese Patient With Normal T Regulatory
        Function Presenting With the CVID Phenotype Free of Autoimmunity-Analysis of all Genotypes
        and Phenotypes.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: |-
        This may have been
        associated with insuﬃcient CD40L expression, which has been
        reported in some patients with CVID and hyper IgM
      explanation: >-
        The authors propose insufficient T-cell help as a contributor to the Taiwanese patient's memory-B-cell
        abnormality; they did not establish an intrinsic B-cell lesion.
      directness: INDIRECT
- name: Immune-Mediated Gastrointestinal Mucosal Injury
  biological_scale: TISSUE
  description: >-
    Autoimmune enteropathy with anti-enterocyte reactivity was demonstrated in the 2021 child, together
    with chronic active gastritis and colitis. Persistent gastrointestinal mucosal injury can account
    for diarrhea and nutritional failure; improvement during immunosuppression and in another patient
    after HSCT supports an immune contribution. The gastric contribution is inferred from the overall
    inflammatory presentation rather than a demonstrated stomach-specific effector. This mechanism is
    not assigned to every infectious or unclassified episode of diarrhea.
  evidence:
  - reference: PMID:33215322
    reference_title: Complete Absence of CD3γ Protein Expression Is Responsible for Combined
      Immunodeficiency with Autoimmunity Rather than SCID.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Upper and lower endoscopy showed chronic active gastritis and colitis, and biopsies of small intestine and colon were consistent with autoimmune enteropathy. Linear staining along the periapical border of the enterocytes was positive for anti-enterocyte auto-antibodies.
    explanation: >-
      Clinical pathology supports immune-mediated intestinal injury in this child; antibody positivity
      alone does not establish the entire effector pathway.
  downstream:
  - target: Protracted diarrhea
    description: >-
      Biopsy-supported autoimmune enteropathy provides a local cause of persistent diarrhea in the 2021
      child, with improvement during combined immunosuppression; infection-associated diarrhea in other
      cases is not assigned this route.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33215322
      reference_title: Complete Absence of CD3γ Protein Expression Is Responsible for Combined
        Immunodeficiency with Autoimmunity Rather than SCID.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        Despite treatment with metronidazole for C. difficile toxin positivity by PCR and repeatedly negative stool cultures, the patient continued to suffer from progressively worsening GI manifestations for the first 2 years of life with consequent failure to thrive (weight below third percentile) and TPN requirement at 22 months of age for 3 months.
      explanation: >-
        Persistent gastrointestinal disease continued despite infection-directed treatment; subsequent
        biopsy and response support an immune-mediated contribution.
  - target: Failure to thrive
    description: >-
      The 2021 clinical course explicitly links worsening gastrointestinal disease to growth failure and
      parenteral nutrition; improvement of diarrhea and weight during immunosuppression supports this
      case-scoped sequence.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33215322
      reference_title: Complete Absence of CD3γ Protein Expression Is Responsible for Combined
        Immunodeficiency with Autoimmunity Rather than SCID.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        Despite treatment with metronidazole for C. difficile toxin positivity by PCR and repeatedly negative stool cultures, the patient continued to suffer from progressively worsening GI manifestations for the first 2 years of life with consequent failure to thrive (weight below third percentile) and TPN requirement at 22 months of age for 3 months.
      explanation: >-
        Persistent gastrointestinal disease continued despite infection-directed treatment; subsequent
        biopsy and response support an immune-mediated contribution.
    - reference: PMID:33215322
      reference_title: Complete Absence of CD3γ Protein Expression Is Responsible for Combined
        Immunodeficiency with Autoimmunity Rather than SCID.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        The patient responded to the immunosuppressant therapy with significant improvement of the diarrhea (weight: 20th percentile), of the AIHA (Hb11.1 g/dL), and partial improvement of the chronic lung disease by chest CT up to transplant.
      explanation: >-
        Clinical response supports an immune contribution but was incomplete and occurred with infection-directed
        treatment.
  - target: Chronic colitis
    description: >-
      Anti-enterocyte reactivity and autoimmune enteropathy provide an immune explanation for the associated
      chronic active colitis in the 2021 child. They do not identify a single pathogenic autoantibody
      as the proven effector.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33215322
      reference_title: Complete Absence of CD3γ Protein Expression Is Responsible for Combined
        Immunodeficiency with Autoimmunity Rather than SCID.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        Upper and lower endoscopy showed chronic active gastritis and colitis, and biopsies of small intestine and colon were consistent with autoimmune enteropathy. Linear staining along the periapical border of the enterocytes was positive for anti-enterocyte auto-antibodies.
      explanation: >-
        Clinical pathology supports immune-mediated intestinal injury in this child; antibody positivity
        alone does not establish the entire effector pathway.
  - target: Anoperineal fistula
    description: >-
      The transplant report attributes fistula improvement to improving inflammatory bowel disease, supporting
      a qualified local inflammatory contribution in that infant.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:18482219
      reference_title: Hematopoietic stem cell transplantation in a CD3 gamma-deficient infant with
        inflammatory bowel disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        A significant improvement in diarrhea, perianal lesions, and rectal fistula was observed suggesting an improvement in inflammatory bowel disease.
      explanation: >-
        The transplant report links improvement of the fistula to improvement of inflammatory bowel disease.
  - target: Chronic gastritis
    description: >-
      The biopsy-supported autoimmune gastrointestinal presentation provides a qualified immune contribution
      to accompanying chronic active gastritis; a stomach-specific effector was not isolated.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33215322
      reference_title: Complete Absence of CD3γ Protein Expression Is Responsible for Combined
        Immunodeficiency with Autoimmunity Rather than SCID.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        Upper and lower endoscopy showed chronic active gastritis and colitis, and biopsies of small intestine and colon were consistent with autoimmune enteropathy. Linear staining along the periapical border of the enterocytes was positive for anti-enterocyte auto-antibodies.
      explanation: >-
        Clinical pathology supports immune-mediated intestinal injury in this child; antibody positivity
        alone does not establish the entire effector pathway.
- name: Suspected Nodular Regenerative Hepatic Remodeling
  biological_scale: TISSUE
  description: >-
    The Taiwanese adult had imaging and clinical findings interpreted as nodular regenerative hyperplasia.
    Liver biopsy was declined. The authors favored a slowly progressive portal-hypertensive pattern after
    an unsuccessful steroid trial for possible autoimmune hepatitis. The upstream relation to CD3G/humoral
    deficiency is not established; the local hepatic-to-portal/splenic interpretation remains provisional.
  evidence:
  - reference: PMID:31921117
    reference_title: A Novel CD3G Mutation in a Taiwanese Patient With Normal T Regulatory Function
      Presenting With the CVID Phenotype Free of Autoimmunity-Analysis of all Genotypes and
      Phenotypes.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: |-
      V ascular engorgement of the portal vein, uneven liver surfac e,
      tortuous splenic artery, splenomegaly, and poor response to
      steroids were characteristic of NRH classiﬁcation II in our patient
      with the CD3 γ Del 213A mutation
    explanation: >-
      The authors interpret a constellation of clinical/imaging findings as a portal-hypertensive NRH
      pattern, without histological confirmation.
    directness: INDIRECT
  - reference: PMID:31921117
    reference_title: A Novel CD3G Mutation in a Taiwanese Patient With Normal T Regulatory Function
      Presenting With the CVID Phenotype Free of Autoimmunity-Analysis of all Genotypes and
      Phenotypes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      he was unwilling to undergo a liver biopsy for pathological proof.
    explanation: >-
      The proposed hepatic substrate was not biopsy-confirmed.
  downstream:
  - target: Portal hypertension
    description: >-
      The authors' suspected NRH pattern provides a qualified local explanation for portal hypertension.
      Unconfirmed histology and unresolved upstream genetic attribution limit this route.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31921117
      reference_title: A Novel CD3G Mutation in a Taiwanese Patient With Normal T Regulatory
        Function Presenting With the CVID Phenotype Free of Autoimmunity-Analysis of all Genotypes
        and Phenotypes.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: |-
        slowly progressing to portal hypertension and splenomegaly
        causing mild ALP elevation
      explanation: >-
        The report applies this proposed NRH course to its patient; the local interpretation is indirect
        and not a proven CD3G-to-liver mechanism.
      directness: INDIRECT
  - target: Splenomegaly
    description: >-
      The authors' suspected NRH pattern provides a qualified local explanation for splenomegaly. Unconfirmed
      histology and unresolved upstream genetic attribution limit this route.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31921117
      reference_title: A Novel CD3G Mutation in a Taiwanese Patient With Normal T Regulatory
        Function Presenting With the CVID Phenotype Free of Autoimmunity-Analysis of all Genotypes
        and Phenotypes.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: |-
        slowly progressing to portal hypertension and splenomegaly
        causing mild ALP elevation
      explanation: >-
        The report applies this proposed NRH course to its patient; the local interpretation is indirect
        and not a proven CD3G-to-liver mechanism.
      directness: INDIRECT
- name: Reduced Thymic Output and Altered T-Cell Homeostasis
  biological_scale: CELLULAR
  description: >-
    Human CD3G case studies infer reduced thymic output from low TRECs and naive-cell numbers despite
    preservation or later accumulation of peripheral polyclonal memory T cells. Absolute CD4/CD8 counts
    vary, and TCR/CD3-dependent gating can underestimate cells. The relative effects of production, selection,
    peripheral survival and treatment cannot be separated in every patient.
  evidence:
  - reference: PMID:17277165
    reference_title: Differential biological role of CD3 chains revealed by human
      immunodeficiencies.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: |-
      Thus, the peripheral T lymphocyte pool was comparatively well preserved in human CD3gamma deficiencies despite poor thymus output or clinical outcome.
    explanation: >-
      The human series distinguishes reduced output from a complete developmental block.
    directness: INDIRECT
  downstream: []
- name: Helicobacter pylori-Associated Gastric Disease
  biological_scale: TISSUE
  description: >-
    Adult P2 developed H. pylori-associated gastric MALT lymphoma, which entered remission after eradication.
    This treatment response supports a local infectious contribution to the lymphoma; the report does
    not establish that CD3G deficiency caused the infection or conferred a general lymphoma predisposition.
  evidence:
  - reference: PMID:42661620
    reference_title: 'Expanding the clinical spectrum of CD3γ deficiency: comprehensive characterization
      of adult-onset disease and integrated reevaluation of all reported patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      At 22 years of age, she was diagnosed with Helicobacter
      pylori -associated gastric mucosa-associated lymphoid tissue
      (MALT) lymphoma. Eradication therapy resulted in complete
      remission.
    explanation: >-
      The lymphoma and eradication response are patient observations; HPO gastric lymphoma is broader
      than the source's MALT subtype.
  downstream:
  - target: Gastric MALT lymphoma
    description: >-
      The reported H. pylori association and complete remission following eradication support a case-scoped
      infectious contribution to gastric MALT lymphoma. The intervening cellular mechanism and upstream
      CD3G attribution were not demonstrated.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:42661620
      reference_title: 'Expanding the clinical spectrum of CD3γ deficiency: comprehensive characterization
        of adult-onset disease and integrated reevaluation of all reported patients.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        At 22 years of age, she was diagnosed with Helicobacter
        pylori -associated gastric mucosa-associated lymphoid tissue
        (MALT) lymphoma. Eradication therapy resulted in complete
        remission.
      explanation: >-
        The lymphoma and eradication response are patient observations; HPO gastric lymphoma is broader
        than the source's MALT subtype.
phenotypes:
- name: Combined immunodeficiency
  category: Immunologic
  diagnostic: true
  description: >-
    CD3G deficiency is classified as a combined cellular/humoral immunodeficiency. Severity ranges from
    predominantly autoimmune disease or a CVID-like presentation to life-threatening infantile SCID-like
    disease; preserved absolute T-cell numbers are not universal.
  phenotype_term:
    preferred_term: Combined immunodeficiency
    term:
      id: HP:0005387
      label: Combined immunodeficiency
  evidence:
  - reference: PMID:40147628
    reference_title: Five Patients With Two Novel Homozygous Variants in CD3 Subunits and
      Comprehensive Review of the Literature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      In contrast, patients with CD3γ deficiency may either show an SCID phenotype or a milder, less severe CID phenotype.
    explanation: >-
      The 2025 analysis distinguishes severe clinical presentations from milder CID within CD3G deficiency;
      CD3D/E/Z cases are not pooled into this phenotype.
  reports_on:
  - target: Impaired T-Cell Proliferative Response
    relationship: READOUT_OF
    description: >-
      The composite clinical immunodeficiency designation summarizes cellular and humoral dysfunction;
      it is not a separate downstream event caused by repeating one of its defining components. Individual
      assay deficits and severity remain variable.
  - target: Humoral Immune Failure
    relationship: READOUT_OF
    description: >-
      The composite clinical immunodeficiency designation summarizes cellular and humoral dysfunction;
      it is not a separate downstream event caused by repeating one of its defining components. Individual
      assay deficits and severity remain variable.
- name: Reduced surface TCR/CD3 expression
  category: Immunologic
  diagnostic: true
  description: >-
    Reduced TCR/CD3 surface abundance is a recurrent flow-cytometric finding, including in patients with
    preserved absolute T-cell numbers. Other patients have T-cell lymphopenia; receptor intensity, proportion
    of positive cells and absolute counts are distinct measurements.
  phenotype_term:
    preferred_term: Reduced surface TCR/CD3 expression
    term:
      id: HP:0011840
      label: Abnormal T cell physiology
  evidence:
  - reference: url:https://www.ucm.es/data/cont/docs/1572-2019-04-22-Blood%202018.pdf
    reference_title: https://www.ucm.es/data/cont/docs/1572-2019-04-22-Blood%202018.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      expression of both CD3 (as indicated by staining with a
      monoclonal antibody speciﬁcf o rt h eC D 3e chain) and TCRab was
      markedly reduced in each of these subsets in all patients with
      CD3G mutations (Figure 1).
    explanation: >-
      Surface CD3/TCR was assessed in five patients P1–P5 across conventional CD4, regulatory CD4 and
      CD8 subsets. Normal total T-cell counts are not part of this phenotype definition.
  reports_on:
  - target: Impaired TCR/CD3 Complex Assembly and Surface Expression
    relationship: READOUT_OF
    description: >-
      Flow-cytometric surface abundance reports on the receptor-expression defect; the available HPO binding
      is broader than this specific assay.
- name: Impaired PHA-induced T-cell proliferation
  category: Immunologic
  diagnostic: true
  description: >-
    Reduced PHA-induced transformation is documented in several patients, but is not universal. The Taiwanese
    adult had normal PHA incorporation and activation with reduced ConA responses. The 2026 11/11 aggregate
    refers to abnormal responses to at least one tested mitogen, and cannot be assigned as the frequency
    of this PHA-specific phenotype.
  phenotype_term:
    preferred_term: Impaired phytohemagglutinin-induced T lymphocyte transformation
    term:
      id: HP:0025834
      label: Impaired phytohemagglutinin-induced T lymphocyte transformation
  evidence:
  - reference: url:https://www.ucm.es/data/cont/docs/1572-2019-04-22-Blood%202018.pdf
    reference_title: https://www.ucm.es/data/cont/docs/1572-2019-04-22-Blood%202018.pdf
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: |-
      When
      stimulated with phytohema gglutinin (PHA), both CD4 1 and
      CD81 T cells in CD3g-deﬁcient patients demonstrated reduced
      cellular division (as shown by CFSE dilution);
    explanation: >-
      The six-patient study measured reduced division after PHA stimulation.
  - reference: PMID:31921117
    reference_title: A Novel CD3G Mutation in a Taiwanese Patient With Normal T Regulatory Function
      Presenting With the CVID Phenotype Free of Autoimmunity-Analysis of all Genotypes and
      Phenotypes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      this was compatible with hypogammaglobulinemia, but normal PHA-lymphocyte proliferation.
    explanation: >-
      The Taiwanese patient is an explicitly scoped exception to universal PHA impairment, not a disease-level
      absence annotation.
  reports_on:
  - target: Impaired T-Cell Proliferative Response
    relationship: READOUT_OF
    description: >-
      The culture-based PHA transformation assay reports a stimulus-specific functional response.
- name: Autoimmune thyroiditis
  category: Endocrine
  frequency: 7/18 in the 2026 reported-case aggregation
  description: >-
    Autoimmune thyroid inflammation was reported in 7/18 cases in the 2026 literature aggregation and
    in all five patients of the 2014 two-family series. Presentations include euthyroid thyroiditis, hypothyroidism/Hashimoto
    disease and hyperthyroidism; the entire 7/18 aggregate is not restricted to Hashimoto thyroiditis.
  phenotype_term:
    preferred_term: Autoimmune thyroiditis
    term:
      id: HP:0100646
      label: Thyroiditis
  evidence:
  - reference: PMID:42661620
    reference_title: "Expanding the clinical spectrum of CD3γ deficiency: comprehensive characterization
      of adult-onset disease and integrated reevaluation of all reported patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most frequently reported autoimmune manifestations included autoimmune thyroiditis (7/18, 38.9%),
      AIHA (7/18, 38.9%), and ITP (4/18, 22.2%)
    explanation: >-
      The published aggregate covers autoimmune thyroiditis broadly, rather than a Hashimoto-only numerator;
      these are selected reported cases.
  - reference: PMID:24910257
    reference_title: CD3G gene defects in familial autoimmune thyroiditis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We found all five patients to display autoimmunity: autoimmune thyroiditis (n = 5), autoimmune haemolytic
      anaemia (n = 2), immune thrombocytopenia (n = 1), autoimmune hepatitis (n = 1), minimal change nephrotic
      syndrome (n = 1), vitiligo (n = 1) and positive antinuclear antibodies (n = 3) as well as high IgE
      (n = 2) and atopic eczema (n = 2).
    explanation: >-
      Autoimmune thyroiditis in all five patients of a two-family series.
- name: Autoimmune hemolytic anemia
  category: Hematologic
  frequency: 7/18 in the 2026 reported-case aggregation
  description: >-
    Autoimmune hemolytic anemia was reported in 7/18 patients in the 2026 aggregation. Both newly described
    adults developed Evans syndrome with AIHA and immune thrombocytopenia. This is an overlapping literature-series
    proportion, not a population penetrance estimate.
  phenotype_term:
    preferred_term: Autoimmune hemolytic anemia
    term:
      id: HP:0001890
      label: Autoimmune hemolytic anemia
  evidence:
  - reference: PMID:42661620
    reference_title: "Expanding the clinical spectrum of CD3γ deficiency: comprehensive characterization
      of adult-onset disease and integrated reevaluation of all reported patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most frequently reported autoimmune manifestations included autoimmune thyroiditis (7/18, 38.9%),
      AIHA (7/18, 38.9%), and ITP (4/18, 22.2%)
    explanation: >-
      The frequency recorded here is the 7/18 figure quoted.
- name: Autoimmune thrombocytopenia
  category: Hematologic
  frequency: 4/18 in the 2026 reported-case aggregation
  description: >-
    Autoimmune thrombocytopenia was reported in 4/18 patients in the 2026 aggregation. Both newly described
    adults developed Evans syndrome with AIHA and immune thrombocytopenia. This is an overlapping literature-series
    proportion, not a population penetrance estimate.
  phenotype_term:
    preferred_term: Autoimmune thrombocytopenia
    term:
      id: HP:0001973
      label: Autoimmune thrombocytopenia
  evidence:
  - reference: PMID:42661620
    reference_title: "Expanding the clinical spectrum of CD3γ deficiency: comprehensive characterization
      of adult-onset disease and integrated reevaluation of all reported patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most frequently reported autoimmune manifestations included autoimmune thyroiditis (7/18, 38.9%),
      AIHA (7/18, 38.9%), and ITP (4/18, 22.2%)
    explanation: >-
      The frequency recorded here is the 4/18 figure quoted.
  - reference: PMID:42661620
    reference_title: "Expanding the clinical spectrum of CD3γ deficiency: comprehensive characterization
      of adult-onset disease and integrated reevaluation of all reported patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both patients presented with humoral immunodeficiency and Evans syndrome responsive to rituximab
      therapy.
    explanation: >-
      Documents the pairing of immune thrombocytopenia with haemolytic anaemia
      as Evans syndrome.
- name: Decreased circulating immunoglobulin concentration
  category: Immunologic
  description: >-
    Low immunoglobulin concentrations occur in a subset, with profound or selective deficiencies. The
    2026 9/18 count combines hypo- and dysgammaglobulinemia and is not a low-IgG-specific denominator.
    The Taiwanese patient had IgG 5.9 mg/dL before regular replacement; normal subsequent IgG values were
    obtained during infusions. Protein loss and immunosuppression are additional potential confounders
    in other patients.
  phenotype_term:
    preferred_term: Decreased circulating immunoglobulin concentration
    term:
      id: HP:0004313
      label: Decreased circulating immunoglobulin concentration
  evidence:
  - reference: PMID:33215322
    reference_title: Complete Absence of CD3γ Protein Expression Is Responsible for Combined
      Immunodeficiency with Autoimmunity Rather than SCID.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Reduced numbers of switched and unswitched memory B cells, hypogammaglobulinemia (IgG 338 mg/dL), and impaired vaccination response to Haemophilus influenzae type B and Pneumococcus were also present (Table 1).
    explanation: >-
      The child had several directly documented humoral defects before replacement therapy.
  - reference: PMID:42661620
    reference_title: 'Expanding the clinical spectrum of CD3γ deficiency: comprehensive characterization
      of adult-onset disease and integrated reevaluation of all reported patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Immunological assessment demonstrated mark-
      edly reduced serum IgG levels, while IgA and IgM were initially
      normal (Table 1).
    explanation: >-
      Adult P1 had a selective initial IgG deficit; other isotypes declined later during glucocorticoid
      treatment.
  reports_on:
  - target: Humoral Immune Failure
    relationship: READOUT_OF
    description: >-
      Serum concentrations measure a variable humoral deficit and require treatment/protein-loss context.
- name: Recurrent respiratory infections
  category: Immunologic
  description: >-
    Recurrent sinopulmonary infections affect a subset, including children and adults. The Taiwanese patient
    required long-term immunoglobulin replacement and antimicrobial treatment; autoimmune-only presentations
    also occur.
  phenotype_term:
    preferred_term: Recurrent respiratory infections
    term:
      id: HP:0002205
      label: Recurrent respiratory infections
  evidence:
  - reference: PMID:31921117
    reference_title: "A Novel CD3G Mutation in a Taiwanese Patient With Normal T Regulatory Function Presenting
      With the CVID Phenotype Free of Autoimmunity-Analysis of all Genotypes and Phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we report the case of a 36-year-old male who presented with recurrent sinopulmonary infections without
      opportunistic infections; this was compatible with hypogammaglobulinemia, but normal PHA-lymphocyte
      proliferation.
    explanation: >-
      Documents recurrent sinopulmonary infection as a presenting feature.
- name: Protracted diarrhea
  category: Gastrointestinal
  description: >-
    Persistent diarrhea occurred in severely affected infants. In the detailed 2021 case, autoimmune enteropathy/chronic
    colitis persisted despite treatment of C. difficile positivity; other cases have infection-associated
    or incompletely classified enteropathy. The mechanism is not uniform.
  phenotype_term:
    preferred_term: Protracted diarrhea
    term:
      id: HP:0004385
      label: Protracted diarrhea
  evidence:
  - reference: PMID:18482219
    reference_title: Hematopoietic stem cell transplantation in a CD3 gamma-deficient infant with
      inflammatory bowel disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient had suffered from intractable diarrhea, recurrent pulmonary infections and oral moniliasis
      since two months of age.
    explanation: >-
      Documents intractable diarrhoea from early infancy in a CD3gamma-deficient
      patient.
- name: Failure to thrive
  category: Growth
  description: >-
    Growth failure accompanied severe prolonged intestinal disease in reported infants. The detailed 2021
    case required parenteral nutrition at 22 months after worsening gastrointestinal manifestations; diarrhea
    and weight improved during combined immunosuppression.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:33215322
    reference_title: Complete Absence of CD3γ Protein Expression Is Responsible for Combined
      Immunodeficiency with Autoimmunity Rather than SCID.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the patient continued to suffer from progressively worsening GI manifestations for the first 2 years
      of life with consequent failure to thrive (weight below third percentile) and TPN requirement at
      22 months of age for 3 months.
    explanation: >-
      Documents growth failure driven by the enteropathy in a severely affected
      infant.
- name: Decreased regulatory T cell proportion
  category: Immunologic
  description: >-
    Reduced circulating Treg proportion was found in the 2018 autoimmune cohort and detailed 2021 child.
    It is not universal: the Taiwanese adult had preserved proportions and suppressive function. Proportion,
    repertoire diversity and coculture suppression are separate measurements.
  phenotype_term:
    preferred_term: Decreased regulatory T cell proportion
    term:
      id: HP:0020113
      label: Decreased regulatory T cell proportion
  evidence:
  - reference: PMID:33215322
    reference_title: Complete Absence of CD3γ Protein Expression Is Responsible for Combined
      Immunodeficiency with Autoimmunity Rather than SCID.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Immunological evaluations revealed a combined immunodeficiency with normal absolute CD3+ T cell
      numbers, CD4+ T cell lymphopenia (627 cells/μl) with a reduced proportion of naïve T cells and T
      regulatory cells, increased frequency of memory CD4+, CD8+ cells, and CD45RA+CCR7− CD8+ T cells
      (TEMRA).
    explanation: >-
      Records the reduced regulatory T-cell proportion alongside the normal
      absolute T-cell count.
  reports_on:
