Immunodeficiency 18

Mendelian MONDO:0014278 Pathograph 17 Show in embeddings browser Severe combined immunodeficiency Inborn error of immunity

Immunodeficiency 18 is an ultra-rare autosomal recessive inborn error of immunity caused by biallelic loss-of-function variants in CD3E, the gene encoding the CD3epsilon invariant chain of the T-cell receptor (TCR)/CD3 complex. CD3epsilon is the chain around which the CD3 core is built: it partners both CD3gamma and CD3delta, so losing it removes two of the three signalling dimers from the pre-TCR and the mature TCR at once. Severity tracks how much functional CD3epsilon is left, and the reported spectrum runs from severe combined immunodeficiency to a considerably milder disorder. At the null end, complete absence of CD3epsilon abrogates human T-cell development: patients have no circulating T cells with normal B and NK cells - the T-B+NK+ pattern - and present in the first months of life with candidiasis, protracted diarrhoea, pneumonitis and failure to thrive, dying of disseminated viral infection unless transplanted. At the hypomorphic end, the child in whom the first CD3E mutations were found carried two different alleles that left an unstable chain and roughly a tenth of the normal surface receptor; that patient had T cells, and an immunodeficiency defined by unresponsiveness to receptor stimulation rather than by the absence of the compartment. Both ends are the same disorder and the same MONDO concept, and the entry is curated as a single graded entity rather than as a uniformly severe one. The boundary that matters clinically is with CD3gamma deficiency, the sibling chain of the same complex. That disorder does not block thymocyte development: patients keep normal T-cell numbers with reduced surface receptor, and their dominant problem is autoimmunity. CD3epsilon and CD3delta deficiency block development; CD3gamma deficiency does not. The one place the two disorders come close is the hypomorphic end of the CD3epsilon spectrum, where reduced rather than absent surface receptor is what is measured - and there the distinction rests on which gene is mutated, not on the flow cytometry. Where the developmental block sits in humans has never been shown directly. No thymus was available from the CD3epsilon-deficient family, so the arrest point is carried over from the mouse, where Cd3e inactivation stops thymocytes at the CD44-low CD25-positive double-negative stage.

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1
Inheritance
10
Pathophys.
9
Phenotypes
2
Gaps
17
Pathograph
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Genes
3
Medical Actions
3
Differentials
2
Models
15
References
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Deep Research
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Classifications

IUIS Category
combined immunodeficiency
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Inheritance

1
Autosomal recessive inheritance HP:0000007
Biallelic CD3E variants. Most reported patients are homozygous and born to consanguineous parents; the original family was compound heterozygous, with a different mutation inherited from each parent. Heterozygous carriers are clinically unaffected, although one study found their T-cell receptor excision circle counts to be measurably lower than a wild-type sibling's.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:8490660 SUPPORT Human Clinical
"We now report that two independent CD3-epsilon gene mutations present in the parents have segregated in the patient, leading to defective CD3-epsilon chain synthesis and preventing normal association and membrane expression of the TCR/CD3 complex."
The compound heterozygous transmission in the first reported family.
PMID:28597365 SUPPORT Human Clinical
"In addition, heterozygous family members showed decreased TREC levels when compared with the wild-type sibling, indicating that carrying this variant in one allele does not cause immunodeficiency, but does effect T cell proliferation."
Establishes that heterozygotes are unaffected while recording the measurable gene-dosage effect on thymic output.
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Discussions and Knowledge Gaps

2
At what stage does thymocyte development actually arrest in human CD3epsilon deficiency, and is the mouse arrest point a safe stand-in for it?
HUMAN MODEL MISMATCH OPEN gap_cd3e_human_arrest_stage
Attached to
pathophysiology#Arrest of Thymocyte Development pathophysiology#Blocked Pre-TCR Signaling at Beta-Selection
Every account of this disorder places the block at beta-selection, and every such account traces back to the Cd3e-null mouse. The authors who first identified CD3epsilon deficiency said so explicitly: no thymus material was available from the affected family, so the stage could not be assessed, and the mouse arrest was offered as a possibility rather than a finding. What is established in humans is only the outcome - absence of CD3epsilon abrogates T-cell development. The gap matters because the neighbouring chain gives a documented precedent for the mouse being wrong about a human CD3 chain: Cd3g-null mice have severe combined immunodeficiency while CD3gamma-deficient patients keep normal T-cell numbers, a discordance with a known structural basis in the composition of the human gamma-delta receptor. The same paper that describes the human CD3delta thymus reports the arrest there at entry to the double-positive stage rather than at the double-negative stage the mouse shows for CD3epsilon, so the two chains do not even arrest at the same point within one species. No human thymus from a CD3epsilon-deficient patient or fetus has been examined since.
Show evidence (2 references)
PMID:15546002 NO_EVIDENCE Human Clinical
"It was not possible to assess at what stage the CD3 ε deficiency blocked T cell differentiation in patients from family I, as no thymus material was available."
States that the human arrest stage was not determined, which is the gap.
PMID:7588594 SUPPORT Model Organism
"In the absence of intact CD3-epsilon subunit, thymocytes do not progress beyond the CD44-/lowCD25+ triple-negative stage and appear to be arrested at the very same developmental control point as RAG-deficient thymocytes."
The mouse result that stands in for the unmeasured human one.
Does residual CD3epsilon protein reliably predict a milder course, and how much is enough to permit T-cell development?
KNOWLEDGE GAP OPEN gap_cd3e_genotype_severity
Attached to
genetic#CD3E pathophysiology#Residual Unstable CD3epsilon in Partial Deficiency
The reported spectrum implies a dose relationship: truncating and splice alleles that abolish the chain give severe combined immunodeficiency, while the two hypomorphic alleles in the family in which CD3E was first implicated left an unstable chain, about a tenth of the normal surface receptor, and a T-cell compartment that existed. But the inference rests on one hypomorphic family against a handful of null families, and nobody has measured residual CD3epsilon protein across a series and related it to outcome. The threshold question is open in both directions: how much residual chain permits thymopoiesis, and whether a patient with an intermediate amount would present as leaky severe combined immunodeficiency, as a milder combined immunodeficiency, or as something resembling CD3gamma deficiency. It is a practical question, because the answer determines whether a newly diagnosed infant should be transplanted urgently, and because newborn screening detects the null form but would not reliably detect a hypomorphic one.
Show evidence (2 references)
PMID:1370449 SUPPORT Human Clinical
"We report on another immunodeficient patient whose T lymphocytes express the T cell receptor at one-tenth of normal fluorescence intensity and are not triggered to proliferate in vitro by anti-CD3 or anti-CD2 antibodies."
The mild end of the spectrum, with T cells present and quantified residual receptor.
PMID:17277165 SUPPORT Human Clinical
"In contrast, all reported human complete CD3delta (or CD3epsilon) deficiencies are in infants with life-threatening SCID and very severe alphabeta and gammadelta T lymphocytopenia."
The severe end, stated as holding for every reported complete deficiency, which is what makes the qualifier "complete" load-bearing.
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Pathophysiology

10
Biallelic CD3E Loss-of-Function Variants
Frameshift, nonsense and splice variants on both alleles. Reported changes include a homozygous two-base deletion in exon 5 that truncates the chain in its extracellular domain, a frameshift found in two Turkish siblings, a homozygous splice-site change that abolishes the protein, and nonsense alleles found in Egyptian and Pakistani families. Two hypomorphic alleles in the original family behaved differently: they permitted some correctly processed protein, which is why that patient was not a classical severe combined immunodeficiency.
CD3E hgnc:1674 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CD3E (hgnc:1674). hgnc:1674 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Loss of the CD3epsilon Chain Truncating and splice alleles abolish production of a usable CD3epsilon polypeptide.
Residual Unstable CD3epsilon in Partial Deficiency Hypomorphic alleles produce an abnormally sized, unstable transcript and a correspondingly reduced amount of chain rather than none at all.
Show evidence (2 references)
PMID:15546002 SUPPORT Human Clinical
"A homozygous 2-bp deletion at nucleotide 128 in exon 5 of CD3E was identified in this patient."
The truncating allele in the first family recognised as CD3epsilon deficiency.
PMID:28597365 SUPPORT Human Clinical
"We found a novel deletion in the CD3E gene (NM000733.3:p.L58Hfs*9) in two T-B+ NK+ patients."
A second, independent frameshift allele with the same T-B+NK+ consequence.
Loss of the CD3epsilon Chain
Complete absence of the CD3epsilon polypeptide. Because CD3epsilon is the common partner of both CD3gamma and CD3delta, its loss takes out the gamma-epsilon and delta-epsilon dimers together, which is why it is more damaging than loss of either partner alone. In mouse thymocytes, disrupting the gene also strongly suppresses expression of CD3gamma and CD3delta, although that turned out to reflect the arrest rather than transcriptional control by CD3epsilon itself.
Downstream
Failure of pre-TCR and TCR Complex Assembly Without CD3epsilon neither invariant dimer can form, so the receptor cannot be assembled or exported.
Show evidence (1 reference)
PMID:8490660 SUPPORT Human Clinical
"The T-cell receptor (TCR) is composed of two glycoproteins (alpha and beta or gamma and delta) associated with four invariant polypeptides (CD3-gamma, delta, epsilon and zeta). The majority of TCR/CD3 complexes contain six polypeptide chains, and although there is some flexibility in the complex..."
States the structural position of CD3epsilon that makes its loss consequential for the whole complex.
Residual Unstable CD3epsilon in Partial Deficiency
The hypomorphic branch. Two CD3E alleles that reduce but do not abolish production of the chain leave a T-cell compartment that exists but carries about a tenth of the normal surface receptor. This is the mechanistic basis of the mild end of the spectrum and the reason severity in this disorder is not uniform. It is curated as its own node because it produces a different downstream chain from the null branch: attenuated signalling in T cells that are present, rather than absence of the cells.
Downstream
Reduced Surface TCR/CD3 with Impaired T-Cell Activation An unstable chain assembles inefficiently, so fewer complexes reach the surface and those T cells that do develop respond poorly to receptor engagement.
Show evidence (1 reference)
PMID:1370449 SUPPORT In Vitro
"These findings suggest that this defect in T cell receptor-CD3 expression involves a mutation in the CD3 epsilon gene leading to the synthesis of an abnormal and unstable CD3 epsilon subunit."
Identifies the lesion as an unstable chain rather than an absent one.
Failure of pre-TCR and TCR Complex Assembly
The pre-TCR (pre-TCRalpha with TCRbeta) and the mature alpha-beta TCR both reach the surface only as complexes with the CD3gamma-epsilon, CD3delta-epsilon and zeta-zeta dimers. Losing CD3epsilon removes two of the three, and the receptor is neither assembled nor exported. Note that TCRbeta gene rearrangement itself proceeds normally, so the defect is in receptor assembly and signalling rather than in recombination.
T cell receptor complex GO:0042101 Gene Ontology (GO) Relation: this pathophysiological event involves this protein complex This pathophysiological event involves absent T cell receptor complex (GO:0042101). GO:0042101 is a protein complex from the Gene Ontology.
Downstream
Blocked Pre-TCR Signaling at Beta-Selection The pre-TCR cannot transmit the survival, proliferation and progression signal that reports a productive TCRbeta rearrangement.
Show evidence (1 reference)
PMID:7588594 SUPPORT Model Organism
"CD3-epsilon-deficient thymocytes do rearrange their T cell receptor (TCR) beta gene segments and produce low levels of full-length TCR beta transcripts."
Establishes that recombination is intact, locating the lesion downstream at receptor assembly and signalling.
Blocked Pre-TCR Signaling at Beta-Selection
Beta-selection is the checkpoint at which a double-negative thymocyte that has made a productive TCRbeta rearrangement is licensed to survive, divide and proceed to the double-positive stage. The pre-TCR is the sensor, and without CD3epsilon it cannot signal, so the checkpoint reads every thymocyte as having failed.
double negative thymocyte CL:0002489 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves double negative thymocyte (CL:0002489). CL:0002489 is a cell type from the Cell Ontology.
T cell receptor signaling pathway GO:0050852 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves absent T cell receptor signaling pathway (GO:0050852). GO:0050852 is a biological process from the Gene Ontology. ∅ ABSENT
Animal models
Cd3e-deficient mouse Mouse measures The knockout separates recombination from signalling: TCRbeta rearrangement proceeds and full-length transcripts are made, so what fails is the receptor that reads the rearrangement, not the rearrangement itself. Reconstitution with a CD3epsilon transgene rescues development from a small subpopulation of prothymocytes, showing the block is CD3epsilon-dependent and reversible.
CD3epsilon basic-rich stretch mutant mouse Mouse partially recapitulates The mutant shows reduced thymic cellularity and a limited double-negative 3 to double-negative 4 transition, so it perturbs the same checkpoint the human disorder blocks - but by excessive rather than absent signalling.
Downstream
Arrest of Thymocyte Development A thymocyte that cannot pass beta-selection does not progress to the double-positive stage.
Show evidence (1 reference)
PMID:7588594 SUPPORT Model Organism
"Taken together, these results establish an essential role for the CD3-epsilon gene products during T cell development and further suggest that the CD3-epsilon polypeptides start to exert their function as part of a pre-TCR through which CD44-/lowCD25+ triple-negative cells monitor the occurrence..."
Places the requirement for CD3epsilon precisely at pre-TCR surveillance of beta-selection.
Arrest of Thymocyte Development
Thymopoiesis stops. In the mouse the arrest is at the CD44-low CD25-positive double-negative stage, phenocopying RAG deficiency despite intact rearrangement. In humans the stage has never been established directly, because no thymus was available from the CD3epsilon-deficient family; what is established is the outcome, that absence of CD3epsilon abrogates human T-cell development altogether.
thymocyte CL:0000893 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves thymocyte (CL:0000893). CL:0000893 is a cell type from the Cell Ontology.
T cell differentiation in thymus GO:0033077 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves absent T cell differentiation in thymus (GO:0033077). GO:0033077 is a biological process from the Gene Ontology. ∅ ABSENT
Animal models
Cd3e-deficient mouse Mouse recapitulates The knockout reproduces the complete developmental block that defines the human null phenotype, and localises it to the pre-TCR checkpoint.
Downstream
Absent Peripheral T Cells No thymocyte completes development, so no mature T cell reaches the periphery.
Show evidence (2 references)
PMID:15546002 SUPPORT Human Clinical
"These observations show that an absence of CD3ε or CD3δ completely abrogates human T cell development."
The human-level conclusion, stated without committing to an arrest stage.
PMID:15546002 NO_EVIDENCE Human Clinical
"It was not possible to assess at what stage the CD3 ε deficiency blocked T cell differentiation in patients from family I, as no thymus material was available."
Records that the human arrest stage was not determined; the mouse stage is an inference, not an observation in patients.
Absent Peripheral T Cells
No circulating CD3-positive T cells, with normal or high B-cell counts and present NK cells. The selectivity is the point: only the T lineage requires the pre-TCR, so B and NK development proceed normally, and the resulting T-B+NK+ pattern is what a diagnostic flow panel sees. Thymic output measured as T-cell receptor excision circles is undetectable, which is what makes the disorder visible to newborn screening.
T cell CL:0000084 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves absent T cell (CL:0000084). CL:0000084 is a cell type from the Cell Ontology. ∅ ABSENT
Downstream
Failure of Cellular Immunity Without T cells there is no cell-mediated defence against viral, fungal and opportunistic pathogens.
Loss of T-Cell Help to B Cells B cells are present and numerically normal but have no T-cell help, so they cannot mount switched, specific antibody responses.
Show evidence (1 reference)
PMID:28597365 SUPPORT Human Clinical
"T cell receptor excision circle (TREC) and kappa-deleting recombination excision circle (KREC) analyses were performed for T and B cell maturation. TRECs were not detected in both patients and the KREC copy numbers were similar to the other family members."
Absent thymic output alongside normal B-cell output, measured in the same patients.
Reduced Surface TCR/CD3 with Impaired T-Cell Activation
The hypomorphic outcome. T cells develop and populate the periphery, but carry roughly a tenth of the normal density of surface receptor and cannot be triggered to proliferate through CD3 or CD2. The immunodeficiency here is functional rather than numerical, and it is the reason this disorder cannot be described as uniformly a severe combined immunodeficiency.
T cell CL:0000084 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves T cell (CL:0000084). CL:0000084 is a cell type from the Cell Ontology.
alpha-beta T cell receptor complex GO:0042105 Gene Ontology (GO) Relation: this pathophysiological event involves this protein complex This pathophysiological event involves decreased alpha-beta T cell receptor complex (GO:0042105). GO:0042105 is a protein complex from the Gene Ontology.
Downstream
Failure of Cellular Immunity T cells that cannot be activated through their receptor cannot mount an effective cellular response, even though they are present.
Show evidence (1 reference)
PMID:1370449 SUPPORT Human Clinical
"We report on another immunodeficient patient whose T lymphocytes express the T cell receptor at one-tenth of normal fluorescence intensity and are not triggered to proliferate in vitro by anti-CD3 or anti-CD2 antibodies."
The defining measurements of the hypomorphic phenotype: reduced receptor density with preserved cells, and failure of receptor-driven proliferation.
Failure of Cellular Immunity
The clinical endpoint of both branches. In the null form it is catastrophic: candidiasis, protracted diarrhoea, pneumonitis and failure to thrive in the first months, and death from disseminated cytomegalovirus or adenovirus without immune reconstitution. In the hypomorphic form it is a milder susceptibility to infection in a child who has T cells.
Show evidence (1 reference)
PMID:33040328 SUPPORT Human Clinical
"All patients had the classic clinical picture for SCID, including failure to thrive (n = 20), oral candidiasis (n = 17), persistent diarrhea (n = 14), pneumonia (n = 13), napkin dermatitis (n = 10), skin rash (n = 7), otitis media (n = 3) and meningitis (n = 2)."
The clinical picture of the T-B+ SCID cohort in which a CD3E patient was identified.
Loss of T-Cell Help to B Cells
B cells are numerically normal but functionally unsupported. IgM is detectable, IgA is not, and IgG falls once maternal antibody wanes. The clearest demonstration comes from a transplanted patient in whom only the T-cell lineage was of donor origin: humoral immunity was adequate for six years and then failed, with loss of switched memory B cells, as T-helper support declined.
B cell CL:0000236 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves B cell (CL:0000236). CL:0000236 is a cell type from the Cell Ontology.
isotype switching GO:0045190 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased isotype switching (GO:0045190). GO:0045190 is a biological process from the Gene Ontology. ↓ DECREASED
Show evidence (2 references)
PMID:15546002 SUPPORT Human Clinical
"IgA was not detected in the serum of any of the patients."
The isotype-specific antibody deficit accompanying preserved B-cell numbers.
PMID:24515816 SUPPORT Human Clinical
"At 6 years after SCT the patient developed signs of humoral immunodeficiency, requiring regular substitution of IgG."
The delayed humoral failure in a split-chimerism patient, which is the natural experiment showing the antibody defect is T-cell dependent.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Immunodeficiency 18 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

