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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

2

Why does loss of CD3gamma cause severe combined immunodeficiency in mice but a comparatively mild, autoimmunity-dominated combined immunodeficiency in humans, and can any available model be used to study the human autoimmune phenotype?

HUMAN MODEL MISMATCH OPEN mismatch_cd3g_mouse_vs_human

Attached to

pathophysiology#Distorted Thymic Selection and Self-Reactive Repertoire pathophysiology#Multisystem Autoimmunity

The Cd3g-null mouse is not a mild model of a mild disease; it is a severe model of a mild disease. Thymic cellularity falls below one per cent of normal and both T-cell lineages fail, whereas patients keep normal T-cell numbers and their dominant problem is autoimmunity. Part of the difference has a definite structural explanation: the human gamma-delta TCR incorporates CD3delta while the mouse one does not, so CD3delta can substitute for the missing chain in patients, and a human but not a mouse CD3delta transgene rescues gamma-delta development in doubly deficient mice. That accounts for the gamma-delta compartment. It does not by itself establish that the same substitution explains the preserved alpha-beta compartment, and the human cell-line models do not close the gap either: CD3G-knockdown Jurkat cells express under 11% of normal surface TCR while patient T cells express over 30%, which the authors attribute to developmental plasticity that a mature transformed line lacks. The practical consequence is that the feature which dominates the human disorder - multisystem autoimmunity arising from distorted thymic selection and defective regulatory T cells - currently has no model system in which it can be studied.

Show evidence (2 references)

PMID:17923503 SUPPORT Model Organism

"Collectively, our results indicate that the different gammadelta T cell phenotypes between CD3gamma-deficient humans and mice can be explained by differences in their gammadelta TCR composition."

The structural explanation for the species difference, stated for the gamma-delta lineage.

PMID:34249896 SUPPORT In Vitro

"Despite the high sequence homology between CD3γ and CD3δ, the clinical consequences of the corresponding immunodeficiencies (ID) in humans are very different (mild and severe, respectively), and mouse models do not recapitulate findings in human ID."

States plainly that the mouse models do not reproduce the human findings.

What determines whether a person homozygous for a null CD3G allele dies in infancy of infection and enteropathy or reaches late adulthood with hypogammaglobulinaemia and autoimmune cytopenias?

KNOWLEDGE GAP OPEN gap_cd3g_genotype_phenotype

Attached to

genetic#CD3G pathophysiology#Multisystem Autoimmunity

Patients homozygous for the same CD3G allele have had opposite outcomes, including within a single family, so the variant itself does not explain the course. Residual CD3gamma protein has been excluded as the explanation for the disorder's mildness generally, since at least one allele is a demonstrated transcript-and-protein null. Two candidate correlates have been proposed - the amount of residual surface TCR/CD3, and whether regulatory T-cell suppressive function is preserved - but each rests on a handful of patients assayed by different methods, and eighteen reported cases is too few to test either. Until it is settled there is no basis for predicting course at diagnosis, which is precisely the question that determines whether to offer transplant.

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 and the reason.

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."

Excludes residual protein as the explanation for the mild phenotype in at least one allele.

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Pathophysiology

10

Biallelic CD3G Loss-of-Function Variants

Splice-site, nonsense, frameshift and initiation-codon variants in CD3G on both alleles. The reported alleles are predicted or shown to abolish protein production rather than to produce a partially functional chain: the c.1A>G initiation-codon change eliminates the transcript as well as the protein, and a homozygous frameshift in the oldest reported patient abolishes CD3gamma expression on Western blot. The mildness of the disorder relative to the other CD3 chain deficiencies is therefore not explained by residual CD3gamma protein.

CD3G hgnc:1675

Downstream

Impaired TCR/CD3 Complex Assembly and Surface Expression Absence of the CD3gamma chain removes one of the invariant CD3 dimers required to assemble and export the receptor.

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

The alpha-beta TCR reaches the cell surface as an octamer of TCRalphabeta with the CD3gamma-epsilon, CD3delta-epsilon and zeta-zeta dimers, assembled in the endoplasmic reticulum. Without CD3gamma, assembly is inefficient and surface receptor density falls. It does not fall to zero: in patients CD3delta can substitute for CD3gamma in the complex, and the residual receptor is enough to support T-cell development. Reduced surface TCR/CD3 with preserved absolute T-cell numbers is the characteristic laboratory signature of the disorder and the feature that separates it from the other CD3 chain defects.

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 Removing CD3gamma from a human T-cell line reproduces the assembly defect: complexes are retained in the endoplasmic reticulum, lack the zeta-zeta dimer, and barely reach the surface. Domain-swap reconstitution localises the requirement to the CD3gamma extracellular domain, which the corresponding CD3delta domain cannot replace.

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 Fewer receptors on the surface, and receptors lacking the CD3gamma cytoplasmic tail, transmit a weaker signal on engagement.

Show evidence (2 references)

PMID:42661620 SUPPORT Human Clinical

"is reduced surface expression of the TCR/CD3 complex despite preserved absolute T cell numbers. In contrast, patients with other forms of CID may retain normal abTCR and CD3z expression."

States the defining laboratory finding of reduced surface receptor with normal T-cell counts.

PMID:36119034 SUPPORT In Vitro

"Since protein homology explains these results better than domain structure, we conclude that CD3γ contributes conformational cues that improve surface TCR expression, likely at the assembly or membrane transport steps."

Domain-swap experiments in a CD3gamma-negative human T-cell line locate the defect at receptor assembly or transport.

Attenuated T-Cell Receptor Signaling

Signalling through the residual receptor is reduced rather than abolished. Proximal responses such as tyrosine phosphorylation are largely preserved in CD3gamma-deficient T cells, but responses requiring the CD3gamma cytoplasmic domain are lost, including cytokine production and CD69 induction, and activation-induced cell death is increased. The clinically visible consequence is a blunted proliferative response to mitogens.

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 Signal strength at the TCR is the variable that thymic positive and negative selection reads, so reducing it changes which thymocytes survive.

Impaired T-Cell Proliferative Response Mitogens act by cross-linking TCR-associated glycoproteins, so a weaker receptor signal translates directly into reduced proliferation.

Show evidence (2 references)

PMID:36119034 SUPPORT In Vitro

"However, an IC domain at CD3γ was required for TCR-induced IL-2 and TNF-α production and CD69 expression, indicating that a TCR without a CD3γ IC domain has altered signalling capabilities."

Identifies the specific effector responses that fail without the CD3gamma intracellular domain.

PMID:12407027 SUPPORT In Vitro

"Our data indicate that CD3 gamma contributes essential specialized signaling functions to certain mature T cell responses."

Establishes that CD3gamma loss selectively impairs a subset of mature T-cell responses rather than abolishing signalling.

Distorted Thymic Selection and Self-Reactive Repertoire

Thymocytes that would normally be deleted survive a weakened selection signal. Deep sequencing of the TCR beta repertoire in patients shows conventional CD4+ T cells enriched for hydrophobic residues at CDR3 positions 6 and 7, a published biomarker of self-reactivity, and clonotypes bearing cysteines at the CDR3 apex. The repertoire is polyclonal but its diversity is reduced and it carries prominent clonal expansions.

thymocyte CL:0000893

thymic T cell selection GO:0045061 ↓ DECREASED

Animal models

Cd3g-deficient mouse Mouse fails to recapitulate In patients, weakened TCR signalling lets self-reactive thymocytes through selection and yields a polyclonal but skewed peripheral repertoire. The mouse has no such repertoire to skew: development arrests at the CD44-CD25+ double-negative stage and both the alpha-beta and gamma-delta lineages fail.

Downstream

Regulatory T-Cell Deficiency and Impaired Suppression Regulatory T-cell selection depends on the same TCR signal, and the regulatory compartment in patients is reduced in number and diversity.

Multisystem Autoimmunity A repertoire enriched for self-reactive specificities is one of the two proposed contributors to the autoimmunity that dominates this disorder.

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."

Direct repertoire evidence that the surviving conventional T-cell pool is enriched for self-reactive specificities.