  - target: Regulatory T-Cell Deficiency and Impaired Suppression
    relationship: READOUT_OF
    description: >-
      Flow-cytometric Treg proportion measures the abundance component of the regulatory-cell abnormality.
- name: Bronchiectasis
  category: Respiratory
  frequency: 4/5 with recurrent sinopulmonary infection in the 2019 review
  description: >-
    Structural bronchiectasis complicates respiratory disease in reported patients. The 2019 review reported
    bronchiectasis in four of five patients with recurrent sinopulmonary infection; this conditional count
    is not four of five unselected CD3G patients.
  phenotype_term:
    preferred_term: Bronchiectasis
    term:
      id: HP:0002110
      label: Bronchiectasis
  evidence:
  - reference: PMID:31921117
    reference_title: "A Novel CD3G Mutation in a Taiwanese Patient With Normal T Regulatory Function Presenting
      With the CVID Phenotype Free of Autoimmunity-Analysis of all Genotypes and Phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Four of the ﬁve patients with recurrent sinopulmonary infections developed bronchiectasis.
    explanation: >-
      The frequency recorded here is the 4/5 figure quoted.
- name: Increased circulating IgE concentration
  category: Immunologic
  frequency: 2/5 in the 2014 two-family series
  description: >-
    High IgE concentrations were reported in two of five affected patients in the 2014 two-family series.
    The primary abstract supports 2/5, not the 3/5 stated in the Falcon report. These are selected relatives
    with one shared splice variant, not an unselected disease-frequency estimate.
  phenotype_term:
    preferred_term: Increased circulating IgE concentration
    term:
      id: HP:0003212
      label: Increased circulating IgE concentration
  evidence:
  - reference: PMID:24910257
    reference_title: CD3G gene defects in familial autoimmune thyroiditis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We found all five patients to display autoimmunity: autoimmune thyroiditis (n = 5), autoimmune haemolytic
      anaemia (n = 2), immune thrombocytopenia (n = 1), autoimmune hepatitis (n = 1), minimal change nephrotic
      syndrome (n = 1), vitiligo (n = 1) and positive antinuclear antibodies (n = 3) as well as high IgE
      (n = 2) and atopic eczema (n = 2).
    explanation: >-
      The frequency recorded here is the high-IgE count of 2 out of the 5
      patients in the series.
- name: Atopic dermatitis
  category: Dermatologic
  frequency: 2/5 in the 2014 two-family series
  description: >-
    Atopic eczema was reported in two of five affected patients in the 2014 two-family series. The primary
    abstract supports 2/5, not the 3/5 stated in the Falcon report. These are selected relatives with
    one shared splice variant, not an unselected disease-frequency estimate.
  phenotype_term:
    preferred_term: Atopic dermatitis
    term:
      id: HP:0001047
      label: Atopic dermatitis
  evidence:
  - reference: PMID:24910257
    reference_title: CD3G gene defects in familial autoimmune thyroiditis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We found all five patients to display autoimmunity: autoimmune thyroiditis (n = 5), autoimmune haemolytic
      anaemia (n = 2), immune thrombocytopenia (n = 1), autoimmune hepatitis (n = 1), minimal change nephrotic
      syndrome (n = 1), vitiligo (n = 1) and positive antinuclear antibodies (n = 3) as well as high IgE
      (n = 2) and atopic eczema (n = 2).
    explanation: >-
      The frequency recorded here is the atopic-eczema count of 2 out of the 5
      patients in the series.
- name: Autoimmune hepatitis
  category: Hepatic
  description: >-
    Autoimmune hepatitis was reported in one patient of the 2014 five-person series, corresponding to
    the more severely affected sister in the earlier two-sibling report. The combined sibling abstract
    must not be read as evidence that both sisters had hepatitis.
  phenotype_term:
    preferred_term: Autoimmune hepatitis
    term:
      id: HP:5210421
      label: Autoimmune hepatitis
  evidence:
  - reference: PMID:24910257
    reference_title: CD3G gene defects in familial autoimmune thyroiditis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      We found all five patients to display autoimmunity: autoimmune thyroiditis (n = 5), autoimmune haemolytic anaemia (n = 2), immune thrombocytopenia (n = 1), autoimmune hepatitis (n = 1), minimal change nephrotic syndrome (n = 1), vitiligo (n = 1) and positive antinuclear antibodies (n = 3) as well as high IgE (n = 2) and atopic eczema (n = 2).
    explanation: >-
      The primary series assigns autoimmune hepatitis to one of five patients, not both siblings collectively.
- name: Vitiligo
  category: Dermatologic
  description: >-
    Vitiligo was reported in one of five patients in the 2014 series and in an older Spanish patient in
    other reports. Counts from successive publications overlap and should not be added as independent
    patients.
  phenotype_term:
    preferred_term: Vitiligo
    term:
      id: HP:0001045
      label: Vitiligo
  evidence:
  - reference: PMID:24910257
    reference_title: CD3G gene defects in familial autoimmune thyroiditis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We found all five patients to display autoimmunity: autoimmune thyroiditis (n = 5), autoimmune haemolytic
      anaemia (n = 2), immune thrombocytopenia (n = 1), autoimmune hepatitis (n = 1), minimal change nephrotic
      syndrome (n = 1), vitiligo (n = 1) and positive antinuclear antibodies (n = 3) as well as high IgE
      (n = 2) and atopic eczema (n = 2).
    explanation: >-
      Records vitiligo among the autoimmune manifestations of the series.
- name: Decreased CD4 T-cell count
  category: Immunologic
  description: >-
    Absolute CD4 lymphopenia is variable. Rowe P4 had a low count; the detailed 2021 report also describes
    CD4 lymphopenia in P1, although the earlier table used a different reference interval. Normal total
    T-cell numbers do not exclude a CD4 subset defect.
  phenotype_term:
    preferred_term: Decreased CD4 T-cell count
    term:
      id: HP:5210418
      label: Decreased total CD4+ T cell count
  evidence:
  - reference: url:https://www.ucm.es/data/cont/docs/1572-2019-04-22-Blood%202018.pdf
    reference_title: https://www.ucm.es/data/cont/docs/1572-2019-04-22-Blood%202018.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      a low CD4 1 cell count was observed in P4,
      and decreased CD8 1 cell counts were detected in P2, P4, and
      P6.
    explanation: >-
      The six-patient study distinguishes absolute CD4 and CD8 count deficits by patient.
  reports_on:
  - target: Reduced Thymic Output and Altered T-Cell Homeostasis
    relationship: READOUT_OF
    description: >-
      The measured subset count/proportion reports on altered T-cell production and homeostasis; it does
      not by itself identify the responsible developmental or peripheral process.
- name: Decreased CD8 T-cell count
  category: Immunologic
  description: >-
    Absolute CD8 counts were low in Rowe P2, P4 and P6; low percentages are not treated as proof of a
    low absolute count.
  phenotype_term:
    preferred_term: Decreased CD8 T-cell count
    term:
      id: HP:5210426
      label: Decreased total CD8+ T cell count
  evidence:
  - reference: url:https://www.ucm.es/data/cont/docs/1572-2019-04-22-Blood%202018.pdf
    reference_title: https://www.ucm.es/data/cont/docs/1572-2019-04-22-Blood%202018.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      a low CD4 1 cell count was observed in P4,
      and decreased CD8 1 cell counts were detected in P2, P4, and
      P6.
    explanation: >-
      Three specified patients had low absolute CD8 counts, unlike the separate CD4 finding.
  reports_on:
  - target: Reduced Thymic Output and Altered T-Cell Homeostasis
    relationship: READOUT_OF
    description: >-
      The measured subset count/proportion reports on altered T-cell production and homeostasis; it does
      not by itself identify the responsible developmental or peripheral process.
- name: Decreased naive CD4 T-cell proportion
  category: Immunologic
  description: >-
    Reduced naive-cell proportions accompany altered T-cell development/homeostasis. All six Rowe patients
    had reduced naive T cells, and the Taiwanese adult had mild naive-CD4 reduction despite normal PHA
    responses.
  phenotype_term:
    preferred_term: Decreased naive CD4 T-cell proportion
    term:
      id: HP:0410378
      label: Decreased naive CD4+ T cell proportion
  evidence:
  - reference: url:https://www.ucm.es/data/cont/docs/1572-2019-04-22-Blood%202018.pdf
    reference_title: https://www.ucm.es/data/cont/docs/1572-2019-04-22-Blood%202018.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      All patients had a reduced proportion of na ¨ıve T cells and
      increased percentage of memory CD41 and CD81 cells,
    explanation: >-
      The six-patient study reported altered naive/memory balance; CD4-specific scope is corroborated
      in the Taiwanese report.
  - reference: PMID:31921117
    reference_title: A Novel CD3G Mutation in a Taiwanese Patient With Normal T Regulatory Function
      Presenting With the CVID Phenotype Free of Autoimmunity-Analysis of all Genotypes and
      Phenotypes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      a mild decrease in naïve T cells
      (CD4+CD45RA+ or CD4 +CD45RO-CCR7+; Table 1 and
      Supplemental Figure 2).
    explanation: >-
      The explicit CD4 phenotype avoids transferring a mixed T-cell count to a specific subset.
  reports_on:
  - target: Reduced Thymic Output and Altered T-Cell Homeostasis
    relationship: READOUT_OF
    description: >-
      The measured subset count/proportion reports on altered T-cell production and homeostasis; it does
      not by itself identify the responsible developmental or peripheral process.
- name: Decreased class-switched memory B-cell proportion
  category: Immunologic
  description: >-
    Class-switched memory B cells were markedly reduced in the Taiwanese adult, and reduced memory B cells
    were also documented in the 2021 child. The proposed CD40L-dependent maturation mechanism is not established
    in every patient.
  phenotype_term:
    preferred_term: Decreased class-switched memory B-cell proportion
    term:
      id: HP:0030388
      label: Decreased class-switched memory B cell proportion
  evidence:
  - reference: PMID:31921117
    reference_title: A Novel CD3G Mutation in a Taiwanese Patient With Normal T Regulatory Function
      Presenting With the CVID Phenotype Free of Autoimmunity-Analysis of all Genotypes and
      Phenotypes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      His CD27 + memory B cells were
      obviously decreased (6.8%), predominantly in switched CD27 +
      memory B cells
    explanation: >-
      The patient's memory-B-cell reduction was predominantly in the switched compartment.
  reports_on:
  - target: Impaired T-Cell Help for Memory B-Cell Maturation
    relationship: READOUT_OF
    description: >-
      Subset flow cytometry is a readout of the proposed memory-B-cell maturation defect; the upstream
      CD40L attribution remains qualified.
- name: Impaired specific antibody response to vaccination
  category: Immunologic
  description: >-
    The 2021 child had impaired responses to Hib and pneumococcal vaccines; the Taiwanese adult had a
    poor polysaccharide response. Vaccine formulation and vaccination history are insufficiently specified
    to bind every observation to one narrower vaccine subtype.
  phenotype_term:
    preferred_term: Impaired specific antibody response to vaccination
    term:
      id: HP:0032140
      label: Decreased specific antibody response to vaccination
  evidence:
  - reference: PMID:33215322
    reference_title: Complete Absence of CD3γ Protein Expression Is Responsible for Combined
      Immunodeficiency with Autoimmunity Rather than SCID.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Reduced numbers of switched and unswitched memory B cells, hypogammaglobulinemia (IgG 338 mg/dL), and impaired vaccination response to Haemophilus influenzae type B and Pneumococcus were also present (Table 1).
    explanation: >-
      The child had several directly documented humoral defects before replacement therapy.
  reports_on:
  - target: Humoral Immune Failure
    relationship: READOUT_OF
    description: >-
      Antigen-specific vaccine response reports on humoral function, rather than constituting a separate
      disease-progression step.
- name: Chronic colitis
  category: Gastrointestinal
  description: >-
    The 2021 child had chronic active colitis and autoimmune enteropathy supported by intestinal biopsy
    and anti-enterocyte staining. This preserves the documented intestinal inflammation without equating
    every CD3G-associated diarrhea episode with autoimmunity.
  phenotype_term:
    preferred_term: Chronic colitis
    term:
      id: HP:0100281
      label: Chronic colitis
  evidence:
  - reference: PMID:33215322
    reference_title: Complete Absence of CD3γ Protein Expression Is Responsible for Combined
      Immunodeficiency with Autoimmunity Rather than SCID.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Upper and lower endoscopy showed chronic active gastritis and colitis, and biopsies of small intestine and colon were consistent with autoimmune enteropathy.
    explanation: >-
      The detailed patient report directly documents chronic colitis and the broader autoimmune enteropathy.
- name: Recurrent oral thrush
  category: Infectious
  description: >-
    Recurrent oral candidiasis occurred in severely affected infants, including the 2008 transplant recipient;
    adult-onset antibody-predominant disease can lack opportunistic infection.
  phenotype_term:
    preferred_term: Recurrent oral thrush
    term:
      id: HP:0009098
      label: Chronic oral candidiasis
  evidence:
  - reference: PMID:18482219
    reference_title: Hematopoietic stem cell transplantation in a CD3 gamma-deficient infant with
      inflammatory bowel disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      The patient had suffered from intractable diarrhea, recurrent pulmonary infections and oral moniliasis since two months of age.
    explanation: >-
      Oral moniliasis was part of the infant's early recurring infectious phenotype.
- name: Severe Epstein-Barr virus infection
  category: Infectious
  description: >-
    The 2021 child had high EBV viremia and EBER-positive interstitial lung infiltrates before transplantation.
    Later post-HCT EBV-associated tumors are not treated as evidence for an intrinsic malignancy phenotype.
  phenotype_term:
    preferred_term: Severe Epstein-Barr virus infection
    term:
      id: HP:0031693
      label: Severe Epstein Barr virus infection
  evidence:
  - reference: PMID:33215322
    reference_title: Complete Absence of CD3γ Protein Expression Is Responsible for Combined
      Immunodeficiency with Autoimmunity Rather than SCID.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      EBV viremia (102,000 copies/mL) was documented. Bronchoalveolar lavage (BAL) showed neutrophilia and led to isolation of Klebsiella pneumoniae. Lung biopsy was significant for interstitial lymphoplasmacytic infiltrate with positive in situ hybridization for Epstein-Barr encoding region (EBER).
    explanation: >-
      The pre-transplant clinical episode combined EBV viremia and EBV-positive lung pathology, with concomitant
      bacterial infection.
- name: Minimal change glomerulonephritis
  category: Renal
  description: >-
    Minimal-change nephrotic syndrome was reported in one patient of the 2014 two-family series and described
    among autoimmune manifestations. The specific renal immune effector route is not established.
  phenotype_term:
    preferred_term: Minimal change glomerulonephritis
    term:
      id: HP:0012579
      label: Minimal change glomerulonephritis
  evidence:
  - reference: PMID:24910257
    reference_title: CD3G gene defects in familial autoimmune thyroiditis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      We found all five patients to display autoimmunity: autoimmune thyroiditis (n = 5), autoimmune haemolytic anaemia (n = 2), immune thrombocytopenia (n = 1), autoimmune hepatitis (n = 1), minimal change nephrotic syndrome (n = 1), vitiligo (n = 1) and positive antinuclear antibodies (n = 3) as well as high IgE (n = 2) and atopic eczema (n = 2).
    explanation: >-
      The explicit minimal-change diagnosis supports the more specific renal binding; this is one affected
      patient.
- name: Antinuclear antibody positivity
  category: Immunologic
  description: >-
    ANA positivity occurred in three of five patients in the 2014 series and in the later lupus-like case.
    ANA alone is not a diagnosis of lupus or proof of the mechanism of each organ lesion.
  phenotype_term:
    preferred_term: Antinuclear antibody positivity
    term:
      id: HP:0003493
      label: Antinuclear antibody positivity
  evidence:
  - reference: PMID:24910257
    reference_title: CD3G gene defects in familial autoimmune thyroiditis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      We found all five patients to display autoimmunity: autoimmune thyroiditis (n = 5), autoimmune haemolytic anaemia (n = 2), immune thrombocytopenia (n = 1), autoimmune hepatitis (n = 1), minimal change nephrotic syndrome (n = 1), vitiligo (n = 1) and positive antinuclear antibodies (n = 3) as well as high IgE (n = 2) and atopic eczema (n = 2).
    explanation: >-
      The five-person series explicitly reports ANA positivity in three patients; it does not diagnose
      lupus in those three individuals.
  reports_on:
  - target: Multisystem Autoimmunity
    relationship: READOUT_OF
    description: >-
      ANA is a laboratory readout of autoantibody-associated dysregulation; it does not measure a specific
      tissue injury.
- name: Interstitial lung disease
  category: Respiratory
  description: >-
    The 2021 child had lymphoplasmacytic interstitial lung disease with EBER positivity, recurrent bacterial
    infection and only partial improvement on immunosuppression. Infection and immune dysregulation may
    both contribute; the report does not isolate a single cause.
  phenotype_term:
    preferred_term: Interstitial lung disease
    term:
      id: HP:0006530
      label: Abnormal pulmonary interstitial morphology
  evidence:
  - reference: PMID:33215322
    reference_title: Complete Absence of CD3γ Protein Expression Is Responsible for Combined
      Immunodeficiency with Autoimmunity Rather than SCID.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      EBV viremia (102,000 copies/mL) was documented. Bronchoalveolar lavage (BAL) showed neutrophilia and led to isolation of Klebsiella pneumoniae. Lung biopsy was significant for interstitial lymphoplasmacytic infiltrate with positive in situ hybridization for Epstein-Barr encoding region (EBER).
    explanation: >-
      The pre-transplant clinical episode combined EBV viremia and EBV-positive lung pathology, with concomitant
      bacterial infection.
  - reference: PMID:33215322
    reference_title: Complete Absence of CD3γ Protein Expression Is Responsible for Combined
      Immunodeficiency with Autoimmunity Rather than SCID.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      The patient responded to the immunosuppressant therapy with significant improvement of the diarrhea (weight: 20th percentile), of the AIHA (Hb11.1 g/dL), and partial improvement of the chronic lung disease by chest CT up to transplant.
    explanation: >-
      Clinical response supports an immune contribution but was incomplete and occurred with infection-directed
      treatment.
- name: Asthma
  category: Respiratory
  description: >-
    Asthma was reported in the Chinese child and several earlier patients. The 2014 authors proposed an
    immune-dysregulation/Th2 contribution to atopy without directly measuring Th2 skewing.
  phenotype_term:
    preferred_term: Asthma
    term:
      id: HP:0002099
      label: Asthma
  evidence:
  - reference: PMID:39094808
    reference_title: A CD3G homozygous pathogenic variant in a Chinese child with lupus-like
      disease, autoimmune thyroiditis and immunodeficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      We report a 10-year-old Chinese boy presented with lupus-like disease in addition to autoimmune thyroiditis, asthma, immunodeficiency and recurrent infection.
    explanation: >-
      Asthma is explicitly reported in the genetically confirmed child; no disease-wide frequency follows.
- name: Hypothyroidism
  category: Endocrine
  description: >-
    Hypothyroidism occurs in a subset with autoimmune thyroid disease, including adult P1 in 2026. Euthyroid
    and hyperthyroid cases are also reported.
  phenotype_term:
    preferred_term: Hypothyroidism
    term:
      id: HP:0000821
      label: Hypothyroidism
  evidence:
  - reference: PMID:42661620
    reference_title: 'Expanding the clinical spectrum of CD3γ deficiency: comprehensive characterization
      of adult-onset disease and integrated reevaluation of all reported patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Until the age of
      37 years, her medical history was unremarkable except for hypothy-
      roidism secondary to Hashimoto thyroiditis.
    explanation: >-
      Adult P1's hypothyroidism is explicitly attributed to Hashimoto disease.
- name: Hyperthyroidism
  category: Endocrine
  description: >-
    Hyperthyroidism occurs in selected autoimmune thyroiditis cases, including the two patient entries
    summarized in the 2026 table. It is not interchangeable with Hashimoto-associated hypothyroidism.
  phenotype_term:
    preferred_term: Hyperthyroidism
    term:
      id: HP:0000836
      label: Hyperthyroidism
  evidence:
  - reference: PMID:42661620
    reference_title: 'Expanding the clinical spectrum of CD3γ deficiency: comprehensive characterization
      of adult-onset disease and integrated reevaluation of all reported patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      lupus-like disease, thyroiditis
      (hyperthyroidism), cytopenias, infections/
      steroids, high dose IVIG
    explanation: >-
      The 2026 table reports hyperthyroidism in the Chinese child; this is a subtype of thyroid dysfunction,
      not all autoimmune thyroiditis.
- name: Short stature
  category: Growth
  description: >-
    Short stature was documented in the older sister from the Turkish autoimmune family. Nutritional disease,
    endocrine dysfunction, chronic illness and treatment are possible contributors, but the reviewed reports
    do not assign one causal route.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:42661620
    reference_title: 'Expanding the clinical spectrum of CD3γ deficiency: comprehensive characterization
      of adult-onset disease and integrated reevaluation of all reported patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      8 F5-2/Turkey f 20 y NM_000073.3:c.80-1G>C (p.)? Hom Hashimoto thyroiditis, AIHA, short stature
    explanation: >-
      The 2026 case table explicitly lists short stature for F5-2; the observation does not establish
      a growth mechanism.
- name: Lymphadenopathy
  category: Immunologic
  description: >-
    Adult P1 developed generalized lymphadenopathy at 37 years. Repeated biopsies showed reactive lymphoid
    hyperplasia, not lymphoma; nodes regressed during immunoglobulin replacement.
  phenotype_term:
    preferred_term: Lymphadenopathy
    term:
      id: HP:0002716
      label: Lymphadenopathy
  evidence:
  - reference: PMID:42661620
    reference_title: 'Expanding the clinical spectrum of CD3γ deficiency: comprehensive characterization
      of adult-onset disease and integrated reevaluation of all reported patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      At 37 years of age, she
      developed generalized lymphadenopathy accompanied by mild pan-
      cytopenia.
    explanation: >-
      Generalized nodal enlargement is a direct clinical observation in adult P1.
  - reference: PMID:42661620
    reference_title: 'Expanding the clinical spectrum of CD3γ deficiency: comprehensive characterization
      of adult-onset disease and integrated reevaluation of all reported patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Histopathological
      examination consistently demonstrated reactive lymphoid hyperpla-
      sia without evidence of lymphoma or other malignancy.
    explanation: >-
      Repeated biopsies distinguished the nodal enlargement from lymphoma.
- name: Gastric MALT lymphoma
  category: Neoplastic
  description: >-
    Adult P2 developed H. pylori-associated gastric MALT lymphoma at 22 years, with remission after eradication.
    The authors explicitly leave CD3G causality uncertain; this single case does not establish a syndrome-wide
    cancer predisposition.
  phenotype_term:
    preferred_term: Gastric MALT lymphoma
    term:
      id: HP:0045038
      label: Gastric lymphoma
  evidence:
  - reference: PMID:42661620
    reference_title: 'Expanding the clinical spectrum of CD3γ deficiency: comprehensive characterization
      of adult-onset disease and integrated reevaluation of all reported patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      At 22 years of age, she was diagnosed with Helicobacter
      pylori -associated gastric mucosa-associated lymphoid tissue
      (MALT) lymphoma. Eradication therapy resulted in complete
      remission.
    explanation: >-
      The lymphoma and eradication response are patient observations; HPO gastric lymphoma is broader
      than the source's MALT subtype.
- name: Portal hypertension
  category: Hepatic
  description: >-
    Portal venous enlargement and hypertension developed in the Taiwanese adult with suspected nodular
    regenerative hyperplasia. Liver biopsy was declined, so the proposed hepatic substrate was not histologically
    confirmed.
  phenotype_term:
    preferred_term: Portal hypertension
    term:
      id: HP:0001409
      label: Portal hypertension
  evidence:
  - reference: PMID:31921117
    reference_title: A Novel CD3G Mutation in a Taiwanese Patient With Normal T Regulatory Function
      Presenting With the CVID Phenotype Free of Autoimmunity-Analysis of all Genotypes and
      Phenotypes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      He was given steroid treatment (1 mg/kg/day) for 2 months in
      an attempt to alleviate portal vein hypertension, which may hav e
      been caused by autoimmune hepatitis, but the treatment failed .
    explanation: >-
      The clinical report documents portal hypertension and an unsuccessful therapeutic hypothesis; it
      does not confirm autoimmune hepatitis.
- name: Splenomegaly
  category: Hematologic
  description: >-
    Splenomegaly accompanied the Taiwanese adult's portal-hypertensive liver presentation. Other CD3G
    cases have lymphoproliferative phenotypes, so the congestive interpretation is case-specific.
  phenotype_term:
    preferred_term: Splenomegaly
    term:
      id: HP:0001744
      label: Splenomegaly
  evidence:
  - reference: PMID:31921117
    reference_title: A Novel CD3G Mutation in a Taiwanese Patient With Normal T Regulatory Function
      Presenting With the CVID Phenotype Free of Autoimmunity-Analysis of all Genotypes and
      Phenotypes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      an engorged
      portal vein, splenomegaly, splenic artery, and coarse liver su rface
      gradually developed
    explanation: >-
      Imaging and examination showed progressive splenic enlargement in the reported hepatic course.
- name: Pulmonary hypertension
  category: Cardiovascular
  description: >-
    The Taiwanese adult developed increased pulmonary artery pressure during worsening bronchiectasis.
    The term describes the reported pulmonary arterial pressure elevation; the report does not establish
    idiopathic/group-1 pulmonary arterial hypertension.
  phenotype_term:
    preferred_term: Pulmonary hypertension
    term:
      id: HP:0002092
      label: Pulmonary arterial hypertension
  evidence:
  - reference: PMID:31921117
    reference_title: A Novel CD3G Mutation in a Taiwanese Patient With Normal T Regulatory Function
      Presenting With the CVID Phenotype Free of Autoimmunity-Analysis of all Genotypes and
      Phenotypes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Exacerbation of his bronchiectasis increased his pulmonary
      artery pressure, reopened a closed atrial septal defect, and
      gradually progressed to cor pulmonale.
    explanation: >-
      The Taiwanese report explicitly describes a longitudinal airway-to-pulmonary-pressure-to-right-heart
      sequence; this is one clinical attribution.
- name: Cor pulmonale
  category: Cardiovascular
  description: >-
    Cor pulmonale developed during worsening bronchiectasis and rising pulmonary artery pressure in the
    Taiwanese adult.
  phenotype_term:
    preferred_term: Cor pulmonale
    term:
      id: HP:0001648
      label: Cor pulmonale
  evidence:
  - reference: PMID:31921117
    reference_title: A Novel CD3G Mutation in a Taiwanese Patient With Normal T Regulatory Function
      Presenting With the CVID Phenotype Free of Autoimmunity-Analysis of all Genotypes and
      Phenotypes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Exacerbation of his bronchiectasis increased his pulmonary
      artery pressure, reopened a closed atrial septal defect, and
      gradually progressed to cor pulmonale.
    explanation: >-
      The Taiwanese report explicitly describes a longitudinal airway-to-pulmonary-pressure-to-right-heart
      sequence; this is one clinical attribution.
- name: Finger clubbing
  category: Respiratory
  description: >-
    Finger clubbing was reported in the Taiwanese adult with longstanding structural airway disease. The