9
Blood 3
Absent circulating T cells with normal B and NK cells HP:0025805 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Absent circulating T cells (HP:0025805). HP:0025805 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:35748970 SUPPORT Other
"CD3 deficiency CD3E AR 186830 Very lowN ormalL ow Normal NK, no T cells"
The IUIS row recording very low T cells with normal B and NK cells for CD3E.
PMID:28597365 SUPPORT Human Clinical
"We found a novel deletion in the CD3E gene (NM000733.3:p.L58Hfs*9) in two T-B+ NK+ patients."
Records the T-B+NK+ classification of two genetically confirmed patients.
Reduced surface TCR/CD3 expression with preserved T cells Abnormal T cell physiology HP:0011840 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal T cell physiology (HP:0011840). HP:0011840 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:1370449 SUPPORT Human Clinical
"We report on another immunodeficient patient whose T lymphocytes express the T cell receptor at one-tenth of normal fluorescence intensity and are not triggered to proliferate in vitro by anti-CD3 or anti-CD2 antibodies."
The measured receptor density and the failed activation response that define this presentation.
Hypogammaglobulinemia Decreased circulating immunoglobulin concentration HP:0004313 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased circulating immunoglobulin concentration (HP:0004313). HP:0004313 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:15546002 SUPPORT Human Clinical
"IgA was not detected in the serum of any of the patients."
The measured immunoglobulin deficit.
PMID:35748970 SUPPORT Other
"CD3 deficiency CD3E AR 186830 Very lowN ormalL ow Normal NK, no T cells"
The IUIS row records low serum immunoglobulins alongside the T-B+NK+ pattern.
Digestive 1
Persistent diarrhea HP:0002014 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Persistent diarrhea, annotated with Diarrhea (HP:0002014), qualified as temporality chronic. HP:0002014 is a phenotype from the Human Phenotype Ontology.
Temporal: CHRONIC
No frequency band is asserted. The count comes from a T-B+ SCID cohort in which JAK3 predominates and CD3E accounts for one patient, so the cohort proportion is a frequency for that mixed genotype set and not for this disease. The numerator and denominator are stated in the snippet.
Show evidence (1 reference)
PMID:33040328 SUPPORT Human Clinical
"All patients had the classic clinical picture for SCID, including failure to thrive (n = 20), oral candidiasis (n = 17), persistent diarrhea (n = 14), pneumonia (n = 13), napkin dermatitis (n = 10), skin rash (n = 7), otitis media (n = 3) and meningitis (n = 2)."
Gives persistent diarrhea in 14 of 20 patients in the T-B+ SCID cohort that includes a CD3E patient.
Head and Neck 1
Oral candidiasis Chronic oral candidiasis HP:0009098 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Oral candidiasis, annotated with Chronic oral candidiasis (HP:0009098). HP:0009098 is a phenotype from the Human Phenotype Ontology.
No frequency band is asserted. The count comes from a T-B+ SCID cohort in which JAK3 predominates and CD3E accounts for one patient, so the cohort proportion is a frequency for that mixed genotype set and not for this disease. The numerator and denominator are stated in the snippet.
Show evidence (1 reference)
PMID:33040328 SUPPORT Human Clinical
"All patients had the classic clinical picture for SCID, including failure to thrive (n = 20), oral candidiasis (n = 17), persistent diarrhea (n = 14), pneumonia (n = 13), napkin dermatitis (n = 10), skin rash (n = 7), otitis media (n = 3) and meningitis (n = 2)."
Gives oral candidiasis in 17 of 20 patients in the T-B+ SCID cohort that includes a CD3E patient.
Immune 3
Severe combined immunodeficiency HP:0004430 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Severe combined immunodeficiency (HP:0004430). HP:0004430 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:16264327 SUPPORT Human Clinical
"Two new severe combined immunodeficiency conditions have been reported as a consequence of either CD3D or CD3E deficiency."
Names CD3E deficiency as a severe combined immunodeficiency condition.
PMID:17277165 SUPPORT Human Clinical
"In contrast, all reported human complete CD3delta (or CD3epsilon) deficiencies are in infants with life-threatening SCID and very severe alphabeta and gammadelta T lymphocytopenia."
States that the complete deficiencies, as reported at that time, were uniformly SCID in infancy.
Recurrent opportunistic infection Recurrent opportunistic infections HP:0005390 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent opportunistic infections (HP:0005390). HP:0005390 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33040328 SUPPORT Human Clinical
"All patients had the classic clinical picture for SCID, including failure to thrive (n = 20), oral candidiasis (n = 17), persistent diarrhea (n = 14), pneumonia (n = 13), napkin dermatitis (n = 10), skin rash (n = 7), otitis media (n = 3) and meningitis (n = 2)."
The infection spectrum in the T-B+ SCID cohort containing a CD3E patient.
Pneumonia HP:0002090 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pneumonia (HP:0002090). HP:0002090 is a phenotype from the Human Phenotype Ontology.
No frequency band is asserted. The count comes from a T-B+ SCID cohort in which JAK3 predominates and CD3E accounts for one patient, so the cohort proportion is a frequency for that mixed genotype set and not for this disease. The numerator and denominator are stated in the snippet.
Show evidence (1 reference)
PMID:33040328 SUPPORT Human Clinical
"All patients had the classic clinical picture for SCID, including failure to thrive (n = 20), oral candidiasis (n = 17), persistent diarrhea (n = 14), pneumonia (n = 13), napkin dermatitis (n = 10), skin rash (n = 7), otitis media (n = 3) and meningitis (n = 2)."
Gives pneumonia in 13 of 20 patients in the T-B+ SCID cohort that includes a CD3E patient.
Growth 1
Failure to thrive HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33040328 SUPPORT Human Clinical
"All patients had the classic clinical picture for SCID, including failure to thrive (n = 20), oral candidiasis (n = 17), persistent diarrhea (n = 14), pneumonia (n = 13), napkin dermatitis (n = 10), skin rash (n = 7), otitis media (n = 3) and meningitis (n = 2)."
Records failure to thrive in every patient of the cohort.
🧬

Genetic Associations

1
CD3E (Causal biallelic variant)
Gene: CD3E hgnc:1674 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CD3E (hgnc:1674). hgnc:1674 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (2 references)
PMID:39287664 SUPPORT Human Clinical
"This included four novel nonsense variants in CD70 p.(Thr126Profs*33), CD3e p.(Trp151*), IL7R p.(Val138Ilefs*10), and ITGB2 p.(Ser627Valfs*61), and one previously reported in ITGB2 p.(Cys62*)."
A further private nonsense allele, illustrating the family-by-family character of the spectrum.
PMID:1370449 SUPPORT In Vitro
"These findings suggest that this defect in T cell receptor-CD3 expression involves a mutation in the CD3 epsilon gene leading to the synthesis of an abnormal and unstable CD3 epsilon subunit."
The hypomorphic end of the allelic spectrum, where residual unstable protein is made.
💊

Medical Actions

3
Protective isolation and anti-infectious prophylaxis
Action: Supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Supportive care that keeps a T-cell-null infant alive until immune reconstitution: protective isolation, antimicrobial prophylaxis, and avoidance of the exposures a patient with no T cells cannot survive. It is a bridge to transplantation rather than a treatment of the lesion, and the entry curates it as such because in this disease the interval before transplant is where patients are lost.
Mechanism Target:
MODULATES Failure of Cellular Immunity — Reduces the pathogen exposure that the absent T-cell compartment cannot answer. It does not restore the compartment, so the mechanism node is unchanged; what changes is the burden placed on it.
Show evidence (1 reference)
PMID:36456361 SUPPORT Other
"strict isolation and anti-infectious prophylaxis until improvements in immunity are achieved"
States the supportive-care approach for severe combined immunodeficiency in the interval before immune reconstitution.
Show evidence (1 reference)
PMID:36456361 SUPPORT Other
"strict isolation and anti-infectious prophylaxis until improvements in immunity are achieved"
Supports curating protective isolation and prophylaxis as the standard holding measure before definitive treatment.
Allogeneic haematopoietic stem cell transplantation
Action: hematopoietic cell transplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is hematopoietic cell transplantation (NCIT:C15431). NCIT:C15431 is a clinical intervention from the NCI Thesaurus. Ontology label: Hematopoietic Cell Transplantation NCIT:C15431
Platform: Cell therapy
The only definitive treatment for the complete-deficiency form. A patient with a homozygous CD3E splice-site variant transplanted haploidentically from his mother developed normal T- and B-cell immunity and was followed for fifteen years. Engraftment was confined to the T-cell lineage, T-cell counts never reached normal, and naive T cells stayed low, which is the pattern that later allowed humoral immunity to fail.
Mechanism Target:
BYPASSES Arrest of Thymocyte Development — Donor progenitors carry wild-type CD3E, so thymopoiesis proceeds from donor-derived precursors; the patient's own precursors remain arrested.
Show evidence (1 reference)
PMID:24515816 SUPPORT Human Clinical
"Despite conditioning donor cell engraftment was confined to T cells, while all other blood cell lineages remained of patient origin (split chimerism). In spite of normal functions, T-cell numbers never reached normal levels and naïve CD45+RA+ T-cells remained low."
Documents that only the T lineage is reconstituted, which is exactly the compartment the arrest affects, and that the reconstitution is partial.
Show evidence (1 reference)
PMID:24515816 SUPPORT Human Clinical
"We report on a patient with SCID due to CD3ε deficiency treated by HLA-haploidentical stem cell transplantation (SCT) (donor: mother) 15 years ago which resulted in development of normal T- and B-cell immunity."
The one long-term transplant outcome reported for this genotype.
Immunoglobulin replacement therapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: therapeutic immune globulin NCIT:C2701 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses therapeutic immune globulin (NCIT:C2701). NCIT:C2701 is a therapeutic agent from the NCI Thesaurus.
Platform: Protein replacement
Regular IgG infusion for the antibody deficiency. It is needed before transplantation and, in the one long-term survivor, became necessary again six years afterwards when T-helper support for the patient's own B cells declined.
Mechanism Target:
BYPASSES Loss of T-Cell Help to B Cells — Replacement antibody substitutes for the switched, specific immunoglobulin the patient's unhelped B cells cannot make; the T-cell defect that causes the humoral failure is untouched.
Show evidence (1 reference)
PMID:24515816 SUPPORT Human Clinical
"At 6 years after SCT the patient developed signs of humoral immunodeficiency, requiring regular substitution of IgG."
The indication, arising specifically from the loss of T-cell help rather than from a B-cell defect.
Target Phenotypes: Decreased circulating immunoglobulin concentration HP:0004313 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Decreased circulating immunoglobulin concentration (HP:0004313). HP:0004313 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24515816 SUPPORT Human Clinical
"The loss of B-cell function as observed in the patient was reflected by a lack of switched memory B cells. To rule out a primary role of CD3ε in B-cell function we studied expression of CD3E in B-cells which was found not to be expressed."
Establishes that the antibody defect being replaced is secondary to lost T-cell help.
🔬

Diagnosis

3
Newborn screening by T-cell receptor excision circle quantitation
Measurement of TRECs in a dried blood spot. Because CD3epsilon deficiency blocks thymopoiesis outright, thymic output is absent and TRECs are undetectable, so the complete-deficiency form is detectable at birth by the universal screen. The hypomorphic form, in which T cells do develop, is not reliably detectable this way.
newborn screening NCIT:C81178 NCI Thesaurus (NCIT)
Results: Undetectable TRECs with normal kappa-deleting recombination excision circles.
Show evidence (2 references)
PMID:28597365 SUPPORT Human Clinical
"T cell receptor excision circle (TREC) and kappa-deleting recombination excision circle (KREC) analyses were performed for T and B cell maturation. TRECs were not detected in both patients and the KREC copy numbers were similar to the other family members."
The measured result in two genetically confirmed CD3E patients: absent TRECs with preserved B-cell output.
PMID:36456361 SUPPORT Other
"Universal NBS for SCID by enumerating T-cell receptor excision circles (TRECs) in dried blood spots collected at birth has radically altered how infants with SCID in the United States and most infants in Canada are now identified."
Establishes TREC-based newborn screening as the route by which severe combined immunodeficiency is now identified.
Lymphocyte immunophenotyping
Flow cytometry for absolute CD3, CD4, CD8, CD19 and CD16/CD56 counts, together with surface TCR/CD3 density. The complete-deficiency result is absent T cells with normal or high B cells and present NK cells; the hypomorphic result is T cells present with markedly reduced surface receptor, so receptor density has to be measured and not just cell number.
flow cytometry NCIT:C16585 NCI Thesaurus (NCIT)
Results: T-B+NK+ pattern with absent CD3+ cells, or preserved T cells with surface TCR/CD3 at about a tenth of normal density.
Show evidence (2 references)
PMID:15546002 SUPPORT Human Clinical
"We investigated the molecular mechanism underlying a severe combined immunodeficiency characterized by the selective and complete absence of T cells."
The complete-deficiency immunophenotype.
PMID:1370449 SUPPORT Human Clinical
"We report on another immunodeficient patient whose T lymphocytes express the T cell receptor at one-tenth of normal fluorescence intensity and are not triggered to proliferate in vitro by anti-CD3 or anti-CD2 antibodies."
The hypomorphic immunophenotype, which is a receptor-density measurement rather than a cell count.
CD3E sequencing
Molecular confirmation by targeted panel, exome or genome sequencing. CD3E is reached through severe combined immunodeficiency and inborn-error-of-immunity panels; in published cohorts it accounts for one or two patients at a time, so it is found by panel breadth rather than by clinical suspicion of this gene.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Results: Biallelic loss-of-function CD3E variants.
Show evidence (1 reference)
PMID:32445296 SUPPORT Human Clinical
"In total, 24 disease-causing variants (17 known and 7 novel) were identified in 23 patients in 9 different SCID genes: RAG1 (n = 5), RAG2 (n = 2), ADA (n = 3), DCLRE1C (n = 2), NHEJ1 (n = 2), CD3E (n = 2), IL2RG (n = 3), JAK3 (n = 4) and IL7R (n = 1)."
Shows CD3E being reached as one gene among many on a severe combined immunodeficiency panel.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
No population estimate exists for CD3epsilon deficiency specifically. The disorder is known from single families and from the occasional CD3E case within larger severe combined immunodeficiency cohorts - two of 23 solved patients in one Turkish series, one of twenty in an Egyptian series - and those denominators are ascertainment-selected cohorts of SCID patients, not populations, so no rate is recorded.
Show evidence (2 references)
PMID:32445296 SUPPORT Human Clinical
"In total, 24 disease-causing variants (17 known and 7 novel) were identified in 23 patients in 9 different SCID genes: RAG1 (n = 5), RAG2 (n = 2), ADA (n = 3), DCLRE1C (n = 2), NHEJ1 (n = 2), CD3E (n = 2), IL2RG (n = 3), JAK3 (n = 4) and IL7R (n = 1)."
The CD3E share of one genetically solved severe combined immunodeficiency cohort.
PMID:33040328 SUPPORT Human Clinical
"IL7Rα and CD3ε variants were found once, with a novel variant each."
A second cohort in which CD3E accounted for a single patient, illustrating how sparse the disorder is even within T-B+ SCID.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Immunodeficiency 18:

Combined immunodeficiency due to CD3gamma deficiency MONDO:0014276
Overlapping Features The sibling chain of the same receptor complex, and the boundary this entry is drawn against. CD3gamma deficiency shares the biochemical lesion - an incomplete TCR/CD3 complex - but does not block thymocyte development: patients have normal absolute T-cell numbers with reduced surface receptor, and their dominant clinical problem is immune dysregulation and autoimmunity rather than infection. The asymmetry is not a matter of degree but of which chain is lost: CD3epsilon partners both CD3gamma and CD3delta, so losing it removes two dimers rather than one. The one point of genuine overlap is the hypomorphic end of the CD3epsilon spectrum, where reduced surface receptor with preserved T cells is also what the flow panel shows; there the two are distinguished by sequencing, not by immunophenotype.
Distinguishing Features
  • Normal absolute T-cell numbers rather than a developmental block
  • Autoimmunity, particularly thyroiditis and cytopenias, as the dominant problem
  • Biallelic CD3G rather than CD3E variants
Show evidence (2 references)
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 in CD3E deficiency and contrasts it with the partial immunodeficiency of CD3G deficiency. This is the same sentence the CD3gamma entry cites from its side of the boundary.
PMID:17277165 SUPPORT Human Clinical
"Thus, the peripheral T lymphocyte pool was comparatively well preserved in human CD3gamma deficiencies despite poor thymus output or clinical outcome."
Records the preserved peripheral T-cell pool in CD3gamma deficiency, the feature that CD3epsilon deficiency lacks.
CD3delta and CD3zeta deficiencies Not Yet Curated MONDO:0015703
Overlapping Features The other two severe CD3 chain defects. All three produce the same T-B+NK+ severe combined immunodeficiency and are indistinguishable on immunophenotype; only sequencing separates them. They are grouped together in MONDO under one T-B+ SCID concept for exactly that reason.
Distinguishing Features
  • Biallelic CD3D or CD247 rather than CD3E variants
Show evidence (1 reference)
PMID:15546002 SUPPORT Human Clinical
"Patients and affected fetuses from 2 families were homozygous for a mutation in the CD3D gene, and patients from the third family were homozygous for a mutation in the CD3E gene."
The study in which CD3D- and CD3E-deficient families presented with the same clinical and immunological picture and were separated only by sequencing.
Other T-B+NK+ severe combined immunodeficiencies MONDO:0015974
Overlapping Features IL7R and PTPRC deficiency produce the same flow cytometry pattern and are commoner than CD3E; in published cohorts they are found alongside it on the same panels. Genetic testing is the discriminator.
Distinguishing Features
  • Causal variants in IL7R, PTPRC or another SCID gene rather than CD3E
Show evidence (1 reference)
PMID:33040328 SUPPORT Human Clinical
"IL7Rα and CD3ε variants were found once, with a novel variant each."
Shows IL7R and CD3E being distinguished within one clinically indistinguishable T-B+ SCID cohort by sequencing alone.
🐁