Regulatory T-Cell Deficiency and Impaired Suppression

Patients have reduced regulatory T-cell proportions, and the regulatory cells they do have are restricted in repertoire diversity, more clonal, and less able to suppress proliferation of conventional T cells in vitro. This is not universal: one adult with a CVID-like presentation and no autoimmunity retained normal regulatory T-cell suppressive function, which is the closest thing the literature has to an explanation for why some patients escape autoimmunity.

regulatory T cell CL:0000815

regulatory T cell differentiation GO:0045066 ↓ DECREASED

Downstream

Multisystem Autoimmunity Failure of dominant peripheral tolerance permits the autoimmune manifestations that dominate the reported phenotype.

Show evidence (2 references)

PMID:29653965 SUPPORT In Vitro

"Treg cells of patients with CD3G defects had reduced diversity, increased clonality, and reduced suppressive function."

Records the three regulatory T-cell abnormalities, the suppressive-function measurement being a suppression co-culture assay.

PMID:31921117 SUPPORT Human Clinical

"However, sufficient Treg suppression function was maintained so that he remained free of autoimmune thyroiditis (AIT), inflammatory bowel disease (IBD), and autoimmune pancytopenia."

A counter-example in which preserved regulatory T-cell suppressive function accompanied absence of autoimmunity, which is why this node is not described as an invariant feature.

Impaired T-Cell Proliferative Response

Reduced proliferation on stimulation with phytohaemagglutinin, concanavalin A and other mitogens. Among the eleven reported patients in whom it was formally tested this was the one functional abnormality found without exception, which makes it the most reliable functional marker of the disorder even though it is not specific to it. The qualifier matters: an adult reported with a common-variable-immunodeficiency-like picture was described as having normal phytohaemagglutinin-induced proliferation, and the 2026 review that assembled the cohort scored that same patient as reduced. Both statements are quoted in this entry, from their own sources.

T cell proliferation GO:0042098 ↓ DECREASED

Downstream

Susceptibility to Recurrent and Chronic Infection Defective T-cell effector expansion is the proposed basis of the infection susceptibility, which in the severe patients includes opportunistic and chronic viral infection.

Humoral Immune Failure Impaired T-cell help limits B-cell class switching and antibody production, though the humoral phenotype is heterogeneous.

Show evidence (1 reference)

PMID:42661620 SUPPORT Human Clinical

"while reduced response to mitogens was consistently reported in all 11 tested patients"

Records that impaired mitogen response was present in every patient tested.

Humoral Immune Failure

Hypogammaglobulinaemia or dysgammaglobulinaemia in half of reported patients, with reduced switched and unswitched memory B cells and impaired responses to polysaccharide and protein vaccines. In two adults the humoral defect was the presenting problem and the diagnosis was initially common variable immunodeficiency.

immunoglobulin production GO:0002377 ↓ DECREASED

Downstream

Susceptibility to Recurrent and Chronic Infection Antibody deficiency contributes the sinopulmonary component of the infection burden and is the component that immunoglobulin replacement addresses.

Show evidence (1 reference)

PMID:42661620 SUPPORT Human Clinical

"Overall, hypogammaglobulinemia or a form of dysgammaglobulinemia was reported in 9/18 patients (50%, Table 2). Defects in memory B cells and the presence of multiple autoantibodies were frequently observed."

Quantifies the humoral defect across the reported cohort.

Multisystem Autoimmunity

The most consistent clinical theme. Autoimmune thyroiditis and autoimmune haemolytic anaemia are each reported in about two in five patients and immune thrombocytopenia in about one in five; autoimmune enteropathy, autoimmune hepatitis, nephrotic syndrome, vitiligo and lupus-like disease have each been reported. Some patients have autoimmunity with no significant infection history at all.

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%)"

Quantifies the three commonest autoimmune manifestations across all reported patients.

PMID:23590417 SUPPORT Human Clinical

"Here, we present two siblings from non-consanguineous family with autoimmunity including Evans syndrome, autoimmune hepatitis, nephrotic syndrome, and Hashimoto's thyroiditis and with no previous history of infections."

Documents patients in whom autoimmunity was the entire presentation.

Susceptibility to Recurrent and Chronic Infection

Recurrent respiratory tract infection, protracted diarrhoea and failure to thrive in the severe infantile presentations, with opportunistic and chronic viral infection in the most severely affected. Patients who experienced opportunistic infection, life-threatening infection requiring transplant, or inflammatory-bowel-disease-like diarrhoea had significantly higher mortality than those who did not.

Downstream

Bronchiectasis from Recurrent Sinopulmonary Infection Repeated lower respiratory tract infection produces irreversible airway dilatation, the principal end-organ sequela of the infection burden.

Show evidence (1 reference)

PMID:31921117 SUPPORT Human Clinical

"Those experiencing opportunistic infections, severe life-threatening infections in need of hematopoietic stem cell transplantation, and IBD-like diarrhea had a significantly higher mortality rate compared with those without these features"

Connects the infectious phenotype to mortality across the reported literature.

Bronchiectasis from Recurrent Sinopulmonary Infection

Irreversible bronchial dilatation following repeated lower respiratory tract infection. It is the principal permanent end-organ consequence of this disorder, it followed sinopulmonary infection in four of the five patients in whom that infection pattern occurred, and it is the reason antimicrobial prophylaxis is given long term rather than only for acute episodes.

Show evidence (1 reference)

PMID:31921117 SUPPORT Human Clinical

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

Records the frequency of bronchiectasis among patients with the sinopulmonary infection phenotype.

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Pathograph

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Phenotypes

16

Blood 4

Autoimmune hemolytic anemia 38.9% 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 22.2% 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 50% HP:0004313

Show evidence (1 reference)

PMID:42661620 SUPPORT Human Clinical

"Overall, hypogammaglobulinemia or a form of dysgammaglobulinemia was reported in 9/18 patients (50%, Table 2). Defects in memory B cells and the presence of multiple autoantibodies were frequently observed."

The 9/18 figure is the frequency recorded here.

Increased circulating IgE concentration 2/5 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.

Immune 3

Combined immunodeficiency HP:0005387

Show evidence (1 reference)

PMID:33215322 SUPPORT Human Clinical

"While human CD3 δ, ε, and ζ deficiency lead to SCID, all the previously reported human cases of CD3γ deficiency (14 subjects described in the literature) manifest with variable degrees of combined immune deficiency (CID)."

States that every reported patient has a combined immunodeficiency, of variable degree, rather than SCID.

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 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.

Respiratory 1

Bronchiectasis 4 of 5 patients with recurrent sinopulmonary infection 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.

Growth 1

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.

Other 7

Reduced surface TCR/CD3 expression with normal T-cell numbers Abnormal T cell physiology HP:0011840

Show evidence (2 references)

PMID:35748970 SUPPORT Other

"CD3 deficiency CD3G AR 186740 Normal number, but low TCR expression Normal Normal Immune deficiency and autoimmunity of variable severity"

The IUIS row records normal T-cell number with low TCR expression as the characteristic finding.

PMID:42661620 SUPPORT Human Clinical

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

Proposes surface receptor measurement as the diagnostic pointer.

Impaired mitogen-induced lymphocyte proliferation Impaired phytohemagglutinin-induced T lymphocyte transformation HP:0025834

Show evidence (1 reference)

PMID:42661620 SUPPORT Human Clinical

"while reduced response to mitogens was consistently reported in all 11 tested patients"

Records the finding and the number of patients tested.

Autoimmune thyroiditis 38.9% Hashimoto thyroiditis HP:0000872

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 7/18 figure quoted.

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.

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.

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.

Autoimmune hepatitis HP:5210421

Show evidence (1 reference)

PMID:23590417 SUPPORT Human Clinical

"Here, we present two siblings from non-consanguineous family with autoimmunity including Evans syndrome, autoimmune hepatitis, nephrotic syndrome, and Hashimoto's thyroiditis and with no previous history of infections."

Documents autoimmune hepatitis in CD3gamma-deficient siblings.

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.

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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.

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Medical Actions

5

Immunoglobulin replacement therapy

Action: Pharmacotherapy NCIT:C15986

Agent: therapeutic immune globulin NCIT:C2701

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 antibody substitutes for the immunoglobulin the patient cannot make; it does not repair the T-cell defect that causes the humoral failure.

