Immunodeficiency 25 is an autosomal recessive combined immunodeficiency caused by biallelic loss-of-function variants in CD247, the gene encoding the T-cell receptor zeta chain (CD3zeta). The alpha-beta T-cell receptor reaches the cell surface only as a complete octamer — the clonotypic TCR alpha-beta heterodimer together with the CD3 gamma-epsilon, CD3 delta-epsilon and zeta-zeta dimers — assembled in the endoplasmic reticulum. CD247 contributes the invariant zeta-zeta homodimer, which does two distinct jobs: it is required for efficient assembly and export of the receptor, and it carries three of the ten immunoreceptor tyrosine-based activation motifs (ITAMs) in the complex, more than any other subunit. Losing it therefore costs both receptor density and signalling capacity, and the resulting failure of thymic selection produces profound T-cell lymphopenia with, in longer-surviving patients, autoimmunity. Two features distinguish this disorder from the neighbouring CD3-chain defects and are the reason it repays curation as its own entry rather than as a variant of them. The first is revertant somatic mosaicism, which is not an incidental finding here but the usual state of affairs: most reported patients carry a minority population of T cells in which a second, spontaneous change at the same codon has partially restored the protein. Those revertant cells recover surface receptor without recovering function, and they have not improved any reported patient's clinical course — a natural experiment separating TCR expression from TCR signalling. The second is that the mouse does not model the human disease: the same nonsense change that restores receptor expression in the classic murine CD247-deficient line fails to do so in human cells, so murine CD247 results cannot be carried across without checking. Reported patients present in early childhood with T-cell lymphopenia and infection, require haematopoietic stem cell transplantation to survive, and the older ones develop autoimmune features attributed to poor thymic selection. The disorder is very rare — the published series total a handful of patients — so the phenotypic range should be read as the reported range.
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Conditions with similar clinical presentations that must be differentiated from Immunodeficiency 25:
name: Immunodeficiency 25
creation_date: "2026-08-31T16:45:00Z"
category: Mendelian
synonyms:
- IMD25
- CD247 deficiency
- CD3 zeta chain deficiency
- CD3zeta deficiency
- TCR zeta chain immunodeficiency
description: >-
Immunodeficiency 25 is an autosomal recessive combined immunodeficiency caused
by biallelic loss-of-function variants in CD247, the gene encoding the T-cell
receptor zeta chain (CD3zeta). The alpha-beta T-cell receptor reaches the cell
surface only as a complete octamer — the clonotypic TCR alpha-beta heterodimer
together with the CD3 gamma-epsilon, CD3 delta-epsilon and zeta-zeta dimers —
assembled in the endoplasmic reticulum. CD247 contributes the invariant
zeta-zeta homodimer, which does two distinct jobs: it is required for efficient
assembly and export of the receptor, and it carries three of the ten
immunoreceptor tyrosine-based activation motifs (ITAMs) in the complex, more
than any other subunit. Losing it therefore costs both receptor density and
signalling capacity, and the resulting failure of thymic selection produces
profound T-cell lymphopenia with, in longer-surviving patients, autoimmunity.
Two features distinguish this disorder from the neighbouring CD3-chain defects
and are the reason it repays curation as its own entry rather than as a variant
of them. The first is revertant somatic mosaicism, which is not an incidental
finding here but the usual state of affairs: most reported patients carry a
minority population of T cells in which a second, spontaneous change at the
same codon has partially restored the protein. Those revertant cells recover
surface receptor without recovering function, and they have not improved any
reported patient's clinical course — a natural experiment separating TCR
expression from TCR signalling. The second is that the mouse does not model the
human disease: the same nonsense change that restores receptor expression in
the classic murine CD247-deficient line fails to do so in human cells, so
murine CD247 results cannot be carried across without checking.
Reported patients present in early childhood with T-cell lymphopenia and
infection, require haematopoietic stem cell transplantation to survive, and the
older ones develop autoimmune features attributed to poor thymic selection. The
disorder is very rare — the published series total a handful of patients — so
the phenotypic range should be read as the reported range.
disease_term:
preferred_term: immunodeficiency 25
term:
id: MONDO:0012426
label: immunodeficiency 25
parents:
- Primary Immunodeficiency
- Combined Immunodeficiency
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). CD3zeta/CD3Z
deficiency is listed there as autosomal recessive with very low T-cell
numbers, which places it alongside the CD3delta and CD3epsilon defects that
present as T-B+NK+ SCID rather than with the milder CD3gamma defect, where
T-cell numbers are normal.
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 CD3Z AR 186780 Very lowN ormalL ow Normal NK, no T cells
explanation: >-
The IUIS classification table row for CD3Z, recording autosomal recessive
inheritance, very low T-cell numbers and preserved NK cells. The spacing
is an artefact of the table extraction in the cached source and is quoted
as it appears there.
references:
- reference: PMID:17170122
title: "T-B+NK+ severe combined immunodeficiency caused by complete deficiency of the CD3zeta subunit of the T-cell antigen receptor complex."
- reference: PMID:16672702
title: "Inherited and somatic CD3zeta mutations in a patient with T-cell deficiency."
- reference: PMID:40711587
title: "Discordant Restoration of TCR Expression and Function by CD247 Somatic Reversions."
- reference: PMID:38992472
title: "Nonsense CD247 mutations show dominant-negative features in T-cell receptor expression and function."
inheritance:
- name: Autosomal recessive inheritance
description: >-
Biallelic CD247 variants cause disease; heterozygous carriers of null alleles
are clinically well but show roughly half-normal surface CD3, so the gene is
dosage-sensitive at the level of receptor density without that being enough to
cause immunodeficiency. Heterozygous nonsense alleles that retain a truncated
protein are a separate case and behave dominant-negatively in vitro.
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
evidence:
- reference: PMID:38992472
reference_title: "Nonsense CD247 mutations show dominant-negative features in T-cell receptor expression and function."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Homozygous null mutations in CD247 lead to immunodeficiency, while carriers
exhibit 50% reduced surface CD3.
explanation: >-
States the recessive inheritance of the null alleles and the intermediate
biochemical phenotype in carriers.
mechanistic_hypotheses:
- hypothesis_group_id: expression_function_uncoupling
hypothesis_label: >-
Restoring TCR surface expression is not sufficient to restore TCR function in
CD247 deficiency
status: EMERGING
description: >-
Somatic revertant variants at the patients' own germline codon recover surface
receptor to varying degrees, yet none of them restores TCR-induced ZAP70
tyrosine phosphorylation, and the hierarchy of expression rescue does not
match the hierarchy of activation rescue. If this holds, the ITAM-bearing
cytoplasmic tail is doing something for signalling that is separable from what
the transmembrane region does for assembly, and any therapy aimed at
restoring receptor density alone would be expected to fail. The clinical
correlate — that revertant T cells did not help any reported patient — is
consistent but is an observation on very few patients.
evidence:
- reference: PMID:40711587
reference_title: "Discordant Restoration of TCR Expression and Function by CD247 Somatic Reversions."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Somatic reversions, such as those detected in patients with pathogenic
CD247 germinal changes, display a discordant capability to rescue TCR
expression versus function.
explanation: >-
States the uncoupling of expression from function that the hypothesis rests
on.
pathophysiology:
- name: Biallelic CD247 Loss-of-Function Variants
biological_scale: MOLECULAR
description: >-
Reported germline alleles include an initiation-codon change (p.M1T) and a
nonsense change truncating the protein before all three ITAMs (p.Q70X). The
two act differently: p.M1T abolishes translation initiation, while p.Q70X
leaves a truncated chain that can still be detected intracellularly with a
transmembrane-directed antibody but not with an ITAM-3-directed one. That
distinction matters, because a retained truncated chain can compete with
wild-type CD247 whereas a true null cannot.
A third reported allele is a homozygous single-C insertion after nucleotide
411 in exon 7. It behaves as a true null at the protein level: no CD3zeta is
detectable in the patient's T cells, and when the mutant cDNA is transduced
into a CD247-deficient background the nascent protein is not detected at all
on metabolic labelling, indicating it is made and then rapidly degraded. That
completes the allelic picture — one allele class is degraded away, another is
retained as a truncated competitor, and the two are not interchangeable when
predicting a novel variant's behaviour.
genes:
- preferred_term: CD247
term:
id: hgnc:1677
label: CD247
genetic_context:
allele_type: NONSENSE
variant_origin: GERMLINE
zygosity: HOMOZYGOUS
functional_impact_category: LOSS_OF_FUNCTION
gene:
preferred_term: CD247
term:
id: hgnc:1677
label: CD247
notes: >-
Recorded for the p.Q70X nonsense allele. The other reported germline change,
p.M1T, is an initiation-codon variant rather than a nonsense one; both are
biallelic and germline.
evidence:
- reference: PMID:40711587
reference_title: "Discordant Restoration of TCR Expression and Function by CD247 Somatic Reversions."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
CD247 deficiency is a rare early-onset primary immunodeficiency disorder
characterized by variants in the CD247 gene
explanation: >-
Establishes CD247 variants as the cause of this primary immunodeficiency.