Animal Models

2
Cd3e-deficient mouse
Mice carrying a targeted mutation of the CD3-epsilon gene. This is the model that supplies the arrest stage the human disorder is described by, since no patient thymus has ever been examined. Thymocytes stop at the CD44-low CD25-positive triple-negative stage, at the same control point as RAG-deficient thymocytes, despite having rearranged TCRbeta normally.
Species
Mouse
Genotype
Cd3e null (targeted mutation of the CD3-epsilon gene)
Publication
PMID:7588594
Pathograph links
Arrest of Thymocyte Development recapitulates fidelity: moderate The knockout reproduces the complete developmental block that defines the human null phenotype, and localises it to the pre-TCR checkpoint.
Limitations: Fidelity is moderate rather than high because the human arrest stage was never established: no thymus was available from the CD3epsilon-deficient family, so the correspondence is between the mouse's arrest and the human outcome, not between two measured arrest points. The species divergence seen for CD3gamma - where the mouse knockout is far more severe than the human disorder - is a standing reason not to assume the stages match.
Readouts
Thymocyte progression beyond the CD44-low CD25-positive stage
Direction: ABOLISHED
Interpretation: Development stops at the pre-TCR checkpoint, identifying where CD3epsilon is required.
Show evidence (1 reference)
PMID:7588594 SUPPORT Model Organism
"In the absence of intact CD3-epsilon subunit, thymocytes do not progress beyond the CD44-/lowCD25+ triple-negative stage and appear to be arrested at the very same developmental control point as RAG-deficient thymocytes."
The measured arrest point.
Show evidence (1 reference)
PMID:15546002 SUPPORT Model Organism
"showing that CD3ε is essential for transduction of the PreTα/TCRβ receptor survival, proliferation, and progression signals"
The interpretation of the mouse result that the human account relies on.
Blocked Pre-TCR Signaling at Beta-Selection measures fidelity: moderate The knockout separates recombination from signalling: TCRbeta rearrangement proceeds and full-length transcripts are made, so what fails is the receptor that reads the rearrangement, not the rearrangement itself. Reconstitution with a CD3epsilon transgene rescues development from a small subpopulation of prothymocytes, showing the block is CD3epsilon-dependent and reversible.
Limitations: A gene-targeted mouse rather than a patient allele; the readouts are thymocyte subset composition and transcript levels rather than any clinical outcome, and the transgene rescue uses non-physiological expression.
Readouts
TCRbeta gene rearrangement and transcript production in arrested thymocytes
Direction: UNCHANGED
Interpretation: Rearrangement is intact in the arrested thymocytes, placing the lesion at pre-TCR signalling rather than at V(D)J recombination.
Show evidence (1 reference)
PMID:7588594 SUPPORT Model Organism
"CD3-epsilon-deficient thymocytes do rearrange their T cell receptor (TCR) beta gene segments and produce low levels of full-length TCR beta transcripts."
The measurement that dissociates recombination from the block.
Thymocyte maturation after CD3epsilon transgene reconstitution
Direction: RESTORED
Interpretation: Restoring CD3epsilon restores progression through the checkpoint, confirming the block is caused by its absence.
Show evidence (1 reference)
PMID:9885898 SUPPORT Model Organism
"However, a very small fraction of prothymocytes that expressed CD3 gamma and delta was rescued upon reconstitution of the CD3 epsilon transgene. Remarkably, this rescue led to a very efficient differentiation and maturation of thymocytes, resulting in a significant T cell population in the periphery."
The rescue experiment.
Show evidence (1 reference)
PMID:9885898 SUPPORT Model Organism
"In the epsilon(delta P) mice, T cell development is arrested at the double-negative stage and targeting the CD3 epsilon gene caused severe inhibition of CD3 gamma and delta gene expression."
Establishes the model and the arrest it produces.
Show evidence (1 reference)
PMID:7588594 SUPPORT Model Organism
"Finally, the absence of intact CD3-epsilon polypeptides had no discernible effect on the completion of TCR gamma and TCR delta gene rearrangements, emphasizing that they are probably not subjected to the same epigenetic controls as those operating on the expression of TCR alpha and beta genes."
A limitation on how far this model speaks to the human gamma-delta compartment, which in patients is also lost.
CD3epsilon basic-rich stretch mutant mouse
A separation-of-function allele rather than a null. The CD3epsilon cytoplasmic tail associates with the plasma membrane through a basic-rich stretch; disabling that association leaves the chain in place but dysregulates signalling. The model matters here because it shows that CD3epsilon contributes more than assembly, which is the part of its role that the null cannot dissect.
Species
Mouse
Genotype
Cd3e with a non-functional cytoplasmic basic-rich stretch (CD3e-BRS)
Publication
PMID:24899501
Pathograph links
Blocked Pre-TCR Signaling at Beta-Selection partially recapitulates fidelity: low The mutant shows reduced thymic cellularity and a limited double-negative 3 to double-negative 4 transition, so it perturbs the same checkpoint the human disorder blocks - but by excessive rather than absent signalling.
Limitations: The direction of the lesion is opposite to the patients'. Here the transition fails because DN4 signalling is enhanced and drives cell death and receptor downregulation; in CD3epsilon deficiency the receptor cannot signal at all. No patient has been reported with a variant confined to the basic-rich stretch, so this allele has no human counterpart.
Readouts
Double-negative 3 to double-negative 4 thymocyte transition
Direction: DECREASED
Interpretation: Confirms that the beta-selection transition is sensitive to the signalling properties of CD3epsilon and not only to its presence.
Show evidence (1 reference)
PMID:24899501 SUPPORT Model Organism
"In this study, we show that mice lacking a functional CD3ε-BRS exhibited substantial reductions in thymic cellularity and limited CD4- CD8- double-negative (DN) 3 to DN4 thymocyte transition, because of enhanced DN4 TCR signaling resulting in increased cell death and TCR downregulation in all..."
The measured effect on the same developmental transition, together with the mechanism, which is the opposite of the patients'.
Show evidence (1 reference)
PMID:24899501 SUPPORT Model Organism
"Collectively, these results indicate that membrane association of the CD3ε signaling domain is required for optimal thymocyte development and peripheral T cell function."
The model's conclusion about the signalling role of CD3epsilon in development.
{ }

Source YAML

click to show 
name: Immunodeficiency 18
creation_date: "2026-09-01T00:00:00Z"
category: Mendelian
synonyms:
- IMD18
- immunodeficiency type 18
- CD3-Epsilon deficiency
- CD3epsilon deficiency
- immunodeficiency 18, SCID variant
- immunodeficiency 18, Severe combined immunodeficiency variant
- T-B+NK+ severe combined immunodeficiency due to CD3E deficiency
description: >-
  Immunodeficiency 18 is an ultra-rare autosomal recessive inborn error of
  immunity caused by biallelic loss-of-function variants in CD3E, the gene
  encoding the CD3epsilon invariant chain of the T-cell receptor (TCR)/CD3
  complex. CD3epsilon is the chain around which the CD3 core is built: it
  partners both CD3gamma and CD3delta, so losing it removes two of the three
  signalling dimers from the pre-TCR and the mature TCR at once.

  Severity tracks how much functional CD3epsilon is left, and the reported
  spectrum runs from severe combined immunodeficiency to a considerably milder
  disorder. At the null end, complete absence of CD3epsilon abrogates human
  T-cell development: patients have no circulating T cells with normal B and NK
  cells - the T-B+NK+ pattern - and present in the first months of life with
  candidiasis, protracted diarrhoea, pneumonitis and failure to thrive, dying of
  disseminated viral infection unless transplanted. At the hypomorphic end, the
  child in whom the first CD3E mutations were found carried two different
  alleles that left an unstable chain and roughly a tenth of the normal surface
  receptor; that patient had T cells, and an immunodeficiency defined by
  unresponsiveness to receptor stimulation rather than by the absence of the
  compartment. Both ends are the same disorder and the same MONDO concept, and
  the entry is curated as a single graded entity rather than as a uniformly
  severe one.

  The boundary that matters clinically is with CD3gamma deficiency, the sibling
  chain of the same complex. That disorder does not block thymocyte development:
  patients keep normal T-cell numbers with reduced surface receptor, and their
  dominant problem is autoimmunity. CD3epsilon and CD3delta deficiency block
  development; CD3gamma deficiency does not. The one place the two disorders
  come close is the hypomorphic end of the CD3epsilon spectrum, where reduced
  rather than absent surface receptor is what is measured - and there the
  distinction rests on which gene is mutated, not on the flow cytometry.