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

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 — Depleting B cells removes the effector arm of the autoantibody-mediated cytopenias without addressing the T-cell tolerance defect upstream.

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

Corticosteroids are the most frequently used immunosuppressant across the reported cohort, given for the autoimmune cytopenias and the enteropathy, usually alongside rituximab and sometimes sirolimus. They come with a specific hazard in this disorder rather than a generic one: glucocorticoids suppress T-cell receptor signalling at several levels, and this is a disease of already-weakened T-cell receptor signalling, so the drug acts on the same node as the lesion and in the same direction. Two patients are reported to have deteriorated immunologically on high-dose glucocorticoids given for autoimmune cytopenias, and control of the autoimmunity was in any case limited. Rituximab controlled the cytopenias in both adults of the 2026 series and allowed glucocorticoid tapering.

Mechanism Target:

INHIBITS Multisystem Autoimmunity — The intended effect: broad immunosuppression damps the autoimmune cytopenias and enteropathy. Efficacy in this disorder has been limited, which is part of why rituximab has become the agent that actually controls the cytopenias.

Show evidence (1 reference)

PMID:33215322 SUPPORT Human Clinical

"Rituximab, Sirolimus, and steroids were initiated for the treatment of AIHA, chronic interstitial lung disease, enteropathy, and EBV viremia."

Documents the indications for which steroids and sirolimus were given in a reported patient.

MODULATES Attenuated T-Cell Receptor Signaling — The unintended effect, and the direction is downward. Glucocorticoids suppress T-cell receptor signalling at several levels, so on this node they add to the lesion rather than opposing it, and the proposed consequence is further impairment of host defence and of tolerogenic mechanisms. MODULATES is used because the treatment-effect vocabulary has no value for a drug that worsens its target node; the direction is stated here rather than encoded.

Show evidence (2 references)

PMID:42661620 SUPPORT Human Clinical

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

Establishes that the drug acts on the same signalling step this node describes.

PMID:42661620 SUPPORT Human Clinical

"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:42661620 SUPPORT Human Clinical

"Importantly, RTX effectively controlled autoimmune cytopenias in both patients described here and enabled glucocorticoid tapering."

Records that the outcome sought from glucocorticoids was achieved by rituximab instead, and that tapering steroids was itself a goal.

Antimicrobial therapy and prophylaxis

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

Treatment of acute infection and long-term antimicrobial prophylaxis. The indication for continuing prophylaxis rather than treating episodes as they arise is the bronchiectasis that follows recurrent sinopulmonary infection in most patients who have that pattern.

Mechanism Target:

BYPASSES Susceptibility to Recurrent and Chronic Infection — Antimicrobials substitute for the T-cell function the patient lacks; they do not restore it, which is why prophylaxis is continued indefinitely.

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:31921117 SUPPORT Human Clinical

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

The complication that makes long-term prophylaxis rather than episode-by-episode treatment the standard approach.

Hematopoietic stem cell transplantation

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

Allogeneic transplant is the only treatment that replaces the defective T-cell compartment, and is used in the severe infantile presentations. Outcomes in the reported patients have been poor: several died of infection or transplant-related complications, and severe disease requiring transplant was itself associated with higher mortality.

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."

Records a good disease response to transplant; the same patient died on day +50 of infection, which is why this is graded partial.

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: Hypogammaglobulinaemia is present in about half of reported patients and is the finding that brings the adult-onset cases to attention. In a severely affected infant IgG was 338 mg/dL with impaired responses to Haemophilus influenzae type b and pneumococcal vaccination.

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 measured IgG value and the functional antibody deficit accompanying it.

PMID:42661620 SUPPORT Human Clinical

"Overall, hypogammaglobulinemia or a form of dysgammaglobulinemia was reported in 9/18 patients (50%, Table 2). Defects in memory B cells and the presence of multiple autoantibodies were frequently observed."

The 9/18 frequency recorded here.

CD4+ T-lymphocyte count (Decreased)

Context: Absolute CD3+ T-cell numbers are characteristically normal, which is what separates this disorder from the other CD3 chain deficiencies, but the CD4+ subset can still be low and the naive and regulatory subsets are commonly reduced.

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)."

The measured CD4 count alongside the normal total T-cell number that characterises the disorder.

🔬

Diagnosis

2

Lymphocyte immunophenotyping with surface TCR/CD3 quantitation

Flow cytometry of peripheral blood measuring absolute T-cell counts together with surface TCRalphabeta and CD3 density. The characteristic result is normal or near-normal T-cell numbers with reduced receptor expression, which is what distinguishes this disorder from the CD3delta, CD3epsilon and CD3zeta deficiencies.

flow cytometry NCIT:C16585

Results: Normal absolute T-cell number with reduced surface TCRalphabeta/CD3 expression; often reduced naive and regulatory T-cell proportions.

Show evidence (1 reference)

PMID:42661620 SUPPORT Human Clinical

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

Proposes exactly this measurement as the diagnostic marker.

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

No population estimate exists. A 2026 review that reassessed the whole literature counted 18 genetically confirmed patients, 16 previously reported plus the two adults it described.

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 published case count, standing in for a population prevalence estimate that has never been made.

🔀

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 The other CD3 chain defects. They share the biochemical lesion - an incomplete TCR/CD3 complex - but block thymocyte development and present as T-B+NK+ severe combined immunodeficiency in infancy rather than as a variable combined immunodeficiency with autoimmunity.

Distinguishing Features

Complete block in T-cell development rather than preserved T-cell numbers
Early-onset life-threatening infection rather than immune dysregulation
Surface CD3 essentially absent rather than reduced

Show evidence (1 reference)

PMID:16264327 SUPPORT Human Clinical

"Homozygous mutations in CD3D and CD3E genes lead to a complete block in T-cell development and thus to an early-onset severe combined immunodeficiency phenotype. Thymic studies have shown that the defect in T-cell development occurs at the transition between 'double-negative' and..."

States the developmental block that separates the other CD3 deficiencies from CD3gamma deficiency.

Common variable immunodeficiency MONDO:0015517

Overlapping Features The label two adult CD3gamma-deficient patients carried before genetic diagnosis. Hypogammaglobulinaemia with reduced switched memory B cells and autoimmune cytopenias is compatible with both; reduced surface TCR/CD3 with impaired mitogen responses is not typical of common variable immunodeficiency and points to the T-cell lesion.

Distinguishing Features

Reduced surface TCRalphabeta and CD3 expression
Impaired proliferative response to mitogens
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 Removing CD3gamma from a human T-cell line reproduces the assembly defect: complexes are retained in the endoplasmic reticulum, lack the zeta-zeta dimer, and barely reach the surface. Domain-swap reconstitution localises the requirement to the CD3gamma extracellular domain, which the corresponding CD3delta domain cannot replace.

Limitations: The quantitative severity does not match the patients. Surface receptor in the knockdown lines falls below 11% of control, whereas mature T cells from CD3gamma-deficient patients express more than 30%. The authors attribute this to plasticity available to developing thymocytes that a mature transformed line does not have, so the line overstates the severity of the human lesion.

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

"This is in sharp contrast to human CD3γ ID, whose mature T cells express higher levels of surface TCR (>30% vs. normal controls)."

The authors' own statement of the gap between the line and the patients, which is why this link is partial rather than full recapitulation.

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: A transformed leukaemia line with a transfected receptor; the readouts are cytokine and activation-marker induction rather than the in vivo T-cell responses that matter clinically.

Readouts

TCR-induced IL-2, TNF-alpha and CD69 induction

Direction: DECREASED

Interpretation: Locates the signalling contribution of CD3gamma to its intracellular domain.

Show evidence (1 reference)

PMID:36119034 SUPPORT In Vitro

"However, an IC domain at CD3γ was required for TCR-induced IL-2 and TNF-α production and CD69 expression, indicating that a TCR without a CD3γ IC domain has altered signalling capabilities."

The measured signalling deficits attributable to the CD3gamma intracellular domain.