    authors' local attribution is retained with single-patient scope.
  phenotype_term:
    preferred_term: Finger clubbing
    term:
      id: HP:0100759
      label: Clubbing of fingers
  evidence:
  - reference: PMID:31921117
    reference_title: A Novel CD3G Mutation in a Taiwanese Patient With Normal T Regulatory Function
      Presenting With the CVID Phenotype Free of Autoimmunity-Analysis of all Genotypes and
      Phenotypes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Atrophic endobronchial mucosa caused
      exercise tachypnea, clubbing of the ﬁngers, and obstructive sleep
      apnea.
    explanation: >-
      The authors attribute these findings to the patient's chronic airway disease; the report does not
      establish this as a universal route in CD3G deficiency.
- name: Obstructive sleep apnea
  category: Respiratory
  description: >-
    Obstructive sleep apnea was reported in the Taiwanese adult with longstanding structural airway disease.
    The authors' local attribution is retained with single-patient scope.
  phenotype_term:
    preferred_term: Obstructive sleep apnea
    term:
      id: HP:0002870
      label: Obstructive sleep apnea
  evidence:
  - reference: PMID:31921117
    reference_title: A Novel CD3G Mutation in a Taiwanese Patient With Normal T Regulatory Function
      Presenting With the CVID Phenotype Free of Autoimmunity-Analysis of all Genotypes and
      Phenotypes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Atrophic endobronchial mucosa caused
      exercise tachypnea, clubbing of the ﬁngers, and obstructive sleep
      apnea.
    explanation: >-
      The authors attribute these findings to the patient's chronic airway disease; the report does not
      establish this as a universal route in CD3G deficiency.
- name: Exertional tachypnea
  category: Respiratory
  description: >-
    Exertional tachypnea was reported in the Taiwanese adult with longstanding structural airway disease.
    The authors' local attribution is retained with single-patient scope.
  phenotype_term:
    preferred_term: Exertional tachypnea
    term:
      id: HP:0002789
      label: Tachypnea
  evidence:
  - reference: PMID:31921117
    reference_title: A Novel CD3G Mutation in a Taiwanese Patient With Normal T Regulatory Function
      Presenting With the CVID Phenotype Free of Autoimmunity-Analysis of all Genotypes and
      Phenotypes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Atrophic endobronchial mucosa caused
      exercise tachypnea, clubbing of the ﬁngers, and obstructive sleep
      apnea.
    explanation: >-
      The authors attribute these findings to the patient's chronic airway disease; the report does not
      establish this as a universal route in CD3G deficiency.
- name: Mastoiditis
  category: Respiratory
  description: >-
    Mastoiditis complicated recurrent sinopulmonary infections in the Taiwanese adult, rather than representing
    a universally present primary malformation.
  phenotype_term:
    preferred_term: Mastoiditis
    term:
      id: HP:0000265
      label: Mastoiditis
  evidence:
  - reference: PMID:31921117
    reference_title: A Novel CD3G Mutation in a Taiwanese Patient With Normal T Regulatory Function
      Presenting With the CVID Phenotype Free of Autoimmunity-Analysis of all Genotypes and
      Phenotypes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      He
      experienced recurrent sinopulmonary infections that were
      complicated by mastoiditis, pleural eﬀusion, and bronchiecta sis
      (Supplemental Figure 1A) and required hospitalization from
      the age of 14-years.
    explanation: >-
      The longitudinal case attributes these pulmonary/ENT complications to recurrent infection.
- name: Pleural effusion
  category: Respiratory
  description: >-
    Pleural effusion complicated recurrent sinopulmonary infections in the Taiwanese adult, rather than
    representing a universally present primary malformation.
  phenotype_term:
    preferred_term: Pleural effusion
    term:
      id: HP:0002202
      label: Pleural effusion
  evidence:
  - reference: PMID:31921117
    reference_title: A Novel CD3G Mutation in a Taiwanese Patient With Normal T Regulatory Function
      Presenting With the CVID Phenotype Free of Autoimmunity-Analysis of all Genotypes and
      Phenotypes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      He
      experienced recurrent sinopulmonary infections that were
      complicated by mastoiditis, pleural eﬀusion, and bronchiecta sis
      (Supplemental Figure 1A) and required hospitalization from
      the age of 14-years.
    explanation: >-
      The longitudinal case attributes these pulmonary/ENT complications to recurrent infection.
- name: Lupus-like systemic autoimmunity
  category: Immunologic
  description: >-
    The 2024 Chinese boy had lupus-like disease and met SLICC classification criteria according to the
    report. This monogenic presentation does not imply that all ANA-positive patients have systemic lupus.
  phenotype_term:
    preferred_term: Lupus-like systemic autoimmunity
    term:
      id: HP:0002725
      label: Systemic lupus erythematosus
  evidence:
  - reference: PMID:39094808
    reference_title: A CD3G homozygous pathogenic variant in a Chinese child with lupus-like
      disease, autoimmune thyroiditis and immunodeficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      This is the first patient who met the diagnostic criteria for systemic lupus erythematosus by the Systemic Lupus International Collaborating Clinics (SLICC) group.
    explanation: >-
      The authors explicitly report fulfillment of lupus criteria; the preferred wording preserves their
      lupus-like terminology.
- name: Alopecia areata
  category: Dermatologic
  description: >-
    Alopecia areata is recorded for adult P1 in the 2026 case table. Patchy alopecia is the HPO binding;
    the report supplies the more specific clinical designation without a prevalence estimate.
  phenotype_term:
    preferred_term: Alopecia areata
    term:
      id: HP:0002232
      label: Patchy alopecia
  evidence:
  - reference: PMID:42661620
    reference_title: 'Expanding the clinical spectrum of CD3γ deficiency: comprehensive characterization
      of adult-onset disease and integrated reevaluation of all reported patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      17 F12-1/Bulgaria f 50 y NM_000073.3:c.213dup (p.
      Trp72Metfs*6)
      Hom Hashimoto thyroiditis, lymphadenopathy,
      AIHA, ITP, alopecia areata/steroids, RTX,
      SCIG
    explanation: >-
      The visually verified P1 row lists alopecia areata; the patient identifier preserves the table attribution.
- name: Anoperineal fistula
  category: Gastrointestinal
  description: >-
    Perianal fistula occurred with severe infantile intestinal disease, including the 2007 Turkish siblings
    and the 2008 transplant recipient. The latter improved after transplantation.
  phenotype_term:
    preferred_term: Anoperineal fistula
    term:
      id: HP:0005218
      label: Anoperineal fistula
  evidence:
  - reference: PMID:18482219
    reference_title: Hematopoietic stem cell transplantation in a CD3 gamma-deficient infant with
      inflammatory bowel disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      A significant improvement in diarrhea, perianal lesions, and rectal fistula was observed suggesting an improvement in inflammatory bowel disease.
    explanation: >-
      The transplant report links improvement of the fistula to improvement of inflammatory bowel disease.
- name: Psoriasis
  category: Dermatologic
  description: >-
    Psoriasis was reported in a Turkish patient with the p.Lys69Ter variant. Its specific relation to
    the tolerance pathway remains an attribution question; it is not automatically equivalent to atopic
    eczema.
  phenotype_term:
    preferred_term: Psoriasis
    term:
      id: HP:0003765
      label: Psoriasiform dermatitis
  evidence:
  - reference: PMID:42661620
    reference_title: 'Expanding the clinical spectrum of CD3γ deficiency: comprehensive characterization
      of adult-onset disease and integrated reevaluation of all reported patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      15 F10-1/Turkey m >30 y NM_000073.3:c.205A>T
      (p.Lys69Ter)
      Hom severe varicella infection, respiratory infections,
      psoriasis, asthma
    explanation: >-
      The visually verified F10-1 row records psoriasis separately from asthma and infection.
- name: Chronic gastritis
  category: Gastrointestinal
  description: >-
    Chronic active gastritis was documented by endoscopy in the 2021 child with autoimmune enteropathy
    and chronic colitis. The immune contribution is inferred from the overall gastrointestinal presentation;
    the report does not identify a stomach-specific effector.
  phenotype_term:
    preferred_term: Chronic gastritis
    term:
      id: HP:0005231
      label: Chronic gastritis
  evidence:
  - reference: PMID:33215322
    reference_title: Complete Absence of CD3γ Protein Expression Is Responsible for Combined
      Immunodeficiency with Autoimmunity Rather than SCID.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Upper and lower endoscopy showed chronic active gastritis and colitis, and biopsies of small intestine and colon were consistent with autoimmune enteropathy.
    explanation: >-
      The detailed patient report directly documents chronic active gastritis at endoscopy, alongside
      colitis and biopsy-supported autoimmune enteropathy.
- name: Severe varicella infection
  category: Infectious
  description: >-
    Severe varicella was reported in Turkish patients summarized in the 2026 table, including F10-1. This
    is severe primary varicella as reported, not a claim of recurrent infection or reactivated zoster.
  phenotype_term:
    preferred_term: Severe varicella infection
    term:
      id: HP:5210299
      label: Severe chickenpox infection
  evidence:
  - reference: PMID:42661620
    reference_title: 'Expanding the clinical spectrum of CD3γ deficiency: comprehensive characterization
      of adult-onset disease and integrated reevaluation of all reported patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      15 F10-1/Turkey m >30 y NM_000073.3:c.205A>T
      (p.Lys69Ter)
      Hom severe varicella infection, respiratory infections,
      psoriasis, asthma
    explanation: >-
      The patient-specific row records severe varicella; the table was visually checked for column identity.
biochemical:
- name: Serum IgG
  context: >-
    Low IgG is variable: the detailed child had IgG 338 mg/dL and impaired vaccine responses, and the
    Taiwanese adult had profound deficiency before replacement. The 9/18 aggregate combines hypo- and
    dysgammaglobulinemia and is not an IgG-specific frequency.
  biomarker_term:
    preferred_term: IgG
    term:
      id: NCIT:C568
      label: IgG
  presence: Decreased
  notes: >-
    Reference intervals and treatment state differ across reports. Subsequent normal IgG values in the
    Taiwanese patient were measured during regular replacement; glucocorticoids and nephrotic protein
    loss can further confound serum values. No pooled reference interval is inferred.
  evidence:
  - reference: PMID:33215322
    reference_title: Complete Absence of CD3γ Protein Expression Is Responsible for Combined
      Immunodeficiency with Autoimmunity Rather than SCID.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Reduced numbers of switched and unswitched memory B cells, hypogammaglobulinemia (IgG 338 mg/dL), and impaired vaccination response to Haemophilus influenzae type B and Pneumococcus were also present (Table 1).
    explanation: >-
      The child had several directly documented humoral defects before replacement therapy.
- name: CD4+ T-lymphocyte count
  context: >-
    Absolute CD4 counts can be low despite preserved total T-cell counts; other patients have normal counts.
    The 2021 report calls 627 cells/μl lymphopenic, whereas the earlier cohort table used a different
    reference interval. Age, laboratory ranges and receptor-dependent gating require attention.
  biomarker_term:
    preferred_term: Absolute Helper T Lymphocyte Count
    term:
      id: NCIT:C201183
      label: Absolute Helper T Lymphocyte Count
  presence: Decreased
  evidence:
  - reference: PMID:33215322
    reference_title: Complete Absence of CD3γ Protein Expression Is Responsible for Combined
      Immunodeficiency with Autoimmunity Rather than SCID.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Immunological evaluations revealed a combined immunodeficiency with normal absolute CD3+ T cell
      numbers, CD4+ T cell lymphopenia (627 cells/μl) with a reduced proportion of naïve T cells and T
      regulatory cells, increased frequency of memory CD4+, CD8+ cells, and CD45RA+CCR7− CD8+ T cells
      (TEMRA).
    explanation: >-
      This report labels the child's measured CD4 count as low; it does not establish universal lymphopenia
      or universal normal total T-cell numbers.
genetic:
- name: CD3G
  association: Causal biallelic variant
  gene_term:
    preferred_term: CD3G
    term:
      id: hgnc:1675
      label: CD3G
  notes: >-
    Reported variants include c.80-1G>C, initiation-codon and truncating changes. The original Spanish
    siblings were compound heterozygotes involving c.1A>G and a splice-site variant; a different child
    was homozygous for c.1A>G. Identical homozygous variants can produce markedly different courses, and
    protein-null status has not been measured for every allele.
  evidence:
  - reference: PMID:42661620
    reference_title: "Expanding the clinical spectrum of CD3γ deficiency: comprehensive characterization
      of adult-onset disease and integrated reevaluation of all reported patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Notably, patients carrying identical deleterious variants exhibited substantial variability in clinical
      presentation and outcomes, indicating that no obvious genotype-phenotype correlation could be established
      based on the currently available data.
    explanation: >-
      States the absence of a genotype-phenotype correlation.
  - reference: PMID:24910257
    reference_title: CD3G gene defects in familial autoimmune thyroiditis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report three new CD3gamma-deficient siblings from a consanguineous family with a combined T-B+NK+
      immunodeficiency and their variable clinical and cellular phenotypes despite the same homozygous
      mutation of the CD3G gene (c.80-1G>C).
    explanation: >-
      Documents variable phenotype within a single family sharing one homozygous
      allele.
environmental: []
treatments:
- name: Immunoglobulin replacement therapy
  description: >-
    Regular immunoglobulin infusion for the hypogammaglobulinaemia and impaired
    vaccine responses. One patient received it for over twenty years before the
    genetic diagnosis was made.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: therapeutic immune globulin
      term:
        id: NCIT:C2701
        label: Therapeutic Immune Globulin
  target_phenotypes:
  - preferred_term: Decreased circulating immunoglobulin concentration
    term:
      id: HP:0004313
      label: Decreased circulating immunoglobulin concentration
  target_mechanisms:
  - target: Humoral Immune Failure
    treatment_effect: BYPASSES
    description: >-
      Replacement immunoglobulin supplies antibody-mediated protection without correcting the cellular
      immune lesion. Long-term use does not prove prevention of every infectious or hepatic complication.
    evidence:
    - reference: PMID:31921117
      reference_title: "A Novel CD3G Mutation in a Taiwanese Patient With Normal T Regulatory Function
        Presenting With the CVID Phenotype Free of Autoimmunity-Analysis of all Genotypes and Phenotypes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        This patient had the common variable immunodeficiency (CVID) phenotype and received regular immunoglobulin
        infusions over 20-years; he gradually developed nodular regenerative hyperplasia over a 5-year
        period.
      explanation: >-
        Documents long-term immunoglobulin replacement given for the humoral
        defect, and that it did not prevent later complications.
  evidence:
  - reference: PMID:33215322
    reference_title: Complete Absence of CD3γ Protein Expression Is Responsible for Combined
      Immunodeficiency with Autoimmunity Rather than SCID.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The child was started on immunoglobulin replacement and antimicrobial therapy, but she continued
      to have frequent respiratory tract infections over the first year of life.
    explanation: >-
      Documents the indication and the incomplete response in a severely
      affected infant.
- name: Rituximab for autoimmune cytopenias
  description: >-
    B-cell depletion for autoimmune haemolytic anaemia and immune
    thrombocytopenia. Both adults in the 2026 series had Evans syndrome that
    responded to it.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: rituximab
      term:
        id: NCIT:C1702
        label: Rituximab
  target_phenotypes:
  - preferred_term: Autoimmune hemolytic anemia
    term:
      id: HP:0001890
      label: Autoimmune hemolytic anemia
  - preferred_term: Autoimmune thrombocytopenia
    term:
      id: HP:0001973
      label: Autoimmune thrombocytopenia
  target_mechanisms:
  - target: Multisystem Autoimmunity
    treatment_effect: INHIBITS
    description: >-
      B-cell depletion suppressed the autoimmune-cytopenia component of immune dysregulation in the two
      adults. Their clinical response does not establish efficacy against every organ manifestation or
      restoration of Treg function.
    evidence:
    - reference: PMID:42661620
      reference_title: "Expanding the clinical spectrum of CD3γ deficiency: comprehensive characterization
        of adult-onset disease and integrated reevaluation of all reported patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Both patients presented with humoral immunodeficiency and Evans syndrome responsive to rituximab
        therapy.
      explanation: >-
        Records the response of the autoimmune cytopenias to B-cell depletion.
  evidence:
  - reference: PMID:42661620
    reference_title: "Expanding the clinical spectrum of CD3γ deficiency: comprehensive characterization
      of adult-onset disease and integrated reevaluation of all reported patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both patients presented with humoral immunodeficiency and Evans syndrome responsive to rituximab
      therapy.
    explanation: >-
      Documents the indication and the observed response.
- name: Glucocorticoids and other immunosuppression for autoimmune manifestations
  description: >-
    Steroids and other immunosuppressants were used for autoimmune cytopenias and enteropathy. A child
    improved on combined rituximab, sirolimus and steroids, with partial lung improvement; the individual
    drug contributions cannot be isolated. In the adult report, immunological deterioration during glucocorticoid
    exposure and later tapering after rituximab support caution. The authors propose additional suppression
    of already impaired TCR signaling, rather than demonstrating that mechanism experimentally in these
    patients.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: glucocorticoid
      term:
        id: CHEBI:24261
        label: glucocorticoid
    - preferred_term: sirolimus
      term:
        id: NCIT:C1212
        label: Sirolimus
  target_phenotypes:
  - preferred_term: Autoimmune hemolytic anemia
    term:
      id: HP:0001890
      label: Autoimmune hemolytic anemia
  - preferred_term: Autoimmune thrombocytopenia
    term:
      id: HP:0001973
      label: Autoimmune thrombocytopenia
  target_mechanisms:
  - target: Multisystem Autoimmunity
    treatment_effect: INHIBITS
    description: >-
      Combined immunosuppression improved the child's diarrhea and AIHA and partially improved lung disease.
      This observed response supports suppression of an immune-mediated component but cannot separate
      steroid, sirolimus and rituximab effects.
    evidence:
    - reference: PMID:33215322
      reference_title: Complete Absence of CD3γ Protein Expression Is Responsible for Combined
        Immunodeficiency with Autoimmunity Rather than SCID.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        The patient responded to the immunosuppressant therapy with significant improvement of the diarrhea (weight: 20th percentile), of the AIHA (Hb11.1 g/dL), and partial improvement of the chronic lung disease by chest CT up to transplant.
      explanation: >-
        Clinical response supports an immune contribution but was incomplete and occurred with infection-directed
        treatment.
  - target: Attenuated T-Cell Receptor Signaling
    treatment_effect: MODULATES
    description: >-
      The authors propose that glucocorticoid inhibition of TCR signaling could worsen host defense in
      CD3G deficiency. MODULATES records this proposed downward signaling effect; it is not a directly
      measured disease-specific pharmacodynamic result.
    evidence:
    - reference: PMID:42661620
      reference_title: "Expanding the clinical spectrum of CD3γ deficiency: comprehensive characterization
        of adult-onset disease and integrated reevaluation of all reported patients."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Glucocorticoids are known to suppress TCR signaling at multiple levels, including modulation of
        downstream signaling kinases and inhibition of TCR-activated transcription factors (20).
      explanation: >-
        This is cited background pharmacology used in the authors' proposed disease-specific interpretation.
      directness: INDIRECT
    - reference: PMID:42661620
      reference_title: "Expanding the clinical spectrum of CD3γ deficiency: comprehensive characterization
        of adult-onset disease and integrated reevaluation of all reported patients."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        In the context of an already impaired TCR/CD3 signaling pathway, these effects may further compromise
        host defense
      explanation: >-
        The authors' statement of the direction of the effect in this specific
        disorder, hedged as a proposal.
      directness: INDIRECT
  evidence:
  - reference: PMID:33215322
    reference_title: Complete Absence of CD3γ Protein Expression Is Responsible for Combined
      Immunodeficiency with Autoimmunity Rather than SCID.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      The patient responded to the immunosuppressant therapy with significant improvement of the diarrhea (weight: 20th percentile), of the AIHA (Hb11.1 g/dL), and partial improvement of the chronic lung disease by chest CT up to transplant.
    explanation: >-
      Clinical response supports an immune contribution but was incomplete and occurred with infection-directed
      treatment.
- name: Antimicrobial therapy and prophylaxis
  description: >-
    Antimicrobials were used to treat infection and as prophylaxis in reported patients. Breakthrough
    infections occurred despite treatment and immunoglobulin replacement. The cases do not establish one
    regimen or indefinite prophylaxis for every patient.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: antibiotic therapy
    term:
      id: NCIT:C15620
      label: Antibiotic Therapy
  target_phenotypes:
  - preferred_term: Recurrent respiratory infections
    term:
      id: HP:0002205
      label: Recurrent respiratory infections
  - preferred_term: Bronchiectasis
    term:
      id: HP:0002110
      label: Bronchiectasis
  target_mechanisms:
  - target: Defective Adaptive Host Defense
    treatment_effect: BYPASSES
    description: >-
      Pathogen-directed drugs bypass deficient host control while leaving the CD3G lesion intact; treatment
      in the reported child did not eliminate respiratory infections.
    evidence:
    - reference: PMID:33215322
      reference_title: Complete Absence of CD3γ Protein Expression Is Responsible for Combined
        Immunodeficiency with Autoimmunity Rather than SCID.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The child was started on immunoglobulin replacement and antimicrobial therapy, but she continued
        to have frequent respiratory tract infections over the first year of life.
      explanation: >-
        Documents antimicrobial therapy given for the infection susceptibility,
        and that it did not abolish it.
  evidence:
  - reference: PMID:33215322
    reference_title: Complete Absence of CD3γ Protein Expression Is Responsible for Combined
      Immunodeficiency with Autoimmunity Rather than SCID.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The child was started on immunoglobulin replacement and antimicrobial therapy, but she continued
      to have frequent respiratory tract infections over the first year of life.
    explanation: >-
      Documents antimicrobial therapy given for the infection susceptibility,
      and that it did not abolish it.
- name: Hematopoietic stem cell transplantation
  description: >-
    Allogeneic HSCT has been used in severe infantile disease. One infant showed donor chimerism, increased
    surface TCR expression and improved intestinal disease before dying on day 50 from infection. Other
    reports also describe transplant-associated deaths. These small, selected cases support possible immune
    restoration but do not establish a comparative survival benefit or a universal indication.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: hematopoietic cell transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  target_phenotypes:
  - preferred_term: Combined immunodeficiency
    term:
      id: HP:0005387
      label: Combined immunodeficiency
  - preferred_term: Protracted diarrhea
    term:
      id: HP:0004385
      label: Protracted diarrhea
  target_mechanisms:
  - target: Impaired TCR/CD3 Complex Assembly and Surface Expression
    treatment_effect: RESTORES
    description: >-
      Donor-derived T cells carry an intact CD3G gene, restoring surface TCR/CD3
      expression; in one transplanted infant TCR alpha/beta expression rose to
      66% with full donor chimerism.
    evidence:
    - reference: PMID:18482219
      reference_title: Hematopoietic stem cell transplantation in a CD3 gamma-deficient infant with
        inflammatory bowel disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        On day +19 after second transplantation, the CD3 TCR alpha/beta chain expression increased to
        66% with development of full donor chimerism (98.6%).
      explanation: >-
        Direct measurement of restored surface receptor expression after
        engraftment.
  evidence:
  - reference: PMID:18482219
    reference_title: Hematopoietic stem cell transplantation in a CD3 gamma-deficient infant with
      inflammatory bowel disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The case was interesting being the first reported case with SCID and inflammatory bowel disease
      who responded very well to HSCT by full recovery of intractable diarrhea, failure to thrive, laboratory
      findings, and improvement of fistula formation.
    explanation: >-
      The infant improved in intestinal disease and laboratory measures after transplantation but died
      on day 50; clinical response and survival are distinct outcomes.
  - reference: PMID:42661620
    reference_title: "Expanding the clinical spectrum of CD3γ deficiency: comprehensive characterization
      of adult-onset disease and integrated reevaluation of all reported patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Reevaluation of all reported cases demonstrated marked phenotypic heterogeneity, ranging from isolated
      autoimmune manifestations to severe early-onset combined immunodeficiency requiring hematopoietic
      stem cell transplantation.
    explanation: >-
      Records that the severe end of the clinical range is what brings patients
      to transplant.
  - reference: PMID:31921117
    reference_title: "A Novel CD3G Mutation in a Taiwanese Patient With Normal T Regulatory Function Presenting
      With the CVID Phenotype Free of Autoimmunity-Analysis of all Genotypes and Phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three patients died, one from a severe infection at 31 months, one from post-transplant respiratory
      failure due to viral pneumonia at 17 months, and one from graft-vs.-host disease at 47 months.
    explanation: >-
      Records the transplant-related deaths behind the statement that outcomes
      have been poor.
diagnosis:
- name: Lymphocyte immunophenotyping with surface TCR/CD3 quantitation
  description: >-
    Flow cytometry assesses surface TCR/CD3 abundance alongside absolute total and subset T-cell counts.
    Reduced receptor expression can be informative even with preserved counts, but normal counts and impaired
    PHA responses are not obligatory findings.
  results: >-
    Reduced surface receptor expression with variable absolute T-cell and subset counts; naive and regulatory
    proportions may be reduced.
  diagnosis_term:
    preferred_term: flow cytometry
    term:
      id: NCIT:C16585
      label: Flow Cytometry
  evidence:
  - reference: PMID:42661620
    reference_title: "Expanding the clinical spectrum of CD3γ deficiency: comprehensive characterization
      of adult-onset disease and integrated reevaluation of all reported patients."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      that assessment of abTCR and CD3 z surface expression may represent a useful diagnostic marker in
      patients with suspected CD3g
    explanation: >-