- reference: PMID:38992472
reference_title: "Nonsense CD247 mutations show dominant-negative features in T-cell receptor expression and function."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Both mutations were associated with low surface CD3 expression and normal
intracellular CD247 levels using a transmembrane-specific antibody, but very
low intracellular CD247 levels using an ITAM-3-specific one, suggesting the
presence of truncated variants in T cells.
explanation: >-
Shows that nonsense alleles leave a detectable truncated chain rather than
nothing, which is what makes them behave differently from nulls.
- reference: PMID:16672702
reference_title: "Inherited and somatic CD3zeta mutations in a patient with T-cell deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A four-month-old boy with primary immunodeficiency was found to have a
homozygous germ-line mutation of the gene encoding the CD3zeta subunit of
the T-cell receptor-CD3 complex.
explanation: >-
The founding report of the disorder, establishing a homozygous germline
CD247 variant as the cause in the index patient.
- reference: PMID:17170122
reference_title: "T-B+NK+ severe combined immunodeficiency caused by complete deficiency of the CD3zeta subunit of the T-cell antigen receptor complex."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We report here a patient with T(-)B(+)NK(+) severe combined
immunodeficiency (SCID) who was homozygous for a single C insertion
following nucleotide 411 in exon 7 of the CD3zeta gene.
explanation: >-
Names the exon 7 frameshift allele and the SCID phenotype it produces.
- reference: PMID:17170122
reference_title: "T-B+NK+ severe combined immunodeficiency caused by complete deficiency of the CD3zeta subunit of the T-cell antigen receptor complex."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Nascent transduced mutant CD3zeta protein was also not detected in
metabolically labeled MA5.8 cells, suggesting that it was unstable and
rapidly degraded.
explanation: >-
Establishes that the frameshift allele's product is degraded rather than
retained, which is what separates it from the nonsense alleles that leave a
competing truncated chain.
downstream:
- target: Impaired TCR/CD3 Complex Assembly and Surface Expression
description: >-
Without the zeta-zeta dimer the receptor cannot be assembled and exported
efficiently.
causal_link_type: DIRECT
evidence:
- reference: PMID:40711587
reference_title: "Discordant Restoration of TCR Expression and Function by CD247 Somatic Reversions."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
These variants can result in a lack of functional CD247 chain expression
in T cells causing severe defects of TCR expression and function
explanation: >-
Links loss of the CD247 chain directly to defective receptor expression.
- name: Impaired TCR/CD3 Complex Assembly and Surface Expression
biological_scale: MOLECULAR
description: >-
The zeta-zeta homodimer is one of the invariant dimers the octameric receptor
needs to complete assembly in the endoplasmic reticulum and leave it. Without
it the incomplete complex is retained rather than exported, and surface
receptor density falls sharply — unlike CD3gamma deficiency, where CD3delta
can partly substitute and T-cell numbers stay normal. This was in fact the
first biochemical description of the disorder, made before the gene was
identified, as a failure of the zeta chain to associate with the rest of the
complex.
protein_complexes:
- preferred_term: alpha-beta T cell receptor complex
modifier: DECREASED
term:
id: GO:0042105
label: alpha-beta T cell receptor complex
cell_types:
- preferred_term: mature alpha-beta T cell
term:
id: CL:0000791
label: mature alpha-beta T cell
evidence:
- reference: PMID:2142600
reference_title: "Congenital T-cell receptor immunodeficiencies in man."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The biochemical basis of the defect in one of the cases thus far studied is
an impaired association of CD3-zeta chain with the other chains of the
complex. This defect prevented the maturation and transport of the
incomplete complex to the cell surface.
explanation: >-
The original biochemical localisation of the lesion to assembly and export,
predating identification of the gene.
- reference: PMID:38992472
reference_title: "Nonsense CD247 mutations show dominant-negative features in T-cell receptor expression and function."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Transduction of the mutations lacking 1, 2, or 3 ITAMs into ZKO cells could
not restore normal surface CD3 expression (only 60%, 22%, and 10%,
respectively), whereas in WT cells, normal surface CD3 expression was
reduced (to 39%, 19%, and 9% of normal levels), and both effects were
dependent on ITAM number.
explanation: >-
Quantifies the assembly defect and shows it scales with the number of ITAMs
lost, in an isogenic CD247-null human T-cell background.
- reference: PMID:17170122
reference_title: "T-B+NK+ severe combined immunodeficiency caused by complete deficiency of the CD3zeta subunit of the T-cell antigen receptor complex."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Taken together, these findings provide the first demonstration that
complete CD3zeta deficiency in humans can cause SCID by preventing normal
TCR assembly and surface expression.
explanation: >-
The first demonstration that complete loss of the chain causes human SCID
specifically by blocking receptor assembly and export, which is the claim
this node makes.
- reference: PMID:17170122
reference_title: "T-B+NK+ severe combined immunodeficiency caused by complete deficiency of the CD3zeta subunit of the T-cell antigen receptor complex."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The few T cells present contained no detectable CD3zeta protein, expressed
low levels of cell surface CD3epsilon, and were nonfunctional.
explanation: >-
Measures the consequence in patient cells: absent CD3zeta, reduced surface
CD3epsilon, and loss of function.
downstream:
- target: Loss of ITAM-Dependent Proximal TCR Signaling
description: >-
Fewer surface receptors, and each surviving complex lacks the three
zeta-chain ITAMs that normally recruit and activate ZAP70.
causal_link_type: DIRECT
evidence:
- reference: PMID:38992472
reference_title: "Nonsense CD247 mutations show dominant-negative features in T-cell receptor expression and function."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
All 6 transfectants showed reduced CD69 induction (25% to 50%),
indicating that they were unable to signal downstream properly, neither
isolated nor associated with WT CD247.
explanation: >-
Shows the signalling failure follows the assembly defect and is not
rescued by the presence of wild-type CD247.
- name: Loss of ITAM-Dependent Proximal TCR Signaling
biological_scale: MOLECULAR
description: >-
CD247 carries three of the ten ITAMs in the receptor complex. Their tyrosines
are the docking sites that, once phosphorylated by LCK, recruit ZAP70 and
start the proximal signalling cascade. In CD247 deficiency this step fails,
and the failure is not repaired by restoring surface receptor: revertant
variants that put the receptor back on the membrane still fail to support
TCR-induced ZAP70 phosphorylation. The activation defect is therefore
partly independent of receptor density.
biological_processes:
- preferred_term: T cell receptor signaling pathway
modifier: DECREASED
term:
id: GO:0050852
label: T cell receptor signaling pathway
evidence:
- reference: PMID:40711587
reference_title: "Discordant Restoration of TCR Expression and Function by CD247 Somatic Reversions."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Furthermore, all CD247 somatic variants failed to induce TCR-mediated ZAP70
tyrosine phosphorylation compared to WT.
explanation: >-
Locates the signalling block at ZAP70 recruitment and shows it persists when
surface expression is restored.
- reference: PMID:38992472
reference_title: "Nonsense CD247 mutations show dominant-negative features in T-cell receptor expression and function."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
The invariant TCR ζ/CD247 homodimer is crucial for TCR/CD3 expression and
signaling through its 3 immunoreceptor tyrosine-based activation motifs
(ITAMs).
explanation: >-
States the dual role of the chain in expression and in ITAM-dependent
signalling.
downstream:
- target: Failed Thymic Selection and T-Cell Development
description: >-
Thymocyte positive and negative selection read the strength of TCR
signalling, so a proximal signalling block disrupts both.
causal_link_type: DIRECT
evidence:
- reference: PMID:40711587
reference_title: "Discordant Restoration of TCR Expression and Function by CD247 Somatic Reversions."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
It plays a key role in T-cell receptor (TCR) assembly and surface
expression by cooperating with other invariant CD3 molecules and in TCR
development and function by transducing signals from the TCR to initiate
the activation and response of T cells for thymus selection or antigen
recognition
explanation: >-
States that the signal CD247 transduces is the one used for thymic
selection.
- name: Failed Thymic Selection and T-Cell Development
biological_scale: CELLULAR
description: >-
Thymocytes need a TCR signal of the right strength to be positively selected,
and a strong one to be negatively selected against self. With the zeta chain
missing, both arms fail: few cells complete development, giving profound
peripheral T-cell lymphopenia, and the self-reactive cells that should have
been deleted are not, which is the accepted explanation for the autoimmunity
that appears in longer-surviving patients.
biological_processes:
- preferred_term: thymic T cell selection
modifier: DECREASED
term:
id: GO:0045061
label: thymic T cell selection
cell_types:
- preferred_term: thymocyte
term:
id: CL:0000893
label: thymocyte
evidence:
- reference: PMID:40711587
reference_title: "Discordant Restoration of TCR Expression and Function by CD247 Somatic Reversions."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
All reported patients showed T cell lymphopenia, suffered infections, and
required stem cell transplantation to survive. Older patients also showed
autoimmune features, suggesting poor T-cell selection.
explanation: >-
Reports the lymphopenia and attributes the autoimmunity to defective thymic
selection.
downstream:
- target: T-Cell Lymphopenia with Impaired Function
description: >-
Failure of development is what depletes the peripheral T-cell compartment.
causal_link_type: DIRECT
evidence:
- reference: PMID:2142600
reference_title: "Congenital T-cell receptor immunodeficiencies in man."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
severe TCR ID behaves as a clinical SCID, with clear autoimmune features
and profound lymphoid tissue depletion
explanation: >-
Describes the severe end of the phenotype as lymphoid depletion with
autoimmunity.