Show evidence (1 reference)

PMID:36119034 SUPPORT In Vitro

"Expression of γγγ, γγδ, γδδ or γγ- in the γ- T cell line JGN, which lacks surface TCR, demonstrated that cell surface TCR levels in JGN were dependent on the EC domain of CD3γ and could not be replaced by the one of CD3δ."

Establishes the system and what it is able to resolve.

🐁

Animal Models

1

Cd3g-deficient mouse

Mice engineered to lack CD3gamma while retaining CD3delta, CD3epsilon, CD3zeta, pTalpha and TCRbeta. They were made to test the role of CD3gamma in the pre-TCR, and they answer that question, but they do not reproduce the human disease: thymic cellularity falls below one per cent of normal and peripheral T cells to two to five per cent, which is a severe combined immunodeficiency rather than the preserved-T-cell disorder seen in patients.

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 reduction is more severe than in patients, and it occurs in a thymus that is nearly empty, so the mouse cannot be used to study the mature T-cell receptor deficit that defines the human disorder.

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 In patients, weakened TCR signalling lets self-reactive thymocytes through selection and yields a polyclonal but skewed peripheral repertoire. The mouse has no such repertoire to skew: development arrests at the CD44-CD25+ double-negative stage and both the alpha-beta and gamma-delta lineages fail.

Limitations: Thymocyte number falls to under one per cent of normal and peripheral T cells to two to five per cent, so the mouse models a developmental block that human patients do not have. The species difference has a known structural basis: the human gamma-delta TCR incorporates CD3delta and the mouse one does not, so CD3delta can substitute for missing CD3gamma in patients but not in mice. Nothing about the human autoimmune phenotype - the dominant clinical problem - can be studied in this 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."

Documents the developmental arrest that human patients do not have.

+ 2 more references

Show evidence (1 reference)

PMID:17923503 SUPPORT Model Organism

"gammadelta T cells do not develop in CD3gamma-deficient mice, whereas human patients lacking CD3gamma have abundant peripheral blood gammadelta T cells expressing high gammadelta TCR levels."

States the discordance that limits how far this model informs the human disorder.

{ }

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: >-
  Combined immunodeficiency due to CD3gamma deficiency is an ultra-rare
  autosomal recessive inborn error of immunity caused by biallelic
  loss-of-function variants in CD3G, the gene encoding the CD3gamma invariant
  chain of the T-cell receptor (TCR)/CD3 complex. Loss of CD3gamma impairs
  assembly and surface expression of the TCR/CD3 complex, so mature T cells
  carry fewer receptors and signal less strongly through them.

  The disorder is defined as much by what it is not as by what it is. Deficiency
  of the other CD3 chains - CD3delta, CD3epsilon and CD3zeta - blocks thymocyte
  development and produces T-B+NK+ severe combined immunodeficiency. CD3gamma
  deficiency does not: patients typically have normal absolute T-cell numbers
  with reduced surface TCR/CD3, and the dominant clinical problem is often
  immune dysregulation rather than infection. Reported patients span a
  remarkable range, from failure to thrive with intractable diarrhoea and early
  death in infancy to an adult first recognised in middle age because of
  hypogammaglobulinaemia and autoimmune cytopenias. Individuals carrying the
  same homozygous variant have had markedly different courses, so no
  genotype-phenotype rule has been established.