      The authors propose surface expression as a diagnostic marker; this is interpretive guidance, not
      a validated sensitivity/specificity estimate.
- name: CD3G sequencing
  description: >-
    Molecular confirmation by gene panel, exome or genome sequencing. Because
    the phenotype ranges from a CVID-like adult presentation to infantile
    SCID-like disease, the gene is reached by different panels in different
    patients.
  results: Biallelic loss-of-function CD3G variants.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:42661620
    reference_title: "Expanding the clinical spectrum of CD3γ deficiency: comprehensive characterization
      of adult-onset disease and integrated reevaluation of all reported patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole-genome sequencing was used to identify pathogenic CD3G variants, and protein expression was
      assessed by Western blot analysis.
    explanation: >-
      Documents the sequencing route to diagnosis.
differential_diagnoses:
- name: CD3delta, CD3epsilon and CD3zeta deficiencies
  description: >-
    CD3D, CD3E and CD247/CD3zeta deficiencies typically present with classical SCID and profound T-cell
    developmental impairment. CD3G deficiency more often retains peripheral T cells, but severe clinical
    SCID-like CD3G presentations also occur; gene and allele-specific evaluation is required.
  disease_term:
    preferred_term: severe combined immunodeficiency
    term:
      id: MONDO:0015974
      label: severe combined immunodeficiency
  distinguishing_features:
  - Typical profound T-cell depletion in other CD3-chain defects
  - Variable retained T-cell numbers and autoimmunity in CD3G deficiency
  - Gene-specific molecular diagnosis rather than clinical severity alone
  evidence:
  - reference: PMID:40147628
    reference_title: Five Patients With Two Novel Homozygous Variants in CD3 Subunits and
      Comprehensive Review of the Literature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Our results show that patients with CD3δ, CD3ε, and CD3ζ deficiencies typically present with a classic SCID phenotype. In contrast, patients with CD3γ deficiency may either show an SCID phenotype or a milder, less severe CID phenotype.
    explanation: >-
      The comparative CD3-subunit analysis supports a typical rather than absolute distinction; its mixed
      49-patient denominator is not assigned to CD3G alone.
- name: Common variable immunodeficiency
  description: >-
    Adult patients with CD3G deficiency have been managed as CVID because of antibody deficiency and low
    memory B cells. Reduced surface TCR/CD3 and biallelic CD3G variants identify the cellular lesion;
    a normal PHA response, as in the Taiwanese patient, does not exclude it.
  disease_term:
    preferred_term: common variable immunodeficiency
    term:
      id: MONDO:0015517
      label: common variable immunodeficiency
  distinguishing_features:
  - Reduced surface TCRalphabeta and CD3 expression
  - Variable proliferative defects; normal PHA does not exclude CD3G deficiency
  - Biallelic CD3G variants on sequencing
  evidence:
  - reference: PMID:31921117
    reference_title: "A Novel CD3G Mutation in a Taiwanese Patient With Normal T Regulatory Function Presenting
      With the CVID Phenotype Free of Autoimmunity-Analysis of all Genotypes and Phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This patient had the common variable immunodeficiency (CVID) phenotype and received regular immunoglobulin
      infusions over 20-years; he gradually developed nodular regenerative hyperplasia over a 5-year period.
    explanation: >-
      A CD3gamma-deficient adult managed for two decades as common variable
      immunodeficiency.
animal_models:
- name: Cd3g-deficient mouse
  species: Mouse
  genotype: Cd3g null (selective loss of CD3gamma expression)
  publication: PMID:9524111
  description: >-
    Cd3g-null mice have thymic cellularity below 1% and peripheral T-cell numbers at 2–5% of normal, with
    severe impairment of both TCR lineages. This differs from the substantial peripheral T-cell compartment
    retained by many human patients, although human clinical disease can also be severe. Residual mouse
    cells are not described as wholly absent.
  modeled_mechanisms:
  - target: Impaired TCR/CD3 Complex Assembly and Surface Expression
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      The mouse does reproduce the receptor-expression defect: surface TCR and
      CD3epsilon are severely reduced on thymocytes and peripheral T cells.
    limitations: >-
      The developmental and quantitative receptor deficits are more severe than in typical human cases.
      This limits direct translation to mature patient T cells, without proving that no mature-cell question
      can be studied in the model.
    readouts:
    - name: Surface TCR and CD3epsilon expression on thymocytes and peripheral T cells
      target: Impaired TCR/CD3 Complex Assembly and Surface Expression
      direction: DECREASED
      interpretation: >-
        The receptor-expression component of the human lesion is present in the
        mouse.
      evidence:
      - reference: PMID:9524111
        reference_title: The CD3gamma chain is essential for development of both the TCRalphabeta
          and TCRgammadelta lineages.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Furthermore, absence of CD3gamma results in a severe reduction in the level of TCR and CD3epsilon
          expression at the cell surface of thymocytes and peripheral T cells.
        explanation: >-
          Direct measurement of the surface receptor deficit in the model.
    evidence:
    - reference: PMID:9524111
      reference_title: The CD3gamma chain is essential for development of both the TCRalphabeta and
        TCRgammadelta lineages.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We generated mice selectively lacking expression of CD3gamma, in which expression of CD3delta,
        CD3epsilon, CD3zeta, pTalpha and TCRbeta remained undisturbed.
      explanation: >-
        Establishes that the model isolates loss of CD3gamma, the same lesion as
        in patients.
  - target: Distorted Thymic Selection and Self-Reactive Repertoire
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >-
      The profound mouse developmental bottleneck does not reproduce the preserved, variably skewed peripheral
      repertoire studied in human autoimmune cohorts. The cited experiments do not directly establish
      fidelity for human Treg dysfunction or clinical autoimmunity.
    limitations: >-
      Peripheral mouse T cells are reduced to 2–5%, not absent. Human CD3delta rescues gamma-delta development
      in double-deficient mice, explaining a lineage-specific compensation mechanism; this does not fully
      explain preserved human alpha-beta development or establish all autoimmune outcomes in the model.
    evidence:
    - reference: PMID:9524111
      reference_title: The CD3gamma chain is essential for development of both the TCRalphabeta and
        TCRgammadelta lineages.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        The number of cells in the thymus is reduced to <1% of that in normal mice, and the large majority
        of thymocytes lack CD4 and CD8 and are arrested at the CD44-CD25+ double negative (DN) stage of
        development.
      explanation: >-
        The mouse developmental bottleneck is much more profound than that in human cohorts retaining
        peripheral T cells.
    - reference: PMID:9524111
      reference_title: The CD3gamma chain is essential for development of both the TCRalphabeta and
        TCRgammadelta lineages.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: |-
        Peripheral lymphoid organs are also practically devoid of T cells, with absolute numbers of peripheral T cells reduced to only 2-5% of those in normal mice.
      explanation: >-
        The model retains a small peripheral population; the result must not be described as complete
        absence.
    - reference: PMID:17923503
      reference_title: Different composition of the human and the mouse gammadelta T cell receptor
        explains different phenotypes of CD3gamma and CD3delta immunodeficiencies.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: |-
        A human, but not a mouse, CD3delta transgene rescues gammadelta T cell development in mice lacking both mouse CD3delta and CD3gamma chains.
      explanation: >-
        The perturbation demonstrates lineage-specific structural compensation in a mouse model; it does
        not by itself resolve human alpha-beta/Treg biology.
  evidence:
  - reference: PMID:9524111
    reference_title: The CD3gamma chain is essential for development of both the TCRalphabeta and
      TCRgammadelta lineages.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: |-
      Peripheral lymphoid organs are also practically devoid of T cells, with absolute numbers of peripheral T cells reduced to only 2-5% of those in normal mice.
    explanation: >-
      The model retains a small peripheral population; the result must not be described as complete absence.
  - reference: PMID:17923503
    reference_title: Different composition of the human and the mouse gammadelta T cell receptor
      explains different phenotypes of CD3gamma and CD3delta immunodeficiencies.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: |-
      A human, but not a mouse, CD3delta transgene rescues gammadelta T cell development in mice lacking both mouse CD3delta and CD3gamma chains.
    explanation: >-
      The perturbation demonstrates lineage-specific structural compensation in a mouse model; it does
      not by itself resolve human alpha-beta/Treg biology.
experimental_models:
- name: CD3G-knockdown human Jurkat T cells and the CD3gamma-negative JGN line
  description: >-
    Human T-cell lines in which CD3gamma is absent or knocked down: the JGN
    variant of Jurkat, which lacks CD3gamma and has no surface TCR, and
    stable short-hairpin knockdowns of CD3G in Jurkat E6-1. They are the systems
    in which the assembly and signalling roles of individual CD3gamma domains
    have been dissected, using domain-swap chimeras with CD3delta.
  experimental_model_type: CELL_LINE
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: Immortalized human T-cell leukaemia lines (Jurkat E6-1, JGN)
  culture_system: Two-dimensional suspension culture with lentiviral shRNA knockdown or retroviral
    domain-swap reconstitution
  publication: PMID:34249896
  modeled_mechanisms:
  - target: Impaired TCR/CD3 Complex Assembly and Surface Expression
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Jurkat knockdown measures receptor assembly, ER retention and low surface export. In JGN, the CD3gamma
      extracellular domain is required for rescue, whereas patient-derived T-cell rescue differs. Domain
      requirements are therefore interpreted within each cellular system.
    limitations: >-
      Knockdown lines have less than 11% surface expression, compared with greater than 30% in congenital
      patient-derived cells. Developmental adaptation is proposed, but the immature thymic-organ-culture
      perturbation used shCD3D, not shCD3G. JGN may carry additional mutations; patient-cell limitations
      restricted biochemical/nanocluster analyses to JGN.
    readouts:
    - name: Surface TCR expression in CD3G-knockdown Jurkat cells
      target: Impaired TCR/CD3 Complex Assembly and Surface Expression
      direction: DECREASED
      interpretation: >-
        Confirms that CD3gamma loss impairs receptor export in a purely human
        system, while showing the magnitude is model-dependent.
      evidence:
      - reference: PMID:34249896
        reference_title: "CD3G or CD3D Knockdown in Mature, but Not Immature, T Lymphocytes Similarly
          Cripples the Human TCRαβ Complex."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          However, both defective TCR ensembles were strongly retained in the ER, lacked ζζ/CD2472, and
          barely reached the T-cell surface (<11% of normal controls) in any of the CD3 KD cells.
        explanation: >-
          The measurement of residual surface receptor in the knockdown lines.
    evidence:
    - reference: PMID:34249896
      reference_title: CD3G or CD3D Knockdown in Mature, but Not Immature, T Lymphocytes Similarly
        Cripples the Human TCRαβ Complex.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: |-
        However, both defective TCR ensembles were strongly retained in the ER, lacked ζζ/CD2472, and barely reached the T-cell surface (<11% of normal controls) in any of the CD3 KD cells.
      explanation: >-
        The assembly/export defect was measured in engineered Jurkat knockdowns; the paper separately
        documents a milder defect in patient-derived cells.
  - target: Attenuated T-Cell Receptor Signaling
    relationship: MEASURES
    fidelity: MODERATE
    description: >-
      Reconstituting the CD3gamma-negative JGN line with chimeric CD3gamma/CD3delta
      constructs measures which signalling outputs require which CD3gamma domain.
    limitations: >-
      JGN is a mutagenized leukemia-derived line with possible additional defects. Cytokine/nanocluster
      experiments were limited to JGN; proximal signaling and CD69 can remain intact despite impaired
      cytokine production, and these results are not clinical cytokine measurements.
    readouts:
    - name: TCR-induced IL-2 and TNF-alpha production
      target: Attenuated T-Cell Receptor Signaling
      direction: DECREASED
      interpretation: >-
        The intracellular-domain-truncated construct had reduced cytokine production, while CD69 induction
        was normal/highest. The two response classes are not a single uniformly reduced activation readout.
      evidence:
      - reference: PMID:36119034
        reference_title: The role of the different CD3γ domains in TCR expression and signaling.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: |-
          Quantification of IL-2 and TNF-α showed differences among the constructs, with γγ- inducing a very poor response compared to γγγ, γγδ or γδδ.
        explanation: >-
          The Results specifically support reduced cytokine output by the truncated construct.
      - reference: PMID:36119034
        reference_title: The role of the different CD3γ domains in TCR expression and signaling.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: |-
          In contrast to cytokine synthesis, CD69 expression and TCR internalization after TCR engagement were normal for all constructs including γγ-, which scored highest for CD69 induction, indicating that it was capable of some functional signal transduction.
        explanation: >-
          The full Results qualify the abstract: the intracellular-domain-truncated construct retained
          CD69 induction; cytokine secretion and CD69 cannot be bundled as uniformly reduced.
    evidence:
    - reference: PMID:36119034
      reference_title: The role of the different CD3γ domains in TCR expression and signaling.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: |-
        In contrast to cytokine synthesis, CD69 expression and TCR internalization after TCR engagement were normal for all constructs including γγ-, which scored highest for CD69 induction, indicating that it was capable of some functional signal transduction.
      explanation: >-
        The full Results qualify the abstract: the intracellular-domain-truncated construct retained CD69
        induction; cytokine secretion and CD69 cannot be bundled as uniformly reduced.
discussions:
- discussion_id: mismatch_cd3g_mouse_vs_human
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Which developmental and receptor-composition differences explain retained human T cells, and how faithfully
    do these systems reproduce human tolerance defects?
  attaches_to:
  - pathophysiology#Distorted Thymic Selection and Self-Reactive Repertoire
  - pathophysiology#Impaired TCR/CD3 Complex Assembly and Surface Expression
  rationale: >-
    Cd3g-null mice retain only 2–5% of normal peripheral T cells. Human CD3delta rescues gamma-delta development
    in double-deficient mice, but this does not reconstruct the human alpha-beta/Treg pathway. Mature
    Jurkat knockdown and congenital patient-derived cells also differ; the immature-organ-culture perturbation
    in the 2021 study was CD3D. None of these observations proves that autoimmunity is absent from every
    model or that no model can study it.
  evidence:
  - reference: PMID:9524111
    reference_title: The CD3gamma chain is essential for development of both the TCRalphabeta and
      TCRgammadelta lineages.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: |-
      Peripheral lymphoid organs are also practically devoid of T cells, with absolute numbers of peripheral T cells reduced to only 2-5% of those in normal mice.
    explanation: >-
      The model retains a small peripheral population; the result must not be described as complete absence.
  - reference: PMID:17923503
    reference_title: Different composition of the human and the mouse gammadelta T cell receptor
      explains different phenotypes of CD3gamma and CD3delta immunodeficiencies.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: |-
      A human, but not a mouse, CD3delta transgene rescues gammadelta T cell development in mice lacking both mouse CD3delta and CD3gamma chains.
    explanation: >-
      The perturbation demonstrates lineage-specific structural compensation in a mouse model; it does
      not by itself resolve human alpha-beta/Treg biology.
- discussion_id: gap_cd3g_genotype_phenotype
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Which modifiers account for different clinical courses among relatives sharing a CD3G variant?
  attaches_to:
  - genetic#CD3G
  - pathophysiology#Multisystem Autoimmunity
  rationale: >-
    Identical variants accompany divergent infection and autoimmune outcomes. Demonstrated protein loss
    for particular alleles shows that residual CD3gamma is not required for all retained human T-cell
    development; it does not exclude allele-specific effects across the whole spectrum. Preserved Taiwanese
    Treg function and variable age/stimulus-dependent proliferation are correlates, not validated prognostic
    rules.
  evidence:
  - reference: PMID:42661620
    reference_title: "Expanding the clinical spectrum of CD3γ deficiency: comprehensive characterization
      of adult-onset disease and integrated reevaluation of all reported patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Notably, patients carrying identical deleterious variants exhibited substantial variability in clinical
      presentation and outcomes, indicating that no obvious genotype-phenotype correlation could be established
      based on the currently available data.
    explanation: >-
      States the absence of a genotype-phenotype correlation.
  - reference: PMID:31921117
    reference_title: A Novel CD3G Mutation in a Taiwanese Patient With Normal T Regulatory Function
      Presenting With the CVID Phenotype Free of Autoimmunity-Analysis of all Genotypes and
      Phenotypes.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: |-
      Treg cells isolated from the CD3 γ Del 213A T cells of the patient
      were able to suﬃciently suppress the proliferation of Teﬀ cells
      upon stimulation
    explanation: >-
      The Taiwanese adult retained suppression in the reported coculture conditions, qualifying universal
      Treg-dysfunction claims.
- discussion_id: interpretation_cd3g_cohorts
  kind: INTERPRETATION
  status: OPEN
  prompt: >-
    How should overlapping case counts and contradictions between primary reports and later summary tables
    be interpreted?
  attaches_to:
  - phenotypes#Autoimmune thyroiditis
  - phenotypes#Decreased circulating immunoglobulin concentration
  - phenotypes#Impaired PHA-induced T-cell proliferation
  rationale: >-
    The 2026 18-patient aggregation overlaps the 2014 families, 2018 mechanistic cohort and detailed later
    case reports. It is not an independent prevalence sample. Its 9/18 antibody category combines hypo-
    and dysgammaglobulinemia, and its 11/11 mitogen category is not PHA-specific. The detailed 2021 child
    had homozygous c.1A>G and died after transplantation; the later table assigns a different variant/alive
    status to that report. Normal Taiwanese IgG measurements were during replacement. The earlier 2007
    sibling VI3 was presumed affected rather than molecularly tested. Frequencies therefore retain reported-series
    scope and detailed primary narratives take precedence for patient facts.
  evidence:
  - reference: PMID:31921117
    reference_title: A Novel CD3G Mutation in a Taiwanese Patient With Normal T Regulatory Function
      Presenting With the CVID Phenotype Free of Autoimmunity-Analysis of all Genotypes and
      Phenotypes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      this was compatible with hypogammaglobulinemia, but normal PHA-lymphocyte proliferation.
    explanation: >-
      The Taiwanese patient is an explicitly scoped exception to universal PHA impairment, not a disease-level
      absence annotation.
  - reference: PMID:42661620
    reference_title: "Expanding the clinical spectrum of CD3γ deficiency: comprehensive characterization
      of adult-onset disease and integrated reevaluation of all reported patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To date, only 16 predominantly pediatric cases have been reported. Here, we describe two additional
      adult patients with CD3γ deficiency and provide a comprehensive reevaluation of all previously published
      cases.
    explanation: >-
      The authors give the literature count and two new cases; this provides no population denominator.
- discussion_id: access_cd3g_2014_fulltext
  kind: CURATION_TODO
  status: OPEN
  prompt: >-
    Which additional 2014 patient findings and proposed atopy mechanism can be encoded after the primary
    full text becomes available through the prescribed reference fetcher?
  attaches_to:
  - phenotypes#Atopic dermatitis
  - phenotypes#Increased circulating IgE concentration
  - phenotypes#Asthma
  rationale: >-
    The Wiley full text was readable for context but the prescribed full-page/PDF fetches returned access
    errors; the PMID cache contains the abstract. The authors propose immune dysregulation/Th2 involvement
    in atopy without assaying Th2 cells. That source-established provisional route is not called a biological
    gap merely because an exact cached quotation is unavailable. The primary abstract supports high IgE
    and eczema in 2/5. Additional body-only findings and table contradictions are recorded in notes pending
    cache access.
  evidence:
  - reference: PMID:24910257
    reference_title: CD3G gene defects in familial autoimmune thyroiditis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We found all five patients to display autoimmunity: autoimmune thyroiditis (n = 5), autoimmune haemolytic
      anaemia (n = 2), immune thrombocytopenia (n = 1), autoimmune hepatitis (n = 1), minimal change nephrotic
      syndrome (n = 1), vitiligo (n = 1) and positive antinuclear antibodies (n = 3) as well as high IgE
      (n = 2) and atopic eczema (n = 2).
    explanation: >-
      The frequency recorded here is the atopic-eczema count of 2 out of the 5
      patients in the series.
- discussion_id: gap_cd3g_growth
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What accounts for short stature in the reported autoimmune family?
  attaches_to:
  - phenotypes#Short stature
  rationale: >-
    The case observation does not distinguish nutrition, thyroid disease, chronic inflammation or treatment
    effects. A specific CD3G-to-growth route is not established in the reviewed sources; this differs
    from the explicitly linked enteropathy-to-failure-to-thrive course.
  evidence:
  - reference: PMID:42661620
    reference_title: 'Expanding the clinical spectrum of CD3γ deficiency: comprehensive characterization
      of adult-onset disease and integrated reevaluation of all reported patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      8 F5-2/Turkey f 20 y NM_000073.3:c.80-1G>C (p.)? Hom Hashimoto thyroiditis, AIHA, short stature
    explanation: >-
      The 2026 case table explicitly lists short stature for F5-2; the observation does not establish
      a growth mechanism.
- discussion_id: gap_cd3g_skin
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    How are alopecia areata and psoriasis related to the measured tolerance defects in these particular
    patients?
  attaches_to:
  - phenotypes#Alopecia areata
  - phenotypes#Psoriasis
  rationale: >-
    The reports list these clinical diagnoses but do not establish their CD3G-specific effectors or directly
    attribute them to the studied Treg/repertoire changes. Their relation to atopy is also unresolved;
    these observations are retained without a fabricated causal edge.
  evidence:
  - reference: PMID:42661620
    reference_title: 'Expanding the clinical spectrum of CD3γ deficiency: comprehensive characterization
      of adult-onset disease and integrated reevaluation of all reported patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      17 F12-1/Bulgaria f 50 y NM_000073.3:c.213dup (p.
      Trp72Metfs*6)
      Hom Hashimoto thyroiditis, lymphadenopathy,
      AIHA, ITP, alopecia areata/steroids, RTX,
      SCIG
    explanation: >-
      The visually verified P1 row lists alopecia areata; the patient identifier preserves the table attribution.
  - reference: PMID:42661620
    reference_title: 'Expanding the clinical spectrum of CD3γ deficiency: comprehensive characterization
      of adult-onset disease and integrated reevaluation of all reported patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      15 F10-1/Turkey m >30 y NM_000073.3:c.205A>T
      (p.Lys69Ter)
      Hom severe varicella infection, respiratory infections,
      psoriasis, asthma
    explanation: >-
      The visually verified F10-1 row records psoriasis separately from asthma and infection.
- discussion_id: gap_cd3g_reactive_nodes
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What drives the adult patient's reactive generalized lymphadenopathy?
  attaches_to:
  - phenotypes#Lymphadenopathy
  rationale: >-
    Repeated biopsies excluded malignancy and identified reactive hyperplasia. Infection, immune dysregulation
    and their interaction remain possible contributors; regression during immunoglobulin treatment does
    not isolate one mechanism.
  evidence:
  - reference: PMID:42661620
    reference_title: 'Expanding the clinical spectrum of CD3γ deficiency: comprehensive characterization
      of adult-onset disease and integrated reevaluation of all reported patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Histopathological
      examination consistently demonstrated reactive lymphoid hyperpla-
      sia without evidence of lymphoma or other malignancy.
    explanation: >-
      Repeated biopsies distinguished the nodal enlargement from lymphoma.
- discussion_id: gap_cd3g_hepatic_attribution
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Is the suspected hepatic remodeling caused by CD3G-associated immune dysfunction, and what is its
    histological substrate?
  attaches_to:
  - pathophysiology#Suspected Nodular Regenerative Hepatic Remodeling
  rationale: >-
    The local proposed hepatic-to-portal/splenic route is represented, but biopsy was declined and a steroid
    trial for possible autoimmune hepatitis failed. These facts do not establish a CD3G-to-NRH mechanism
    or confirm autoimmune hepatitis in the Taiwanese adult.
  evidence:
  - reference: PMID:31921117
    reference_title: A Novel CD3G Mutation in a Taiwanese Patient With Normal T Regulatory Function
      Presenting With the CVID Phenotype Free of Autoimmunity-Analysis of all Genotypes and
      Phenotypes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      he was unwilling to undergo a liver biopsy for pathological proof.
    explanation: >-
      The proposed hepatic substrate was not biopsy-confirmed.
- discussion_id: gap_cd3g_malt_attribution
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Does CD3G deficiency contribute to gastric MALT lymphoma risk beyond the local H. pylori-associated
    process?
  attaches_to:
  - pathophysiology#Helicobacter pylori-Associated Gastric Disease
  - phenotypes#Gastric MALT lymphoma
  rationale: >-
    A single patient had an H. pylori-associated lymphoma that remitted after eradication. The local contribution
    is represented, but a syndrome-wide tumor predisposition or upstream CD3G effect is not established.
  evidence:
  - reference: PMID:42661620
    reference_title: 'Expanding the clinical spectrum of CD3γ deficiency: comprehensive characterization
      of adult-onset disease and integrated reevaluation of all reported patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      At 22 years of age, she was diagnosed with Helicobacter
      pylori -associated gastric mucosa-associated lymphoid tissue
      (MALT) lymphoma. Eradication therapy resulted in complete
      remission.
    explanation: >-
      The lymphoma and eradication response are patient observations; HPO gastric lymphoma is broader
      than the source's MALT subtype.
clinical_trials: []
datasets: []
notes: >-
  Phenotype review used the complete Falcon report as navigation, with direct primary-source and whole-paper
  context taking precedence. The official NCBI Genetic Testing Registry CD3G gene page lists GeneReviews
  as not available; no CD3G-specific chapter was identified. Other CD3-chain SCID sources were not imported
  as CD3G phenotype evidence. The UCM author-hosted PDF URL and PMID:29653965 are the same Rowe study,
  not independent cohorts.