- name: T-Cell Lymphopenia with Impaired Function
biological_scale: ORGANISM
description: >-
Peripheral T-cell numbers are very low, and the cells that are present carry
little surface receptor and respond poorly through it while responding
normally to TCR-independent stimuli such as anti-CD2, phorbol esters and
IL-2. That dissociation — bad through the receptor, fine around it — is the
laboratory signature of the disorder and separates it from lymphopenias with
a general proliferative defect.
cell_types:
- preferred_term: T cell
term:
id: CL:0000084
label: T cell
biological_processes:
- preferred_term: T cell activation
modifier: DECREASED
term:
id: GO:0042110
label: T cell activation
evidence:
- reference: PMID:2142600
reference_title: "Congenital T-cell receptor immunodeficiencies in man."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In contrast, normal proliferative responses were recorded to
TCR-independent activation or proliferation signals (i.e: anti-CD2, phorbol
esters and IL-2).
explanation: >-
Establishes that the functional defect is receptor-specific rather than a
general failure of T-cell proliferation.
- name: Revertant Somatic Mosaicism
biological_scale: CELLULAR
description: >-
A second, spontaneous change at or near the germline codon arises in a
subset of T cells and partially restores CD247. This is the usual course in
this disorder rather than a rarity, and the revertant cells are selected for
because they can express a receptor. Crucially the rescue is partial in a
specific way: expression comes back, function does not, and the revertant
population stays a minority and has not altered any reported patient's
clinical status. The node is a modifier of the disease course rather than a
step in the causal chain, so it carries no downstream edge.
cell_types:
- preferred_term: T cell
term:
id: CL:0000084
label: T cell
evidence:
- reference: PMID:40711587
reference_title: "Discordant Restoration of TCR Expression and Function by CD247 Somatic Reversions."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
CD247 deficiency frequently associates with revertant somatic mosaicism (4
of 5 patients, Table S1), likely due to the propensity of CD247 to vary
explanation: >-
Establishes how common reversion is in this disorder specifically.
- reference: PMID:40711587
reference_title: "Discordant Restoration of TCR Expression and Function by CD247 Somatic Reversions."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
However, the revertant T cells remained a minority and did not improve the
patients' clinical status.
explanation: >-
Records that reversion has no observed clinical benefit, which is why it is
curated as a modifier rather than as a rescue.
- reference: PMID:40711587
reference_title: "Discordant Restoration of TCR Expression and Function by CD247 Somatic Reversions."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
In human cell models, all somatic revertant variants restored TCR
expression with varying degrees (WT = Q70L > Q70W > Q70Y).
explanation: >-
Quantifies the partial restoration of surface receptor by the revertant
alleles.
- reference: PMID:16672702
reference_title: "Inherited and somatic CD3zeta mutations in a patient with T-cell deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Some of the patient's T cells had low levels of the T-cell receptor-CD3
complex and carried the Q70X mutation in both alleles of CD3zeta, whereas
other T cells had normal levels of the complex and bore the Q70X mutation on
only one allele of CD3zeta, plus one of three heterozygous somatic mutations
of CD3zeta on the other allele, allowing expression of poorly functional
T-cell receptor-CD3 complexes.
explanation: >-
The original description of the two T-cell populations, and of the fact that
the restored complexes are poorly functional — the expression-versus-function
split, present in the founding case.
- reference: PMID:28743717
reference_title: "Analysis of the recovery of CD247 expression in a PID patient: insights into the spontaneous repair of defective genes."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
The recovery of CD247 expression in some patient T cells was associated with
both reversion of the inactivating mutation and a variant with a
compensating mutation that could reconstitute TCR expression, but not as
efficiently as wild-type CD247.
explanation: >-
Distinguishes true reversion from second-site compensation, and records that
neither restores wild-type-level expression.
phenotypes:
- category: Immunologic
name: Combined Immunodeficiency
description: >-
Cellular and humoral immunity are both compromised, since the antibody
response depends on T-cell help. IUIS places CD3Z deficiency in the combined
immunodeficiency table.
phenotype_term:
preferred_term: Combined immunodeficiency
term:
id: HP:0005387
label: Combined immunodeficiency
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 CD3Z AR 186780 Very lowN ormalL ow Normal NK, no T cells
explanation: >-
The IUIS row placing CD3Z deficiency among the combined immunodeficiencies,
with very low T cells and preserved NK cells.
- category: Immunologic
name: T-B+NK+ Immunophenotype
description: >-
Circulating T cells are profoundly reduced while B cells and NK cells are
present, giving the T-B+NK+ pattern that separates this from
the T-B- recombination defects. The NK compartment is present but not normal: an
unusual CD56-negative CD16-positive population with diminished cytolytic
activity has been described, so "NK preserved" describes cell number rather
than cell function.
phenotype_term:
preferred_term: Decreased natural killer cell-induced killing of target cells
term:
id: HP:0025808
label: Decreased natural killer cell-induced killing of target cells
evidence:
- reference: PMID:17170122
reference_title: "T-B+NK+ severe combined immunodeficiency caused by complete deficiency of the CD3zeta subunit of the T-cell antigen receptor complex."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We report here a patient with T(-)B(+)NK(+) severe combined
immunodeficiency (SCID) who was homozygous for a single C insertion
following nucleotide 411 in exon 7 of the CD3zeta gene.
explanation: >-
States the T-B+NK+ pattern directly, which the previous evidence for this
claim did not.
- reference: PMID:17170122
reference_title: "T-B+NK+ severe combined immunodeficiency caused by complete deficiency of the CD3zeta subunit of the T-cell antigen receptor complex."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
the patient also exhibited an unusual population of CD56(-)CD16(+) NK cells
with diminished cytolytic activity
explanation: >-
Qualifies the NK preservation: the cells are there but functionally and
phenotypically abnormal.
- category: Immunologic
name: Reduced Surface TCR/CD3 Expression
description: >-
The defining laboratory finding, and the one that points at a TCR-complex
gene rather than a recombination or signalling defect: the few T cells
present carry markedly reduced surface CD3. HPO has no term for reduced
surface TCR or CD3 density on T cells, so this is recorded with a free-text
preferred_term and no binding.
phenotype_term:
preferred_term: Reduced surface TCR/CD3 complex density on T cells
notes: >-
Needs an ontology term. HPO was searched through the OAK ols:hp adapter for
"T cell receptor", "CD3", "surface CD3" and "TCR expression", with
HP:0031382 used as a positive control to confirm the search was returning
results rather than failing silently. Nothing matches receptor density per
cell. The nearest hits are counts and proportions — HP:0005403 Decreased
total T cell count, HP:5210413 Decreased total T cell proportion — which
measure how many T cells there are rather than how much receptor each one
carries. Those are the wrong measurement here and binding to one would
misstate the finding, so this is recorded unbound.
evidence:
- reference: PMID:17170122
reference_title: "T-B+NK+ severe combined immunodeficiency caused by complete deficiency of the CD3zeta subunit of the T-cell antigen receptor complex."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The few T cells present contained no detectable CD3zeta protein, expressed
low levels of cell surface CD3epsilon, and were nonfunctional.
explanation: >-
Documents the reduced surface CD3 on the residual T cells.
- category: Immunologic
name: Decreased Anti-CD3/CD28-Induced T-Cell Proliferation
description: >-
T cells respond poorly to stimulation through the receptor while responding
normally to TCR-independent stimuli. That dissociation is what localises the
functional defect to the receptor rather than to a general proliferative
failure.
phenotype_term:
preferred_term: Decreased anti-CD3/28-induced T-cell proliferation
term:
id: HP:0031382
label: Decreased anti-CD3/28-induced T-cell proliferation
evidence:
- reference: PMID:2142600
reference_title: "Congenital T-cell receptor immunodeficiencies in man."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
As a consequence of the surface defect, an impaired T-lymphocyte activation
through the TCR and CD3 complex by both antigens and mitogens is observed
in this type of immunodeficiency (ID) for which we propose the name TCR ID.
explanation: >-
Records impaired activation specifically through the TCR/CD3 complex.
- category: Immunologic
name: T-Cell Lymphopenia
description: >-
Very low circulating T-cell counts, present in every reported patient. NK
cells are preserved, giving a T-B+NK+ pattern.
phenotype_term:
preferred_term: Decreased total T cell count
term:
id: HP:0005403
label: Decreased total T cell count
evidence:
- reference: PMID:40711587
reference_title: "Discordant Restoration of TCR Expression and Function by CD247 Somatic Reversions."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
All reported patients showed T cell lymphopenia, suffered infections, and
required stem cell transplantation to survive.
explanation: >-
Records T-cell lymphopenia in all reported patients.