  Where the developmental block sits in humans has never been shown directly.
  No thymus was available from the CD3epsilon-deficient family, so the arrest
  point is carried over from the mouse, where Cd3e inactivation stops
  thymocytes at the CD44-low CD25-positive double-negative stage.
disease_term:
  preferred_term: immunodeficiency 18
  term:
    id: MONDO:0014278
    label: immunodeficiency 18
parents:
- Severe combined immunodeficiency
- Inborn error of immunity
references:
- reference: PMID:15546002
  title: Severe combined immunodeficiency caused by deficiency in either the delta or the epsilon subunit of CD3.
- reference: PMID:8490660
  title: Independent mutations of the human CD3-epsilon gene resulting in a T cell receptor/CD3 complex immunodeficiency.
- reference: PMID:1370449
  title: Structural analysis of low TCR-CD3 complex expression in T cells of an immunodeficient patient.
- reference: PMID:17277165
  title: Differential biological role of CD3 chains revealed by human immunodeficiencies.
- reference: PMID:16264327
  title: CD3 deficiencies.
- reference: PMID:28597365
  title: A novel pathogenic frameshift variant of CD3E gene in two T-B+ NK+ SCID patients from Turkey.
- reference: PMID:24515816
  title: "Successful haploidentical hematopoietic stem cell transplantation in a patient with SCID due to CD3ε deficiency: need for IgG-substitution 6 years later."
- reference: PMID:39287664
  title: Sequence variants underlying severe combined immunodeficiency and leukocyte adhesion deficiency type 1 in six consanguineous families.
- reference: PMID:33040328
  title: "Whole-exome sequencing of T(-) B(+) severe combined immunodeficiency in Egyptian infants, JAK3 predominance and novel variants."
- reference: PMID:32445296
  title: Mutational landscape of severe combined immunodeficiency patients from Turkey.
- reference: PMID:36456361
  title: "The diagnosis of severe combined immunodeficiency (SCID): The Primary Immune Deficiency Treatment Consortium (PIDTC) 2022 Definitions."
- reference: PMID:7588594
  title: Altered T cell development in mice with a targeted mutation of the CD3-epsilon gene.
- reference: PMID:9885898
  title: Expression of a CD3 epsilon transgene in CD3 epsilon(null) mice does not restore CD3 gamma and delta expression but efficiently rescues T cell development from a subpopulation of prothymocytes.
- reference: PMID:24899501
  title: Membrane association of the CD3ε signaling domain is required for optimal T cell development and function.
- 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). CD3E is
      listed there among the T-B+NK+ severe combined immunodeficiencies,
      alongside CD3D and CD3Z, and separately from the CD3G row, which the same
      table records as having normal T-cell numbers with low TCR expression.
    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 CD3E AR 186830 Very lowN ormalL ow Normal NK, no T cells
      explanation: >-
        The IUIS table row for CD3E, recording very low T cells, normal B cells,
        low immunoglobulins and normal NK cells - the T-B+NK+ pattern that places
        this disorder in the severe combined immunodeficiency table.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Biallelic CD3E variants. Most reported patients are homozygous and born to
    consanguineous parents; the original family was compound heterozygous, with
    a different mutation inherited from each parent. Heterozygous carriers are
    clinically unaffected, although one study found their T-cell receptor
    excision circle counts to be measurably lower than a wild-type sibling's.
  evidence:
  - reference: PMID:8490660
    reference_title: Independent mutations of the human CD3-epsilon gene resulting in a T cell receptor/CD3 complex immunodeficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We now report that two independent CD3-epsilon gene mutations present in the parents have segregated in the patient, leading to defective CD3-epsilon chain synthesis and preventing normal association and membrane expression of the TCR/CD3 complex.
    explanation: >-
      The compound heterozygous transmission in the first reported family.
  - reference: PMID:28597365
    reference_title: A novel pathogenic frameshift variant of CD3E gene in two T-B+ NK+ SCID patients from Turkey.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition, heterozygous family members showed decreased TREC levels when compared with the wild-type sibling, indicating that carrying this variant in one allele does not cause immunodeficiency, but does effect T cell proliferation.
    explanation: >-
      Establishes that heterozygotes are unaffected while recording the
      measurable gene-dosage effect on thymic output.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    No population estimate exists for CD3epsilon deficiency specifically. The
    disorder is known from single families and from the occasional CD3E case
    within larger severe combined immunodeficiency cohorts - two of 23 solved
    patients in one Turkish series, one of twenty in an Egyptian series - and
    those denominators are ascertainment-selected cohorts of SCID patients, not
    populations, so no rate is recorded.
  evidence:
  - reference: PMID:32445296
    reference_title: Mutational landscape of severe combined immunodeficiency patients from Turkey.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In total, 24 disease-causing variants (17 known and 7 novel) were identified in 23 patients in 9 different SCID genes: RAG1 (n = 5), RAG2 (n = 2), ADA (n = 3), DCLRE1C (n = 2), NHEJ1 (n = 2), CD3E (n = 2), IL2RG (n = 3), JAK3 (n = 4) and IL7R (n = 1).
    explanation: >-
      The CD3E share of one genetically solved severe combined immunodeficiency
      cohort.
  - reference: PMID:33040328
    reference_title: "Whole-exome sequencing of T(-) B(+) severe combined immunodeficiency in Egyptian infants, JAK3 predominance and novel variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      IL7Rα and CD3ε variants were found once, with a novel variant each.
    explanation: >-
      A second cohort in which CD3E accounted for a single patient, illustrating
      how sparse the disorder is even within T-B+ SCID.
pathophysiology:
- name: Biallelic CD3E Loss-of-Function Variants
  biological_scale: MOLECULAR
  description: >-
    Frameshift, nonsense and splice variants on both alleles. Reported changes
    include a homozygous two-base deletion in exon 5 that truncates the chain in
    its extracellular domain, a frameshift found in two Turkish siblings, a
    homozygous splice-site change that abolishes the protein, and nonsense
    alleles found in Egyptian and Pakistani families. Two hypomorphic alleles in
    the original family behaved differently: they permitted some correctly
    processed protein, which is why that patient was not a classical severe
    combined immunodeficiency.
  genes:
  - preferred_term: CD3E
    term:
      id: hgnc:1674
      label: CD3E
  evidence:
  - reference: PMID:15546002
    reference_title: Severe combined immunodeficiency caused by deficiency in either the delta or the epsilon subunit of CD3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A homozygous 2-bp deletion at nucleotide 128 in exon 5 of CD3E was identified in this patient.
    explanation: >-
      The truncating allele in the first family recognised as CD3epsilon
      deficiency.
  - reference: PMID:28597365
    reference_title: A novel pathogenic frameshift variant of CD3E gene in two T-B+ NK+ SCID patients from Turkey.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We found a novel deletion in the CD3E gene (NM000733.3:p.L58Hfs*9) in two T-B+ NK+ patients.
    explanation: >-
      A second, independent frameshift allele with the same T-B+NK+ consequence.
  downstream:
  - target: Loss of the CD3epsilon Chain
    description: >-
      Truncating and splice alleles abolish production of a usable CD3epsilon
      polypeptide.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:24515816
      reference_title: "Successful haploidentical hematopoietic stem cell transplantation in a patient with SCID due to CD3ε deficiency: need for IgG-substitution 6 years later."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In a retrospective genetic work up 11 years after SCT, a homozygous splice site mutation in CD3E was identified resulting in the loss of CD3ε protein.
      explanation: >-
        Links a specific CD3E genotype directly to absence of the protein.
  - target: Residual Unstable CD3epsilon in Partial Deficiency
    description: >-
      Hypomorphic alleles produce an abnormally sized, unstable transcript and a
      correspondingly reduced amount of chain rather than none at all.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:1370449
      reference_title: Structural analysis of low TCR-CD3 complex expression in T cells of an immunodeficient patient.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Northern blot analysis revealed normal levels of normal-size TCR beta and CD3 gamma, delta gene-specific mRNAs and decreased levels of TCR alpha mARN; CD3 epsilon gene transcripts were of abnormal size and present in lower than normal amounts.
      explanation: >-
        The transcript-level evidence that the hypomorphic genotype reduces
        rather than abolishes CD3epsilon.
- name: Loss of the CD3epsilon Chain
  biological_scale: MOLECULAR
  description: >-
    Complete absence of the CD3epsilon polypeptide. Because CD3epsilon is the
    common partner of both CD3gamma and CD3delta, its loss takes out the
    gamma-epsilon and delta-epsilon dimers together, which is why it is more
    damaging than loss of either partner alone. In mouse thymocytes, disrupting
    the gene also strongly suppresses expression of CD3gamma and CD3delta,
    although that turned out to reflect the arrest rather than transcriptional
    control by CD3epsilon itself.
  evidence:
  - reference: PMID:8490660
    reference_title: Independent mutations of the human CD3-epsilon gene resulting in a T cell receptor/CD3 complex immunodeficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The T-cell receptor (TCR) is composed of two glycoproteins (alpha and beta or gamma and delta) associated with four invariant polypeptides (CD3-gamma, delta, epsilon and zeta). The majority of TCR/CD3 complexes contain six polypeptide chains, and although there is some flexibility in the complex subunit stoichiometry the CD3-epsilon chain is central to CD3 core assembly and full complex formation.
    explanation: >-
      States the structural position of CD3epsilon that makes its loss
      consequential for the whole complex.
  downstream:
  - target: Failure of pre-TCR and TCR Complex Assembly
    description: >-
      Without CD3epsilon neither invariant dimer can form, so the receptor
      cannot be assembled or exported.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:8490660
      reference_title: Independent mutations of the human CD3-epsilon gene resulting in a T cell receptor/CD3 complex immunodeficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We now report that two independent CD3-epsilon gene mutations present in the parents have segregated in the patient, leading to defective CD3-epsilon chain synthesis and preventing normal association and membrane expression of the TCR/CD3 complex.
      explanation: >-
        Links defective CD3epsilon synthesis directly to failed assembly and
        surface expression of the complex.
- name: Residual Unstable CD3epsilon in Partial Deficiency
  biological_scale: MOLECULAR
  description: >-
    The hypomorphic branch. Two CD3E alleles that reduce but do not abolish
    production of the chain leave a T-cell compartment that exists but carries
    about a tenth of the normal surface receptor. This is the mechanistic basis
    of the mild end of the spectrum and the reason severity in this disorder is
    not uniform. It is curated as its own node because it produces a different
    downstream chain from the null branch: attenuated signalling in T cells that
    are present, rather than absence of the cells.
  evidence:
  - reference: PMID:1370449
    reference_title: Structural analysis of low TCR-CD3 complex expression in T cells of an immunodeficient patient.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These findings suggest that this defect in T cell receptor-CD3 expression involves a mutation in the CD3 epsilon gene leading to the synthesis of an abnormal and unstable CD3 epsilon subunit.
    explanation: >-
      Identifies the lesion as an unstable chain rather than an absent one.
  downstream:
  - target: Reduced Surface TCR/CD3 with Impaired T-Cell Activation
    description: >-
      An unstable chain assembles inefficiently, so fewer complexes reach the
      surface and those T cells that do develop respond poorly to receptor
      engagement.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:1370449
      reference_title: Structural analysis of low TCR-CD3 complex expression in T cells of an immunodeficient patient.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We report on another immunodeficient patient whose T lymphocytes express the T cell receptor at one-tenth of normal fluorescence intensity and are not triggered to proliferate in vitro by anti-CD3 or anti-CD2 antibodies.
      explanation: >-
        The measured receptor density and the functional consequence in the same
        patient.
- name: Failure of pre-TCR and TCR Complex Assembly
  biological_scale: MOLECULAR
  description: >-
    The pre-TCR (pre-TCRalpha with TCRbeta) and the mature alpha-beta TCR both
    reach the surface only as complexes with the CD3gamma-epsilon,
    CD3delta-epsilon and zeta-zeta dimers. Losing CD3epsilon removes two of the
    three, and the receptor is neither assembled nor exported. Note that TCRbeta
    gene rearrangement itself proceeds normally, so the defect is in receptor
    assembly and signalling rather than in recombination.
  protein_complexes:
  - preferred_term: T cell receptor complex
    modifier: ABSENT
    term:
      id: GO:0042101
      label: T cell receptor complex
  evidence:
  - reference: PMID:7588594
    reference_title: Altered T cell development in mice with a targeted mutation of the CD3-epsilon gene.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      CD3-epsilon-deficient thymocytes do rearrange their T cell receptor (TCR) beta gene segments and produce low levels of full-length TCR beta transcripts.
    explanation: >-
      Establishes that recombination is intact, locating the lesion downstream at
      receptor assembly and signalling.
  downstream:
  - target: Blocked Pre-TCR Signaling at Beta-Selection
    description: >-
      The pre-TCR cannot transmit the survival, proliferation and progression
      signal that reports a productive TCRbeta rearrangement.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:15546002
      reference_title: Severe combined immunodeficiency caused by deficiency in either the delta or the epsilon subunit of CD3.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        showing that CD3ε is essential for transduction of the PreTα/TCRβ receptor survival, proliferation, and progression signals
      explanation: >-
        Names the specific pre-TCR signal that requires CD3epsilon.
- name: Blocked Pre-TCR Signaling at Beta-Selection
  biological_scale: CELLULAR
  description: >-
    Beta-selection is the checkpoint at which a double-negative thymocyte that
    has made a productive TCRbeta rearrangement is licensed to survive, divide
    and proceed to the double-positive stage. The pre-TCR is the sensor, and
    without CD3epsilon it cannot signal, so the checkpoint reads every
    thymocyte as having failed.
  biological_processes:
  - preferred_term: T cell receptor signaling pathway
    modifier: ABSENT
    term:
      id: GO:0050852
      label: T cell receptor signaling pathway
  cell_types:
  - preferred_term: double negative thymocyte
    term:
      id: CL:0002489
      label: double negative thymocyte
  evidence:
  - reference: PMID:7588594
    reference_title: Altered T cell development in mice with a targeted mutation of the CD3-epsilon gene.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Taken together, these results establish an essential role for the CD3-epsilon gene products during T cell development and further suggest that the CD3-epsilon polypeptides start to exert their function as part of a pre-TCR through which CD44-/lowCD25+ triple-negative cells monitor the occurrence of productive TCR beta gene rearrangements.
    explanation: >-
      Places the requirement for CD3epsilon precisely at pre-TCR surveillance of
      beta-selection.
  downstream:
  - target: Arrest of Thymocyte Development
    description: >-
      A thymocyte that cannot pass beta-selection does not progress to the
      double-positive stage.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:7588594
      reference_title: Altered T cell development in mice with a targeted mutation of the CD3-epsilon gene.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In the absence of intact CD3-epsilon subunit, thymocytes do not progress beyond the CD44-/lowCD25+ triple-negative stage and appear to be arrested at the very same developmental control point as RAG-deficient thymocytes.
      explanation: >-
        The measured arrest point in the model that the human arrest is inferred
        from.
- name: Arrest of Thymocyte Development
  biological_scale: CELLULAR
  description: >-
    Thymopoiesis stops. In the mouse the arrest is at the CD44-low CD25-positive
    double-negative stage, phenocopying RAG deficiency despite intact
    rearrangement. In humans the stage has never been established directly,
    because no thymus was available from the CD3epsilon-deficient family; what
    is established is the outcome, that absence of CD3epsilon abrogates human
    T-cell development altogether.
  biological_processes:
  - preferred_term: T cell differentiation in thymus
    modifier: ABSENT
    term:
      id: GO:0033077
      label: T cell differentiation in thymus
  cell_types:
  - preferred_term: thymocyte
    term:
      id: CL:0000893
      label: thymocyte
  evidence:
  - reference: PMID:15546002
    reference_title: Severe combined immunodeficiency caused by deficiency in either the delta or the epsilon subunit of CD3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These observations show that an absence of CD3ε or CD3δ completely abrogates human T cell development.
    explanation: >-
      The human-level conclusion, stated without committing to an arrest stage.
  - reference: PMID:15546002
    reference_title: Severe combined immunodeficiency caused by deficiency in either the delta or the epsilon subunit of CD3.
    supports: NO_EVIDENCE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It was not possible to assess at what stage the CD3 ε deficiency blocked T cell differentiation in patients from family I, as no thymus material was available.
    explanation: >-
      Records that the human arrest stage was not determined; the mouse stage is
      an inference, not an observation in patients.
  downstream:
  - target: Absent Peripheral T Cells
    description: >-
      No thymocyte completes development, so no mature T cell reaches the
      periphery.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:15546002
      reference_title: Severe combined immunodeficiency caused by deficiency in either the delta or the epsilon subunit of CD3.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We investigated the molecular mechanism underlying a severe combined immunodeficiency characterized by the selective and complete absence of T cells.
      explanation: >-
        The peripheral consequence in the patients, described as selective and
        complete.
- name: Absent Peripheral T Cells
  biological_scale: ORGANISM
  description: >-
    No circulating CD3-positive T cells, with normal or high B-cell counts and
    present NK cells. The selectivity is the point: only the T lineage requires
    the pre-TCR, so B and NK development proceed normally, and the resulting
    T-B+NK+ pattern is what a diagnostic flow panel sees. Thymic output measured
    as T-cell receptor excision circles is undetectable, which is what makes the
    disorder visible to newborn screening.
  cell_types:
  - preferred_term: T cell
    modifier: ABSENT
    term:
      id: CL:0000084
      label: T cell
  evidence:
  - reference: PMID:28597365
    reference_title: A novel pathogenic frameshift variant of CD3E gene in two T-B+ NK+ SCID patients from Turkey.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      T cell receptor excision circle (TREC) and kappa-deleting recombination excision circle (KREC) analyses were performed for T and B cell maturation. TRECs were not detected in both patients and the KREC copy numbers were similar to the other family members.
    explanation: >-
      Absent thymic output alongside normal B-cell output, measured in the same
      patients.
  downstream:
  - target: Failure of Cellular Immunity
    description: >-
      Without T cells there is no cell-mediated defence against viral, fungal
      and opportunistic pathogens.
    causal_link_type: DIRECT
    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 causal chain from the developmental block to the severe
        combined immunodeficiency phenotype.
  - target: Loss of T-Cell Help to B Cells
    description: >-
      B cells are present and numerically normal but have no T-cell help, so
      they cannot mount switched, specific antibody responses.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:24515816
      reference_title: "Successful haploidentical hematopoietic stem cell transplantation in a patient with SCID due to CD3ε deficiency: need for IgG-substitution 6 years later."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The loss of B-cell function as observed in the patient was reflected by a lack of switched memory B cells. To rule out a primary role of CD3ε in B-cell function we studied expression of CD3E in B-cells which was found not to be expressed.
      explanation: >-
        Establishes that the humoral defect is secondary to lost T-cell help
        rather than a B-cell-intrinsic role for CD3epsilon, which the authors
        excluded by showing the gene is not expressed in B cells.
- name: Reduced Surface TCR/CD3 with Impaired T-Cell Activation
  biological_scale: CELLULAR
  description: >-
    The hypomorphic outcome. T cells develop and populate the periphery, but
    carry roughly a tenth of the normal density of surface receptor and cannot
    be triggered to proliferate through CD3 or CD2. The immunodeficiency here is
    functional rather than numerical, and it is the reason this disorder cannot
    be described as uniformly a severe combined immunodeficiency.
  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: T cell
    term:
      id: CL:0000084
      label: T cell
  evidence:
  - reference: PMID:1370449
    reference_title: Structural analysis of low TCR-CD3 complex expression in T cells of an immunodeficient patient.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report on another immunodeficient patient whose T lymphocytes express the T cell receptor at one-tenth of normal fluorescence intensity and are not triggered to proliferate in vitro by anti-CD3 or anti-CD2 antibodies.
    explanation: >-
      The defining measurements of the hypomorphic phenotype: reduced receptor
      density with preserved cells, and failure of receptor-driven proliferation.
  downstream:
  - target: Failure of Cellular Immunity
    description: >-
      T cells that cannot be activated through their receptor cannot mount an
      effective cellular response, even though they are present.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:1370449
      reference_title: Structural analysis of low TCR-CD3 complex expression in T cells of an immunodeficient patient.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We report on another immunodeficient patient whose T lymphocytes express the T cell receptor at one-tenth of normal fluorescence intensity and are not triggered to proliferate in vitro by anti-CD3 or anti-CD2 antibodies.
      explanation: >-
        The same measurement links the receptor deficit to functional
        unresponsiveness in a patient described as immunodeficient.
- name: Failure of Cellular Immunity
  biological_scale: ORGANISM
  description: >-
    The clinical endpoint of both branches. In the null form it is
    catastrophic: candidiasis, protracted diarrhoea, pneumonitis and failure to
    thrive in the first months, and death from disseminated cytomegalovirus or
    adenovirus without immune reconstitution. In the hypomorphic form it is a
    milder susceptibility to infection in a child who has T cells.
  evidence:
  - reference: PMID:33040328
    reference_title: "Whole-exome sequencing of T(-) B(+) severe combined immunodeficiency in Egyptian infants, JAK3 predominance and novel variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients had the classic clinical picture for SCID, including failure to thrive (n = 20), oral candidiasis (n = 17), persistent diarrhea (n = 14), pneumonia (n = 13), napkin dermatitis (n = 10), skin rash (n = 7), otitis media (n = 3) and meningitis (n = 2).
    explanation: >-
      The clinical picture of the T-B+ SCID cohort in which a CD3E patient was
      identified.
- name: Loss of T-Cell Help to B Cells
  biological_scale: ORGANISM
  description: >-
    B cells are numerically normal but functionally unsupported. IgM is
    detectable, IgA is not, and IgG falls once maternal antibody wanes. The
    clearest demonstration comes from a transplanted patient in whom only the
    T-cell lineage was of donor origin: humoral immunity was adequate for six
    years and then failed, with loss of switched memory B cells, as T-helper
    support declined.
  biological_processes:
  - preferred_term: isotype switching
    modifier: DECREASED
    term:
      id: GO:0045190
      label: isotype switching
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  evidence:
  - reference: PMID:15546002
    reference_title: Severe combined immunodeficiency caused by deficiency in either the delta or the epsilon subunit of CD3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      IgA was not detected in the serum of any of the patients.
    explanation: >-
      The isotype-specific antibody deficit accompanying preserved B-cell
      numbers.
  - reference: PMID:24515816
    reference_title: "Successful haploidentical hematopoietic stem cell transplantation in a patient with SCID due to CD3ε deficiency: need for IgG-substitution 6 years later."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At 6 years after SCT the patient developed signs of humoral immunodeficiency, requiring regular substitution of IgG.
    explanation: >-
      The delayed humoral failure in a split-chimerism patient, which is the
      natural experiment showing the antibody defect is T-cell dependent.
phenotypes:
- name: Severe combined immunodeficiency
  category: Immunologic
  diagnostic: true
  description: >-
    The presentation of the complete-deficiency form: profound T-cell deficiency
    with preserved humoral cell numbers, manifesting in the first months of
    life and fatal without immune reconstitution.
  phenotype_term:
    preferred_term: Severe combined immunodeficiency
    term:
      id: HP:0004430
      label: Severe combined immunodeficiency
  evidence:
  - reference: PMID:16264327
    reference_title: CD3 deficiencies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two new severe combined immunodeficiency conditions have been reported as a consequence of either CD3D or CD3E deficiency.
    explanation: >-
      Names CD3E deficiency as a severe combined immunodeficiency condition.
  - reference: PMID:17277165
    reference_title: Differential biological role of CD3 chains revealed by human immunodeficiencies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In contrast, all reported human complete CD3delta (or CD3epsilon) deficiencies are in infants with life-threatening SCID and very severe alphabeta and gammadelta T lymphocytopenia.
    explanation: >-
      States that the complete deficiencies, as reported at that time, were
      uniformly SCID in infancy.
- name: Absent circulating T cells with normal B and NK cells
  category: Immunologic
  diagnostic: true
  description: >-
    The T-B+NK+ flow cytometry pattern. In complete deficiency no CD3-positive
    cells are detected, while B-cell counts sit at or above the upper limit of
    normal and NK cells are present. This pattern narrows the differential to a
    handful of genes and is what a SCID panel is chosen on.
  phenotype_term:
    preferred_term: Absent circulating T cells
    term:
      id: HP:0025805
      label: Absent circulating T cells
  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 CD3E AR 186830 Very lowN ormalL ow Normal NK, no T cells
    explanation: >-
      The IUIS row recording very low T cells with normal B and NK cells for
      CD3E.
  - reference: PMID:28597365
    reference_title: A novel pathogenic frameshift variant of CD3E gene in two T-B+ NK+ SCID patients from Turkey.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We found a novel deletion in the CD3E gene (NM000733.3:p.L58Hfs*9) in two T-B+ NK+ patients.
    explanation: >-
      Records the T-B+NK+ classification of two genetically confirmed patients.
- name: Reduced surface TCR/CD3 expression with preserved T cells
  category: Immunologic
  diagnostic: true
  description: >-
    The alternative laboratory presentation, seen in partial CD3epsilon
    deficiency: T cells are present but express about a tenth of the normal
    surface receptor and cannot be triggered through it. This is the finding
    that superficially resembles CD3gamma deficiency, and the reason a
    reduced-receptor result should not be taken to exclude CD3E.
  phenotype_term:
    preferred_term: Abnormal T cell physiology
    term:
      id: HP:0011840
      label: Abnormal T cell physiology
  evidence:
  - reference: PMID:1370449
    reference_title: Structural analysis of low TCR-CD3 complex expression in T cells of an immunodeficient patient.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report on another immunodeficient patient whose T lymphocytes express the T cell receptor at one-tenth of normal fluorescence intensity and are not triggered to proliferate in vitro by anti-CD3 or anti-CD2 antibodies.
    explanation: >-
      The measured receptor density and the failed activation response that
      define this presentation.
- name: Hypogammaglobulinemia
  category: Immunologic
  description: >-
    IgG falls once maternal antibody wanes and IgA is undetectable, while IgM
    persists. The defect is secondary to absent T-cell help rather than
    intrinsic to the B cells, which are present in normal or increased numbers.
  phenotype_term:
    preferred_term: Decreased circulating immunoglobulin concentration
    term:
      id: HP:0004313
      label: Decreased circulating immunoglobulin concentration
  evidence:
  - reference: PMID:15546002
    reference_title: Severe combined immunodeficiency caused by deficiency in either the delta or the epsilon subunit of CD3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      IgA was not detected in the serum of any of the patients.
    explanation: >-
      The measured immunoglobulin deficit.
  - 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 CD3E AR 186830 Very lowN ormalL ow Normal NK, no T cells
    explanation: >-
      The IUIS row records low serum immunoglobulins alongside the T-B+NK+
      pattern.
- name: Recurrent opportunistic infection
  category: Immunologic
  description: >-
    Candidiasis, pneumonitis, protracted diarrhoea and disseminated viral
    infection. Disseminated cytomegalovirus and adenovirus were the causes of
    death in the first recognised CD3epsilon-deficient family.
  phenotype_term:
    preferred_term: Recurrent opportunistic infections
    term:
      id: HP:0005390
      label: Recurrent opportunistic infections
  evidence:
  - reference: PMID:33040328
    reference_title: "Whole-exome sequencing of T(-) B(+) severe combined immunodeficiency in Egyptian infants, JAK3 predominance and novel variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients had the classic clinical picture for SCID, including failure to thrive (n = 20), oral candidiasis (n = 17), persistent diarrhea (n = 14), pneumonia (n = 13), napkin dermatitis (n = 10), skin rash (n = 7), otitis media (n = 3) and meningitis (n = 2).
    explanation: >-
      The infection spectrum in the T-B+ SCID cohort containing a CD3E patient.
- name: Failure to thrive
  category: Growth
  description: >-
    Growth failure in infancy, secondary to persistent infection and
    enteropathy rather than to a primary growth defect.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:33040328
    reference_title: "Whole-exome sequencing of T(-) B(+) severe combined immunodeficiency in Egyptian infants, JAK3 predominance and novel variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients had the classic clinical picture for SCID, including failure to thrive (n = 20), oral candidiasis (n = 17), persistent diarrhea (n = 14), pneumonia (n = 13), napkin dermatitis (n = 10), skin rash (n = 7), otitis media (n = 3) and meningitis (n = 2).
    explanation: >-
      Records failure to thrive in every patient of the cohort.
- name: Oral candidiasis
  category: Infectious
  description: >-
    Mucosal candidal infection of the mouth, one of the presenting infections in
    the first recognised CD3epsilon-deficient family and in the T-B+ SCID cohort
    below. The source reports "oral candidiasis" without stating duration; the
    bound HPO term is the chronic one, which is the closest available and the
    same binding this KB uses for an equivalent cohort count elsewhere.
  phenotype_term:
    preferred_term: Oral candidiasis
    term:
      id: HP:0009098
      label: Chronic oral candidiasis
  notes: >-
    No frequency band is asserted. The count comes from a T-B+ SCID cohort in
    which JAK3 predominates and CD3E accounts for one patient, so the cohort
    proportion is a frequency for that mixed genotype set and not for this
    disease. The numerator and denominator are stated in the snippet.
  evidence:
  - reference: PMID:33040328
    reference_title: "Whole-exome sequencing of T(-) B(+) severe combined immunodeficiency in Egyptian infants, JAK3 predominance and novel variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients had the classic clinical picture for SCID, including failure to thrive (n = 20), oral candidiasis (n = 17), persistent diarrhea (n = 14), pneumonia (n = 13), napkin dermatitis (n = 10), skin rash (n = 7), otitis media (n = 3) and meningitis (n = 2).
    explanation: >-
      Gives oral candidiasis in 17 of 20 patients in the T-B+ SCID cohort that
      includes a CD3E patient.
- name: Persistent diarrhea
  category: Gastrointestinal
  description: >-