  The web-readable 2014 full text reports bone-density abnormalities, gastrointestinal Giardia, and additional
  clinical findings that could not all be quoted from the prescribed fetched abstract. Reported osteopenia
  (Z −1.4) was not upgraded to pediatric osteoporosis; the separate osteoporosis case had severe hyperthyroidism.
  Table/narrative inconsistencies affect respiratory infections, T-cell/NK counts and untested-family
  autoimmunity, so no carrier penetrance or universal mitogen deficit is inferred. Giardia is retained
  as an infection observation rather than forced into HPO terms requiring recurrent, persistent or severe
  infection not established by the available quotation.


  Evidence grades follow each claim: direct patient observations are HUMAN_CLINICAL, cultured/engineered
  functional experiments are IN_VITRO, mouse perturbations MODEL_ORGANISM, and mechanistic interpretations
  or diagnostic proposals OTHER. Literal quotations retain fetched extraction artifacts. Clinical immune-deficiency
  findings and experimental assay readouts are distinct; reports_on records observed readouts without
  identity-like causal arrows.


  The disease remains a gene-specific combined immunodeficiency within the existing IUIS classification.
  No additional grouping or conserved mechanism module is introduced: the reviewed changes concern variable
  CD3G-dependent receptor/tolerance behavior and case-specific complications, not a newly established
  shared disease union or reusable pathway implementation. The candidate germinal-center-reaction module
  was considered, but the proposed CD40L/memory-B relation does not establish the full reaction defect;
  the cDC1 tolerogenic module requires a distinct EPOR/DC pathway not demonstrated here. The general erythrocyte-destruction
  module does not match the current broad tolerance node, which retains a qualified organ-specific AIHA
  route without asserting a measured clearance pathway.