  Autoimmunity is the most consistent thread: autoimmune thyroiditis, autoimmune
  haemolytic anaemia and immune thrombocytopenia together account for most
  reported manifestations. The mechanistic account offered for this is that
  weakened TCR signalling distorts thymic selection and leaves a regulatory
  T-cell compartment that is reduced in number, restricted in repertoire
  diversity and impaired in suppressive function, alongside a conventional
  T-cell repertoire enriched for self-reactive specificities.
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."
classifications:
  iuis_category:
    classification_value: combined immunodeficiency
    notes: >-
      IUIS 2022 phenotypic classification of inborn errors of immunity, Table 1
      (immunodeficiencies affecting cellular and humoral immunity). CD3gamma
      deficiency is listed there as an autosomal recessive CD3G defect with
      normal T-cell numbers but low TCR expression, distinguishing it from the
      CD3delta/CD3epsilon/CD3zeta defects that appear as T-B+NK+ SCID.
    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: >-
    No population estimate exists. A 2026 review that reassessed the whole
    literature counted 18 genetically confirmed patients, 16 previously reported
    plus the two adults it described.
  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 published case count, standing in for a population prevalence estimate
      that has never been made.
pathophysiology:
- name: Biallelic CD3G Loss-of-Function Variants
  biological_scale: MOLECULAR
  description: >-
    Splice-site, nonsense, frameshift and initiation-codon variants in CD3G on
    both alleles. The reported alleles are predicted or shown to abolish protein
    production rather than to produce a partially functional chain: the
    c.1A>G initiation-codon change eliminates the transcript as well as the
    protein, and a homozygous frameshift in the oldest reported patient
    abolishes CD3gamma expression on Western blot. The mildness of the disorder
    relative to the other CD3 chain deficiencies is therefore not explained by
    residual CD3gamma protein.
  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: >-
      Absence of the CD3gamma chain removes one of the invariant CD3 dimers
      required to assemble and export the receptor.
    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: >-
        One patient, currently the oldest reported individual with CD3γ deficiency, harbored a novel homozygous frameshift variant in CD3G (c.213dupA, p.(Trp72Metfs*6)) resulting in complete loss of CD3γ expression.
      explanation: >-
        Links a biallelic CD3G variant directly to loss of the CD3gamma chain
        that the complex needs.
- name: Impaired TCR/CD3 Complex Assembly and Surface Expression
  biological_scale: MOLECULAR
  description: >-
    The alpha-beta TCR reaches the cell surface as an octamer of TCRalphabeta
    with the CD3gamma-epsilon, CD3delta-epsilon and zeta-zeta dimers, assembled
    in the endoplasmic reticulum. Without CD3gamma, assembly is inefficient and
    surface receptor density falls. It does not fall to zero: in patients CD3delta
    can substitute for CD3gamma in the complex, and the residual receptor is
    enough to support T-cell development. Reduced surface TCR/CD3 with preserved
    absolute T-cell numbers is the characteristic laboratory signature of the
    disorder and the feature that separates it from the other CD3 chain defects.
  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: >-
      is reduced surface expression of the TCR/CD3 complex despite preserved absolute T cell numbers. In contrast, patients with other forms of CID may retain normal abTCR and CD3z expression.
    explanation: >-
      States the defining laboratory finding of reduced surface receptor with
      normal T-cell counts.
  - reference: PMID:36119034
    reference_title: The role of the different CD3γ domains in TCR expression and signaling.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Since protein homology explains these results better than domain structure, we conclude that CD3γ contributes conformational cues that improve surface TCR expression, likely at the assembly or membrane transport steps.
    explanation: >-
      Domain-swap experiments in a CD3gamma-negative human T-cell line locate
      the defect at receptor assembly or transport.
  downstream:
  - target: Attenuated T-Cell Receptor Signaling
    description: >-
      Fewer receptors on the surface, and receptors lacking the CD3gamma
      cytoplasmic tail, transmit a weaker signal on engagement.
    causal_link_type: DIRECT
    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: >-
        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: >-
        States the proposed causal chain from altered surface expression to
        reduced signalling strength.
- name: Attenuated T-Cell Receptor Signaling
  biological_scale: CELLULAR
  description: >-
    Signalling through the residual receptor is reduced rather than abolished.
    Proximal responses such as tyrosine phosphorylation are largely preserved in
    CD3gamma-deficient T cells, but responses requiring the CD3gamma
    cytoplasmic domain are lost, including cytokine production and CD69
    induction, and activation-induced cell death is increased. The clinically
    visible consequence is a blunted proliferative response to mitogens.
  biological_processes:
  - preferred_term: T cell receptor signaling pathway
    modifier: DECREASED
    term:
      id: GO:0050852
      label: T cell receptor signaling pathway
  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: >-
      However, an IC domain at CD3γ was required for TCR-induced IL-2 and TNF-α production and CD69 expression, indicating that a TCR without a CD3γ IC domain has altered signalling capabilities.
    explanation: >-
      Identifies the specific effector responses that fail without the CD3gamma
      intracellular domain.
  - 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: >-
      Our data indicate that CD3 gamma contributes essential specialized signaling functions to certain mature T cell responses.
    explanation: >-
      Establishes that CD3gamma loss selectively impairs a subset of mature
      T-cell responses rather than abolishing signalling.
  downstream:
  - target: Distorted Thymic Selection and Self-Reactive Repertoire
    description: >-
      Signal strength at the TCR is the variable that thymic positive and
      negative selection reads, so reducing it changes which thymocytes survive.
    causal_link_type: DIRECT
    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: >-
        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: >-
        Names thymic selection as the step affected by the reduced signalling
        strength.
  - target: Impaired T-Cell Proliferative Response
    description: >-
      Mitogens act by cross-linking TCR-associated glycoproteins, so a weaker
      receptor signal translates directly into reduced proliferation.
    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: >-
        reduced proliferation is likely a direct consequence of impaired TCR/CD3-mediated signaling resulting from defective CD3 g expression
      explanation: >-
        States the causal link from defective CD3gamma expression through
        impaired receptor signalling to the reduced proliferative response.
- name: Distorted Thymic Selection and Self-Reactive Repertoire
  biological_scale: CELLULAR
  description: >-
    Thymocytes that would normally be deleted survive a weakened selection
    signal. Deep sequencing of the TCR beta repertoire in patients shows
    conventional CD4+ T cells enriched for hydrophobic residues at CDR3
    positions 6 and 7, a published biomarker of self-reactivity, and clonotypes
    bearing cysteines at the CDR3 apex. The repertoire is polyclonal but its
    diversity is reduced and it carries prominent clonal expansions.
  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: >-
      Direct repertoire evidence that the surviving conventional T-cell pool is
      enriched for self-reactive specificities.
  downstream:
  - target: Regulatory T-Cell Deficiency and Impaired Suppression
    description: >-
      Regulatory T-cell selection depends on the same TCR signal, and the
      regulatory compartment in patients is reduced in number and diversity.
    causal_link_type: DIRECT
    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: >-
        Integrity of the T-cell receptor/CD3 complex is crucial for positive and negative selection of T cells in the thymus and for effector and regulatory functions of peripheral T lymphocytes.
      explanation: >-
        States the dependence of both thymic selection and peripheral regulatory
        function on an intact TCR/CD3 complex.
  - target: Multisystem Autoimmunity
    description: >-
      A repertoire enriched for self-reactive specificities is one of the two
      proposed contributors to the autoimmunity that dominates this disorder.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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: >-
        These data demonstrate that the T-cell repertoire of patients with CD3G mutations is characterized by a molecular signature that may contribute to the increased rate of autoimmunity associated with this condition.
      explanation: >-
        The authors state the link as a contribution that may explain the
        autoimmunity, not as a demonstrated mechanism, which is why this edge is
        marked indirect with unknown intermediates.
- name: Regulatory T-Cell Deficiency and Impaired Suppression
  biological_scale: CELLULAR
  description: >-
    Patients have reduced regulatory T-cell proportions, and the regulatory
    cells they do have are restricted in repertoire diversity, more clonal, and
    less able to suppress proliferation of conventional T cells in vitro. This
    is not universal: one adult with a CVID-like presentation and no
    autoimmunity retained normal regulatory T-cell suppressive function, which
    is the closest thing the literature has to an explanation for why some
    patients escape autoimmunity.
  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: 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: IN_VITRO
    snippet: >-
      Treg cells of patients with CD3G defects had reduced diversity, increased clonality, and reduced suppressive function.
    explanation: >-
      Records the three regulatory T-cell abnormalities, the suppressive-function
      measurement being a suppression co-culture assay.
  - 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: >-
      However, sufficient Treg suppression function was maintained so that he remained free of autoimmune thyroiditis (AIT), inflammatory bowel disease (IBD), and autoimmune pancytopenia.
    explanation: >-
      A counter-example in which preserved regulatory T-cell suppressive function
      accompanied absence of autoimmunity, which is why this node is not
      described as an invariant feature.
  downstream:
  - target: Multisystem Autoimmunity
    description: >-
      Failure of dominant peripheral tolerance permits the autoimmune
      manifestations that dominate the reported phenotype.
    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: >-
        Our patient with the novel CD3G mutation presented with predominant B-cell deficiency overlapping with the CVID phenotype but without recognizable autoimmunity, which was consistent with his normal Treg suppression function.
      explanation: >-