- category: Immunologic
name: Recurrent Infections
description: >-
Infection is the presenting problem and the reason patients come to
attention in early childhood.
phenotype_term:
preferred_term: Recurrent infections
term:
id: HP:0002719
label: Recurrent infections
evidence:
- reference: PMID:40711587
reference_title: "Discordant Restoration of TCR Expression and Function by CD247 Somatic Reversions."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
All reported patients showed T cell lymphopenia, suffered infections, and
required stem cell transplantation to survive.
explanation: >-
Records infection in all reported patients.
- category: Immunologic
name: Autoimmunity
description: >-
Appears in the longer-surviving patients and is attributed to defective
negative selection in the thymus rather than to a peripheral tolerance
defect.
phenotype_term:
preferred_term: Autoimmunity
term:
id: HP:0002960
label: Autoimmunity
evidence:
- reference: PMID:40711587
reference_title: "Discordant Restoration of TCR Expression and Function by CD247 Somatic Reversions."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Older patients also showed autoimmune features, suggesting poor T-cell
selection.
explanation: >-
Records the autoimmune features and the selection failure they are
attributed to.
prevalence:
- population: Worldwide, published cases
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >-
Fewer than ten reported patients. No incidence or prevalence estimate exists
at the level of this gene; the figure recorded here is a count of the
literature, not a rate. SCID as a class is picked up by newborn screening at
roughly 1 in 50,000, but CD247 is a very small fraction of that.
evidence:
- reference: PMID:40711587
reference_title: "Discordant Restoration of TCR Expression and Function by CD247 Somatic Reversions."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
CD247 deficiency frequently associates with revertant somatic mosaicism (4
of 5 patients, Table S1), likely due to the propensity of CD247 to vary
explanation: >-
The denominator in this sentence gives the size of the reported cohort,
which is the only quantitative handle on how rare the disorder is.
genetic:
- name: CD247
notes: >-
Encodes the TCR zeta chain (CD3zeta), the invariant subunit that homodimerises
within the TCR/CD3 octamer and carries three of the complex's ten ITAMs.
Reported germline disease alleles include p.M1T and p.Q70X. The locus appears
unusually prone to somatic change, which is the proposed reason revertant
mosaicism is so frequent here — a propensity that has been measured rather
than assumed, and that generalises across the primary immunodeficiency genes
in which reversion is seen.
gene_term:
preferred_term: CD247
term:
id: hgnc:1677
label: CD247
relationship_type: CAUSATIVE
variant_origin: GERMLINE
evidence:
- reference: PMID:40711587
reference_title: "Discordant Restoration of TCR Expression and Function by CD247 Somatic Reversions."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The CD247 chain of the T-cell receptor (TCR) is essential for normal T cell
development and function.
explanation: >-
States the gene's requirement for T-cell development, which is what its loss
removes.
- reference: PMID:38992472
reference_title: "Nonsense CD247 mutations show dominant-negative features in T-cell receptor expression and function."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Homozygous null mutations in CD247 lead to immunodeficiency, while carriers
exhibit 50% reduced surface CD3.
explanation: >-
Establishes the gene-disease relationship and the recessive mode.
- reference: PMID:28743717
reference_title: "Analysis of the recovery of CD247 expression in a PID patient: insights into the spontaneous repair of defective genes."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Analyses of other genes mutated in primary immunodeficiency diseases (PIDs)
where reversions have been described also revealed a higher rate of mutation
than that observed for genes mutated in PIDs where revertants have not been
identified or control genes.
explanation: >-
Supports the elevated mutation propensity of CD247 and comparable genes as
the reason reversion is common in this disorder rather than incidental.
- name: CD247 heterozygous nonsense alleles
notes: >-
A separate, non-recessive situation worth recording because it is easy to
misread as carrier status. Heterozygous nonsense alleles that retain a
truncated ITAM-deficient chain suppress wild-type receptor expression and
signalling in vitro, so they are not equivalent to heterozygous nulls. The
reported patients carrying them had signs of immunodeficiency or
autoimmunity, but the dominant-negative effect is demonstrated in cell lines
rather than established as the cause of their clinical features.
gene_term:
preferred_term: CD247
term:
id: hgnc:1677
label: CD247
relationship_type: DISPUTED
variant_origin: GERMLINE
evidence:
- reference: PMID:38992472
reference_title: "Nonsense CD247 mutations show dominant-negative features in T-cell receptor expression and function."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Our results suggest that CD247 variants lacking ITAMs due to nonsense, but
not null, mutations are defective for normal TCR assembly and exert a
dominant-negative effect on TCR expression and signaling in vitro.
explanation: >-
States the dominant-negative effect and, in the authors' own hedging,
confines it to in vitro observation.
- reference: PMID:38992472
reference_title: "Nonsense CD247 mutations show dominant-negative features in T-cell receptor expression and function."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Two heterozygous nonsense CD247 mutations were identified (p.Y152X and
p.Q101X), which affected ITAM-3 and ITAM-2 and ITAM-3, respectively.
explanation: >-
Names the heterozygous nonsense alleles found in patients.
experimental_models:
- name: MA5.8 murine CD247-deficient T-cell line
experimental_model_type: CELL_LINE
description: >-
The classic CD247-deficient mouse T-cell line, long used as the reconstitution
background for zeta-chain work. It is included here as an explicit negative:
on the specific question of whether a truncating CD247 allele can support
receptor expression, it gives the opposite answer to human cells.
modeled_mechanisms:
- target: Impaired TCR/CD3 Complex Assembly and Surface Expression
relationship: FAILS_TO_RECAPITULATE
fidelity: LOW
description: >-
The Q70X allele restores surface TCR in MA5.8 but not in human T cells, so
the murine line scores a truncating allele as functional for assembly when
in human cells it is not.
limitations: >-
Species divergence at the assembly step itself, which is the mechanism under
study rather than a peripheral difference. A reconstitution result obtained
in MA5.8 cannot be assumed to transfer to human CD247 deficiency, and the
direction of the error is optimistic — it makes a damaging allele look
tolerated.
readouts:
- name: Surface TCR/CD3 expression after Q70X reconstitution
target: Impaired TCR/CD3 Complex Assembly and Surface Expression
direction: RESTORED
interpretation: >-
Restored in the murine line and not in human cells; the discrepancy is the
finding, not the restoration.
evidence:
- reference: PMID:40711587
reference_title: "Discordant Restoration of TCR Expression and Function by CD247 Somatic Reversions."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
MA5.8 mouse T cells do not accurately model human CD247 deficiencies, as
Q70X restores TCR expression in MA5.8 but not in human cells.
explanation: >-
Reports the divergent reconstitution result in the two species.
evidence:
- reference: PMID:40711587
reference_title: "Discordant Restoration of TCR Expression and Function by CD247 Somatic Reversions."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
MA5.8 mouse T cells do not accurately model human CD247 deficiencies, as
Q70X restores TCR expression in MA5.8 but not in human cells.
explanation: >-
States directly that the murine line does not model the human disorder.
- name: ZKO CRISPR/Cas9 CD247-knockout Jurkat line
experimental_model_type: CELL_LINE
description: >-
A human T-cell line in which CD247 has been knocked out, giving an isogenic
null background for reconstitution with wild-type or mutant CD247. This is the
system that carries most of the mechanistic argument in the entry, and the
one against which the murine line was found wanting.
modeled_mechanisms:
- target: Loss of ITAM-Dependent Proximal TCR Signaling
relationship: RECAPITULATES
fidelity: MODERATE
description: >-
Reconstituting the null background with ITAM-truncated CD247 reproduces both
the assembly defect and the downstream activation failure, and grades them by
the number of ITAMs lost.
limitations: >-
Jurkat is a transformed leukaemic line with known deficiencies in
phosphoinositide phosphatase regulation, and reconstitution is by
overexpression rather than at endogenous level. It also cannot model thymic
selection, which is where the clinical phenotype is generated.
readouts:
- name: CD69 induction after TCR stimulation
target: Loss of ITAM-Dependent Proximal TCR Signaling
direction: DECREASED
interpretation: >-
Activation marker induction falls with ITAM loss, reporting the proximal
signalling block.
evidence:
- reference: PMID:38992472
reference_title: "Nonsense CD247 mutations show dominant-negative features in T-cell receptor expression and function."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
All 6 transfectants showed reduced CD69 induction (25% to 50%),
indicating that they were unable to signal downstream properly, neither
isolated nor associated with WT CD247.
explanation: >-
Measures the activation defect in the isogenic human background.
evidence:
- reference: PMID:38992472
reference_title: "Nonsense CD247 mutations show dominant-negative features in T-cell receptor expression and function."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Jurkat T cells, either wild-type (WT) or CRISPR/Cas9-edited
CD247-deficient (ZKO), were lentivirally transduced with WT CD247 or
mutations ablating 1 (Q142X), 2 (Q101X), or 3 (Q70X) ITAMs.
explanation: >-
Describes the isogenic human reconstitution system used.
diagnosis:
- name: Flow cytometry for surface CD3 and T-cell subsets
description: >-
The disorder is picked up as very low T-cell counts with low surface CD3 on
the cells that are present. Because revertant cells carry higher surface TCR,
a bimodal CD3 histogram in a lymphopenic child is itself a pointer to CD247
deficiency rather than to a CD3-chain defect without reversion.
evidence:
- reference: PMID:40711587
reference_title: "Discordant Restoration of TCR Expression and Function by CD247 Somatic Reversions."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Reported CD247-deficient patients showed severe immunodeficiency despite the
presence of two populations of peripheral T cells, most with low TCR levels
carrying the germline variant and a few with higher TCR levels due to
somatic reversion.
explanation: >-
Describes the two-population surface-TCR pattern that flow cytometry shows.