📚

References & Deep Research

References

18

PMID:42661620

Expanding the clinical spectrum of CD3γ deficiency: comprehensive characterization of adult-onset disease and integrated reevaluation of all reported patients.

No top-level findings curated for this source.

PMID:33215322

Complete Absence of CD3γ Protein Expression Is Responsible for Combined Immunodeficiency with Autoimmunity Rather than SCID.

No top-level findings curated for this source.

PMID:29653965

Patients with CD3G mutations reveal a role for human CD3γ in T(reg) diversity and suppressive function.

No top-level findings curated for this source.

PMID:24910257

CD3G gene defects in familial autoimmune thyroiditis.

No top-level findings curated for this source.

PMID:23590417

Variable presentation of primary immune deficiency: two cases with CD3 gamma deficiency presenting with only autoimmunity.

No top-level findings curated for this source.

PMID:31921117

A Novel CD3G Mutation in a Taiwanese Patient With Normal T Regulatory Function Presenting With the CVID Phenotype Free of Autoimmunity-Analysis of all Genotypes and Phenotypes.

No top-level findings curated for this source.

PMID:18482219

Hematopoietic stem cell transplantation in a CD3 gamma-deficient infant with inflammatory bowel disease.

No top-level findings curated for this source.

PMID:16264327

CD3 deficiencies.

No top-level findings curated for this source.

PMID:34249896

CD3G or CD3D Knockdown in Mature, but Not Immature, T Lymphocytes Similarly Cripples the Human TCRαβ Complex.

No top-level findings curated for this source.

PMID:17923503

Different composition of the human and the mouse gammadelta T cell receptor explains different phenotypes of CD3gamma and CD3delta immunodeficiencies.

No top-level findings curated for this source.

PMID:9524111

The CD3gamma chain is essential for development of both the TCRalphabeta and TCRgammadelta lineages.

No top-level findings curated for this source.

PMID:35748970

Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee.

No top-level findings curated for this source.

PMID:12407027

Contribution of CD3 gamma to TCR regulation and signaling in human mature T lymphocytes.

No top-level findings curated for this source.

PMID:17277165

Differential biological role of CD3 chains revealed by human immunodeficiencies.

No top-level findings curated for this source.

PMID:36119034

The role of the different CD3γ domains in TCR expression and signaling.

No top-level findings curated for this source.

PMID:39094808

A CD3G homozygous pathogenic variant in a Chinese child with lupus-like disease, autoimmune thyroiditis and immunodeficiency.

No top-level findings curated for this source.

PMID:40147628

Five Patients With Two Novel Homozygous Variants in CD3 Subunits and Comprehensive Review of the Literature.

No top-level findings curated for this source.

url:https://www.ucm.es/data/cont/docs/1572-2019-04-22-Blood%202018.pdf

https://www.ucm.es/data/cont/docs/1572-2019-04-22-Blood%202018.pdf

No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (1)

Create: Combined immunodeficiency due to CD3gamma deficiency (MONDO:0014276) · 2026-08-29T02:27:16Z · View source

New de novo Disease entry for combined immunodeficiency due to CD3gamma deficiency (MONDO:0014276, CD3G, hgnc:1675). entry_type decided as DISEASE: the disorder has its own MONDO term under combined immunodeficiency, a single conserved pathograph (biallelic CD3G null -> impaired TCR/CD3 assembly -> reduced surface receptor -> attenuated TCR signalling -> distorted thymic selection and Treg failure -> autoimmunity plus infection susceptibility), and no existing kb entry mentions CD3G. Named Entity Confusion check: 'just preflight-dr' PASS on the falcon deep-research report (CD3G mentioned 40 times, top gene by a wide margin, OMIM 615607 consistent). The main same-gene confusion risk here is with the other CD3 chain deficiencies (CD3D/CD3E/CD3Z), which are severe combined immunodeficiencies rather than this disorder; every citation was checked to be about CD3G/CD3gamma specifically, and the CD3D/CD3E material is confined to the differential_diagnoses entry where it belongs. Evidence-source convention, stated in the entry notes and applied consistently: patient-sample measurements (flow cytometry, repertoire sequencing, clinical course) HUMAN_CLINICAL; culture-dependent or engineered-line work (PHA-driven T-cell blasts, Treg suppression co-cultures, Jurkat and JGN lines) IN_VITRO; mouse data MODEL_ORGANISM. Deliberately curated as a negative-result model link: the Cd3g-null mouse (PMID:9524111) PARTIALLY_RECAPITULATES the receptor-expression defect but FAILS_TO_RECAPITULATE the preserved peripheral T-cell compartment and skewed repertoire, with the species basis (human but not mouse gamma-delta TCR incorporates CD3delta) from PMID:17923503. Paired with a HUMAN_MODEL_MISMATCH discussion. A second KNOWLEDGE_GAP records the absent genotype-phenotype correlation. Not curated: no clinical_trials (none registered for this disorder), no datasets, no environmental factors, no biochemical reference ranges. Membership of an existing IEI grouping (Combined_Immunodeficiencies_IEIs) was noted as a follow-up rather than made here, to keep this PR to its own entry. Validation: just validate exit 0 (72/72 snippets verified), just validate-terms exit 0, check-duplicate-keys, check-entity-refs, check-folded-hyphens, check-snippet-length, check-title-snippets, check-snippet-grading, check-environmental-evidence all exit 0.

Falcon ▸

Disease Characteristics Research Template

Edison Scientific Literature 18 citations 2026-08-28T19:11:23.017695

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

Disease Name: combined immunodeficiency due to CD3gamma deficiency (CD3G deficiency, immunodeficiency 17)
MONDO ID: MONDO:0014276 (if available)
Category: Mendelian

Research Objectives

Please provide a comprehensive research report on combined immunodeficiency due to CD3gamma deficiency (CD3G deficiency, immunodeficiency 17) covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

What is the disease? Provide a concise overview.
What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
What are the common synonyms and alternative names?
Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
Risk Factors:

Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Genetic risk factors (causal variants, susceptibility loci, modifier genes)
Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
Protective Factors:

Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Genetic protective factors (protective variants, modifier alleles)
Environmental protective factors (diet, lifestyle, exposures that reduce risk)
Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
Pathogenic Variants:
Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
Variant type/class (missense, frameshift, nonsense, splice-site, structural)
Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
Functional consequences (loss of function, gain of function, dominant negative)
Modifier Genes: Genes that modify disease severity or expression
Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

Search first: CDC databases, WHO, PubMed, NHANES
Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

Search first: PubMed, Gene Ontology, Reactome
Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Molecular Profiling (if available):
Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
Advanced Technologies (if applicable):
Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

Organ Level:
Primary organs directly affected
Secondary organ involvement (complications, secondary effects)
Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Tissue and Cell Level:
Specific tissue types affected (epithelial, connective, muscle, nervous)
Specific cell populations targeted (with Cell Ontology terms)

Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Subcellular Level:
Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Localization:
Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

Onset:
Typical age of onset (congenital, pediatric, adult, geriatric)
Onset pattern (acute, subacute, chronic, insidious)

Search first: OMIM, Orphanet, HPO, PubMed
Progression:
Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
Progression rate (rapid, slow, variable)
Disease course pattern (episodic, relapsing-remitting, progressive, stable)
Disease duration (self-limited, chronic lifelong)

Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Patterns:
Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

Epidemiology:
Prevalence (cases per 100,000 at given time)
Incidence (new cases per 100,000 per year)

Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
For Genetic Etiology:
Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
Population Demographics:
Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
Geographic distribution of specific variants
Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

Clinical Tests:
Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
Genetic Testing:

Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
Overview of recommended genetic testing approach
Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
FISH > Search first: ClinVar, cytogenetics databases, PubMed
Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
Omics-Based Diagnostics (if applicable):
RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
Clinical Criteria:
Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
Screening:
Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

Survival and Mortality:
Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
Morbidity and Function:
Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
Disease Course:
Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
Prediction:
Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

Pharmacotherapy:
Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
Advanced Therapeutics:
Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
Surgical and Interventional:
Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
Supportive and Rehabilitative:
Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
Experimental:
Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
Treatment Outcomes:
Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
Treatment Strategy:
Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

Prevention Levels:
Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
Immunization: Vaccine strategies (if applicable)

Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
Screening and Early Detection:
Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
Behavioral Interventions: Lifestyle modifications to reduce risk

Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Counseling: Genetic counseling (risk assessment, family planning guidance)

Search first: NSGC resources, ACMG guidelines, GeneReviews
Public Health:
Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
Prophylaxis: Preventive medications or procedures

Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

Taxonomy: Species affected (with NCBI Taxon identifiers)

Search first: NCBI Taxonomy
Breed: Specific breeds affected (with VBO identifiers if applicable)

Search first: VBO (Vertebrate Breed Ontology)
Gene: Orthologous genes in other species (with NCBI Gene IDs)

Search first: NCBI Gene
Natural Disease:
Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
Comparative Biology:
Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
Transmission (if applicable):
Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

Model Types:
Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
Genetic Models:
Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
Model Characteristics:
Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
Applications:
Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
Resources:
Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic and clinical claims
Prioritize recent reviews and landmark papers
Include direct quotes from abstracts where possible to support key statements
Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Combined immunodeficiency due to CD3γ deficiency

Executive summary

Combined immunodeficiency due to CD3γ deficiency is an ultrarare, autosomal-recessive inborn error of immunity caused by biallelic loss-of-function variants in CD3G, encoding the γ chain of the T-cell receptor (TCR)–CD3 complex. Unlike complete CD3δ or CD3ε deficiency, it usually permits development of circulating, polyclonal T cells. These cells nevertheless express markedly less surface TCR/CD3, signal and proliferate inefficiently, and have abnormal repertoire selection. The resulting phenotype ranges from apparently isolated autoimmunity or adult CVID-like antibody deficiency to severe childhood combined immunodeficiency (CID) with opportunistic infection, enteropathy, and transplant requirement. Autoimmune thyroiditis, autoimmune cytopenias, and inflammatory bowel disease–like enteropathy are especially characteristic. Human evidence remains limited to small families and case reports; therefore, frequencies below are descriptive rather than population estimates. (rowe2018patientswithcd3g pages 9-13, rowe2018patientswithcd3g pages 1-6, rowe2018patientswithcd3g pages 6-9)

domain	established finding	quantitative/patient evidence	evidence type	ontology suggestions
Gene / inheritance	CD3G deficiency is an ultrarare autosomal-recessive inborn error of immunity caused by biallelic CD3G variants; disease spectrum spans combined immunodeficiency with immune dysregulation rather than uniformly classic SCID.	2019 review found 10 reported cases from 5 unrelated families; 2021 report noted 14 previously reported cases; later 2026 synthesis reported 18 total patients and explicitly called the disorder autosomal recessive (later than requested 2023-2024 window) (lee2019anovelcd3g pages 1-2, delmonte2021completeabsenceof pages 1-3, obeng2026expandingtheclinical pages 1-2)	Human case series/review	MONDO:0014276; CD3G (HGNC gene); HP:0000007 Autosomal recessive inheritance; NCIT: Inborn Error of Immunity
TCR-CD3 mechanism	CD3γ is required for optimal surface expression of the TCR/CD3 complex; deficiency lowers CD3ε and TCRαβ expression and weakens TCR signaling without abolishing polyclonal T-cell development in humans.	In 6 bi-allelic cases, all showed markedly reduced CD3ε/TCRαβ on T cells and impaired proliferation to PHA; anti-CD3/CD28 partly restored responses (rowe2018patientswithcd3g pages 6-9). Later 2026 cases also had reduced TCR/CD3 expression despite normal T-cell counts (obeng2026expandingtheclinical pages 5-6)	Human functional immunology	GO:0050852 T cell receptor signaling pathway; GO:0042102 positive regulation of T cell proliferation; CL:0000624 CD4-positive, alpha-beta T cell; CL:0000625 CD8-positive, alpha-beta T cell
Infections	Clinical infectious susceptibility is variable, from recurrent sinopulmonary infections to severe/opportunistic infections.	2019 analysis: infections in 7 patients; 4/5 with sinopulmonary infections developed bronchiectasis; reported opportunistic infections included Candida, Giardia, and severe EBV; one patient had pneumonia by 6-9 months and EBV viremia 102,000 copies/mL (lee2019anovelcd3g pages 4-6, delmonte2021completeabsenceof pages 1-3)	Human case reports/review	HP:0002719 Recurrent infections; HP:0012735 Recurrent respiratory infections; HP:0002110 Bronchiectasis; NCBITaxon:10376 Epstein-Barr virus
Autoimmunity / immune dysregulation	Autoimmunity is a major and often dominant manifestation; autoimmune cytopenias, thyroiditis, enteropathy/IBD-like disease, vitiligo, hepatitis, and Evans syndrome are reported.	In one 2014 family series, 5/5 had autoimmune thyroiditis, 2/5 autoimmune hemolytic anemia, 1/5 immune thrombocytopenia, 1/5 autoimmune hepatitis, 1/5 vitiligo (gokturk2014cd3ggenedefects pages 1-2). In the 2018 cohort, all 6 patients had autoimmunity (rowe2018patientswithcd3g pages 6-9). Later 2026 adult cases highlighted Evans syndrome responsive to rituximab (later than requested window) (obeng2026expandingtheclinical pages 1-2)	Human case series	HP:0002716 Autoimmunity; HP:0001890 Autoimmune hemolytic anemia; HP:0001973 Autoimmune thrombocytopenia; HP:0000824 Autoimmune thyroiditis; HP:0002037 Inflammatory bowel disease; HP:0005603 Vitiligo
Laboratory phenotype	Typical immunophenotype includes reduced TCR/CD3 surface expression, reduced naïve T cells, variable CD4/CD8 lymphopenia, hypogammaglobulinemia, impaired vaccine responses, reduced switched memory B cells, and sometimes high IgE.	2014 series: all 5 had low CD3+TCRαβ+ percentages; only 1 had overall lymphopenia; 3 had CD3+ T-cell lymphopenia; 3/5 had high IgE; 3/5 had ANA positivity (gokturk2014cd3ggenedefects pages 1-2). 2021 case: CD4 count 627/µL, IgG 338 mg/dL, impaired vaccination responses (delmonte2021completeabsenceof pages 1-3). 2019 case had decreased switched memory B cells and diminished CD40L expression (lee2019anovelcd3g pages 1-2)	Human laboratory/clinical	HP:0005403 Decreased alpha-beta T-cell count; HP:0002841 Hypogammaglobulinemia; HP:0010976 Reduced memory B-cell count; HP:0002910 Elevated IgE level; HP:0002720 Impaired vaccine response
Treg / tolerance mechanism	A leading mechanism of immune dysregulation is defective regulatory T-cell biology: reduced Treg proportion/diversity, restricted TCR repertoire, impaired suppressive function, and enrichment of self-reactive conventional T cells.	In the 2018 study, Treg cells from CD3G-mutated patients failed to suppress Teff proliferation at 1:2 ratios and showed reduced suppression at 1:1 ratios; 6 patients showed repertoire restriction and self-reactivity signatures (rowe2018patientswithcd3g pages 9-13, rowe2018patientswithcd3g pages 13-18)	Human mechanistic study	GO:0002507 tolerance induction; GO:0043029 T cell homeostasis; CL:0000815 regulatory T cell; HP:0002960 Autoimmune disease
B-cell / humoral involvement	Some patients show a CVID-like or predominant humoral phenotype, indicating downstream B-cell dysfunction despite the primary T-cell signaling defect.	2019 Taiwanese adult case had recurrent sinopulmonary infections, hypogammaglobulinemia, decreased switched memory B cells, diminished CD40L expression, and 20 years of immunoglobulin replacement, yet no overt autoimmunity (lee2019anovelcd3g pages 1-2, lee2019anovelcd3g pages 2-3, lee2019anovelcd3g pages 4-6)	Human case report	HP:0002721 Immunoglobulin deficiency; HP:0010976 Reduced memory B-cell count; NCIT: Common Variable Immunodeficiency-like phenotype
Diagnosis	Diagnosis relies on clinical suspicion for CID/immune dysregulation plus flow cytometry showing reduced TCR/CD3 expression and confirmatory sequencing (targeted NGS, WES, or WGS).	2024 Algerian flow-cytometry experience reported CD3γ deficiency diagnosed in 2 siblings presenting with recurrent infections; the paper emphasized FCM as a direct or highly informative IEI diagnostic tool (paper search summary). 2024 WES study from Türkiye supports molecular diagnosis in IEI cohorts though not CD3G-specific in the excerpt (obeng2026expandingtheclinical pages 5-6)	Human diagnostic practice / cohort	NCIT: Flow Cytometry; NCIT: Whole Exome Sequencing; NCIT: Whole Genome Sequencing; NCIT: Genetic Testing
Treatment	Management is individualized and case-based: immunoglobulin replacement, prophylactic/therapeutic antimicrobials, steroids, rituximab, sirolimus, and HSCT in severe cases.	2019 patient received IVIG for ~20 years plus antibiotics/steroids (lee2019anovelcd3g pages 2-3). 2021 patient received immunoglobulin replacement, antibiotics, rituximab, sirolimus, steroids (delmonte2021completeabsenceof pages 1-3). Severe life-threatening infections requiring HSCT were associated with worse outcomes in 2019 analysis (lee2019anovelcd3g pages 1-2)	Human case reports/review	NCIT:C80687 Immunoglobulin Therapy; NCIT:C15543 Anti-Infective Therapy; NCIT:C1802 Rituximab; NCIT:C29457 Sirolimus; NCIT:C15206 Hematopoietic Stem Cell Transplantation
Prognosis	Prognosis is highly variable, from isolated autoimmune thyroiditis to fatal infantile disease; severe infections, opportunistic infections, IBD-like disease, and HSCT-related complications drive poorer outcomes.	2019 review reported 3 deaths: severe infection at 31 months, post-transplant viral pneumonia at 17 months, and graft-versus-host disease at 47 months; worse prognosis associated with opportunistic infections (p=0.0124), severe life-threatening infections needing HSCT (p=0.01), and IBD-like diarrhea (p=0.0124); autoimmune thyroiditis associated with better prognosis (p=0.0124) (lee2019anovelcd3g pages 1-2, lee2019anovelcd3g pages 4-6)	Human case aggregation	HP:0003819 Death in infancy; HP:0006538 Chronic course; HP:0002583 Chronic diarrhea; NCIT: Prognosis
Epidemiology limits	No robust population prevalence, incidence, carrier-frequency, penetrance, or sex-ratio estimates were identified; evidence remains almost entirely from published families/case reports.	Disease totals in the literature remained in the low double digits across reports (10, 14, then 18 in later 2026 synthesis) (lee2019anovelcd3g pages 1-2, delmonte2021completeabsenceof pages 1-3, obeng2026expandingtheclinical pages 1-2)	Evidence-gap statement from literature scope	NCIT: Rare Disease; MONDO:0014276
Environmental / infectious modifiers	No disease-specific environmental or lifestyle risk factors were identified; infectious exposures act mainly as complications or triggers that reveal the immune defect.	Reported pathogens/complications include H. influenzae, Pseudomonas aeruginosa, S. aureus cellulitis, E. coli epididymoorchitis, EBV viremia, Candida, Giardia, and H. pylori-associated gastric MALT lymphoma in a later 2026 report (later than requested window) (lee2019anovelcd3g pages 2-3, obeng2026expandingtheclinical pages 5-6)	Human case reports	NCBITaxon:727 Haemophilus influenzae; NCBITaxon:287 Pseudomonas aeruginosa; NCBITaxon:1280 Staphylococcus aureus; NCBITaxon:562 Escherichia coli; NCBITaxon:210 Helicobacter pylori
Model-organism limitations	Mouse CD3-chain knockout biology does not fully recapitulate human disease; no single CD3 subunit is absolutely required for murine T-cell maturation, limiting direct translation from knockout models. Human-CD3 replacement mice are useful for therapeutic studies but are not disease models of CD3G deficiency.	Review evidence notes fundamental mouse-human differences in CD3 subunit requirements (grunebaum2006humantcell pages 5-7). Human CD3E/D/G-replaced mice are immune competent and were developed to test human CD3-directed therapeutics, not to model CD3G deficiency pathogenesis (paper search summary for Ueda 2017)	Comparative/model evidence	NCBITaxon:10090 Mus musculus; GO:0046649 lymphocyte activation; NCIT: Disease Model