    Protracted diarrhoea, named in the original CD3epsilon-deficient family
    alongside candidiasis and pneumonitis, and one of the infections driving the
    failure to thrive curated below.
  phenotype_term:
    preferred_term: Persistent diarrhea
    term:
      id: HP:0002014
      label: Diarrhea
    temporality: CHRONIC
  notes: >-
    No frequency band is asserted. The count comes from a T-B+ SCID cohort in
    which JAK3 predominates and CD3E accounts for one patient, so the cohort
    proportion is a frequency for that mixed genotype set and not for this
    disease. The numerator and denominator are stated in the snippet.
  evidence:
  - reference: PMID:33040328
    reference_title: "Whole-exome sequencing of T(-) B(+) severe combined immunodeficiency in Egyptian infants, JAK3 predominance and novel variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients had the classic clinical picture for SCID, including failure to thrive (n = 20), oral candidiasis (n = 17), persistent diarrhea (n = 14), pneumonia (n = 13), napkin dermatitis (n = 10), skin rash (n = 7), otitis media (n = 3) and meningitis (n = 2).
    explanation: >-
      Gives persistent diarrhea in 14 of 20 patients in the T-B+ SCID cohort that
      includes a CD3E patient.
- name: Pneumonia
  category: Respiratory
  description: >-
    Pneumonitis, including the interstitial pneumonitis typical of Pneumocystis
    jirovecii in a T-cell-null infant. Named in the original CD3epsilon-deficient
    family and counted in the cohort below.
  phenotype_term:
    preferred_term: Pneumonia
    term:
      id: HP:0002090
      label: Pneumonia
  notes: >-
    No frequency band is asserted. The count comes from a T-B+ SCID cohort in
    which JAK3 predominates and CD3E accounts for one patient, so the cohort
    proportion is a frequency for that mixed genotype set and not for this
    disease. The numerator and denominator are stated in the snippet.
  evidence:
  - reference: PMID:33040328
    reference_title: "Whole-exome sequencing of T(-) B(+) severe combined immunodeficiency in Egyptian infants, JAK3 predominance and novel variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients had the classic clinical picture for SCID, including failure to thrive (n = 20), oral candidiasis (n = 17), persistent diarrhea (n = 14), pneumonia (n = 13), napkin dermatitis (n = 10), skin rash (n = 7), otitis media (n = 3) and meningitis (n = 2).
    explanation: >-
      Gives pneumonia in 13 of 20 patients in the T-B+ SCID cohort that includes a
      CD3E patient.
genetic:
- name: CD3E
  association: Causal biallelic variant
  gene_term:
    preferred_term: CD3E
    term:
      id: hgnc:1674
      label: CD3E
  notes: >-
    The reported allelic spectrum is small and largely private to individual
    families: a homozygous two-base deletion in exon 5, a homozygous frameshift
    (p.L58Hfs*9) in two Turkish siblings, a homozygous splice-site change
    abolishing the protein, and nonsense alleles including p.Trp151* in a
    Pakistani family and one reported in an Egyptian cohort. The genotype does
    appear to set the severity in this disorder, unlike in CD3gamma deficiency:
    truncating and splice alleles that abolish the chain give severe combined
    immunodeficiency, while the two hypomorphic alleles in the original family
    left residual protein and a milder disease. That inference rests on a
    handful of families and has never been tested systematically.
  evidence:
  - reference: PMID:39287664
    reference_title: Sequence variants underlying severe combined immunodeficiency and leukocyte adhesion deficiency type 1 in six consanguineous families.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This included four novel nonsense variants in CD70 p.(Thr126Profs*33), CD3e p.(Trp151*), IL7R p.(Val138Ilefs*10), and ITGB2 p.(Ser627Valfs*61), and one previously reported in ITGB2 p.(Cys62*).
    explanation: >-
      A further private nonsense allele, illustrating the family-by-family
      character of the spectrum.
  - reference: PMID:1370449
    reference_title: Structural analysis of low TCR-CD3 complex expression in T cells of an immunodeficient patient.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These findings suggest that this defect in T cell receptor-CD3 expression involves a mutation in the CD3 epsilon gene leading to the synthesis of an abnormal and unstable CD3 epsilon subunit.
    explanation: >-
      The hypomorphic end of the allelic spectrum, where residual unstable
      protein is made.
environmental: []
treatments:
- name: Protective isolation and anti-infectious prophylaxis
  description: >-
    Supportive care that keeps a T-cell-null infant alive until immune
    reconstitution: protective isolation, antimicrobial prophylaxis, and
    avoidance of the exposures a patient with no T cells cannot survive. It is
    a bridge to transplantation rather than a treatment of the lesion, and the
    entry curates it as such because in this disease the interval before
    transplant is where patients are lost.
  treatment_term:
    preferred_term: Supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  notes: >-
    `therapeutic_modality` is deliberately absent. The bundle spans a
    non-pharmacological measure (isolation) and drug prophylaxis, and
    `TherapeuticModalityEnum` is single-valued, so any choice would misdescribe
    half of it. Individual prophylactic agents are not curated separately
    because no cached source names a regimen given to a CD3epsilon-deficient
    patient.
  target_mechanisms:
  - target: Failure of Cellular Immunity
    treatment_effect: MODULATES
    description: >-
      Reduces the pathogen exposure that the absent T-cell compartment cannot
      answer. It does not restore the compartment, so the mechanism node is
      unchanged; what changes is the burden placed on it.
    evidence:
    - reference: PMID:36456361
      reference_title: "The diagnosis of severe combined immunodeficiency (SCID): The Primary Immune Deficiency Treatment Consortium (PIDTC) 2022 Definitions."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        strict isolation and anti-infectious prophylaxis until improvements in immunity are achieved
      explanation: >-
        States the supportive-care approach for severe combined immunodeficiency
        in the interval before immune reconstitution.
  evidence:
  - reference: PMID:36456361
    reference_title: "The diagnosis of severe combined immunodeficiency (SCID): The Primary Immune Deficiency Treatment Consortium (PIDTC) 2022 Definitions."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      strict isolation and anti-infectious prophylaxis until improvements in immunity are achieved
    explanation: >-
      Supports curating protective isolation and prophylaxis as the standard
      holding measure before definitive treatment.
- name: Allogeneic haematopoietic stem cell transplantation
  description: >-
    The only definitive treatment for the complete-deficiency form. A patient
    with a homozygous CD3E splice-site variant transplanted haploidentically
    from his mother developed normal T- and B-cell immunity and was followed for
    fifteen years. Engraftment was confined to the T-cell lineage, T-cell counts
    never reached normal, and naive T cells stayed low, which is the pattern
    that later allowed humoral immunity to fail.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: hematopoietic cell transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  target_mechanisms:
  - target: Arrest of Thymocyte Development
    treatment_effect: BYPASSES
    description: >-
      Donor progenitors carry wild-type CD3E, so thymopoiesis proceeds from
      donor-derived precursors; the patient's own precursors remain arrested.
    evidence:
    - reference: PMID:24515816
      reference_title: "Successful haploidentical hematopoietic stem cell transplantation in a patient with SCID due to CD3ε deficiency: need for IgG-substitution 6 years later."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Despite conditioning donor cell engraftment was confined to T cells, while all other blood cell lineages remained of patient origin (split chimerism). In spite of normal functions, T-cell numbers never reached normal levels and naïve CD45+RA+ T-cells remained low.
      explanation: >-
        Documents that only the T lineage is reconstituted, which is exactly the
        compartment the arrest affects, and that the reconstitution is partial.
  evidence:
  - reference: PMID:24515816
    reference_title: "Successful haploidentical hematopoietic stem cell transplantation in a patient with SCID due to CD3ε deficiency: need for IgG-substitution 6 years later."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report on a patient with SCID due to CD3ε deficiency treated by HLA-haploidentical stem cell transplantation (SCT) (donor: mother) 15 years ago which resulted in development of normal T- and B-cell immunity.
    explanation: >-
      The one long-term transplant outcome reported for this genotype.
- name: Immunoglobulin replacement therapy
  description: >-
    Regular IgG infusion for the antibody deficiency. It is needed before
    transplantation and, in the one long-term survivor, became necessary again
    six years afterwards when T-helper support for the patient's own B cells
    declined.
  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: Loss of T-Cell Help to B Cells
    treatment_effect: BYPASSES
    description: >-
      Replacement antibody substitutes for the switched, specific immunoglobulin
      the patient's unhelped B cells cannot make; the T-cell defect that causes
      the humoral failure is untouched.
    evidence:
    - reference: PMID:24515816
      reference_title: "Successful haploidentical hematopoietic stem cell transplantation in a patient with SCID due to CD3ε deficiency: need for IgG-substitution 6 years later."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        At 6 years after SCT the patient developed signs of humoral immunodeficiency, requiring regular substitution of IgG.
      explanation: >-
        The indication, arising specifically from the loss of T-cell help rather
        than from a B-cell defect.
  evidence:
  - reference: PMID:24515816
    reference_title: "Successful haploidentical hematopoietic stem cell transplantation in a patient with SCID due to CD3ε deficiency: need for IgG-substitution 6 years later."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The loss of B-cell function as observed in the patient was reflected by a lack of switched memory B cells. To rule out a primary role of CD3ε in B-cell function we studied expression of CD3E in B-cells which was found not to be expressed.
    explanation: >-
      Establishes that the antibody defect being replaced is secondary to lost
      T-cell help.
diagnosis:
- name: Newborn screening by T-cell receptor excision circle quantitation
  description: >-
    Measurement of TRECs in a dried blood spot. Because CD3epsilon deficiency
    blocks thymopoiesis outright, thymic output is absent and TRECs are
    undetectable, so the complete-deficiency form is detectable at birth by the
    universal screen. The hypomorphic form, in which T cells do develop, is not
    reliably detectable this way.
  results: Undetectable TRECs with normal kappa-deleting recombination excision circles.
  diagnosis_term:
    preferred_term: newborn screening
    term:
      id: NCIT:C81178
      label: Newborn Screening
  evidence:
  - reference: PMID:28597365
    reference_title: A novel pathogenic frameshift variant of CD3E gene in two T-B+ NK+ SCID patients from Turkey.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      T cell receptor excision circle (TREC) and kappa-deleting recombination excision circle (KREC) analyses were performed for T and B cell maturation. TRECs were not detected in both patients and the KREC copy numbers were similar to the other family members.
    explanation: >-
      The measured result in two genetically confirmed CD3E patients: absent
      TRECs with preserved B-cell output.
  - reference: PMID:36456361
    reference_title: "The diagnosis of severe combined immunodeficiency (SCID): The Primary Immune Deficiency Treatment Consortium (PIDTC) 2022 Definitions."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Universal NBS for SCID by enumerating T-cell receptor excision circles (TRECs) in dried blood spots collected at birth has radically altered how infants with SCID in the United States and most infants in Canada are now identified.
    explanation: >-
      Establishes TREC-based newborn screening as the route by which severe
      combined immunodeficiency is now identified.
- name: Lymphocyte immunophenotyping
  description: >-
    Flow cytometry for absolute CD3, CD4, CD8, CD19 and CD16/CD56 counts,
    together with surface TCR/CD3 density. The complete-deficiency result is
    absent T cells with normal or high B cells and present NK cells; the
    hypomorphic result is T cells present with markedly reduced surface
    receptor, so receptor density has to be measured and not just cell number.
  results: >-
    T-B+NK+ pattern with absent CD3+ cells, or preserved T cells with surface
    TCR/CD3 at about a tenth of normal density.
  diagnosis_term:
    preferred_term: flow cytometry
    term:
      id: NCIT:C16585
      label: Flow Cytometry
  evidence:
  - reference: PMID:15546002
    reference_title: Severe combined immunodeficiency caused by deficiency in either the delta or the epsilon subunit of CD3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We investigated the molecular mechanism underlying a severe combined immunodeficiency characterized by the selective and complete absence of T cells.
    explanation: >-
      The complete-deficiency immunophenotype.
  - reference: PMID:1370449
    reference_title: Structural analysis of low TCR-CD3 complex expression in T cells of an immunodeficient patient.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report on another immunodeficient patient whose T lymphocytes express the T cell receptor at one-tenth of normal fluorescence intensity and are not triggered to proliferate in vitro by anti-CD3 or anti-CD2 antibodies.
    explanation: >-
      The hypomorphic immunophenotype, which is a receptor-density measurement
      rather than a cell count.
- name: CD3E sequencing
  description: >-
    Molecular confirmation by targeted panel, exome or genome sequencing. CD3E
    is reached through severe combined immunodeficiency and
    inborn-error-of-immunity panels; in published cohorts it accounts for one or
    two patients at a time, so it is found by panel breadth rather than by
    clinical suspicion of this gene.
  results: Biallelic loss-of-function CD3E variants.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:32445296
    reference_title: Mutational landscape of severe combined immunodeficiency patients from Turkey.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In total, 24 disease-causing variants (17 known and 7 novel) were identified in 23 patients in 9 different SCID genes: RAG1 (n = 5), RAG2 (n = 2), ADA (n = 3), DCLRE1C (n = 2), NHEJ1 (n = 2), CD3E (n = 2), IL2RG (n = 3), JAK3 (n = 4) and IL7R (n = 1).
    explanation: >-
      Shows CD3E being reached as one gene among many on a severe combined
      immunodeficiency panel.
differential_diagnoses:
- name: Combined immunodeficiency due to CD3gamma deficiency
  description: >-
    The sibling chain of the same receptor complex, and the boundary this entry
    is drawn against. CD3gamma deficiency shares the biochemical lesion - an
    incomplete TCR/CD3 complex - but does not block thymocyte development:
    patients have normal absolute T-cell numbers with reduced surface receptor,
    and their dominant clinical problem is immune dysregulation and
    autoimmunity rather than infection. The asymmetry is not a matter of degree
    but of which chain is lost: CD3epsilon partners both CD3gamma and CD3delta,
    so losing it removes two dimers rather than one. The one point of genuine
    overlap is the hypomorphic end of the CD3epsilon spectrum, where reduced
    surface receptor with preserved T cells is also what the flow panel shows;
    there the two are distinguished by sequencing, not by immunophenotype.
  disease_term:
    preferred_term: combined immunodeficiency due to CD3gamma deficiency
    term:
      id: MONDO:0014276
      label: combined immunodeficiency due to CD3gamma deficiency
  distinguishing_features:
  - Normal absolute T-cell numbers rather than a developmental block
  - Autoimmunity, particularly thyroiditis and cytopenias, as the dominant problem
  - Biallelic CD3G rather than CD3E variants
  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 in CD3E deficiency and contrasts it with
      the partial immunodeficiency of CD3G deficiency. This is the same sentence
      the CD3gamma entry cites from its side of the boundary.
  - reference: PMID:17277165
    reference_title: Differential biological role of CD3 chains revealed by human immunodeficiencies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thus, the peripheral T lymphocyte pool was comparatively well preserved in human CD3gamma deficiencies despite poor thymus output or clinical outcome.
    explanation: >-
      Records the preserved peripheral T-cell pool in CD3gamma deficiency, the
      feature that CD3epsilon deficiency lacks.
- name: CD3delta and CD3zeta deficiencies
  description: >-
    The other two severe CD3 chain defects. All three produce the same T-B+NK+
    severe combined immunodeficiency and are indistinguishable on
    immunophenotype; only sequencing separates them. They are grouped together
    in MONDO under one T-B+ SCID concept for exactly that reason.
  disease_term:
    preferred_term: T-B+ severe combined immunodeficiency due to CD3delta/CD3epsilon/CD3zeta
    term:
      id: MONDO:0015703
      label: T-B+ severe combined immunodeficiency due to CD3delta/CD3epsilon/CD3zeta
  distinguishing_features:
  - Biallelic CD3D or CD247 rather than CD3E variants
  evidence:
  - reference: PMID:15546002
    reference_title: Severe combined immunodeficiency caused by deficiency in either the delta or the epsilon subunit of CD3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients and affected fetuses from 2 families were homozygous for a mutation in the CD3D gene, and patients from the third family were homozygous for a mutation in the CD3E gene.
    explanation: >-
      The study in which CD3D- and CD3E-deficient families presented with the
      same clinical and immunological picture and were separated only by
      sequencing.
- name: Other T-B+NK+ severe combined immunodeficiencies
  description: >-
    IL7R and PTPRC deficiency produce the same flow cytometry pattern and are
    commoner than CD3E; in published cohorts they are found alongside it on the
    same panels. Genetic testing is the discriminator.
  disease_term:
    preferred_term: severe combined immunodeficiency
    term:
      id: MONDO:0015974
      label: severe combined immunodeficiency
  distinguishing_features:
  - Causal variants in IL7R, PTPRC or another SCID gene rather than CD3E
  evidence:
  - reference: PMID:33040328
    reference_title: "Whole-exome sequencing of T(-) B(+) severe combined immunodeficiency in Egyptian infants, JAK3 predominance and novel variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      IL7Rα and CD3ε variants were found once, with a novel variant each.
    explanation: >-
      Shows IL7R and CD3E being distinguished within one clinically
      indistinguishable T-B+ SCID cohort by sequencing alone.
animal_models:
- name: Cd3e-deficient mouse
  species: Mouse
  genotype: Cd3e null (targeted mutation of the CD3-epsilon gene)
  publication: PMID:7588594
  description: >-
    Mice carrying a targeted mutation of the CD3-epsilon gene. This is the model
    that supplies the arrest stage the human disorder is described by, since no
    patient thymus has ever been examined. Thymocytes stop at the CD44-low
    CD25-positive triple-negative stage, at the same control point as
    RAG-deficient thymocytes, despite having rearranged TCRbeta normally.
  modeled_mechanisms:
  - target: Arrest of Thymocyte Development
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      The knockout reproduces the complete developmental block that defines the
      human null phenotype, and localises it to the pre-TCR checkpoint.
    limitations: >-
      Fidelity is moderate rather than high because the human arrest stage was
      never established: no thymus was available from the CD3epsilon-deficient
      family, so the correspondence is between the mouse's arrest and the human
      outcome, not between two measured arrest points. The species divergence
      seen for CD3gamma - where the mouse knockout is far more severe than the
      human disorder - is a standing reason not to assume the stages match.
    readouts:
    - name: Thymocyte progression beyond the CD44-low CD25-positive stage
      target: Arrest of Thymocyte Development
      direction: ABOLISHED
      interpretation: >-
        Development stops at the pre-TCR checkpoint, identifying where CD3epsilon
        is required.
      evidence:
      - reference: PMID:7588594
        reference_title: Altered T cell development in mice with a targeted mutation of the CD3-epsilon gene.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          In the absence of intact CD3-epsilon subunit, thymocytes do not progress beyond the CD44-/lowCD25+ triple-negative stage and appear to be arrested at the very same developmental control point as RAG-deficient thymocytes.
        explanation: >-
          The measured arrest point.
    evidence:
    - reference: PMID:15546002
      reference_title: Severe combined immunodeficiency caused by deficiency in either the delta or the epsilon subunit of CD3.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        showing that CD3ε is essential for transduction of the PreTα/TCRβ receptor survival, proliferation, and progression signals
      explanation: >-
        The interpretation of the mouse result that the human account relies on.
  - target: Blocked Pre-TCR Signaling at Beta-Selection
    relationship: MEASURES
    fidelity: MODERATE
    description: >-
      The knockout separates recombination from signalling: TCRbeta
      rearrangement proceeds and full-length transcripts are made, so what fails
      is the receptor that reads the rearrangement, not the rearrangement
      itself. Reconstitution with a CD3epsilon transgene rescues development from
      a small subpopulation of prothymocytes, showing the block is
      CD3epsilon-dependent and reversible.
    limitations: >-
      A gene-targeted mouse rather than a patient allele; the readouts are
      thymocyte subset composition and transcript levels rather than any clinical
      outcome, and the transgene rescue uses non-physiological expression.
    readouts:
    - name: TCRbeta gene rearrangement and transcript production in arrested thymocytes
      target: Blocked Pre-TCR Signaling at Beta-Selection
      direction: UNCHANGED
      interpretation: >-
        Rearrangement is intact in the arrested thymocytes, placing the lesion at
        pre-TCR signalling rather than at V(D)J recombination.
      evidence:
      - reference: PMID:7588594
        reference_title: Altered T cell development in mice with a targeted mutation of the CD3-epsilon gene.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          CD3-epsilon-deficient thymocytes do rearrange their T cell receptor (TCR) beta gene segments and produce low levels of full-length TCR beta transcripts.
        explanation: >-
          The measurement that dissociates recombination from the block.
    - name: Thymocyte maturation after CD3epsilon transgene reconstitution
      target: Blocked Pre-TCR Signaling at Beta-Selection
      direction: RESTORED
      interpretation: >-
        Restoring CD3epsilon restores progression through the checkpoint,
        confirming the block is caused by its absence.
      evidence:
      - reference: PMID:9885898
        reference_title: Expression of a CD3 epsilon transgene in CD3 epsilon(null) mice does not restore CD3 gamma and delta expression but efficiently rescues T cell development from a subpopulation of prothymocytes.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          However, a very small fraction of prothymocytes that expressed CD3 gamma and delta was rescued upon reconstitution of the CD3 epsilon transgene. Remarkably, this rescue led to a very efficient differentiation and maturation of thymocytes, resulting in a significant T cell population in the periphery.
        explanation: >-
          The rescue experiment.
    evidence:
    - reference: PMID:9885898
      reference_title: Expression of a CD3 epsilon transgene in CD3 epsilon(null) mice does not restore CD3 gamma and delta expression but efficiently rescues T cell development from a subpopulation of prothymocytes.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In the epsilon(delta P) mice, T cell development is arrested at the double-negative stage and targeting the CD3 epsilon gene caused severe inhibition of CD3 gamma and delta gene expression.
      explanation: >-
        Establishes the model and the arrest it produces.
  evidence:
  - reference: PMID:7588594
    reference_title: Altered T cell development in mice with a targeted mutation of the CD3-epsilon gene.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Finally, the absence of intact CD3-epsilon polypeptides had no discernible effect on the completion of TCR gamma and TCR delta gene rearrangements, emphasizing that they are probably not subjected to the same epigenetic controls as those operating on the expression of TCR alpha and beta genes.
    explanation: >-
      A limitation on how far this model speaks to the human gamma-delta
      compartment, which in patients is also lost.
- name: CD3epsilon basic-rich stretch mutant mouse
  species: Mouse
  genotype: Cd3e with a non-functional cytoplasmic basic-rich stretch (CD3e-BRS)
  publication: PMID:24899501
  description: >-
    A separation-of-function allele rather than a null. The CD3epsilon
    cytoplasmic tail associates with the plasma membrane through a basic-rich
    stretch; disabling that association leaves the chain in place but
    dysregulates signalling. The model matters here because it shows that
    CD3epsilon contributes more than assembly, which is the part of its role
    that the null cannot dissect.
  modeled_mechanisms:
  - target: Blocked Pre-TCR Signaling at Beta-Selection
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      The mutant shows reduced thymic cellularity and a limited double-negative
      3 to double-negative 4 transition, so it perturbs the same checkpoint the
      human disorder blocks - but by excessive rather than absent signalling.
    limitations: >-
      The direction of the lesion is opposite to the patients'. Here the
      transition fails because DN4 signalling is enhanced and drives cell death
      and receptor downregulation; in CD3epsilon deficiency the receptor cannot
      signal at all. No patient has been reported with a variant confined to the
      basic-rich stretch, so this allele has no human counterpart.
    readouts:
    - name: Double-negative 3 to double-negative 4 thymocyte transition
      target: Blocked Pre-TCR Signaling at Beta-Selection
      direction: DECREASED
      interpretation: >-
        Confirms that the beta-selection transition is sensitive to the
        signalling properties of CD3epsilon and not only to its presence.
      evidence:
      - reference: PMID:24899501
        reference_title: Membrane association of the CD3ε signaling domain is required for optimal T cell development and function.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          In this study, we show that mice lacking a functional CD3ε-BRS exhibited substantial reductions in thymic cellularity and limited CD4- CD8- double-negative (DN) 3 to DN4 thymocyte transition, because of enhanced DN4 TCR signaling resulting in increased cell death and TCR downregulation in all subsequent populations.
        explanation: >-
          The measured effect on the same developmental transition, together with
          the mechanism, which is the opposite of the patients'.
    evidence:
    - reference: PMID:24899501
      reference_title: Membrane association of the CD3ε signaling domain is required for optimal T cell development and function.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Collectively, these results indicate that membrane association of the CD3ε signaling domain is required for optimal thymocyte development and peripheral T cell function.
      explanation: >-
        The model's conclusion about the signalling role of CD3epsilon in
        development.
discussions:
- discussion_id: gap_cd3e_human_arrest_stage
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    At what stage does thymocyte development actually arrest in human
    CD3epsilon deficiency, and is the mouse arrest point a safe stand-in for it?
  attaches_to:
  - pathophysiology#Arrest of Thymocyte Development
  - pathophysiology#Blocked Pre-TCR Signaling at Beta-Selection
  rationale: >-
    Every account of this disorder places the block at beta-selection, and every
    such account traces back to the Cd3e-null mouse. The authors who first
    identified CD3epsilon deficiency said so explicitly: no thymus material was
    available from the affected family, so the stage could not be assessed, and
    the mouse arrest was offered as a possibility rather than a finding. What is
    established in humans is only the outcome - absence of CD3epsilon abrogates
    T-cell development. The gap matters because the neighbouring chain gives a
    documented precedent for the mouse being wrong about a human CD3 chain:
    Cd3g-null mice have severe combined immunodeficiency while CD3gamma-deficient
    patients keep normal T-cell numbers, a discordance with a known structural
    basis in the composition of the human gamma-delta receptor. The same paper
    that describes the human CD3delta thymus reports the arrest there at entry to
    the double-positive stage rather than at the double-negative stage the mouse
    shows for CD3epsilon, so the two chains do not even arrest at the same point
    within one species. No human thymus from a CD3epsilon-deficient patient or
    fetus has been examined since.
  evidence:
  - reference: PMID:15546002
    reference_title: Severe combined immunodeficiency caused by deficiency in either the delta or the epsilon subunit of CD3.
    supports: NO_EVIDENCE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It was not possible to assess at what stage the CD3 ε deficiency blocked T cell differentiation in patients from family I, as no thymus material was available.
    explanation: >-
      States that the human arrest stage was not determined, which is the gap.
  - reference: PMID:7588594
    reference_title: Altered T cell development in mice with a targeted mutation of the CD3-epsilon gene.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In the absence of intact CD3-epsilon subunit, thymocytes do not progress beyond the CD44-/lowCD25+ triple-negative stage and appear to be arrested at the very same developmental control point as RAG-deficient thymocytes.
    explanation: >-
      The mouse result that stands in for the unmeasured human one.
- discussion_id: gap_cd3e_genotype_severity
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Does residual CD3epsilon protein reliably predict a milder course, and how
    much is enough to permit T-cell development?
  attaches_to:
  - genetic#CD3E
  - pathophysiology#Residual Unstable CD3epsilon in Partial Deficiency
  rationale: >-
    The reported spectrum implies a dose relationship: truncating and splice
    alleles that abolish the chain give severe combined immunodeficiency, while
    the two hypomorphic alleles in the family in which CD3E was first implicated
    left an unstable chain, about a tenth of the normal surface receptor, and a
    T-cell compartment that existed. But the inference rests on one hypomorphic
    family against a handful of null families, and nobody has measured residual
    CD3epsilon protein across a series and related it to outcome. The threshold
    question is open in both directions: how much residual chain permits
    thymopoiesis, and whether a patient with an intermediate amount would present
    as leaky severe combined immunodeficiency, as a milder combined
    immunodeficiency, or as something resembling CD3gamma deficiency. It is a
    practical question, because the answer determines whether a newly diagnosed
    infant should be transplanted urgently, and because newborn screening detects
    the null form but would not reliably detect a hypomorphic one.
  evidence:
  - reference: PMID:1370449
    reference_title: Structural analysis of low TCR-CD3 complex expression in T cells of an immunodeficient patient.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report on another immunodeficient patient whose T lymphocytes express the T cell receptor at one-tenth of normal fluorescence intensity and are not triggered to proliferate in vitro by anti-CD3 or anti-CD2 antibodies.
    explanation: >-
      The mild end of the spectrum, with T cells present and quantified residual
      receptor.
  - reference: PMID:17277165
    reference_title: Differential biological role of CD3 chains revealed by human immunodeficiencies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In contrast, all reported human complete CD3delta (or CD3epsilon) deficiencies are in infants with life-threatening SCID and very severe alphabeta and gammadelta T lymphocytopenia.
    explanation: >-
      The severe end, stated as holding for every reported complete deficiency,
      which is what makes the qualifier "complete" load-bearing.
clinical_trials: []
datasets: []
notes: >-
  Scope and boundary with CD3gamma deficiency. This entry and
  Combined_Immunodeficiency_Due_To_CD3gamma_Deficiency describe adjacent chains
  of one receptor complex and were curated to agree on where the line falls.
  That entry confined the CD3delta/epsilon/zeta literature to its
  differential-diagnoses section in order to protect the CD3gamma entity; here
  the polarity is reversed and some of that literature is primary. The shared
  claim, cited from PMID:16264327 on both sides, is that homozygous CD3D and
  CD3E mutations block T-cell development and give early-onset severe combined
  immunodeficiency, whereas CD3G deficiency causes a partial T-cell
  immunodeficiency. Nothing here contradicts that. What this entry adds, and
  what the CD3gamma entry had no reason to consider, is that CD3epsilon
  deficiency is not uniformly complete: hypomorphic alleles produce reduced
  rather than absent surface receptor with T cells present, which is the one
  presentation that could be mistaken for CD3gamma deficiency on
  immunophenotype. The distinction there is the gene, not the flow panel.