- name: Newborn screening by T-cell receptor excision circle assay
description: >-
The population-level route to a presymptomatic diagnosis. Profound T-cell
lymphopenia gives low or absent TRECs, so an affected infant is expected to
screen positive. One caveat specific to this disorder: revertant mosaicism
expands a T-cell population, and because reversion is the usual state of
affairs in CD247 deficiency rather than a rarity, a partly restored T-cell
compartment could in principle raise the TREC value — the same way ZAP70
deficiency with normal T-cell numbers escapes the assay. That has not been
reported in a CD247 patient and is a stated concern rather than an observed
failure.
evidence:
- reference: PMID:41441645
reference_title: "BCGitis and BCGosis: Clinical Spectrum, Immunological Mechanisms, and Risk Management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: >-
Implementation of universal newborn screening for severe combined
immunodeficiency (SCID) using the T-cell receptor excision circle (TREC)
assay now enables prospective identification and deferral of these
high-risk neonates, virtually eliminating fatal BCGosis.
explanation: >-
Establishes TREC screening as the route to presymptomatic identification in
SCID. Indirect because it is stated for the SCID class rather than for
CD247 deficiency specifically.
- name: Distinguishing combined immunodeficiency from typical SCID by T-cell count
description: >-
A general framework rather than a CD247-specific test, included because the
placement of this disorder relative to typical SCID turns on it. Patients with
fewer than 500 circulating CD3-positive T cells per microlitre are classed as
typical SCID; the IUIS row for CD3Z records very low T cells, which puts it at
that end of the spectrum.
evidence:
- reference: PMID:22664165
reference_title: "Defining combined immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: >-
Patients with typical SCID can be defined as having fewer than 500
circulating CD3(+) T cells.
explanation: >-
Gives the T-cell count threshold used to separate typical SCID from other
combined immunodeficiencies. This cohort did not include CD247-deficient
patients, so it supplies the classification framework rather than direct
evidence about this disorder.
treatments:
- name: Allogeneic haematopoietic stem cell transplantation
description: >-
The only reported curative option, and one that every reported patient
required in order to survive. It replaces the defective T-cell compartment
with donor-derived cells; it does not correct CD247 in the patient's own
haematopoietic stem cells.
treatment_term:
preferred_term: Hematopoietic Cell Transplantation
term:
id: NCIT:C15431
label: Hematopoietic Cell Transplantation
therapeutic_modality: CELL_THERAPY
target_mechanisms:
- target: T-Cell Lymphopenia with Impaired Function
description: >-
Donor-derived progenitors reconstitute a T-cell compartment with an intact
CD247 locus, bypassing the patient's assembly and signalling defect rather
than repairing it.
evidence:
- reference: PMID:40711587
reference_title: "Discordant Restoration of TCR Expression and Function by CD247 Somatic Reversions."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
All reported patients showed T cell lymphopenia, suffered infections, and
required stem cell transplantation to survive.
explanation: >-
Records transplantation as necessary for survival in every reported
patient.
evidence:
- reference: PMID:40711587
reference_title: "Discordant Restoration of TCR Expression and Function by CD247 Somatic Reversions."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
All reported patients showed T cell lymphopenia, suffered infections, and
required stem cell transplantation to survive.
explanation: >-
Establishes transplantation as the reported definitive treatment.
- name: Deferral of live vaccines
description: >-
The most time-critical intervention, and the one that is lost if diagnosis is
late. An infant with profound T-cell lymphopenia given a live vaccine is at
risk of disseminated disease from the vaccine strain itself — BCGosis where
BCG is given at birth, vaccine-associated paralytic poliomyelitis where oral
polio vaccine is used. Both are preventable by deferring the vaccine, which
requires knowing the diagnosis before the vaccine is given, which in turn is
what newborn screening buys.
treatment_term:
preferred_term: Supportive Care
term:
id: NCIT:C15747
label: Supportive Care
evidence:
- reference: PMID:41441645
reference_title: "BCGitis and BCGosis: Clinical Spectrum, Immunological Mechanisms, and Risk Management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: >-
Implementation of universal newborn screening for severe combined
immunodeficiency (SCID) using the T-cell receptor excision circle (TREC)
assay now enables prospective identification and deferral of these
high-risk neonates, virtually eliminating fatal BCGosis.
explanation: >-
Establishes deferral of live BCG in screen-identified SCID as effectively
eliminating fatal disseminated BCG disease. Indirect because the evidence
is for SCID as a class rather than for CD247 deficiency specifically; IUIS
places this disorder in that class with very low T-cell numbers.
- reference: PMID:41727494
reference_title: "Case Report: Infant with vaccine-associated paralytic poliomyelitis unveils global disparities in care for inborn errors of immunity."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: >-
The lack of NBS for SCID, together with the continued usage of OPV in the
routine childhood vaccination program in most lower to middle income
countries is the perfect storm for VAPP in children born with IEIs in these
settings.
explanation: >-
Documents the oral polio vaccine counterpart of the same hazard and ties it
to absent newborn screening. Indirect for the same reason: a RAG1 Omenn
case, not CD247, but the exposure risk follows from the T-cell lymphopenia
this disorder shares.
differential_diagnoses:
- name: CD3gamma deficiency (CD3G)
description: >-
The instructive contrast within the same complex. CD3gamma deficiency leaves
T-cell numbers normal with reduced surface TCR, because CD3delta can partly
substitute for the missing chain, and the disease is correspondingly milder.
CD247 deficiency has no such substitute and presents with very low T cells.
The discriminator at the bench is the T-cell count, not the surface TCR level,
since both show reduced receptor.
evidence:
- reference: PMID:35748970
reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
CD3 deficiency CD3G AR 186740 Normal number, but low TCR expression Normal Normal Immune deficiency and autoimmunity of variable severity
explanation: >-
The IUIS row for CD3G, recording normal T-cell numbers with low TCR
expression, against the very low T-cell numbers recorded for CD3Z.
- name: CD3delta and CD3epsilon deficiency (CD3D, CD3E)
description: >-
The other CD3-chain defects that present as T-B+NK+ SCID, and the closest
clinical mimics. They are separated from CD247 deficiency only by gene
identity, so the practical route is a sequencing panel rather than a
laboratory discriminator.
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: >-
Shows CD3E defects produce the same terminal lesion — failure of complex
assembly and membrane expression — from a different subunit.
discussions:
- discussion_id: mouse_does_not_model_cd247
kind: HUMAN_MODEL_MISMATCH
prompt: >-
Can murine CD247 reconstitution data be used to predict the effect of a human
CD247 allele, given that the same truncating allele behaves differently in the
two species?
attaches_to:
- pathophysiology#Impaired TCR/CD3 Complex Assembly and Surface Expression
rationale: >-
The mismatch is allele-specific, not global, and that is the useful form of
the statement. MA5.8 handles a true null correctly: the exon 7 frameshift
allele fails to rescue TCR assembly or surface expression in that line, which
is exactly what it does in the patient. What MA5.8 gets wrong is the
retained-truncated-chain class — Q70X restores surface TCR there and does not
in human cells. So the practical rule is that a murine reconstitution result
can be trusted for an allele whose product is degraded away, and cannot be
trusted for an allele that leaves a partial chain behind.
The direction of the error matters: it is optimistic, so a damaging human
allele of the retained class looks tolerated in the mouse. And this is not an
isolated quirk of CD247 — the CD3 chains already have partly reciprocal roles
across the two species, with CD3delta loss permitting some T-cell development
in mice while causing SCID in humans, and CD3gamma loss doing the reverse.
Whether the human-specific requirement reflects different subunit
stoichiometry, different ER quality control, or something else has not been
established.
evidence:
- reference: PMID:40711587
reference_title: "Discordant Restoration of TCR Expression and Function by CD247 Somatic Reversions."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
MA5.8 mouse T cells do not accurately model human CD247 deficiencies, as
Q70X restores TCR expression in MA5.8 but not in human cells.
explanation: >-
The direct observation of the species mismatch.
- reference: PMID:17170122
reference_title: "T-B+NK+ severe combined immunodeficiency caused by complete deficiency of the CD3zeta subunit of the T-cell antigen receptor complex."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Additional studies demonstrated that retrovirally transduced patient mutant
CD3zeta cDNA failed to rescue assembly of nascent complete TCR complexes or
surface TCR expression in CD3zeta-deficient MA5.8 murine T-cell hybridoma
cells.
explanation: >-
The other half of the mismatch, and the reason it is allele-specific rather
than global: MA5.8 scores the frameshift allele correctly as failing to
rescue, while mis-scoring the retained-truncated-chain allele Q70X.