Table: This table condenses the strongest gathered evidence on combined immunodeficiency due to CD3G deficiency across genetics, mechanism, phenotype, diagnosis, treatment, prognosis, and model limitations. It is designed for rapid knowledge-base ingestion and flags where later 2026 evidence falls outside the user's preferred 2023-2024 priority window.

1. Disease information

Definition and nomenclature

The preferred name is combined immunodeficiency due to CD3γ deficiency. Common alternatives are CD3-gamma deficiency, CD3G deficiency, immunodeficiency 17, T-cell receptor complex deficiency due to CD3γ deficiency, and, in some reports, CD3γ-deficient CID. “SCID due to CD3G deficiency” should be used cautiously: even complete absence of CD3γ has produced residual polyclonal T-cell development and CID with autoimmunity rather than uniform classic SCID. (delmonte2021completeabsenceof pages 1-3)

Recommended identifiers are:

MONDO: MONDO:0014276, as supplied in the disease template.
OMIM phenotype: Immunodeficiency 17, commonly catalogued as IMD17/615607; gene entry CD3G/186740. These database identifiers should be validated against the current OMIM release before automated ingestion.
Gene: CD3G; NCBI reference transcript used in recent case aggregation: NM_000073.3.
Orphanet: typically represented within rare combined T- and B-cell immunodeficiencies/TCR-complex deficiencies; a stable disease-specific ORPHA number was not established from the retrieved primary texts.
ICD-10: no specific code; usually coded under D81.8, Other combined immunodeficiencies or an appropriate national modification.
ICD-11: no confidently verified disease-specific code in the retrieved evidence; use the relevant combined-immunodeficiency category.
MeSH: no disease-specific descriptor identified; useful broader headings include Combined Immunodeficiencies, Primary Immunodeficiency Diseases, and T-Cell Receptor-CD3 Complex.

The evidence is aggregated disease-level evidence derived from published individual patients and families, not population EHR data. The 2019 analysis included ten cases from five unrelated families, whereas the 2021 report referred to 14 previously reported cases—illustrating the small and evolving evidence base. (lee2019anovelcd3g pages 1-2, delmonte2021completeabsenceof pages 1-3, lee2019anovelcd3g pages 10-11)

2. Etiology, risk, and protective factors

Causal factor

The primary cause is germline biallelic pathogenic loss-of-function CD3G variation. Reported classes include splice-site, start-loss/missense, nonsense, and frameshift/deletion variants. The 2019 aggregation counted 20 disease alleles: 14 c.80-1G>C splice alleles, two c.1G>A alleles, two reported nonsense alleles, and two c.213 deletion alleles. Nomenclature differed between publications, so all legacy calls should be remapped to a single transcript and genome build before database loading. (lee2019anovelcd3g pages 1-2)

Reported variants include c.80-1G>C, c.1A>G/p.(Met1Val), c.205A>T/p.(Lys69Ter), c.213del/p.(Lys71fs), and later c.213dup/p.(Trp72Metfs*6). The frameshift around residue 71–72 disrupts or removes the cytoplasmic immunoreceptor tyrosine-based activation motif and can abolish detectable CD3γ protein. (lee2019anovelcd3g pages 2-3, obeng2026expandingtheclinical pages 8-9, obeng2026expandingtheclinical pages 7-8)

Risk factors

Genetic: two pathogenic alleles are the established risk factor. Consanguinity has been common in reported families but is not required. Family history of childhood infections, autoimmunity, unexplained cytopenias, hypogammaglobulinemia, or early deaths should increase suspicion.
Environmental/lifestyle: no toxin, diet, smoking, alcohol, occupational, sex-specific, or age-related causal risk factor has been demonstrated.
Infectious exposure: infection does not cause the Mendelian disorder, but exposure reveals impaired immunity and can accelerate organ damage.
Modifiers: striking intrafamilial variability with the same c.80-1G>C genotype implies genetic, epigenetic, microbial, treatment, or stochastic modifiers, but no modifier gene has been validated. (gokturk2014cd3ggenedefects pages 1-2)

No reproducible protective genetic variant is known. Early diagnosis, infection avoidance, antimicrobial prophylaxis where indicated, immunoglobulin replacement in antibody-deficient patients, and avoidance of unsafe live vaccines are clinically protective measures rather than etiologic protective factors.

3. Phenotypes

Clinical and laboratory spectrum

Phenotype	Character, onset/course, frequency evidence	Suggested HPO term
Recurrent respiratory infection	Childhood or adolescent onset is common, but severity is variable. Infections occurred in 7 patients in the 2019 aggregation.	HP:0012735 Recurrent respiratory infections
Bronchiectasis	Progressive structural complication: 4 of 5 patients with sinopulmonary infection developed bronchiectasis. It may cause exertional dyspnea, clubbing, hospitalization, and impaired quality of life.	HP:0002110 Bronchiectasis
Opportunistic/severe infection	Candida, Giardia, severe EBV, viral pneumonia, and life-threatening bacterial disease have occurred; associated with poor lymphocyte proliferation and higher mortality.	HP:0002719 Recurrent infections; HP:0002721 Immunodeficiency
Autoimmune thyroiditis	May be an isolated or predominant manifestation. Five of five patients in one familial series had thyroiditis; six cases were counted in the 2019 review.	HP:0000824 Autoimmune thyroiditis
Autoimmune cytopenia	AIHA, immune thrombocytopenia, pancytopenia, and Evans syndrome occur from early childhood through adulthood and may be episodic/relapsing.	HP:0001890 AIHA; HP:0001973 Autoimmune thrombocytopenia
Enteropathy/IBD-like disease	Chronic diarrhea, autoimmune enteropathy, gastritis/colitis, or fistulizing IBD-like disease; potentially severe and associated with worse prognosis.	HP:0002037 Inflammatory bowel disease; HP:0002014 Diarrhea
Other autoimmunity	Autoimmune hepatitis, nephrotic syndrome, vitiligo, positive ANA, and inflammatory lung disease have been reported.	HP:0002716 Autoimmunity; HP:0005603 Vitiligo
T-cell abnormality	Reduced surface CD3/TCRαβ, reduced naïve T cells, variable CD4/CD8 lymphopenia, memory/TEMRA skewing, and impaired mitogen response.	HP:0005403 Decreased alpha-beta T-cell count; HP:0031392 Abnormal lymphocyte proliferation
Humoral abnormality	Hypogammaglobulinemia, low IgG/IgG2, impaired vaccine/polysaccharide response, and reduced switched-memory B cells; sometimes a CVID-like presentation.	HP:0004313 Decreased circulating antibody level; HP:0002720 Impaired vaccine response
Atopy/high IgE	Atopic eczema and elevated IgE occurred in 3/5 patients in one familial series.	HP:0000964 Eczema; HP:0002910 Elevated IgE

The underlying datasets are too small for reliable penetrance estimates. In the 2014 five-patient series, autoimmune thyroiditis occurred in 100%, AIHA in 40%, and thrombocytopenia, autoimmune hepatitis, nephrotic syndrome, and vitiligo in 20% each; 60% had high IgE/eczema and 60% ANA positivity. These are family-series proportions, not general population frequencies. (gokturk2014cd3ggenedefects pages 1-2)

The broader 2019 aggregation found autoimmunity in nine patients—thyroiditis in six, IBD-like diarrhea in four, and hemolytic anemia in four. Four of five patients with sinopulmonary infections had bronchiectasis. (lee2019anovelcd3g pages 4-6)

Quality of life: no CD3G-specific EQ-5D, SF-36, PROMIS, disability-weight, or formal patient-reported outcome study was found. Case-level burdens include repeated hospitalization, chronic IVIG and antibiotic treatment, exercise limitation, obstructive sleep apnea, clubbing, chronic diarrhea, immunosuppressive toxicity, and transplant morbidity. One adult had received immunoglobulin for approximately 20 years and developed bronchiectasis and portal-hypertensive nodular regenerative hyperplasia. (lee2019anovelcd3g pages 2-3)

4. Genetic and molecular information

Causal gene: CD3G, encoding CD3γ, a transmembrane component of the TCR-CD3 complex. Recommended gene annotation: HGNC-approved symbol CD3G; transcript NM_000073.3. Variants are germline, usually homozygous in reported consanguineous families; compound heterozygosity is biologically possible.

Functional class: available disease alleles act predominantly through loss of function—abnormal splicing, absent translation, truncation, loss of the cytoplasmic signaling domain, reduced protein, or complete protein absence. There is no established gain-of-function or dominant-negative CD3G deficiency mechanism. (lee2019anovelcd3g pages 4-6, obeng2026expandingtheclinical pages 5-6)

Variant interpretation: classifications should be obtained from the current ClinVar submission and reassessed under ACMG/AMP criteria. Strong applicable evidence may include a null variant in a loss-of-function disease mechanism, extreme rarity, segregation in affected relatives, reduced/absent protein, reduced surface TCR/CD3, and functional T-cell defects. No trustworthy gnomAD/TOPMed allele-frequency values were present in the retrieved primary texts; do not infer carrier frequency from the case literature.

Genotype–phenotype relationship: no robust correlation is established. Identical c.80-1G>C alleles produced isolated thyroid autoimmunity, broader autoimmune disease, infection susceptibility, or severe CID. One c.213-deletion patient retained normal Treg suppression and lacked autoimmunity despite a CVID-like phenotype, whereas other patients showed profound Treg dysfunction. (gokturk2014cd3ggenedefects pages 1-2, lee2019anovelcd3g pages 4-6)

No validated disease-specific modifier gene, methylation signature, histone abnormality, recurrent copy-number variant, translocation, inversion, aneuploidy, or somatic CD3G mechanism was identified.

5. Environmental and infectious information

No non-genetic exposure causes CD3G deficiency. Documented infectious complications include Haemophilus influenzae, Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, Candida, Giardia, and EBV. In the Taiwanese adult, chronic respiratory infection led to bronchiectasis despite prophylaxis; other infections included preseptal staphylococcal cellulitis and E. coli epididymo-orchitis. (lee2019anovelcd3g pages 4-6, lee2019anovelcd3g pages 2-3)

A 2021 patient had EBV viremia of 102,000 copies/mL, enteropathy, inflammatory lung disease, and recurrent respiratory infection. (delmonte2021completeabsenceof pages 1-3) No disease-specific association with pollution, radiation, diet, exercise, smoking, or alcohol is reported.

6. Mechanism and pathophysiology

Causal chain

Upstream genetic lesion: biallelic CD3G loss of function reduces or eliminates CD3γ.
Complex-level defect: TCR/CD3 assembly, stability, and surface expression fall; CD3ε and TCRαβ are markedly reduced on CD4, CD8, and regulatory T cells.
Signal defect: antigen-receptor signal strength and proliferative responses decline. In six patients, PHA responses showed reduced CFSE dilution, CD25, and Ki-67; CD3/CD28 costimulation partially rescued activation.
Development/selection defect: some thymic T-cell development persists, but selection is distorted. Naïve cells are reduced, memory/exhausted populations expand, and the repertoire becomes restricted and clonally skewed.
Tolerance defect: Treg proportion and repertoire diversity may fall; Tregs can have severely impaired suppressive function. Conventional CD4 cells are enriched for hydrophobic CDR3 features associated with self-reactivity.
Clinical outputs: weak antimicrobial responses produce recurrent/severe infection; defective central and peripheral tolerance produces thyroiditis, cytopenias, enteropathy, and other autoimmunity; inadequate T-cell help contributes to hypogammaglobulinemia, poor vaccine response, and reduced switched-memory B cells. (rowe2018patientswithcd3g pages 9-13, rowe2018patientswithcd3g pages 13-18, rowe2018patientswithcd3g pages 6-9)

An informative functional result was that patient Tregs “completely failed to suppress T effector cell proliferation at 1:2 ratios,” with reduced suppression even at 1:1, directly supporting loss of peripheral tolerance. (rowe2018patientswithcd3g pages 9-13) Conversely, the Taiwanese c.213 deletion case retained normal FOXP3-positive Treg number and suppression, demonstrating that Treg failure is important but not obligatory. (lee2019anovelcd3g pages 4-6)

Suggested annotations:

GO biological process: GO:0050852 T-cell receptor signaling pathway; GO:0031295 T-cell costimulation; GO:0042110 T-cell activation; GO:0042098 T-cell proliferation; GO:0002507 tolerance induction; GO:0043029 T-cell homeostasis.
GO cellular component: T-cell receptor complex; plasma membrane; immunological synapse.
Cell Ontology: CL:0000084 T cell; CL:0000624 CD4-positive αβ T cell; CL:0000625 CD8-positive αβ T cell; CL:0000815 regulatory T cell; CL:0000785 mature B cell.
Metabolic/tissue-damage mechanisms: no primary metabolic defect is established. Bronchiectasis and inflammatory enteropathy are downstream consequences of repeated infection and immune dysregulation rather than intrinsic epithelial disease.

No disease-specific single-cell, spatial-transcriptomic, proteomic, metabolomic, lipidomic, CRISPR-screen, or integrated multi-omic signature was identified. TCR repertoire sequencing is the best developed molecular-profiling application. (rowe2018patientswithcd3g pages 1-6)

7. Anatomical structures affected

The primary biological sites are hematopoietic/lymphoid tissues, especially developing thymocytes and peripheral T cells. Suggested locations are thymus (UBERON:0002370), blood (UBERON:0000178), bone marrow (UBERON:0002371), lymph node (UBERON:0000029), and spleen (UBERON:0002106).

Secondary clinical injury affects bilateral airways/lungs through recurrent infection and bronchiectasis; intestine through autoimmune enteropathy/IBD-like inflammation; thyroid through autoimmune thyroiditis; blood through immune destruction of erythrocytes and platelets; and occasionally liver, kidney, skin, and interstitial lung. No intrinsic lateralization is expected. At the subcellular level, the critical compartment is the plasma-membrane TCR-CD3 complex and immunological synapse. (lee2019anovelcd3g pages 2-3, delmonte2021completeabsenceof pages 1-3)

8. Temporal development

The molecular defect is congenital, but clinical onset is highly variable. Severe cases present in infancy with pneumonia, diarrhea, candidiasis, or cytopenias; one detailed patient developed pneumonia at 6–9 months and severe AIHA at age two. Other patients first present during childhood, adolescence, or adulthood with thyroiditis, antibody deficiency, or autoimmune cytopenia. Median diagnosis in the five-patient 2014 series was 11 years, range 14 months–20 years. (gokturk2014cd3ggenedefects pages 1-2, delmonte2021completeabsenceof pages 1-3)

Untreated disease is chronic and potentially progressive, but may be episodic: infections accumulate structural lung damage, while autoimmune cytopenias relapse and remit. There is no validated staging system. Critical intervention windows are before irreversible bronchiectasis, severe opportunistic infection, chronic enteropathy, or transplant-compromising organ injury.

9. Inheritance and population

Inheritance is autosomal recessive. For two carrier parents, each pregnancy has an expected 25% affected, 50% carrier, and 25% non-carrier/non-affected probability. Anticipation is not expected. Germline mosaicism has not been documented but cannot be categorically excluded.

Reliable prevalence, incidence, carrier frequency, penetrance, sex ratio, and geographic rate estimates do not exist. Published patients include Turkish, Spanish, Taiwanese/Chinese, and other families; Turkish enrichment partly reflects ascertainment and consanguinity rather than a demonstrated population prevalence. The 2019 review found seven Turkish and two Spanish earlier patients plus the Taiwanese case. (lee2019anovelcd3g pages 1-2)

Heterozygous relatives with autoimmunity were reported in one family investigation, but this does not establish dominant CD3G disease or carrier penetrance and may reflect familial background risk. (gokturk2014cd3ggenedefects pages 1-2)

10. Diagnostics

Recommended diagnostic pathway

Clinical suspicion: recurrent/severe infection, bronchiectasis, chronic diarrhea, autoimmune cytopenia or thyroiditis—especially when multiple features coexist or there is consanguinity/family history.
Baseline tests: CBC/differential; quantitative IgG, IgA, IgM, IgE and IgG subclasses; vaccine antibody responses; EBV/CMV testing when indicated.
Flow cytometry: CD3, CD4, CD8, CD19, NK cells; naïve/memory subsets; switched-memory B cells; and, critically, compare surface CD3ε and TCRαβ mean fluorescence intensity with age-matched controls. Normal total T-cell numbers do not exclude CD3G deficiency.
Functional assays: PHA/ConA proliferation, anti-CD3 and anti-CD3/CD28 responses; CD25/Ki-67 induction. Treg number/function and TCR repertoire sequencing are valuable in complex immune-dysregulation cases.
Molecular confirmation: an IEI/CID panel containing CD3G or WES; deletion/duplication analysis if sequencing is negative. WGS is appropriate for unresolved cases, splice/regulatory lesions, or structural variants. Confirm variants by orthogonal testing and parental segregation.
Protein/RNA validation: Western blot for CD3γ and RNA studies for splice variants can establish functional consequence. (rowe2018patientswithcd3g pages 6-9, obeng2026expandingtheclinical pages 5-6, lee2019anovelcd3g pages 1-2)

A 2024 Algerian diagnostic cohort reported two siblings with CD3γ deficiency and illustrates the real-world value of flow cytometry in resource-constrained IEI diagnosis, although sequencing remains necessary for definitive genotype assignment. More broadly, a 2024 Turkish multicenter WES study obtained likely diagnoses in 122/297 evaluable IEI patients (41.1%), supporting exome sequencing when phenotypes overlap; this statistic is not CD3G-specific.