  Evidence-source convention. Sentences whose subject is a patient's clinical
  state, immunophenotype, immunoglobulins, thymic output or genotype are graded
  HUMAN_CLINICAL. Measurements requiring culture or molecular work on patient
  material - Northern blot of CD3E transcripts, in vitro proliferation assays -
  are graded IN_VITRO. Mouse data are MODEL_ORGANISM, including sentences in
  human papers whose subject is the mouse. The IUIS classification table and the
  PIDTC consensus definitions are OTHER, since neither reports primary study
  data.

  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 separated from their preceding token ("CD3 ε") in
  the 2004 JCI article, and column runs such as "Very lowN ormalL ow" in the
  IUIS table where a line break fell inside a word. Entry prose uses ordinary
  spellings throughout.

  Two case reports deliberately not cited. PMID:32016651 (biallelic form of a
  known CD3E mutation) and PMID:33655388 (novel CD3Z and CD3E deficiency in two
  unrelated females) are the two most recent CD3E case reports, and both are
  journal letters whose PubMed records carry no abstract; fetching either yields
  a cache whose content is reported unavailable. Neither can therefore carry an
  evidence item without violating the exact-quote rule, and a title is not a
  finding. Their
  clinical content is represented instead through PMID:15546002 and
  PMID:28597365, which report the same phenotype with quotable text.

  IUIS release. The 2022 update (PMID:35748970) is cited rather than the 2024
  one, deliberately: the CD3gamma entry uses 2022, and the value of the
  classification here is partly that the two adjacent CD3 entries can be read
  against one row each of the same table.

  Grouping membership is out of scope for this entry. Neither this entry nor the
  CD3gamma entry is currently a member of the combined-immunodeficiency or
  inborn-errors-of-immunity groupings; adding them touches shared files and
  belongs in its own change.

  Not curated. No biochemical block: the laboratory findings in this disorder
  are cell counts and receptor density, which are curated as phenotypes and
  under diagnosis, rather than analyte measurements with reference intervals. No
  environmental entry: nothing initiates this Mendelian disorder, and the
  opportunistic pathogens that determine its course act on an immune system that
  has already failed rather than on a mechanism node. No datasets or clinical
  trials specific to CD3epsilon deficiency were identified; the transplant and
  gene-therapy trials returned by a search are severe-combined-immunodeficiency
  cohorts defined by other genes.
📚

References & Deep Research

References

15
PMID:15546002
Severe combined immunodeficiency caused by deficiency in either the delta or the epsilon subunit of CD3.
No top-level findings curated for this source.
PMID:8490660
Independent mutations of the human CD3-epsilon gene resulting in a T cell receptor/CD3 complex immunodeficiency.
No top-level findings curated for this source.
PMID:1370449
Structural analysis of low TCR-CD3 complex expression in T cells of an immunodeficient patient.
No top-level findings curated for this source.
PMID:17277165
Differential biological role of CD3 chains revealed by human immunodeficiencies.
No top-level findings curated for this source.
PMID:16264327
CD3 deficiencies.
No top-level findings curated for this source.
PMID:28597365
A novel pathogenic frameshift variant of CD3E gene in two T-B+ NK+ SCID patients from Turkey.
No top-level findings curated for this source.
PMID:24515816
Successful haploidentical hematopoietic stem cell transplantation in a patient with SCID due to CD3ε deficiency: need for IgG-substitution 6 years later.
No top-level findings curated for this source.
PMID:39287664
Sequence variants underlying severe combined immunodeficiency and leukocyte adhesion deficiency type 1 in six consanguineous families.
No top-level findings curated for this source.
PMID:33040328
Whole-exome sequencing of T(-) B(+) severe combined immunodeficiency in Egyptian infants, JAK3 predominance and novel variants.
No top-level findings curated for this source.
PMID:32445296
Mutational landscape of severe combined immunodeficiency patients from Turkey.
No top-level findings curated for this source.
PMID:36456361
The diagnosis of severe combined immunodeficiency (SCID): The Primary Immune Deficiency Treatment Consortium (PIDTC) 2022 Definitions.
No top-level findings curated for this source.
PMID:7588594
Altered T cell development in mice with a targeted mutation of the CD3-epsilon gene.
No top-level findings curated for this source.
PMID:9885898
Expression of a CD3 epsilon transgene in CD3 epsilon(null) mice does not restore CD3 gamma and delta expression but efficiently rescues T cell development from a subpopulation of prothymocytes.
No top-level findings curated for this source.
PMID:24899501
Membrane association of the CD3ε signaling domain is required for optimal T cell development and function.
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

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

Evaluations and curation notes (1)

Create: Immunodeficiency 18 (CD3E deficiency, MONDO:0014278) · 2026-09-02T02:00:10Z · View source

De novo curation of immunodeficiency 18 (CD3E) from the stubs/ queue, claim issue #10462. entry_type recorded as DISEASE: one conserved pathograph (loss of CD3epsilon -> failed pre-TCR/TCR assembly -> blocked beta-selection -> thymocyte arrest), with a second, genotype-dependent hypomorphic branch curated explicitly rather than flattened away. Boundary with the sibling entry Combined_Immunodeficiency_Due_To_CD3gamma_Deficiency (curated 2026-08-28): that entry confined the CD3delta/epsilon/zeta literature to differential_diagnoses to protect the CD3gamma entity; here that literature is primary. Both sides cite the same sentence from PMID:16264327 - homozygous CD3D/CD3E mutations block T-cell development, in contrast with the partial immunodeficiency of CD3G. This entry adds only that CD3epsilon deficiency is not uniformly complete, and states that the hypomorphic presentation is separated from CD3gamma deficiency by the gene rather than by immunophenotype. The CD3gamma entry was read but not edited. Severity spectrum modelled as two branches off the variant node rather than as a single severity claim: a null branch (Loss of the CD3epsilon Chain -> ... -> Absent Peripheral T Cells) and a hypomorphic branch (Residual Unstable CD3epsilon in Partial Deficiency -> Reduced Surface TCR/CD3 with Impaired T-Cell Activation), both converging on Failure of Cellular Immunity. The hypomorphic branch rests on the original 1992/1993 family (PMID:1370449, PMID:8490660). Two discussions: HUMAN_MODEL_MISMATCH on the arrest stage, which in humans was never measured (PMID:15546002 states no thymus material was available) and is carried over from the Cd3e-null mouse; and a KNOWLEDGE_GAP on whether residual protein predicts course. Deep research: Falcon report research/Immunodeficiency_18-deep-research-falcon.md, preflight-dr PASS against MONDO:0014278 (CD3E mentioned 77 times, top gene). Used as leads only; every snippet re-verified against its cached reference. Two DR leads were dropped for lack of a resolvable citation. Validation (all exit 0): just validate (schema, terms, 64/64 snippets verified), check-duplicate-keys, check-entity-refs, check-causal-targets, plus the whole-KB advisory gates. NCIT:C16360 was drafted for newborn screening and corrected to NCIT:C81178 after OLS resolved C16360 to 'Book'.

Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 42 citations 2026-09-01T18:44:01.669997

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: immunodeficiency 18 (CD3epsilon deficiency, biallelic CD3E loss of function)
  • MONDO ID: MONDO:0014278 (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on immunodeficiency 18 (CD3epsilon deficiency, biallelic CD3E loss of function) 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

Present this section as an ordered causal chain first, then the detail below. Open with a numbered sequence of mechanistic steps running from the initiating lesion (mutation, exposure, infection) to the clinical manifestation, one step per line, each naming what it causes next. State the causal verb explicitly ("leads to", "results in") and say where a step is inferred rather than demonstrated. Where the mechanism branches, show the branch. The categories below are a checklist of what to cover within those steps, not the organizing structure — a step may draw on several of them, and a category may contribute to several steps.

  • 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

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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

Immunodeficiency 18 due to biallelic CD3E loss of function

Scope and evidence standard. Immunodeficiency 18 is exceptionally rare; its evidence base consists chiefly of individual families, case reports, and small SCID cohorts. Consequently, frequencies calculated from published cases are highly ascertainment-biased. Statements explicitly marked SCID-wide extrapolation derive from broader severe combined immunodeficiency evidence rather than CD3E-specific trials or cohorts.

Executive summary

Immunodeficiency 18 is an autosomal-recessive inborn error of immunity caused by biallelic loss-of-function variants in CD3E, encoding the CD3ε component of the pre-T-cell receptor (pre-TCR) and mature TCR–CD3 complexes. Complete loss usually produces congenital T−B+NK+ SCID, with absent or nearly absent αβ and γδ T cells, preserved B- and NK-cell development, secondary failure of antibody production, and life-threatening infections beginning in early infancy. Hypomorphic alleles retaining residual CD3ε can produce a milder combined immunodeficiency rather than classic SCID. The disease is curable in principle by hematopoietic stem-cell transplantation (HSCT), but no CD3E-specific gene therapy or interventional trial was identified. TREC newborn screening, rapid molecular diagnosis, infection prevention, and transplantation before infection are the most important current implementations. (notarangelo2024geneticallydetermineddefectsof pages 4-6, basile2004severecombinedimmunodeficiency pages 1-2, basile2004severecombinedimmunodeficiency pages 3-4, fuehrer2014successfulhaploidenticalhematopoietic pages 1-2)

Domain Curated finding Evidence scope Suggested ontology/identifier
Disease identity Immunodeficiency 18 is a Mendelian inborn error of immunity caused by biallelic loss-of-function of CD3E, typically presenting as T−B+NK+ severe combined immunodeficiency (SCID). (OpenTargets Search: immunodeficiency 18-CD3E, basile2004severecombinedimmunodeficiency pages 1-2, notarangelo2024geneticallydetermineddefectsof pages 4-6) Human disease-level resources + primary human cases MONDO:0014278; OMIM phenotype: 615615
Gene Causal gene: CD3E (CD3 epsilon subunit of T-cell receptor complex); Open Targets links CD3E to immunodeficiency 18. (OpenTargets Search: immunodeficiency 18-CD3E) Curated disease-target association + literature-backed evidence CD3E; Ensembl: ENSG00000198851
Inheritance Inheritance is autosomal recessive; early reports showed affected children from consanguineous families and unaffected heterozygous relatives. (basile2004severecombinedimmunodeficiency pages 1-2, basile2004severecombinedimmunodeficiency pages 3-4) Primary human families HP:0000007 Autosomal recessive inheritance
Core immunophenotype Typical immune phenotype is absence or near-absence of peripheral T cells with preserved/elevated B cells and present NK cells: T−B+NK+. Low/absent IgA and low IgG after maternal IgG wanes are reported. (basile2004severecombinedimmunodeficiency pages 1-2, basile2004severecombinedimmunodeficiency pages 2-3, notarangelo2024geneticallydetermineddefectsof pages 4-6) Primary human cases HP:0005403 Absence of T cells; HP:0002841 Hypogammaglobulinemia; SCID phenotype
Key infectious/clinical phenotypes Reported manifestations include early-onset diarrhea, pneumonitis/pneumonia, oral/perineal candidiasis, CMV/adenovirus/EBV infections, failure to thrive, and lymphopenia. (basile2004severecombinedimmunodeficiency pages 4-6, basile2004severecombinedimmunodeficiency pages 1-2) Primary human cases HP:0002014 Diarrhea; HP:0006532 Oral candidiasis; HP:0006538 Recurrent pneumonia; HP:0001875 Neutropenia not core/optional; HP:0001888 Lymphopenia; HP:0001508 Failure to thrive
Representative variant 1 c.128_129del in exon 5 (legacy description: “homozygous 2-bp deletion at nucleotide 128”) causes frameshift with downstream premature stop; associated with complete CD3ε deficiency in family I. (basile2004severecombinedimmunodeficiency pages 2-3, basile2004severecombinedimmunodeficiency pages 4-6) Primary human molecular report CD3E loss-of-function variant
Representative variant 2 c.49+1G>C (NM_000733.3), homozygous donor splice-site variant in intron 2; abolishes exon 2 including the start codon and is functionally a null mutation. (fuehrer2014successfulhaploidenticalhematopoietic pages 1-2, fuehrer2014successfulhaploidenticalhematopoietic pages 2-3, fuehrer2014successfulhaploidenticalhematopoietic pages 4-5, fuehrer2014successfulhaploidenticalhematopoietic media 0f49bd22) Primary human molecular + post-transplant follow-up CD3E splice donor LoF
Representative variant 3 c.269T>A, p.Leu90Ter, a novel nonsense variant, was reported in an Egyptian T-B+ SCID patient. (hawary2021wholeexomesequencingof pages 9-12, hawary2021wholeexomesequencingof pages 7-9) Cohort report; limited single-patient detail in available text CD3E nonsense LoF
Turkish variant note A novel pathogenic CD3E frameshift was reported in Turkish patients, but the exact HGVS was not available in the retrieved full text; do not invent nomenclature. (hawary2021wholeexomesequencingof pages 12-14, firtina2020mutationallandscapeof pages 6-7, firtina2020mutationallandscapeof pages 4-5) Secondary mention within cohort literature CD3E pathogenic frameshift, HGVS unavailable here
Mechanism Biallelic CD3E LoF impairs assembly/signaling of the pre-TCR/TCR-CD3 complex, leading to failed thymocyte development and profound deficiency of αβ and γδ T cells; human stage of block is inferred for complete CD3E loss from mouse and related human data. (li2009theimportanceof pages 36-40, malissen1995alteredtcell pages 1-2, recio2007differentialbiologicalrole pages 1-2, basile2004severecombinedimmunodeficiency pages 4-6) Human + mouse; some human-stage detail inferred GO:0042110 T cell activation; GO:0045058 T cell selection; CL:0000084 T cell; UBERON:0002370 thymus
Diagnosis Diagnosis rests on TREC-based newborn screening, confirmatory lymphocyte subsets (CD3/CD4/CD8, B, NK), naïve/memory T-cell phenotyping, proliferation testing, maternal engraftment studies, and molecular testing (panel/WES/WGS). SCID-wide extrapolation. (dvorak2023thediagnosisof pages 5-7, notarangelo2024geneticallydetermineddefectsof pages 4-6, dvorak2023thediagnosisof pages 3-5) SCID-wide consensus/guideline extrapolation, not CD3E-specific validation PIDTC 2022 SCID definitions; TREC screening workflow
Treatment Definitive therapy is hematopoietic stem cell transplantation (HSCT). One CD3E-deficient patient had long-term survival after haploidentical SCT with split chimerism but later required IVIG for humoral deficiency; early historical cases often died pre/post-transplant. No CD3E-specific gene therapy found. (fuehrer2014successfulhaploidenticalhematopoietic pages 1-2, fuehrer2014successfulhaploidenticalhematopoietic pages 2-3, fuehrer2014successfulhaploidenticalhematopoietic pages 4-5, basile2004severecombinedimmunodeficiency pages 4-6) Primary CD3E cases + SCID practice context NCIT: Hematopoietic Stem Cell Transplantation; Intravenous Immune Globulin
Prognosis Untreated SCID is often fatal in infancy; for SCID broadly, outcomes are best with diagnosis by newborn screening and HSCT before 3.5 months and before active infection. Historical CD3E cases had high mortality, but long-term survival after SCT is possible. SCID-wide extrapolation for timing/survival rates. (notarangelo2024geneticallydetermineddefectsof pages 4-6, mongkonsritragoon2023positivenewbornscreening pages 1-2, soomann2024reducingmortalityand pages 1-2, fuehrer2014successfulhaploidenticalhematopoietic pages 2-3) Mixed: primary CD3E + SCID-wide outcomes Prognostic factors: age at HSCT; infection status
Prevention/supportive care While awaiting definitive therapy: protective isolation, TMP-SMX for PCP prophylaxis after 30 days, IVIG, avoidance of live vaccines and unirradiated blood products, CMV risk mitigation, palivizumab seasonally. SCID-wide extrapolation. (notarangelo2024geneticallydetermineddefectsof pages 4-6, mongkonsritragoon2023positivenewbornscreening pages 1-2) SCID-wide management guidance NCIT/clinical terms: prophylaxis, immunoglobulin replacement
Mouse model Cd3e-null mice show early thymocyte developmental arrest at the CD44low CD25+ DN3 stage, supporting the causal role of CD3ε in pre-TCR signaling and thymocyte progression. (malissen1995alteredtcell pages 1-2, wang1998expressionofa pages 11-12, bettini2014membraneassociationof pages 1-2) Model organism evidence Mouse Cd3e knockout; GO:0070231 T cell apoptotic process (context-dependent); CL:0000791 thymocyte
Major gaps Extremely few published human cases; no robust CD3E-specific prevalence/incidence estimates, penetrance data, natural-history cohorts, validated biomarker studies, or interventional trials specific to CD3E deficiency. Many management statements are extrapolated from broader SCID literature. (haskologlu2024newbornscreeningfor pages 5-6, firatoglu2025evaluationofpatients pages 1-3, notarangelo2024geneticallydetermineddefectsof pages 4-6, dvorak2023thediagnosisof pages 3-5) Evidence-gap statement Rare-disease evidence limitation

Table: This table condenses the core disease-identity, molecular, phenotypic, mechanistic, diagnostic, treatment, prognosis, model-organism, and evidence-gap facts for immunodeficiency 18 due to biallelic CD3E loss of function. It is designed as a compact knowledge-base curation aid and clearly labels where statements are extrapolated from broader SCID literature.

1. Disease information

Definition and identifiers

  • Preferred name: immunodeficiency 18.
  • Definition: autosomal-recessive CD3ε deficiency, generally manifesting as T−B+NK+ SCID when both alleles cause complete loss of function.
  • MONDO: MONDO:0014278.
  • OMIM phenotype: 615615; the causal gene is CD3E.
  • Gene identifiers: CD3E; Ensembl ENSG00000198851; approved name “CD3 epsilon subunit of T-cell receptor complex.” Open Targets links only CD3E to MONDO:0014278 and cites the foundational human reports, including PMID 8490660 and PMID 15546002. (OpenTargets Search: immunodeficiency 18-CD3E)
  • Synonyms: CD3 epsilon deficiency; CD3ε deficiency; CD3E-related SCID; severe combined immunodeficiency due to CD3ε deficiency; T−B+NK+ SCID due to CD3E deficiency.
  • ICD/MeSH: no uniquely specific ICD-10/ICD-11 or MeSH code was verified. Coding ordinarily falls under broader SCID/combined-immunodeficiency categories; a CD3E-specific molecular diagnosis should be retained separately.
  • Orphanet: a disease-specific Orphanet identifier was not established from the retrieved evidence and should not be inferred.

The foundational publication described five patients and two affected fetuses from three consanguineous families, but only one family had CD3E deficiency; the other two had CD3D deficiency. Its abstract states that the findings “extend the known molecular mechanisms underlying severe combined immunodeficiency to a new deficiency, i.e., CD3ε deficiency.” Published evidence is therefore aggregated at disease level from a very small number of deeply characterized individuals—not population EHR data. (basile2004severecombinedimmunodeficiency pages 1-2)

2. Etiology, risk, protection, and gene–environment interaction

The necessary cause is biallelic germline CD3E dysfunction. Complete null variants prevent production of functional CD3ε; splice, nonsense, and frameshift alleles are documented. Environmental exposures do not cause this Mendelian disorder.

  • Genetic risk: having two pathogenic CD3E alleles. For two heterozygous parents, each pregnancy has the standard autosomal-recessive probabilities: 25% affected, 50% carrier, and 25% unaffected/non-carrier.
  • Family-history/consanguinity: consanguinity increases the probability that both parents carry the same rare allele. The original complete-loss family involved third-cousin parents; Turkish SCID cohorts also show enrichment of recessive disease in consanguineous families. (basile2004severecombinedimmunodeficiency pages 4-6, haskologlu2024newbornscreeningfor pages 5-6, firtina2020mutationallandscapeof pages 4-5)
  • Sex: both sexes are affected; no sex-linked risk is expected.
  • Modifiers/protective alleles: no validated genetic modifier or protective CD3E allele is known. Residual expression from hypomorphic alleles modifies severity but is not “protective” in a population-health sense. An earlier compound-heterozygous patient retained residual correctly spliced CD3E and developed a milder phenotype, whereas complete absence produced SCID. (zapata2000cd3immunodeficiencies pages 4-7, basile2004severecombinedimmunodeficiency pages 3-4)
  • Environmental interaction: pathogens and live vaccines determine when and how severely the congenital defect becomes clinically apparent. CMV, adenovirus, EBV, fungi, and respiratory pathogens do not initiate the disease but exploit profound T-cell deficiency. Avoiding exposure and infection before HSCT markedly improves prognosis. (basile2004severecombinedimmunodeficiency pages 4-6, soomann2024reducingmortalityand pages 1-2)
  • Lifestyle/toxicant factors: smoking, diet, exercise, alcohol, pollution, radiation, and occupational exposure have no established etiologic role.

3. Phenotypes

Core phenotype profile

Phenotype Type and typical behavior Evidence/frequency limitations Suggested HPO term
Profound T-cell lymphopenia/absence Laboratory abnormality; congenital, severe, persistent without immune reconstitution Complete-loss cases had no or nearly no CD3+ cells; core feature Decreased/absent T-cell number; lymphopenia
Preserved B and NK cells Laboratory pattern; B cells often normal/high and NK cells present Defines T−B+NK+ phenotype Normal B-cell number; normal NK-cell number
Hypogammaglobulinemia Laboratory abnormality; becomes clearer after maternal IgG wanes IgG low after four months, IgA absent, IgM detectable in original series Hypogammaglobulinemia; decreased IgA
Candidiasis Infection/sign; often oral or perineal in infancy Repeated in historical cases; percentage unreliable Oral candidiasis; cutaneous candidiasis
Pneumonitis/pneumonia Clinical sign; severe, recurrent/progressive Frequent presenting and fatal manifestation Recurrent pneumonia; pneumonitis
Chronic/protracted diarrhea Symptom; early infancy, persistent Present in multiple foundational patients Chronic diarrhea
Failure to thrive Physical manifestation, secondary to infection/enteropathy Common across SCID; reported in CD3E cohorts Failure to thrive
Severe viral/opportunistic infection Clinical complication CMV, adenovirus, EBV and molluscum documented Recurrent opportunistic infections
Reduced thymic output Biomarker/physiology Expected low/absent TRECs; post-HSCT naïve T cells may remain low Abnormal thymic T-cell production

In the original complete-loss family, one infant presented at one month with diarrhea, pneumonitis, oral candidiasis, and lymphopenia (1,105 lymphocytes/µL), then died at three months with disseminated CMV. A sibling diagnosed at birth died 25 days after haploidentical BMT from disseminated adenovirus. Laboratory data showed CD3 cells at zero in the tested CD3E patient, CD19 cells 1,750/µL (70%), CD56 cells 300/µL (12%), IgG 360 mg/dL, IgA <4 mg/dL, and IgM 20 mg/dL. (basile2004severecombinedimmunodeficiency pages 2-3, basile2004severecombinedimmunodeficiency pages 1-2, basile2004severecombinedimmunodeficiency pages 4-6)

A hypomorphic compound-heterozygous patient differed substantially: recurrent Haemophilus influenzae pneumonia and otitis began around age two, and prophylactic antibiotics plus IVIG kept the child infection-free through age seven. This demonstrates genotype-dependent expressivity and cautions against assigning classic SCID to every biallelic CD3E genotype. (zapata2000cd3immunodeficiencies pages 7-9, zapata2000cd3immunodeficiencies pages 4-7)

No CD3E-specific EQ-5D, SF-36, PROMIS, behavioral, or neuropsychiatric study exists. Before definitive treatment, isolation, repeated hospitalization, diarrhea, growth failure, and infection substantially impair development and family life; after successful HSCT, ordinary functioning is possible, although chronic IVIG and follow-up may remain necessary. (fuehrer2014successfulhaploidenticalhematopoietic pages 1-2, fuehrer2014successfulhaploidenticalhematopoietic pages 2-3)

4. Genetic and molecular information

CD3E, at chromosome 11q23.3, has nine exons and encodes a type-I membrane component of the TCR–CD3 complex. The disorder is germline, not somatic. No recurrent aneuploidy, translocation, inversion, disease-specific methylation signature, or validated modifier gene has been reported. (hawary2021wholeexomesequencingof pages 9-12)

Reported representative alleles

  1. Homozygous two-base deletion at nucleotide 128 in exon 5—reported in legacy nomenclature and often rendered c.128_129del depending on transcript normalization. It causes a frameshift at residue 43 and a stop 13 residues later, predicting truncation within the extracellular region and complete CD3ε deficiency. It segregated from the heterozygous father; maternal DNA was unavailable. (basile2004severecombinedimmunodeficiency pages 2-3)
  2. NM_000733.3:c.49+1G>C, homozygous. This canonical splice-donor variant removes exon 2, including the translation start codon. No proposed alternative 20-kDa product was detected, supporting a null effect. Both parents and a healthy sibling were heterozygous. (fuehrer2014successfulhaploidenticalhematopoietic pages 2-3, fuehrer2014successfulhaploidenticalhematopoietic pages 4-5)
  3. c.269T>A, p.Leu90Ter, homozygous nonsense variant in an Egyptian patient, predicting truncation at amino acid 90. (hawary2021wholeexomesequencingof pages 9-12, hawary2021wholeexomesequencingof pages 7-9)
  4. A pathogenic homozygous frameshift CD3E allele was found in two Turkish T−B+NK+ SCID patients. The exact HGVS expression was unavailable in the retrieved primary text and should be curated directly from Fırtına et al., Immunogenetics 2017, DOI: https://doi.org/10.1007/s00251-017-1005-7, before database entry. In a later 38-patient Turkish SCID cohort, two CD3E cases comprised 5.2% of that selected cohort: a three-month-old female who died without HSCT and a two-month-old male alive after HSCT. This is not a population prevalence estimate. (firtina2020mutationallandscapeof pages 4-5, firtina2020mutationallandscapeof pages 6-7)
  5. An earlier compound-heterozygous genotype consisted of a paternal nonsense allele converting a tryptophan codon to stop and a maternal intron-7 splice-site substitution causing near-complete exon-7 skipping. Residual normal splicing apparently permitted T-cell development and a milder combined immunodeficiency. (zapata2000cd3immunodeficiencies pages 4-7, basile2004severecombinedimmunodeficiency pages 3-4)