- reference: PMID:17291425
reference_title: "[Expression anomalies of the CD3-TCR complex expression and immunodeficiencies]."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: INDIRECT
snippet: >-
The main differences observed involve the respective roles of the CD3gamma
chain as well as the CD3delta, whose functions seem to be reciprocal between
the two species.
explanation: >-
Establishes that mouse-human divergence is a general feature of the CD3
complex rather than specific to CD247, which is why the mismatch should be
assumed rather than discovered for each subunit.
- discussion_id: reversion_expression_function_gap
kind: KNOWLEDGE_GAP
prompt: >-
Why does restoring CD247 surface expression by somatic reversion fail to
restore TCR signalling?
attaches_to:
- pathophysiology#Revertant Somatic Mosaicism
- pathophysiology#Loss of ITAM-Dependent Proximal TCR Signaling
rationale: >-
Revertant variants recover surface receptor in a graded way and none of them
recovers ZAP70 phosphorylation, and the ordering of expression rescue does not
match the ordering of activation rescue. Candidate explanations — that the
revertant residue supports folding but not ITAM phosphorylation, that
stoichiometry within the complex is wrong, or that the revertant cells are
developmentally abnormal because they arose after thymic selection — have not
been distinguished. This matters beyond CD247, because it is a natural
experiment on whether receptor density is a sufficient therapeutic target.
- discussion_id: heterozygous_nonsense_clinical_significance
kind: OPEN_QUESTION
prompt: >-
Do heterozygous CD247 nonsense alleles cause disease in their carriers, or are
they dominant-negative only in vitro?
attaches_to:
- genetic#CD247 heterozygous nonsense alleles
rationale: >-
Three patients with heterozygous nonsense CD247 alleles had signs of
immunodeficiency or autoimmunity, and the alleles suppress wild-type receptor
expression and signalling when transduced into wild-type Jurkat cells. But the
in vitro effect is measured under overexpression, no segregation or penetrance
data are reported, and the authors themselves state the correlation with
clinical features only as a possibility. Until that is settled the relationship
is recorded as disputed rather than causative.
notes: >-
Very few patients have been reported, so severity, frequency and treatment
statements here describe the published series rather than an established
disease spectrum.
Two nodes deliberately have no downstream edge. "Revertant Somatic Mosaicism"
modifies the disease course without being a step toward the phenotype, and
including it as a causal step would wrongly imply it contributes to the
immunodeficiency. The MA5.8 model link is recorded as FAILS_TO_RECAPITULATE
rather than omitted, because a negative model result is the substantive finding
that a curator reaching for murine CD247 data needs to see.
The second `genetic` entry uses relationship_type DISPUTED on purpose. The
dominant-negative effect of heterozygous nonsense alleles is well demonstrated
in cell lines but is not established as the cause of the carriers' clinical
features, and recording it as CAUSATIVE would overstate what the source claims.
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.
Create: Immunodeficiency 25 (CD247/CD3zeta deficiency) · 2026-08-31T17:38:55Z · View source
De novo curation of immunodeficiency 25 (MONDO:0012426), CD247/CD3zeta deficiency. One openscientist deep-research report was generated and preflighted with "just preflight-dr ... MONDO:0012426", which PASSed with CD247 as the dominant gene mention and matching OMIM 610163. The deep-research report made a material contribution here rather than merely confirming the entry. The first draft was written from a PubMed-led search that had surfaced the two recent Regueiro-group papers but not the founding case. The report identified Rieux-Laucat et al. NEJM 2006, PMID:16672702, the four-month-old boy with homozygous Q70X and three heterozygous somatic second-site changes; that reference was fetched and its quoted sentences verified against the cache before being added. PMID:28743717 was added alongside it, distinguishing true reversion from second-site compensation and supplying the measured mutation-propensity explanation for why reversion is common in this gene. Pathograph: biallelic CD247 loss-of-function variants, impaired TCR/CD3 complex assembly and surface expression, loss of ITAM-dependent proximal TCR signaling, failed thymic selection and T-cell development, T-cell lymphopenia with impaired function. A sixth node, Revertant Somatic Mosaicism, is curated with no downstream edge because it modifies the disease course without being a step toward the phenotype; treating it as a causal step would wrongly imply it contributes to the immunodeficiency. Two model systems are curated. The MA5.8 murine CD247-deficient T-cell line is recorded as FAILS_TO_RECAPITULATE, because the Q70X allele restores surface TCR in that line and not in human cells; the error direction is optimistic, making a damaging human allele look tolerated. That grounds a HUMAN_MODEL_MISMATCH discussion, supported additionally by the established mouse-human reciprocity of CD3gamma and CD3delta roles, which means the mismatch should be assumed across the CD3 complex rather than rediscovered per subunit. The ZKO CRISPR Jurkat line carries the positive mechanistic argument. A second genetic entry records heterozygous nonsense CD247 alleles with relationship_type DISPUTED. Their dominant-negative effect is well demonstrated in cell lines under overexpression, but no segregation or penetrance data are reported and the source states the correlation with clinical features only as a possibility, so recording it as CAUSATIVE would overstate the claim. An OPEN_QUESTION discussion records what would settle it. Validated with just validate for schema and references, 42 of 42 snippets verified against cached references, plus just validate-terms, just check-entity-refs and just check-duplicate-keys, all passing.
Disease: Immunodeficiency 25 (IMD25) Identifiers: MONDO:0012426 · OMIM #610163 · MeSH C565712 · UMLS C1857798 · MedGen 346666 · GARD 0018294 · DOID:0060007 / DOID:0111942 Causal gene: CD247 (CD3ζ/zeta chain), 1q24.2 · HGNC:1677 · NCBI Gene 919 · Ensembl ENSG00000198821 · UniProt P20963 Category: Mendelian, autosomal-recessive inborn error of immunity (T–B+NK+ SCID)
Immunodeficiency 25 (IMD25) is a rare autosomal-recessive severe combined immunodeficiency (SCID) caused by biallelic loss-of-function mutations in CD247, the gene on chromosome 1q24.2 encoding CD3ζ (the zeta signal-transducing subunit of the T-cell receptor [TCR]/CD3 complex). CD3ζ assembles as an invariant homodimer bearing three immunoreceptor tyrosine-based activation motifs (ITAMs) and is required both to assemble the TCR/CD3 complex and export it to the cell surface, and to transduce activating signals after antigen engagement. When CD3ζ is absent or non-functional, thymic T-cell development and peripheral T-cell signaling fail, producing the characteristic T-cell-low/absent, B-cell-normal, NK-cell-normal (T–B+NK+) SCID immunophenotype with low surface CD3 expression.
The disease was first defined by two landmark reports. Rieux-Laucat et al. (NEJM 2006) described a 4-month-old boy with a homozygous germline nonsense mutation (Q70X) in CD247 and, remarkably, somatic revertant mosaicism in which second-site somatic mutations partially restored TCR/CD3 expression in a subset of T cells. Roberts et al. (2007) reported a T–B+NK+ SCID patient homozygous for a frameshifting single-C insertion in exon 7, whose T cells had no detectable CD3ζ protein, low surface CD3ε, and were non-functional; transduced mutant CD3ζ failed to rescue TCR assembly and was unstable/degraded. Subsequent work (Briones et al. 2024) established that CD3ζ ITAMs are dosage-sensitive and that certain heterozygous truncating alleles behave as dominant negatives, expanding the phenotype toward a leakier combined immunodeficiency with autoimmune features.
Clinically, IMD25 behaves like other CD3-chain SCIDs: it presents in early infancy with recurrent/severe/opportunistic infections, failure to thrive, and susceptibility to disseminated disease from live vaccines (e.g., BCGosis). It is one of the ~19+ genetic causes of SCID, an emergency group with a modern population incidence of roughly 1 in 46,000–58,000 live births. Left untreated, SCID is usually fatal within the first year of life. The established curative treatment is allogeneic hematopoietic stem-cell transplantation (HCT), and outcomes are markedly improved by early (pre-symptomatic) diagnosis, which is now achievable through TREC-based newborn screening. IMD25 is very rare — only a handful of families have been reported worldwide — so many disease characteristics are extrapolated from the broader T–B+NK+ SCID / CD3-chain deficiency literature, and this is flagged throughout.
Roberts et al. (2007) reported a patient with T–B+NK+ SCID who was homozygous for a single C insertion following nucleotide 411 in exon 7 of the CD3zeta (CD247) gene. The patient's T cells had no detectable CD3ζ protein, expressed only low levels of surface CD3ε, and were functionally inert. In a mechanistic complementation experiment, the mutant CD3ζ transduced into CD3ζ-deficient murine hybridoma cells failed to rescue TCR assembly and surface expression, and the mutant protein was unstable and rapidly degraded. This provided the first demonstration that complete CD3ζ deficiency in humans causes SCID specifically by preventing normal TCR assembly and surface expression. The corresponding OMIM phenotype entry is #610163, and the gene CD247 maps to 1q24.2 (HGNC:1677).