        Correlative rather than experimental support for the regulatory-cell
        route to autoimmunity, which is why the edge is indirect.
- name: Impaired T-Cell Proliferative Response
  biological_scale: CELLULAR
  description: >-
    Reduced proliferation on stimulation with phytohaemagglutinin, concanavalin
    A and other mitogens. Among the eleven reported patients in whom it was
    formally tested this was the one functional abnormality found without
    exception, which makes it the most reliable functional marker of the
    disorder even though it is not specific to it. The qualifier matters: an
    adult reported with a common-variable-immunodeficiency-like picture was
    described as having normal phytohaemagglutinin-induced proliferation, and
    the 2026 review that assembled the cohort scored that same patient as
    reduced. Both statements are quoted in this entry, from their own sources.
  biological_processes:
  - preferred_term: T cell proliferation
    modifier: DECREASED
    term:
      id: GO:0042098
      label: T cell proliferation
  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: >-
      while reduced response to mitogens was consistently reported in all 11 tested patients
    explanation: >-
      Records that impaired mitogen response was present in every patient tested.
  downstream:
  - target: Susceptibility to Recurrent and Chronic Infection
    description: >-
      Defective T-cell effector expansion is the proposed basis of the infection
      susceptibility, which in the severe patients includes opportunistic and
      chronic viral infection.
    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: >-
        The patient had suffered from intractable diarrhea, recurrent pulmonary infections and oral moniliasis since two months of age.
      explanation: >-
        Documents the infectious phenotype in a CD3gamma-deficient infant. The
        step from the measured proliferative defect to clinical infection is
        inferred rather than demonstrated, which is why this edge is indirect
        with unknown intermediates.
  - target: Humoral Immune Failure
    description: >-
      Impaired T-cell help limits B-cell class switching and antibody
      production, though the humoral phenotype is heterogeneous.
    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: >-
        Overall, hypogammaglobulinemia or a form of dysgammaglobulinemia was reported in 9/18 patients (50%, Table 2). Defects in memory B cells and the presence of multiple autoantibodies were frequently observed.
      explanation: >-
        The humoral consequence is real but variable and its mechanism is not
        worked out, which is why this edge is indirect with unknown
        intermediates.
- name: Humoral Immune Failure
  biological_scale: ORGANISM
  description: >-
    Hypogammaglobulinaemia or dysgammaglobulinaemia in half of reported
    patients, with reduced switched and unswitched memory B cells and impaired
    responses to polysaccharide and protein vaccines. In two adults the humoral
    defect was the presenting problem and the diagnosis was initially common
    variable immunodeficiency.
  biological_processes:
  - preferred_term: immunoglobulin production
    modifier: DECREASED
    term:
      id: GO:0002377
      label: immunoglobulin production
  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: >-
      Overall, hypogammaglobulinemia or a form of dysgammaglobulinemia was reported in 9/18 patients (50%, Table 2). Defects in memory B cells and the presence of multiple autoantibodies were frequently observed.
    explanation: >-
      Quantifies the humoral defect across the reported cohort.
  downstream:
  - target: Susceptibility to Recurrent and Chronic Infection
    description: >-
      Antibody deficiency contributes the sinopulmonary component of the
      infection burden and is the component that immunoglobulin replacement
      addresses.
    causal_link_type: DIRECT
    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: >-
        A patient in whom the antibody deficiency, not the T-cell defect,
        produced the infection phenotype.
- name: Multisystem Autoimmunity
  biological_scale: ORGANISM
  description: >-
    The most consistent clinical theme. Autoimmune thyroiditis and autoimmune
    haemolytic anaemia are each reported in about two in five patients and
    immune thrombocytopenia in about one in five; autoimmune enteropathy,
    autoimmune hepatitis, nephrotic syndrome, vitiligo and lupus-like disease
    have each been reported. Some patients have autoimmunity with no significant
    infection history at all.
  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: >-
      Quantifies the three commonest autoimmune manifestations across all
      reported patients.
  - reference: PMID:23590417
    reference_title: "Variable presentation of primary immune deficiency: two cases with CD3 gamma deficiency presenting with only autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we present two siblings from non-consanguineous family with autoimmunity including Evans syndrome, autoimmune hepatitis, nephrotic syndrome, and Hashimoto's thyroiditis and with no previous history of infections.
    explanation: >-
      Documents patients in whom autoimmunity was the entire presentation.
- name: Susceptibility to Recurrent and Chronic Infection
  biological_scale: ORGANISM
  downstream:
  - target: Bronchiectasis from Recurrent Sinopulmonary Infection
    description: >-
      Repeated lower respiratory tract infection produces irreversible airway
      dilatation, the principal end-organ sequela of the infection burden.
    causal_link_type: DIRECT
    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: >-
        Directly links recurrent sinopulmonary infection to bronchiectasis in the
        reported cohort, and quantifies how often it follows.
  description: >-
    Recurrent respiratory tract infection, protracted diarrhoea and failure to
    thrive in the severe infantile presentations, with opportunistic and chronic
    viral infection in the most severely affected. Patients who experienced
    opportunistic infection, life-threatening infection requiring transplant, or
    inflammatory-bowel-disease-like diarrhoea had significantly higher mortality
    than those who did not.
  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: >-
      Those experiencing opportunistic infections, severe life-threatening infections in need of hematopoietic stem cell transplantation, and IBD-like diarrhea had a significantly higher mortality rate compared with those without these features
    explanation: >-
      Connects the infectious phenotype to mortality across the reported
      literature.
- name: Bronchiectasis from Recurrent Sinopulmonary Infection
  biological_scale: ORGANISM
  description: >-
    Irreversible bronchial dilatation following repeated lower respiratory tract
    infection. It is the principal permanent end-organ consequence of this
    disorder, it followed sinopulmonary infection in four of the five patients
    in whom that infection pattern occurred, and it is the reason antimicrobial
    prophylaxis is given long term rather than only for acute episodes.
  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: >-
      Records the frequency of bronchiectasis among patients with the
      sinopulmonary infection phenotype.
phenotypes:
- name: Combined immunodeficiency
  category: Immunologic
  diagnostic: true
  description: >-
    A combined cellular and humoral immunodeficiency of variable severity, which
    is how the disorder is classified in the IUIS nosology.
  phenotype_term:
    preferred_term: Combined immunodeficiency
    term:
      id: HP:0005387
      label: Combined immunodeficiency
  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: >-
      While human CD3 δ, ε, and ζ deficiency lead to SCID, all the previously reported human cases of CD3γ deficiency (14 subjects described in the literature) manifest with variable degrees of combined immune deficiency (CID).
    explanation: >-
      States that every reported patient has a combined immunodeficiency, of
      variable degree, rather than SCID.
- name: Reduced surface TCR/CD3 expression with normal T-cell numbers
  category: Immunologic
  diagnostic: true
  description: >-
    Flow cytometry shows reduced surface TCRalphabeta and CD3 with preserved
    absolute T-cell counts. This combination is the most useful single pointer
    to the diagnosis, since most other combined immunodeficiencies do not
    produce it.
  phenotype_term:
    preferred_term: Abnormal T cell physiology
    term:
      id: HP:0011840
      label: Abnormal T cell physiology
  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 row records normal T-cell number with low TCR expression as the
      characteristic finding.
  - 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: >-
      that assessment of abTCR and CD3 z surface expression may represent a useful diagnostic marker in patients with suspected CD3g
    explanation: >-
      Proposes surface receptor measurement as the diagnostic pointer.
- name: Impaired mitogen-induced lymphocyte proliferation
  category: Immunologic
  diagnostic: true
  description: >-
    Reduced proliferative response to phytohaemagglutinin and other mitogens,
    reported in every patient in whom it was measured.
  phenotype_term:
    preferred_term: Impaired phytohemagglutinin-induced T lymphocyte transformation
    term:
      id: HP:0025834
      label: Impaired phytohemagglutinin-induced T lymphocyte transformation
  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: >-
      while reduced response to mitogens was consistently reported in all 11 tested patients
    explanation: >-
      Records the finding and the number of patients tested.
- name: Autoimmune thyroiditis
  category: Endocrine
  frequency: 38.9%
  description: >-
    Hashimoto thyroiditis, reported in 7 of 18 patients and in some the only
    manifestation of the disorder.
  phenotype_term:
    preferred_term: Hashimoto thyroiditis
    term:
      id: HP:0000872
      label: Hashimoto 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 frequency recorded here is the 7/18 figure quoted.
  - 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: 38.9%
  description: >-
    Reported in 7 of 18 patients, in several as part of Evans syndrome with
    immune thrombocytopenia.
  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: 22.2%
  description: >-
    Immune thrombocytopenia, reported in 4 of 18 patients; with autoimmune
    haemolytic anaemia it constitutes the Evans syndrome seen in both adults of
    the 2026 series.
  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
  frequency: 50%
  description: >-
    Hypogammaglobulinaemia or dysgammaglobulinaemia in half of reported
    patients, ranging from severe panhypogammaglobulinaemia to isolated subclass
    deficiency. It is the indication for immunoglobulin replacement.
  phenotype_term:
    preferred_term: Decreased circulating immunoglobulin concentration
    term:
      id: HP:0004313
      label: Decreased circulating immunoglobulin concentration
  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: >-
      Overall, hypogammaglobulinemia or a form of dysgammaglobulinemia was reported in 9/18 patients (50%, Table 2). Defects in memory B cells and the presence of multiple autoantibodies were frequently observed.
    explanation: >-
      The 9/18 figure is the frequency recorded here.
- name: Recurrent respiratory infections
  category: Immunologic
  description: >-
    Recurrent pneumonia and sinopulmonary infection, present in both the