Differential diagnosis: CD3D/CD3E/CD247 deficiency; partial RAG1/RAG2 defects; ZAP70, LCK, LAT, TRAC, CORO1A, MHC-II, IL7R, JAK3, and IL2RG defects; CTLA4 or LRBA deficiency; activated PI3Kδ syndrome; autoimmune lymphoproliferative syndrome; common variable immunodeficiency; secondary immunodeficiency; HIV; and immunosuppressive drug effects. Profoundly reduced TCR/CD3 intensity with residual T cells and biallelic CD3G variants is distinguishing.

CMA, routine karyotype, FISH, mitochondrial sequencing, and repeat-expansion testing are not first-line unless another phenotype suggests them. Imaging is complication-directed—high-resolution chest CT for bronchiectasis/interstitial disease; endoscopy/biopsy for enteropathy; liver evaluation for portal hypertension. No standardized disease-specific clinical diagnostic criteria exist.

Newborn TREC screening may detect severe lymphopenic cases but can miss CD3G-deficient infants with near-normal T-cell counts. Thus, a normal TREC result does not exclude later CID/immune dysregulation.

11. Outcome and prognosis

No actuarial survival curve, five-/ten-year survival, mortality rate, or life-expectancy estimate exists. In the 2019 ten-case aggregation, three deaths occurred: severe infection at 31 months, post-HSCT respiratory failure from viral pneumonia at 17 months, and graft-versus-host disease at 47 months. Opportunistic infection, life-threatening infection requiring HSCT, and IBD-like diarrhea were associated with higher mortality (respectively p=0.0124, p=0.01, p=0.0124); thyroiditis was associated with better prognosis (p=0.0124). These exploratory p-values derive from extremely small numbers and should not be treated as validated prognostic models. (lee2019anovelcd3g pages 1-2, lee2019anovelcd3g pages 4-6)

Major morbidity comprises bronchiectasis, chronic enteropathy, recurrent cytopenia, chronic lung inflammation, organ toxicity from infection or immune suppression, and HSCT complications. Favorable factors likely include preserved proliferation/Treg function, absence of opportunistic infection, early IVIG where indicated, infection control, and treatment before irreversible organ injury, but none is validated as a formal biomarker.

12. Treatment and current implementation

There is no approved CD3G-specific drug, RNA therapy, or gene therapy, and the clinical-trial search identified no disease-specific interventional trial.

Immunoglobulin replacement for hypogammaglobulinemia or poor specific-antibody responses; the adult CVID-like patient received regular infusions for approximately 20 years. Suggested NCIT concept: immunoglobulin replacement therapy. (lee2019anovelcd3g pages 1-2, lee2019anovelcd3g pages 2-3)
Antimicrobials: prompt pathogen-directed treatment and individualized antibacterial, antiviral, antifungal, or antiparasitic prophylaxis. Suggested NCIT: anti-infective therapy.
Autoimmunity: corticosteroids and steroid-sparing therapy according to organ involvement. Rituximab treated severe cytopenias; sirolimus was used for immune dysregulation in the 2021 case. Suggested NCIT: Rituximab; Sirolimus; corticosteroid therapy. (delmonte2021completeabsenceof pages 1-3)
Pulmonary/gastrointestinal supportive care: airway clearance, pulmonary monitoring, nutrition support, vaccination of household contacts, and specialist treatment of enteropathy, bronchiectasis, and portal hypertension.
Allogeneic HSCT: potentially definitive immune reconstitution for severe/refractory CID, opportunistic infection, life-threatening autoimmunity, or progressive organ disease. Decisions require individualized risk assessment because reported deaths included viral pneumonia and graft-versus-host disease after transplantation. Suggested NCIT: allogeneic hematopoietic stem cell transplantation. (lee2019anovelcd3g pages 1-2)

Evidence does not support a single treatment algorithm. A pragmatic strategy is phenotype-guided: observe mild isolated autoimmunity with immunologic surveillance; add IVIG/prophylaxis for humoral or infectious disease; use targeted immunosuppression for organ-threatening autoimmunity; and refer early to an IEI transplant center when disease is severe or progressive. No CD3G-specific pharmacogenomic association is known.

13. Prevention

Primary prevention of the genotype: genetic counseling, carrier testing of relatives, and reproductive options—prenatal diagnosis or preimplantation genetic testing—after familial variants are established.

Secondary prevention: cascade testing; early immunologic evaluation of siblings; CBC, immunoglobulins, vaccine responses, and TCR/CD3 flow cytometry; periodic pulmonary assessment; and prompt genetic confirmation. Population carrier screening is not currently evidence-based.

Tertiary prevention: immunoglobulin replacement when indicated, antimicrobial prophylaxis, rapid fever/infection management, airway clearance, and surveillance for cytopenias, thyroid disease, enteropathy, chronic lung disease, EBV, and treatment toxicity.

Live-attenuated vaccines should be deferred in patients with significant T-cell dysfunction until evaluated by an immunologist. Inactivated vaccines are generally safer but may be poorly immunogenic; responses should be measured where clinically useful. Household and close-contact immunization helps reduce exposure. No lifestyle intervention prevents the inherited defect.

14. Other species and natural disease

No well-established naturally occurring veterinary CD3G-deficiency syndrome, breed predisposition, zoonotic transmission, or cross-species infectious transmission was identified. Relevant taxonomy includes Homo sapiens (NCBI Taxon 9606) and experimental Mus musculus (10090). CD3-complex biology is evolutionarily conserved, but chain-level redundancy differs materially between species.

15. Model organisms

CD3-chain knockout mice demonstrate reduced TCR/CD3 expression, impaired thymocyte maturation, and reduced lymphoid cellularity, but mouse models do not fully reproduce human CD3-chain disease. A key limitation is that no single CD3 subunit appears absolutely required for murine T-cell maturation, whereas human CD3δ/ε defects can block T-cell development and human CD3γ deficiency produces its own distinctive residual-T-cell/autoimmune phenotype. (grunebaum2006humantcell pages 5-7)

Human CD3E/CD3D/CD3G replacement mice are immune competent and useful for evaluating human CD3-directed antibodies or bispecific therapeutics, but they are not CD3G-deficiency models. Cellular systems—patient lymphocytes, immortalized T-cell lines, CD3G complementation, Treg suppression assays, and TCR-repertoire sequencing—currently provide the most disease-relevant functional evidence.

Recent developments and evidence limitations

The most informative mechanistic study remains the 2018 Blood analysis, which linked reduced TCR signaling to restricted Treg diversity, defective suppression, and a self-reactive conventional repertoire (published May 2018; DOI 10.1182/blood-2018-02-835561). Its central conclusion was that CD3G mutations reveal “a role for human CD3γ in Treg diversity and suppressive function.” (rowe2018patientswithcd3g pages 9-13, rowe2018patientswithcd3g pages 1-6)

The 2019 genotype–phenotype analysis expanded the disease to a CVID-like adult presentation (published December 2019; DOI 10.3389/fimmu.2019.02833). Its abstract states that the patient had “recurrent sinopulmonary infections without opportunistic infections” and received immunoglobulin for over 20 years, emphasizing that infection-predominant disease without autoimmunity is possible. (lee2019anovelcd3g pages 1-2)

A 2021 report demonstrated that even “complete absence of CD3γ protein expression” can cause CID with autoimmunity rather than classic SCID (DOI 10.1007/s10875-020-00918-z). (delmonte2021completeabsenceof pages 1-3)

The principal 2024 advances are broader IEI sequencing and flow-cytometry implementation rather than a large CD3G-specific cohort. Disease-specific 2024 reports include Chinese cases with lupus-like disease/thyroiditis or recurrent thrombocytopenia, but their full primary data were not available in the retrieved corpus and therefore are not used for quantitative conclusions. A later 2026 synthesis—outside the requested priority window—reported 18 total cases, 9/18 with hypo-/dysgammaglobulinemia and two adult patients with Evans syndrome, reinforcing broad age range and absent genotype–phenotype correlation; it should be treated as an emerging update rather than 2023–2024 evidence. (obeng2026expandingtheclinical pages 5-6, obeng2026expandingtheclinical pages 1-2)

PMIDs were not printed in the retrieved full-text metadata, so DOI URLs are provided rather than potentially unreliable PMID reconstruction. The rarity, publication bias toward severe or unusual cases, inconsistent historical HGVS nomenclature, family clustering, and absence of prospective natural-history cohorts substantially limit estimates of frequency, penetrance, treatment response, and prognosis.

References

(rowe2018patientswithcd3g pages 9-13): Jared H. Rowe, Ottavia M. Delmonte, Sevgi Keles, Brian D. Stadinski, Adam K. Dobbs, Lauren A. Henderson, Yasuhiro Yamazaki, Luis M. Allende, Francisco A. Bonilla, Luis I. Gonzalez-Granado, Seyma Celikbilek Celik, Sukru N. Guner, Hasan Kapakli, Christina Yee, Sung-Yun Pai, Eric S. Huseby, Ismail Reisli, Jose R. Regueiro, and Luigi D. Notarangelo. Patients with cd3g mutations reveal a role for human cd3γ in treg diversity and suppressive function. Blood, 131 21:2335-2344, May 2018. URL: https://doi.org/10.1182/blood-2018-02-835561, doi:10.1182/blood-2018-02-835561. This article has 83 citations and is from a highest quality peer-reviewed journal.
(rowe2018patientswithcd3g pages 1-6): Jared H. Rowe, Ottavia M. Delmonte, Sevgi Keles, Brian D. Stadinski, Adam K. Dobbs, Lauren A. Henderson, Yasuhiro Yamazaki, Luis M. Allende, Francisco A. Bonilla, Luis I. Gonzalez-Granado, Seyma Celikbilek Celik, Sukru N. Guner, Hasan Kapakli, Christina Yee, Sung-Yun Pai, Eric S. Huseby, Ismail Reisli, Jose R. Regueiro, and Luigi D. Notarangelo. Patients with cd3g mutations reveal a role for human cd3γ in treg diversity and suppressive function. Blood, 131 21:2335-2344, May 2018. URL: https://doi.org/10.1182/blood-2018-02-835561, doi:10.1182/blood-2018-02-835561. This article has 83 citations and is from a highest quality peer-reviewed journal.
(rowe2018patientswithcd3g pages 6-9): Jared H. Rowe, Ottavia M. Delmonte, Sevgi Keles, Brian D. Stadinski, Adam K. Dobbs, Lauren A. Henderson, Yasuhiro Yamazaki, Luis M. Allende, Francisco A. Bonilla, Luis I. Gonzalez-Granado, Seyma Celikbilek Celik, Sukru N. Guner, Hasan Kapakli, Christina Yee, Sung-Yun Pai, Eric S. Huseby, Ismail Reisli, Jose R. Regueiro, and Luigi D. Notarangelo. Patients with cd3g mutations reveal a role for human cd3γ in treg diversity and suppressive function. Blood, 131 21:2335-2344, May 2018. URL: https://doi.org/10.1182/blood-2018-02-835561, doi:10.1182/blood-2018-02-835561. This article has 83 citations and is from a highest quality peer-reviewed journal.
(lee2019anovelcd3g pages 1-2): Wen-I Lee, Wen-Lang Fan, Chun-Hao Lu, Shih-Hsiang Chen, Ming-Ling Kuo, Syh-Jae Lin, Weng-Sheng Tsai, Tang-Her Jaing, Li-Chen Chen, Kuo-Wei Yeh, Tsung-Chieh Yao, and Jing-Long Huang. A novel cd3g mutation in a taiwanese patient with normal t regulatory function presenting with the cvid phenotype free of autoimmunity—analysis of all genotypes and phenotypes. Frontiers in Immunology, Dec 2019. URL: https://doi.org/10.3389/fimmu.2019.02833, doi:10.3389/fimmu.2019.02833. This article has 22 citations and is from a peer-reviewed journal.
(delmonte2021completeabsenceof pages 1-3): Ottavia M. Delmonte, Jared H. Rowe, Adam K. Dobbs, Boaz Palterer, Riccardo Castagnoli, and Luigi D. Notarangelo. Complete absence of cd3γ protein expression is responsible for combined immunodeficiency with autoimmunity rather than scid. Journal of Clinical Immunology, 41:482-485, Nov 2021. URL: https://doi.org/10.1007/s10875-020-00918-z, doi:10.1007/s10875-020-00918-z. This article has 6 citations and is from a domain leading peer-reviewed journal.
(obeng2026expandingtheclinical pages 1-2): Raphaela Obeng, Abdulwahab Elsayed, Amos Takyi, Sandra von Hardenberg, Faranaz Atschekzei, Torsten Witte, and Georgios Sogkas. Expanding the clinical spectrum of cd3γ deficiency: comprehensive characterization of adult-onset disease and integrated reevaluation of all reported patients. Frontiers in Immunology, Aug 2026. URL: https://doi.org/10.3389/fimmu.2026.1889169, doi:10.3389/fimmu.2026.1889169. This article has 0 citations and is from a peer-reviewed journal.
(obeng2026expandingtheclinical pages 5-6): Raphaela Obeng, Abdulwahab Elsayed, Amos Takyi, Sandra von Hardenberg, Faranaz Atschekzei, Torsten Witte, and Georgios Sogkas. Expanding the clinical spectrum of cd3γ deficiency: comprehensive characterization of adult-onset disease and integrated reevaluation of all reported patients. Frontiers in Immunology, Aug 2026. URL: https://doi.org/10.3389/fimmu.2026.1889169, doi:10.3389/fimmu.2026.1889169. This article has 0 citations and is from a peer-reviewed journal.
(lee2019anovelcd3g pages 4-6): Wen-I Lee, Wen-Lang Fan, Chun-Hao Lu, Shih-Hsiang Chen, Ming-Ling Kuo, Syh-Jae Lin, Weng-Sheng Tsai, Tang-Her Jaing, Li-Chen Chen, Kuo-Wei Yeh, Tsung-Chieh Yao, and Jing-Long Huang. A novel cd3g mutation in a taiwanese patient with normal t regulatory function presenting with the cvid phenotype free of autoimmunity—analysis of all genotypes and phenotypes. Frontiers in Immunology, Dec 2019. URL: https://doi.org/10.3389/fimmu.2019.02833, doi:10.3389/fimmu.2019.02833. This article has 22 citations and is from a peer-reviewed journal.
(gokturk2014cd3ggenedefects pages 1-2): Bahar Göktürk, S. Keleş, Mine Kiraç, H. Artaç, H. Tokgoz, Ş. Guner, Umran Caliskan, Z. Caliskaner, M.E.L. van der Burg, J. Dongen, Neil V. Morgan, and I. Reisli. Cd3g gene defects in familial autoimmune thyroiditis. Scandinavian Journal of Immunology, 80:354-361, Nov 2014. URL: https://doi.org/10.1111/sji.12200, doi:10.1111/sji.12200. This article has 38 citations and is from a peer-reviewed journal.
(rowe2018patientswithcd3g pages 13-18): Jared H. Rowe, Ottavia M. Delmonte, Sevgi Keles, Brian D. Stadinski, Adam K. Dobbs, Lauren A. Henderson, Yasuhiro Yamazaki, Luis M. Allende, Francisco A. Bonilla, Luis I. Gonzalez-Granado, Seyma Celikbilek Celik, Sukru N. Guner, Hasan Kapakli, Christina Yee, Sung-Yun Pai, Eric S. Huseby, Ismail Reisli, Jose R. Regueiro, and Luigi D. Notarangelo. Patients with cd3g mutations reveal a role for human cd3γ in treg diversity and suppressive function. Blood, 131 21:2335-2344, May 2018. URL: https://doi.org/10.1182/blood-2018-02-835561, doi:10.1182/blood-2018-02-835561. This article has 83 citations and is from a highest quality peer-reviewed journal.
(lee2019anovelcd3g pages 2-3): Wen-I Lee, Wen-Lang Fan, Chun-Hao Lu, Shih-Hsiang Chen, Ming-Ling Kuo, Syh-Jae Lin, Weng-Sheng Tsai, Tang-Her Jaing, Li-Chen Chen, Kuo-Wei Yeh, Tsung-Chieh Yao, and Jing-Long Huang. A novel cd3g mutation in a taiwanese patient with normal t regulatory function presenting with the cvid phenotype free of autoimmunity—analysis of all genotypes and phenotypes. Frontiers in Immunology, Dec 2019. URL: https://doi.org/10.3389/fimmu.2019.02833, doi:10.3389/fimmu.2019.02833. This article has 22 citations and is from a peer-reviewed journal.
(grunebaum2006humantcell pages 5-7): Eyal Grunebaum, Nigel Sharfe, and Chaim M. Roifman. Human t cell immunodeficiency. Immunologic Research, 35:117-125, Jan 2006. URL: https://doi.org/10.1385/ir:35:1:117, doi:10.1385/ir:35:1:117. This article has 28 citations and is from a peer-reviewed journal.
(lee2019anovelcd3g pages 10-11): Wen-I Lee, Wen-Lang Fan, Chun-Hao Lu, Shih-Hsiang Chen, Ming-Ling Kuo, Syh-Jae Lin, Weng-Sheng Tsai, Tang-Her Jaing, Li-Chen Chen, Kuo-Wei Yeh, Tsung-Chieh Yao, and Jing-Long Huang. A novel cd3g mutation in a taiwanese patient with normal t regulatory function presenting with the cvid phenotype free of autoimmunity—analysis of all genotypes and phenotypes. Frontiers in Immunology, Dec 2019. URL: https://doi.org/10.3389/fimmu.2019.02833, doi:10.3389/fimmu.2019.02833. This article has 22 citations and is from a peer-reviewed journal.
(obeng2026expandingtheclinical pages 8-9): Raphaela Obeng, Abdulwahab Elsayed, Amos Takyi, Sandra von Hardenberg, Faranaz Atschekzei, Torsten Witte, and Georgios Sogkas. Expanding the clinical spectrum of cd3γ deficiency: comprehensive characterization of adult-onset disease and integrated reevaluation of all reported patients. Frontiers in Immunology, Aug 2026. URL: https://doi.org/10.3389/fimmu.2026.1889169, doi:10.3389/fimmu.2026.1889169. This article has 0 citations and is from a peer-reviewed journal.
(obeng2026expandingtheclinical pages 7-8): Raphaela Obeng, Abdulwahab Elsayed, Amos Takyi, Sandra von Hardenberg, Faranaz Atschekzei, Torsten Witte, and Georgios Sogkas. Expanding the clinical spectrum of cd3γ deficiency: comprehensive characterization of adult-onset disease and integrated reevaluation of all reported patients. Frontiers in Immunology, Aug 2026. URL: https://doi.org/10.3389/fimmu.2026.1889169, doi:10.3389/fimmu.2026.1889169. This article has 0 citations and is from a peer-reviewed journal.

Artifacts

Edison artifact artifact-00

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	6
Resolved	6
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	6
On topic	2
Off topic	0

All extracted references resolved successfully.

Term Validation

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

Outcome	Count
Terms checked	55
Resolved	55
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	0
Terms whose name was checked	1
Terms named correctly	0
Terms named as a different term	1

Terms the report names something else

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

MONDO:0014276 (4 mentions) - the report calls it "if available"; MONDO calls it combined immunodeficiency due to CD3gamma deficiency

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OpenScientist Report

Classifications

Inheritance

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Biochemical Markers

Diagnosis

Prevalence

Differential Diagnoses

Experimental Models

Animal Models

Source YAML

References & Deep Research

References

Deep Research

Disease Characteristics Research Template

Target Disease

Research Objectives

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Citation Requirements

Output Format

Combined immunodeficiency due to CD3γ deficiency

Executive summary

1. Disease information

Definition and nomenclature

2. Etiology, risk, and protective factors

Causal factor

Risk factors

3. Phenotypes

Clinical and laboratory spectrum

4. Genetic and molecular information

5. Environmental and infectious information

6. Mechanism and pathophysiology

Causal chain

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

Recommended diagnostic pathway

11. Outcome and prognosis

12. Treatment and current implementation

13. Prevention

14. Other species and natural disease

15. Model organisms

Recent developments and evidence limitations

Artifacts

Reference Validation

Term Validation

Terms the report names something else