"We report here a patient with T(-)B(+)NK(+) severe combined immunodeficiency (SCID) who was homozygous for a single C insertion following nucleotide 411 in exon 7 of the CD3zeta gene." — PMID: 17170122
"these findings provide the first demonstration that complete CD3zeta deficiency in humans can cause SCID by preventing normal TCR assembly and surface expression." — PMID: 17170122
This finding anchors the disease definition: the initiating molecular lesion (biallelic CD247 LOF) has a direct, demonstrated causal link to the cellular defect (no TCR assembly/surface export) and the clinical phenotype (T–B+NK+ SCID).
Briones et al. (2024) dissected genotype–phenotype relationships using CD247 variants modeled in Jurkat T cells. They established that the invariant TCRζ/CD247 homodimer is crucial for TCR/CD3 expression and signaling through its three ITAMs, that homozygous null mutations cause immunodeficiency, and that heterozygous carriers exhibit ~50% reduced surface CD3 — evidence of a strict gene-dosage relationship. Nonsense mutations ablating 1, 2, or 3 ITAMs restored only 60%, 22%, and 10% of surface CD3 in knockout cells, respectively, and, when co-expressed with wild-type CD3ζ, reduced WT surface CD3 to 39%, 19%, and 9% — a clear, ITAM-count-dependent dominant-negative effect. Two heterozygous nonsense variants (p.Y152X, p.Q101X) were identified in patients showing signs of immunodeficiency and autoimmunity, broadening the allelic/inheritance spectrum beyond classic recessive nulls.
"The invariant TCR ζ/CD247 homodimer is crucial for TCR/CD3 expression and signaling through its 3 immunoreceptor tyrosine-based activation motifs (ITAMs). Homozygous null mutations in CD247 lead to immunodeficiency, while carriers exhibit 50% reduced surface CD3." — PMID: 38992472
This finding is important for variant interpretation: truncating alleles that retain part of the protein but ablate ITAMs can poison WT complexes, meaning some heterozygotes are not silent carriers but may develop a milder combined immunodeficiency/autoimmunity phenotype.
The founding case of IMD25 (Rieux-Laucat et al., NEJM 2006) was a 4-month-old boy with primary immunodeficiency and a homozygous germline CD247 (CD3ζ) mutation, Q70X. Some of his T cells carried Q70X on both alleles and showed low surface TCR/CD3, while other T cells had normal complex levels because they retained Q70X on only one allele plus one of three heterozygous somatic second-site mutations on the other allele, restoring poorly functional TCR/CD3 complexes. This established both germline causation and the striking phenomenon of somatic reversion in CD247 deficiency.
"A four-month-old boy with primary immunodeficiency was found to have a homozygous germ-line mutation of the gene encoding the CD3zeta subunit of the T-cell receptor-CD3 complex." — PMID: 16672702
"other T cells had normal levels of the complex and bore the Q70X mutation on only one allele of CD3zeta, plus one of three heterozygous somatic mutations of CD3zeta on the other allele, allowing expression of poorly functional T-cell receptor-CD3 complexes." — PMID: 16672702
Follow-up work confirmed and mechanistically explained the phenomenon. Marin et al. (2017; PMID: 27555457) reported "primary T-cell immunodeficiency with functional revertant somatic mosaicism in CD247," and Blázquez-Moreno et al. (2017) showed that recovery of CD247/TCR surface expression occurred through both true reversion of the inactivating mutation and a compensating second-site mutation, and that CD247 has a higher-than-expected mutation rate, with PID genes prone to reversion showing elevated mutation propensity.
"Mutations in T-cell antigen receptor (TCR) subunit genes cause rare immunodeficiency diseases characterized by impaired expression of the TCR at the cell surface and selective T lymphopenia." — PMID: 28743717
"The recovery of CD247 expression in some patient T cells was associated with both reversion of the inactivating mutation and a variant with a compensating mutation that could reconstitute TCR expression" — PMID: 28743717
Clinically, revertant mosaicism can partially blunt lymphopenia and complicate diagnosis (a subset of T cells may show near-normal surface CD3), and it is a natural proof-of-concept that even partial restoration of CD3ζ can restore some TCR expression.
CD3ζ/CD247 deficiency is a very rare subtype within the SCID group, for which contemporary TREC-based newborn screening provides population-level incidence estimates. Screening programs report an incidence of 1:46,753 in Catalonia (105 screen-positive among 420,263 newborns; PMID: 42079620), ~1:49,800–57,000 in Ukraine (PMID: 41459527), and a severe T/B immunodeficiency birth prevalence of 1:12,298 in Russia (2.3 million newborns; PMID: 41727503). Universal TREC screening enables presymptomatic diagnosis and, by deferring live BCG vaccination in affected neonates, "virtually eliminates fatal BCGosis."
"Among 420,263 screened newborns, 105 screened positive (0.02%). SCID was diagnosed in eight infants and congenital athymia in one, corresponding to an overall incidence of 1:46,753 live births." — PMID: 42079620
"Implementation of universal newborn screening for severe combined immunodeficiency (SCID) using the T-cell receptor excision circle (TREC) assay now enables prospective identification and deferral of these high-risk neonates, virtually eliminating fatal BCGosis." — PMID: 41441645
Because CD3ζ deficiency causes profound T-lymphopenia, affected infants are expected to have low/absent TREC values on newborn screening and would be detected by these assays (an important caveat: revertant mosaicism could theoretically raise TREC values in rare cases, analogous to how ZAP70 deficiency with normal T-cell numbers has been missed).
Allogeneic HCT is the established curative therapy for SCID, including CD3-chain defects. The PIDTC analysis of 796 children with SCID receiving non-sibling HCT (1982–2020) found that newborn screening "was associated with earlier diagnosis, reduced infection at HCT, and elimination of survival disparities" (PMID: 42416786). Screening programs likewise report that early definitive treatment yields "excellent survival outcomes" (PMID: 42079620). This paradigm applies directly to CD3-chain SCID: durable T-cell reconstitution after HCT has been documented for CD3ε deficiency (PMID: 24515816) and CD3γ deficiency with resolution of inflammatory bowel disease (PMID: 18482219).
"NBS was associated with earlier diagnosis, reduced infection at HCT, and elimination of survival disparities between Black and non-Hispanic White patients." — PMID: 42416786
"enabling early definitive treatment and excellent survival outcomes with a low false-positive burden" — PMID: 42079620
EBI OLS4 (Mondo) resolves "immunodeficiency 25" to MONDO:0012426 with equivalentTo cross-references OMIM:610163, MeSH:C565712, UMLS:C1857798, MedGen:346666, GARD:0018294, and DOID:0060007/DOID:0111942. Mondo synonyms include "CD3zeta deficiency," "severe combined immunodeficiency caused by mutation in CD247," "CD247 severe combined immunodeficiency," and "IMD25." No direct Orphanet equivalentTo xref is listed in Mondo. mygene.info confirms human CD247: HGNC:1677, OMIM gene 186780, Ensembl ENSG00000198821, UniProt P20963, cytoband 1q24.2, NCBI Gene 919, protein-coding; the mouse ortholog Cd247 is NCBI Gene 12503 (chromosome 1).
Overview. Immunodeficiency 25 is a Mendelian, autosomal-recessive inborn error of immunity in which biallelic loss-of-function mutations in CD247 abolish or cripple the CD3ζ subunit of the TCR/CD3 complex. The result is a failure of TCR assembly, surface export, and signaling, blocking T-cell development and producing a T–B+NK+ SCID (T cells low/absent; B and NK cells present in number, though B-cell function is impaired secondary to the lack of T-cell help).
Key identifiers.
| Resource | Identifier |
|---|---|
| MONDO | MONDO:0012426 |
| OMIM (phenotype) | #610163 |
| OMIM (gene CD247) | 186780 |
| MeSH | C565712 |
| UMLS | C1857798 |
| MedGen | 346666 |
| GARD | 0018294 |
| DOID | 0060007 / 0111942 |
| HGNC (gene) | HGNC:1677 |
| ICD-10 | D81.x (combined immunodeficiencies; no CD247-specific code) |
| ICD-11 | 4A01.1 (Combined immunodeficiencies; no CD247-specific code) |
| Orphanet | Falls within "Severe combined immunodeficiency" / T-B+ SCID group; no direct Mondo xref |
Synonyms / alternative names. CD3ZETA deficiency; CD3ζ deficiency; CD247 SCID; severe combined immunodeficiency due to CD247 (CD3zeta) deficiency; T-cell receptor/CD3 complex zeta-chain deficiency; IMD25.
Information source. The disease-level knowledge is derived predominantly from aggregated resources (OMIM, Mondo, ClinVar) and from a very small number of individual patient case reports (Rieux-Laucat 2006; Roberts 2007; Marin/Blázquez-Moreno 2017; Briones 2024). It is not an EHR/population-derived phenotype; conclusions rest on <10 reported families plus extrapolation from the broader CD3-chain SCID literature.
Disease causal factors. Purely genetic and monogenic: biallelic (homozygous or compound-heterozygous) loss-of-function variants in CD247. No environmental or infectious cause; infections are downstream consequences, not causes. Certain heterozygous truncating alleles (e.g., p.Y152X, p.Q101X) act dominant-negatively and can produce a milder immunodeficiency/autoimmunity phenotype (F002).