    infantile and the adult-onset presentations.
  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: >-
    Intractable diarrhoea, in the severe infantile presentations frequently with
    autoimmune enteropathy or inflammatory-bowel-disease-like colitis on biopsy.
    It is one of the features associated with higher mortality.
  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 in the severe infantile presentations, in the reported cases
    driven by the enteropathy and the infection burden.
  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 proportion of regulatory T cells, with reduced repertoire diversity
    and impaired suppressive capacity.
  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.
- name: Bronchiectasis
  category: Respiratory
  frequency: 4 of 5 patients with recurrent sinopulmonary infection
  description: >-
    Irreversible bronchial dilatation, the principal permanent end-organ
    complication. It followed recurrent sinopulmonary infection in four of the
    five patients in whom that pattern occurred, and it is the indication for
    long-term antimicrobial prophylaxis.
  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
  description: >-
    Elevated IgE, reported in two of five patients in a two-family series and
    accompanying atopic eczema in the same patients.
  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
  description: >-
    Atopic eczema in two of five patients of the same series, alongside the
    elevated IgE.
  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: >-
    Reported in individual patients as part of the autoimmune spectrum.
  phenotype_term:
    preferred_term: Autoimmune hepatitis
    term:
      id: HP:5210421
      label: Autoimmune hepatitis
  evidence:
  - reference: PMID:23590417
    reference_title: "Variable presentation of primary immune deficiency: two cases with CD3 gamma deficiency presenting with only autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we present two siblings from non-consanguineous family with autoimmunity including Evans syndrome, autoimmune hepatitis, nephrotic syndrome, and Hashimoto's thyroiditis and with no previous history of infections.
    explanation: >-
      Documents autoimmune hepatitis in CD3gamma-deficient siblings.
- name: Vitiligo
  category: Dermatologic
  description: >-
    Reported in individual patients as part of the autoimmune spectrum.
  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.
biochemical:
- name: Serum IgG
  context: >-
    Hypogammaglobulinaemia is present in about half of reported patients and is
    the finding that brings the adult-onset cases to attention. In a severely
    affected infant IgG was 338 mg/dL with impaired responses to Haemophilus
    influenzae type b and pneumococcal vaccination.
  biomarker_term:
    preferred_term: IgG
    term:
      id: NCIT:C568
      label: IgG
  presence: Decreased
  frequency: 9/18
  notes: >-
    No reference_ranges block is curated: the cited sources report patient
    values without stating the laboratory intervals they were compared against.
  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 measured IgG value and the functional antibody deficit accompanying
      it.
  - 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: >-
      Overall, hypogammaglobulinemia or a form of dysgammaglobulinemia was reported in 9/18 patients (50%, Table 2). Defects in memory B cells and the presence of multiple autoantibodies were frequently observed.
    explanation: >-
      The 9/18 frequency recorded here.
- name: CD4+ T-lymphocyte count
  context: >-
    Absolute CD3+ T-cell numbers are characteristically normal, which is what
    separates this disorder from the other CD3 chain deficiencies, but the CD4+
    subset can still be low and the naive and regulatory subsets are commonly
    reduced.
  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: >-
      The measured CD4 count alongside the normal total T-cell number that
      characterises the disorder.
genetic:
- name: CD3G
  association: Causal biallelic variant
  gene_term:
    preferred_term: CD3G
    term:
      id: hgnc:1675
      label: CD3G
  notes: >-
    The reported allelic spectrum is small and recurrent: the splice variant
    c.80-1G>C accounts for most Turkish alleles and the initiation-codon change
    c.1A>G for the original Spanish family. Patients homozygous for the same
    allele have had very different courses, so the variant does not predict the
    phenotype and the modifiers responsible are unknown.
  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 antibody substitutes for the immunoglobulin the patient cannot
      make; it does not repair the T-cell defect that causes the humoral failure.
    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: >-
      Depleting B cells removes the effector arm of the autoantibody-mediated
      cytopenias without addressing the T-cell tolerance defect upstream.
    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: >-
    Corticosteroids are the most frequently used immunosuppressant across the
    reported cohort, given for the autoimmune cytopenias and the enteropathy,
    usually alongside rituximab and sometimes sirolimus. They come with a
    specific hazard in this disorder rather than a generic one: glucocorticoids
    suppress T-cell receptor signalling at several levels, and this is a disease
    of already-weakened T-cell receptor signalling, so the drug acts on the same
    node as the lesion and in the same direction. Two patients are reported to
    have deteriorated immunologically on high-dose glucocorticoids given for
    autoimmune cytopenias, and control of the autoimmunity was in any case
    limited. Rituximab controlled the cytopenias in both adults of the 2026
    series and allowed glucocorticoid tapering.
  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: >-
      The intended effect: broad immunosuppression damps the autoimmune
      cytopenias and enteropathy. Efficacy in this disorder has been limited,
      which is part of why rituximab has become the agent that actually
      controls the cytopenias.
    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: >-
        Rituximab, Sirolimus, and steroids were initiated for the treatment of AIHA, chronic interstitial lung disease, enteropathy, and EBV viremia.
      explanation: >-
        Documents the indications for which steroids and sirolimus were given in
        a reported patient.
  - target: Attenuated T-Cell Receptor Signaling
    treatment_effect: MODULATES
    description: >-
      The unintended effect, and the direction is downward. Glucocorticoids
      suppress T-cell receptor signalling at several levels, so on this node
      they add to the lesion rather than opposing it, and the proposed
      consequence is further impairment of host defence and of tolerogenic
      mechanisms. MODULATES is used because the treatment-effect vocabulary has
      no value for a drug that worsens its target node; the direction is stated
      here rather than encoded.
    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: >-
        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: >-
        Establishes that the drug acts on the same signalling step this node
        describes.
    - 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: >-
        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.
  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: >-
      Importantly, RTX effectively controlled autoimmune cytopenias in both patients described here and enabled glucocorticoid tapering.
    explanation: >-
      Records that the outcome sought from glucocorticoids was achieved by
      rituximab instead, and that tapering steroids was itself a goal.
- name: Antimicrobial therapy and prophylaxis
  description: >-
    Treatment of acute infection and long-term antimicrobial prophylaxis. The
    indication for continuing prophylaxis rather than treating episodes as they
    arise is the bronchiectasis that follows recurrent sinopulmonary infection
    in most patients who have that pattern.
  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: Susceptibility to Recurrent and Chronic Infection
    treatment_effect: BYPASSES
    description: >-
      Antimicrobials substitute for the T-cell function the patient lacks; they
      do not restore it, which is why prophylaxis is continued indefinitely.
    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: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 complication that makes long-term prophylaxis rather than
      episode-by-episode treatment the standard approach.
- name: Hematopoietic stem cell transplantation
  description: >-
    Allogeneic transplant is the only treatment that replaces the defective T-cell
    compartment, and is used in the severe infantile presentations. Outcomes in
    the reported patients have been poor: several died of infection or
    transplant-related complications, and severe disease requiring transplant
    was itself associated with higher mortality.
  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: >-
      Records a good disease response to transplant; the same patient died on
      day +50 of infection, which is why this is graded partial.
  - 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 of peripheral blood measuring absolute T-cell counts together
    with surface TCRalphabeta and CD3 density. The characteristic result is
    normal or near-normal T-cell numbers with reduced receptor expression, which
    is what distinguishes this disorder from the CD3delta, CD3epsilon and
    CD3zeta deficiencies.
  results: >-
    Normal absolute T-cell number with reduced surface TCRalphabeta/CD3
    expression; often reduced naive and regulatory T-cell proportions.
  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: HUMAN_CLINICAL
    snippet: >-
      that assessment of abTCR and CD3 z surface expression may represent a useful diagnostic marker in patients with suspected CD3g
    explanation: >-
      Proposes exactly this measurement as the diagnostic marker.
- 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: >-
    The other CD3 chain defects. They share the biochemical lesion - an
    incomplete TCR/CD3 complex - but block thymocyte development and present as
    T-B+NK+ severe combined immunodeficiency in infancy rather than as a
    variable combined immunodeficiency with autoimmunity.
  disease_term:
    preferred_term: severe combined immunodeficiency
    term:
      id: MONDO:0015974
      label: severe combined immunodeficiency
  distinguishing_features:
  - Complete block in T-cell development rather than preserved T-cell numbers
  - Early-onset life-threatening infection rather than immune dysregulation
  - Surface CD3 essentially absent rather than reduced
  evidence:
  - reference: PMID:16264327
    reference_title: CD3 deficiencies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Homozygous mutations in CD3D and CD3E genes lead to a complete block in T-cell development and thus to an early-onset severe combined immunodeficiency phenotype. Thymic studies have shown that the defect in T-cell development occurs at the transition between 'double-negative' and 'double-positive' thymocytes. These results contrast with the partial T-cell immunodeficiency caused by a deficiency in CD3G.
    explanation: >-
      States the developmental block that separates the other CD3 deficiencies
      from CD3gamma deficiency.
- name: Common variable immunodeficiency
  description: >-
    The label two adult CD3gamma-deficient patients carried before genetic