The pathogenic mechanism for classic disease is loss of function. Allele frequencies were not supplied in the retrieved papers; the early truncating alleles were absent from more than 90 control chromosomes, but contemporary gnomAD frequencies and current ClinVar classifications should be checked variant by variant rather than assumed. (basile2004severecombinedimmunodeficiency pages 2-3)

5. Environmental and infectious information

No toxin, radiation, pollutant, occupational, dietary, or behavioral cause is established. Relevant agents are secondary infectious threats: CMV, EBV, adenovirus, Candida, Aspergillus, Pneumocystis jirovecii, BCG, and common respiratory/bacterial pathogens. In historical CD3E cases, disseminated CMV and adenovirus were fatal; BCGitis occurred in the long-term transplant survivor before immune reconstitution. (basile2004severecombinedimmunodeficiency pages 4-6, fuehrer2014successfulhaploidenticalhematopoietic pages 2-3)

6. Mechanism and pathophysiology

Ordered causal chain

  1. Biallelic pathogenic CD3E variants lead to absent or markedly reduced functional CD3ε protein.
  2. Loss of CD3ε leads to defective assembly, surface transport, and signaling of CD3γε/CD3δε-containing pre-TCR and mature TCR complexes.
  3. Defective pre-TCR signaling leads to failure of β-selection-associated survival, proliferation, and progression of developing thymocytes; the precise arrest stage in complete human CD3E deficiency is inferred primarily from Cd3e-null mice, because affected human thymus was unavailable.
  4. Failed thymopoiesis results in absent or nearly absent mature αβ and γδ T cells and profoundly reduced thymic output/TRECs, while B- and NK-cell development remains largely intact.
  5. Loss of helper and cytotoxic T-cell function leads to two downstream branches:
  6. cellular-immunity failure leads to opportunistic, viral, fungal, and recurrent respiratory/gastrointestinal infection;
  7. loss of T-cell help to B cells leads to impaired class switching, specific-antibody production, and hypogammaglobulinemia despite preserved B-cell counts.
  8. Uncontrolled infection and enteropathy lead to pneumonitis, diarrhea, failure to thrive, disseminated infection, organ injury, and death unless immune reconstitution is achieved. (malissen1995alteredtcell pages 1-2, recio2007differentialbiologicalrole pages 1-2, notarangelo2024geneticallydetermineddefectsof pages 4-6, basile2004severecombinedimmunodeficiency pages 1-2, basile2004severecombinedimmunodeficiency pages 4-6)

The normal TCR–CD3 complex comprises an antigen-binding αβ or γδ heterodimer associated with CD3γε, CD3δε, and ζζ signaling dimers. Ligand-induced signaling involves Src-family kinases LCK/FYN, phosphorylation of CD3 immunoreceptor tyrosine-based activation motifs, recruitment of ZAP70, and downstream LAT/SLP76 signaling. CD3ε also has structural and membrane-association functions: mice with a disrupted basic-rich stretch had abnormal DN3→DN4 progression, excessive signaling/apoptosis, impaired positive selection, and weak influenza responses even when the ITAM itself was intact. (bettini2014membraneassociationof pages 1-2, recio2007differentialbiologicalrole pages 1-2)

Cd3e-null mice arrest at the CD44-low/CD25-positive triple-negative/DN3 checkpoint, similar to RAG-deficient thymocytes, despite TCRβ rearrangement. This experimentally supports a role in pre-TCR surveillance of productive TCRβ rearrangement. Human arrest at the same stage remains plausible but not directly demonstrated. (malissen1995alteredtcell pages 1-2, basile2004severecombinedimmunodeficiency pages 3-4)

Suggested ontology annotations: GO: T-cell receptor signaling pathway; pre-TCR signaling; T-cell differentiation in thymus; β-selection; αβ T-cell differentiation; γδ T-cell differentiation; T-cell activation; positive T-cell selection; immunoglobulin class switching. Cell Ontology: hematopoietic stem cell, T-cell lineage committed progenitor, DN3 thymocyte, double-positive thymocyte, naïve αβ T cell, γδ T cell, B cell, NK cell, thymic epithelial cell. No disease-specific metabolomic, lipidomic, spatial-transcriptomic, single-cell, proteomic, or epigenomic profile was identified.

7. Anatomical structures affected

The thymus is the primary organ of pathogenesis; the causal lesion is intrinsic to hematopoietic T-lineage precursors rather than thymic stroma. Peripheral blood and lymphoid tissues consequently lack mature T cells. B cells remain in lymph nodes, but T-cell paracortical zones are depleted. Secondary injury affects lungs, gastrointestinal tract, skin/mucosa, liver, and other infection-involved organs. There is no lateralization. (basile2004severecombinedimmunodeficiency pages 1-2, basile2004severecombinedimmunodeficiency pages 4-6)

Suggested UBERON terms include thymus (UBERON:0002370), blood, lymph node, lung, gastrointestinal tract, skin, and liver. Relevant subcellular locations are plasma membrane/TCR complex, endoplasmic reticulum and Golgi secretory pathway for complex assembly, and cytoplasmic signaling domain; suggested GO cellular-component terms are T-cell receptor complex and plasma membrane.

8. Temporal development

The molecular and thymopoietic defect is congenital. Infants may appear healthy at birth because exposure is limited and transplacental maternal IgG temporarily masks humoral failure. Complete-loss disease generally manifests during the first months with candidiasis, diarrhea, pneumonia, or opportunistic infection and then progresses rapidly without treatment. (notarangelo2024geneticallydetermineddefectsof pages 4-6, basile2004severecombinedimmunodeficiency pages 4-6)

There are no validated CD3E-specific stages. Clinically useful phases are: presymptomatic low-TREC newborn; confirmed T−B+NK+ lymphopenia; infection-free pre-HSCT; infection-complicated SCID; early post-HSCT immune reconstitution; and long-term follow-up for chimerism, naïve T-cell output, antibodies, and late complications. The critical intervention window is before active infection and preferably before 3.5 months—SCID-wide evidence. (notarangelo2024geneticallydetermineddefectsof pages 4-6, mongkonsritragoon2023positivenewbornscreening pages 1-2)

9. Inheritance and population

Inheritance is autosomal recessive. Heterozygotes in reported families were clinically unaffected, supporting recessive penetrance, but formal penetrance estimates are unavailable. Complete null genotypes appear highly penetrant for severe T-cell deficiency; expressivity varies with residual CD3ε, infection timing, and treatment. Anticipation is not expected. Germline mosaicism has not been demonstrated but cannot be excluded in counseling. (basile2004severecombinedimmunodeficiency pages 3-4, fuehrer2014successfulhaploidenticalhematopoietic pages 2-3)

CD3E-specific incidence, prevalence, carrier frequency, sex ratio, and geographic distribution are unknown. Cases have been reported in European, Turkish, Egyptian, and Indian-associated literature, often in consanguineous families, but no validated founder allele was established. SCID overall occurs around 1:50,000–66,000 births in several Western estimates, whereas a 2024 Turkish pilot found two SCID cases among 20,253 screened newborns—at least 1:10,000 in that regional sample, not specifically CD3E. (haskologlu2024newbornscreeningfor pages 5-6, firatoglu2025evaluationofpatients pages 1-3, soomann2024reducingmortalityand pages 1-2)

10. Diagnostics

Current workflow

  1. Newborn screening: quantify TRECs by PCR from dried blood spots. CD3E-null disease should produce very low/undetectable TRECs because thymic T-cell output is blocked.
  2. Confirmatory immunology: CBC/differential and flow cytometry for absolute CD3, CD4, CD8, CD19, and CD16/CD56 counts; quantify naïve CD4+CD45RA+ versus activated/memory CD45RO+ cells.
  3. SCID characterization: immunoglobulins, maternal T-cell engraftment using STR/HLA methods, and, where informative, TCR repertoire and flow-based proliferation after PHA or anti-CD3/CD28.
  4. Molecular confirmation: an accredited SCID/inborn-error-of-immunity panel including CD3E, CD3D, CD247, IL7R, PTPRC, IL2RG, JAK3, RAG1/2, DCLRE1C, followed by trio WES or WGS if nondiagnostic. Sanger/orthogonal confirmation and segregation analysis are appropriate.
  5. Functional confirmation for novel alleles: RNA studies for splicing, CD3ε protein assessment, and evidence of absent surface TCR/CD3 may support ACMG classification. (notarangelo2024geneticallydetermineddefectsof pages 4-6, dvorak2023thediagnosisof pages 5-7, fuehrer2014successfulhaploidenticalhematopoietic pages 2-3, fuehrer2014successfulhaploidenticalhematopoietic pages 4-5)

The 2022 PIDTC definition calls “suspected SCID” CD3 T cells <0.3×10⁹/L or naïve CD4 cells <20% plus abnormal TRECs, family history, or opportunistic infection. For typical SCID without maternal engraftment, the revised profound threshold is <0.05×10⁹/L CD3 T cells. These are SCID consensus criteria, not CD3E-specific criteria. (dvorak2023thediagnosisof pages 7-8, dvorak2023thediagnosisof pages 5-7)

Differential diagnosis: IL7R deficiency has the same T−B+NK+ pattern; CD3D and CD247 deficiencies also lack αβ and γδ T cells. PTPRC/CD45 deficiency may preserve γδ cells. CD3G deficiency is generally milder with appreciable T-cell numbers and reduced surface TCR. Congenital athymia has low T cells but is stromal rather than hematopoietic; RAG/NHEJ disorders typically reduce both T and B cells. HIV and secondary/transient neonatal lymphopenia must also be excluded. (notarangelo2024geneticallydetermineddefectsof pages 4-6, recio2007differentialbiologicalrole pages 1-2)

CMA, karyotype, FISH, mitochondrial sequencing, repeat-expansion testing, imaging, electrophysiology, and liquid biopsy are not routine for isolated CD3E deficiency. Imaging may document infection or thymic shadow but is not diagnostic.

11. Outcome and prognosis

Without immune reconstitution, classic SCID is usually fatal in infancy or early childhood. In the original complete-loss CD3E family, all three described siblings died: at five months with pneumonitis, at three months with disseminated CMV, and 25 days post-BMT with adenovirus. These historical outcomes reflect delayed diagnosis, active infection, and older transplant practice, not inevitable modern prognosis. (basile2004severecombinedimmunodeficiency pages 4-6)

Long-term survival is documented. A patient with homozygous c.49+1G>C received maternal haploidentical SCT and remained free of serious opportunistic infection over 15 years. Nevertheless, donor engraftment was restricted to T cells; CD3 counts remained approximately 200–1,200/µL and naïve T cells remained under 10%. Six years after SCT, immunoglobulins declined, switched-memory B cells were nearly absent (0.48%), invasive Hib meningitis occurred, and regular IVIG became necessary. The authors considered gradual loss of T-helper support more likely than a direct B-cell CD3E defect. (fuehrer2014successfulhaploidenticalhematopoietic pages 1-2, fuehrer2014successfulhaploidenticalhematopoietic pages 2-3, fuehrer2014successfulhaploidenticalhematopoietic pages 3-4, fuehrer2014successfulhaploidenticalhematopoietic pages 4-5, fuehrer2014successfulhaploidenticalhematopoietic media 0f49bd22)

Recent SCID-wide Swiss data provide contemporary context: newborn-screened patients were diagnosed at median 9 days versus 9 months, had infection before HSCT in 29% versus 93% (P=.004), and had observed survival of 86% versus 67%; active infection at transplant significantly worsened survival. These figures must not be represented as CD3E-specific. (soomann2024reducingmortalityand pages 1-2)

12. Treatment

Definitive therapy

Allogeneic HSCT is the current definitive treatment for CD3E-null SCID. Donor selection, graft manipulation, and conditioning require specialist SCID-transplant evaluation. A matched sibling is preferred when available; haploidentical transplantation can work but may produce incomplete or split chimerism. Genotype, infection status, donor availability, maternal engraftment, and institutional protocol guide conditioning. Suggested NCIT concepts: hematopoietic stem-cell transplantation; allogeneic stem-cell transplantation; haploidentical transplantation; bone-marrow transplantation. (notarangelo2024geneticallydetermineddefectsof pages 4-6, fuehrer2014successfulhaploidenticalhematopoietic pages 1-2)

Bridging/supportive therapy

SCID-wide management includes protective isolation; IVIG; TMP–SMX against Pneumocystis after approximately 30 days of life; organism- and center-tailored antiviral/antifungal prophylaxis; irradiated, leukoreduced, CMV-safe blood products; avoidance of live vaccines; breastfeeding interruption until maternal CMV seronegativity is established; and palivizumab during RSV season where indicated. Active infections require aggressive organism-directed treatment. Suggested NCIT concepts include intravenous immunoglobulin therapy, anti-infective prophylaxis, antibacterial agent, antifungal agent, antiviral agent, and protective isolation. (notarangelo2024geneticallydetermineddefectsof pages 4-6)

No pharmacogenomic recommendation specific to CD3E exists. No surgery or rehabilitation treats the molecular defect, although nutrition, developmental therapy, pulmonary care, and rehabilitation may address complications.

Experimental therapy and trials

The trial search identified SCID-wide transplant studies such as NCT01652092 and NCT04172181, and gene-therapy programs for IL2RG-, ADA-, DCLRE1C/Artemis-, or RAG1-related SCID—not CD3E. No CD3E-specific gene replacement, CRISPR, RNA, or cellular trial was identified. Gene correction is biologically conceivable but remains preclinical/undeveloped for this ultra-rare genotype.

13. Prevention

The germline disorder cannot be prevented by diet or lifestyle. Primary genetic prevention consists of carrier testing in relatives, counseling, partner testing, prenatal diagnosis, and preimplantation genetic testing for a known familial variant. Prenatal fetal-blood immunophenotyping was historically used, but targeted molecular testing by chorionic-villus sampling or amniocentesis is now preferable when the familial genotype is known. (dvorak2023thediagnosisof pages 7-8, basile2004severecombinedimmunodeficiency pages 4-6)

Secondary prevention is TREC newborn screening and immediate confirmatory testing, including testing at birth regardless of screening result when family history is positive. Tertiary prevention includes infection avoidance, antimicrobial prophylaxis, IVIG, vaccine restrictions, safe blood products, and early HSCT. Household members should avoid live viral vaccines when specialist guidance identifies transmission risk. (notarangelo2024geneticallydetermineddefectsof pages 4-6)

14. Other species and natural disease

No well-established naturally occurring veterinary CD3E-deficiency syndrome was identified. The disorder is not infectious and has no zoonotic or cross-species transmission. Orthologous Cd3e is evolutionarily conserved in laboratory mouse (Mus musculus, NCBI Taxonomy 10090), but this is an engineered model rather than documented natural disease.

15. Model organisms

The principal model is the Cd3e-targeted knockout mouse. Cd3e-null thymocytes arrest at an early CD44-low/CD25-positive triple-negative checkpoint, retain TCRβ rearrangement but have low full-length TCRβ transcripts, and fail to generate normal mature T cells. This model establishes causality between CD3ε loss, failed pre-TCR checkpoint signaling, and T-cell developmental arrest. (malissen1995alteredtcell pages 1-2)

Transgenic restoration of CD3ε can rescue development from a prothymocyte subset, providing genetic rescue evidence. Signaling-domain and basic-rich-stretch mutants further dissect structural, membrane-association, ITAM-dependent, and ITAM-independent functions. (bettini2014membraneassociationof pages 1-2, wang1998expressionofa pages 11-12)

Limitations are important: mouse and human CD3-chain requirements are not identical, and no thymus from a complete-loss human CD3E patient was available in the foundational report. Thus, the exact human arrest stage is inferred rather than demonstrated. Human patient-derived iPSCs, thymic organoids, or CRISPR-corrected progenitors were not identified as established disease models. (recio2007differentialbiologicalrole pages 1-2, basile2004severecombinedimmunodeficiency pages 3-4)

Recent developments and expert interpretation

The major 2023–2024 advances are not new CD3E-specific therapies but improved SCID ascertainment and care infrastructure. PIDTC’s 2022 definitions, published in February 2023, introduced contemporary thresholds, a “suspected SCID” category, standardized maternal-engraftment assessment, and panel/WES/WGS integration; pathogenic variants can now be identified in more than 90% of SCID overall. (dvorak2023thediagnosisof pages 3-5, dvorak2023thediagnosisof pages 5-7)

Notarangelo’s September 2024 review classifies CD3D, CD3E, and CD247 defects together as autosomal-recessive T−B+NK+ SCID lacking both αβ and γδ T cells, while emphasizing that newborn screening permits survival above 90% in well-resourced programs. The practical expert consensus is therefore to treat a low-TREC CD3E-null infant as a medical emergency even when clinically well. (notarangelo2024geneticallydetermineddefectsof pages 4-6)

A 2024 Swiss implementation study supplied real-world evidence that newborn screening advances diagnosis by months and sharply reduces pre-HSCT infection. A 2024 Turkish pilot screened 20,253 newborns and demonstrated feasibility in a population with substantial consanguinity, although neither study identified a CD3E case. (haskologlu2024newbornscreeningfor pages 5-6, soomann2024reducingmortalityand pages 1-2)

Key evidence gaps

There is no reliable CD3E-specific prevalence, incidence, carrier frequency, survival curve, quality-of-life instrument, penetrance estimate, natural-history registry, biomarker-validation study, multi-omics signature, or interventional trial. Several published variants also require transcript-normalized HGVS reconciliation and contemporary ClinVar/gnomAD review. The strongest disease-specific conclusions are therefore: biallelic complete loss causes T−B+NK+ SCID; residual expression can attenuate severity; HSCT can restore clinically meaningful immunity; and long-term immune reconstitution may remain incomplete. All numerical treatment benchmarks beyond the individual CD3E cases should be stored as SCID-wide contextual evidence, not as genotype-specific estimates.

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