    diagnosis. Hypogammaglobulinaemia with reduced switched memory B cells and
    autoimmune cytopenias is compatible with both; reduced surface TCR/CD3 with
    impaired mitogen responses is not typical of common variable
    immunodeficiency and points to the T-cell lesion.
  disease_term:
    preferred_term: common variable immunodeficiency
    term:
      id: MONDO:0015517
      label: common variable immunodeficiency
  distinguishing_features:
  - Reduced surface TCRalphabeta and CD3 expression
  - Impaired proliferative response to mitogens
  - 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: >-
    Mice engineered to lack CD3gamma while retaining CD3delta, CD3epsilon,
    CD3zeta, pTalpha and TCRbeta. They were made to test the role of CD3gamma in
    the pre-TCR, and they answer that question, but they do not reproduce the
    human disease: thymic cellularity falls below one per cent of normal and
    peripheral T cells to two to five per cent, which is a severe combined
    immunodeficiency rather than the preserved-T-cell disorder seen in patients.
  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 reduction is more severe than in patients, and it occurs in a thymus
      that is nearly empty, so the mouse cannot be used to study the mature
      T-cell receptor deficit that defines the human disorder.
    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: >-
      In patients, weakened TCR signalling lets self-reactive thymocytes through
      selection and yields a polyclonal but skewed peripheral repertoire. The
      mouse has no such repertoire to skew: development arrests at the
      CD44-CD25+ double-negative stage and both the alpha-beta and gamma-delta
      lineages fail.
    limitations: >-
      Thymocyte number falls to under one per cent of normal and peripheral
      T cells to two to five per cent, so the mouse models a developmental block
      that human patients do not have. The species difference has a known
      structural basis: the human gamma-delta TCR incorporates CD3delta and the
      mouse one does not, so CD3delta can substitute for missing CD3gamma in
      patients but not in mice. Nothing about the human autoimmune phenotype -
      the dominant clinical problem - can be studied in this 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: >-
        Documents the developmental arrest that human patients do not have.
    - 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: MODEL_ORGANISM
      snippet: >-
        Similarly, Cd3g−/− mice show complete loss of T cell development and SCID [7].
      explanation: >-
        States the mouse phenotype that is contrasted with the human one.
    - 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 transgenic rescue experiment that identifies the species difference
        responsible for the discordant phenotypes.
  evidence:
  - 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: >-
      gammadelta T cells do not develop in CD3gamma-deficient mice, whereas human patients lacking CD3gamma have abundant peripheral blood gammadelta T cells expressing high gammadelta TCR levels.
    explanation: >-
      States the discordance that limits how far this model informs the human
      disorder.
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: >-
      Removing CD3gamma from a human T-cell line reproduces the assembly defect:
      complexes are retained in the endoplasmic reticulum, lack the zeta-zeta
      dimer, and barely reach the surface. Domain-swap reconstitution localises
      the requirement to the CD3gamma extracellular domain, which the
      corresponding CD3delta domain cannot replace.
    limitations: >-
      The quantitative severity does not match the patients. Surface receptor in
      the knockdown lines falls below 11% of control, whereas mature T cells from
      CD3gamma-deficient patients express more than 30%. The authors attribute
      this to plasticity available to developing thymocytes that a mature
      transformed line does not have, so the line overstates the severity of the
      human lesion.
    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: >-
        This is in sharp contrast to human CD3γ ID, whose mature T cells express higher levels of surface TCR (>30% vs. normal controls).
      explanation: >-
        The authors' own statement of the gap between the line and the patients,
        which is why this link is partial rather than full recapitulation.
  - 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: >-
      A transformed leukaemia line with a transfected receptor; the readouts are
      cytokine and activation-marker induction rather than the in vivo T-cell
      responses that matter clinically.
    readouts:
    - name: TCR-induced IL-2, TNF-alpha and CD69 induction
      target: Attenuated T-Cell Receptor Signaling
      direction: DECREASED
      interpretation: >-
        Locates the signalling contribution of CD3gamma to its intracellular
        domain.
      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: >-
          However, an IC domain at CD3γ was required for TCR-induced IL-2 and TNF-α production and CD69 expression, indicating that a TCR without a CD3γ IC domain has altered signalling capabilities.
        explanation: >-
          The measured signalling deficits attributable to the CD3gamma
          intracellular domain.
    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: >-
        Expression of γγγ, γγδ, γδδ or γγ- in the γ- T cell line JGN, which lacks surface TCR, demonstrated that cell surface TCR levels in JGN were dependent on the EC domain of CD3γ and could not be replaced by the one of CD3δ.
      explanation: >-
        Establishes the system and what it is able to resolve.
discussions:
- discussion_id: mismatch_cd3g_mouse_vs_human
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Why does loss of CD3gamma cause severe combined immunodeficiency in mice but
    a comparatively mild, autoimmunity-dominated combined immunodeficiency in
    humans, and can any available model be used to study the human autoimmune
    phenotype?
  attaches_to:
  - pathophysiology#Distorted Thymic Selection and Self-Reactive Repertoire
  - pathophysiology#Multisystem Autoimmunity
  rationale: >-
    The Cd3g-null mouse is not a mild model of a mild disease; it is a severe
    model of a mild disease. Thymic cellularity falls below one per cent of
    normal and both T-cell lineages fail, whereas patients keep normal T-cell
    numbers and their dominant problem is autoimmunity. Part of the difference
    has a definite structural explanation: the human gamma-delta TCR incorporates
    CD3delta while the mouse one does not, so CD3delta can substitute for the
    missing chain in patients, and a human but not a mouse CD3delta transgene
    rescues gamma-delta development in doubly deficient mice. That accounts for
    the gamma-delta compartment. It does not by itself establish that the same
    substitution explains the preserved alpha-beta compartment, and the human
    cell-line models do not close the gap either: CD3G-knockdown Jurkat cells
    express under 11% of normal surface TCR while patient T cells express over
    30%, which the authors attribute to developmental plasticity that a mature
    transformed line lacks. The practical consequence is that the feature which
    dominates the human disorder - multisystem autoimmunity arising from
    distorted thymic selection and defective regulatory T cells - currently has
    no model system in which it can be studied.
  evidence:
  - 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: >-
      Collectively, our results indicate that the different gammadelta T cell phenotypes between CD3gamma-deficient humans and mice can be explained by differences in their gammadelta TCR composition.
    explanation: >-
      The structural explanation for the species difference, stated for the
      gamma-delta lineage.
  - 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: >-
      Despite the high sequence homology between CD3γ and CD3δ, the clinical consequences of the corresponding immunodeficiencies (ID) in humans are very different (mild and severe, respectively), and mouse models do not recapitulate findings in human ID.
    explanation: >-
      States plainly that the mouse models do not reproduce the human findings.
- discussion_id: gap_cd3g_genotype_phenotype
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What determines whether a person homozygous for a null CD3G allele dies in
    infancy of infection and enteropathy or reaches late adulthood with
    hypogammaglobulinaemia and autoimmune cytopenias?
  attaches_to:
  - genetic#CD3G
  - pathophysiology#Multisystem Autoimmunity
  rationale: >-
    Patients homozygous for the same CD3G allele have had opposite outcomes,
    including within a single family, so the variant itself does not explain the
    course. Residual CD3gamma protein has been excluded as the explanation for
    the disorder's mildness generally, since at least one allele is a
    demonstrated transcript-and-protein null. Two candidate correlates have been
    proposed - the amount of residual surface TCR/CD3, and whether regulatory
    T-cell suppressive function is preserved - but each rests on a handful of
    patients assayed by different methods, and eighteen reported cases is too few
    to test either. Until it is settled there is no basis for predicting course
    at diagnosis, which is precisely the question that determines whether to
    offer transplant.
  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 and the reason.
  - 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: >-
      Excludes residual protein as the explanation for the mild phenotype in at
      least one allele.
clinical_trials: []
datasets: []
notes: >-
  Evidence-source convention used throughout this entry: measurements made
  directly on patient samples (flow cytometry, repertoire sequencing, clinical
  course) are graded HUMAN_CLINICAL; measurements requiring culture, expansion
  or an engineered line (phytohaemagglutinin-driven T-cell blasts, regulatory
  T-cell suppression co-cultures, Jurkat and JGN cell lines) are graded
  IN_VITRO; mouse data are graded MODEL_ORGANISM.

  Where a snippet is drawn from a cached PDF extraction, it reproduces that text
  verbatim as exact-quote validation requires, including artefacts of the
  extraction: Greek letters rendered as Latin characters ("CD3 g" for CD3gamma,
  "abTCR" for alpha-beta TCR) in the 2026 Frontiers review, and the "fi"
  ligature in the bronchiectasis sentence from the 2019 Frontiers case report.
  Entry prose uses ordinary spellings throughout.

  Grading follows what the quoted sentence asserts, not only where the
  measurement was taken. A sentence reporting a co-culture suppression assay is
  IN_VITRO; a sentence whose subject is the patient's clinical state is
  HUMAN_CLINICAL even when it refers to an assay result as supporting evidence.

📚

References & Deep Research

References

12

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.

Deep Research

1

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.

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References weighed for topical relevance	6
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MONDO:0014276 (4 mentions) - the report calls it "if available"; MONDO calls it combined immunodeficiency due to CD3gamma deficiency

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Combined immunodeficiency due to CD3γ deficiency

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