Genetic risk factors. The causal variants are the risk factor. Reported alleles include Q70X (nonsense; founding case), a frameshifting single-C insertion in exon 7, and ITAM-truncating nonsense variants. Consanguinity raises the risk of homozygous recessive disease, as with other rare autosomal-recessive SCIDs.
Environmental risk factors. None established as causal. Live vaccines (BCG, oral polio) are a major iatrogenic hazard in undiagnosed infants (disseminated BCGosis, vaccine-associated paralytic polio; PMID: 41441645, PMID: 41727494), but they trigger complications rather than cause the disease.
Protective factors. No germline protective alleles are known. A disease-intrinsic partial "rescue" occurs via somatic revertant mosaicism (true reversion or compensating second-site mutation), which can partly restore TCR expression in a subset of T cells (F003/F004).
Gene–environment interactions. The dominant interaction is genotype × vaccination: the underlying T-cell defect converts attenuated live vaccines into life-threatening infections. Otherwise the disorder is essentially fully genetically determined.
Because IMD25 is a SCID, phenotypes overlap those of other T–B+NK+ SCID/CD3-chain defects. Frequencies are qualitative given the tiny case series.
| Phenotype | Type | HPO term (suggested) | Onset | Frequency |
|---|---|---|---|---|
| Severe/recurrent infections | Clinical | HP:0002719 (Recurrent infections) | Neonatal–early infancy | Near-universal |
| T-lymphopenia | Lab abnormality | HP:0005403 (Decreased circulating T cell count) | Congenital | Near-universal (may be attenuated by reversion) |
| Reduced surface CD3/TCR | Lab abnormality | HP:0410002 (Abnormal T cell count) / low CD3 | Congenital | Characteristic |
| Impaired T-cell function/proliferation | Lab abnormality | HP:0002850 (Decreased proliferation of T cells) | Congenital | Characteristic |
| Failure to thrive | Sign | HP:0001508 (Failure to thrive) | Infancy | Common |
| Chronic diarrhea | Sign | HP:0002028 (Chronic diarrhea) | Infancy | Common (CD3-chain SCID) |
| Recurrent respiratory infection/pneumonia | Sign | HP:0002090 (Pneumonia) | Infancy | Common |
| Normal B- and NK-cell counts | Lab | HP:0010976 (Abnormal B-cell morphology — normal count) | Congenital | Defining (T–B+NK+) |
| Autoimmune features (with DN alleles) | Sign/lab | HP:0002960 (Autoimmunity) | Variable | Subset (dominant-negative truncating alleles, F002) |
| Susceptibility to disseminated BCG/live vaccines | Clinical | HP:0410282 (BCG-related complication) | Post-vaccination | High if vaccinated |
Characteristics. Onset is neonatal/early-infantile; severity is severe (classic SCID) but variable and can be leakier where hypomorphic/dominant-negative alleles or revertant mosaicism partly restore function; course is progressive and fatal without treatment.
Quality-of-life impact. Untreated SCID is incompatible with survival beyond infancy; after successful HCT, most survivors achieve durable immune reconstitution with good QoL, though some develop late humoral defects requiring immunoglobulin replacement (analogous to the CD3ε-SCID case, PMID: 24515816). No IMD25-specific EQ-5D/SF-36 data exist.
Causal gene. CD247 (CD3ζ), 1q24.2; HGNC:1677; NCBI Gene 919; Ensembl ENSG00000198821; UniProt P20963; OMIM gene 186780. Encodes the invariant ζ-chain that homodimerizes and contributes three of the ten ITAMs in the TCR/CD3 complex.
Pathogenic variants (reported).
| Variant | Type | Zygosity | Consequence | Reference |
|---|---|---|---|---|
| c.Q70X (p.Gln70*) | Nonsense | Homozygous germline (+ somatic reversion) | LOF; low surface TCR/CD3 | PMID: 16672702 |
| Single-C insertion after nt 411, exon 7 | Frameshift | Homozygous | No CD3ζ protein; unstable/degraded; TCR assembly failure | PMID: 17170122 |
| p.Y152X | Nonsense (ITAM-truncating) | Heterozygous | Dominant-negative; immunodeficiency/autoimmunity | PMID: 38992472 |
| p.Q101X | Nonsense (ITAM-truncating) | Heterozygous | Dominant-negative | PMID: 38992472 |
| Somatic second-site/reversion variants | Missense/reversion | Somatic (in T cells) | Partially restores TCR/CD3 | PMID: 16672702, PMID: 28743717 |
Classification. Homozygous/compound-heterozygous null variants are pathogenic (ACMG); the ITAM-truncating heterozygous alleles are supported as pathogenic by functional dominant-negative evidence (PS3).
Allele frequency. Pathogenic CD247 LOF alleles are exceedingly rare/private in gnomAD; carrier frequency for classic recessive disease is not established but is expected to be very low.
Functional consequences. Predominantly loss of function (no protein / unstable protein / failed TCR assembly). ITAM-truncating alleles additionally exert a dominant-negative effect on WT complexes (F002).
Somatic vs germline. Disease-causing alleles are germline; the disorder is notable for recurrent somatic revertant mosaicism in T cells (F003/F004).
Modifier genes / epigenetics / chromosomal abnormalities. None specifically identified for IMD25. The main "modifier" is intrinsic — the presence and extent of somatic reversion.
There are no environmental, toxic, lifestyle, or infectious causal factors. Infectious agents (bacteria, viruses, fungi, opportunists) are downstream consequences of the immunodeficiency, and live-attenuated vaccines are a specific iatrogenic danger (BCGosis, VAPP) in undiagnosed infants (PMID: 41441645, PMID: 41727494).
Ordered causal chain (initiating lesion → clinical manifestation):
Branch A — dominant-negative alleles: ITAM-truncating heterozygous variants → poison WT ζ-containing complexes (surface CD3 reduced to 39%/19%/9% for 1/2/3 ITAMs lost) → partial signaling deficiency → leakier combined immunodeficiency with autoimmunity (PMID: 38992472).
Branch B — somatic reversion: true reversion or compensating second-site somatic mutation in a T-cell precursor → restored (poorly functional) TCR/CD3 → partial reconstitution of a T-cell subset → attenuated lymphopenia and diagnostic mosaicism (PMID: 16672702, PMID: 28743717).
Molecular pathway. TCR/CD3 signaling (Reactome "TCR signaling"; KEGG hsa04660 "T cell receptor signaling pathway"). Downstream, ITAM phosphorylation by Lck recruits ZAP-70 (whose thymic role in sustaining pre-TCR/TCR signaling is established, PMID: 17606633); loss of CD3ζ abolishes the ITAM platform upstream of ZAP-70.
Suggested GO / CL terms. GO:0050852 (T cell receptor signaling pathway); GO:0007166 (cell surface receptor signaling); GO:0030217 (T cell differentiation); GO:0033077 (T cell differentiation in thymus); GO:0002250 (adaptive immune response). Cell types: CL:0000084 (T cell), CL:0000893 (thymocyte), CL:0000625 (CD8-positive αβ T cell), CL:0000624 (CD4-positive αβ T cell).
Suggested LOINC/lab categories: lymphocyte subset enumeration (CD3/CD4/CD8/CD19/CD16-56), TREC quantification, lymphocyte proliferation assays, immunoglobulin levels.
GERMLINE MOLECULAR CELLULAR CLINICAL
───────────── ───────────── ───────────── ─────────────
Biallelic CD247 LOF ──▶ Absent/unstable CD3ζ ──▶ TCR/CD3 fails to ──▶ Thymic T-cell
(Q70X; fs exon7) homodimer (no 3 ITAMs) assemble & reach developmental block
the cell surface → T-lymphopenia (T–)
│ │
│ ▼
│ Loss of T-cell help
│ → B cells present but
│ antibody-deficient (B+)
│ NK cells preserved (NK+)
▼ │
No ITAM platform for ▼
ZAP-70 → no TCR signaling Recurrent/opportunistic
infections, FTT, BCGosis
→ SCID, fatal untreated
┌──────────────────────────────────────────────────────────────────────────────────────┐
│ BRANCH A (dominant-negative ITAM-truncating heterozygous alleles, e.g. Y152X, Q101X): │
│ mutant ζ poisons WT complexes → partial surface CD3 (9–39%) → leaky CID + autoimmunity│
│ BRANCH B (somatic revertant mosaicism): true reversion or 2nd-site somatic mutation in │
│ a T-cell precursor → partial TCR restoration → attenuated lymphopenia, diagnostic │
│ mosaicism (natural proof-of-concept for gene correction) │
└──────────────────────────────────────────────────────────────────────────────────────┘
│
▼
INTERVENTION: TREC newborn screening → early diagnosis
→ infection prophylaxis + live-vaccine deferral
→ allogeneic HCT (curative)
The upstream lesion (biallelic CD247 LOF) is directly and experimentally connected to the downstream immunophenotype: the absence of a functional CD3ζ homodimer removes both the structural scaffold needed to assemble/export the TCR/CD3 complex and the three ITAMs needed to nucleate ZAP-70-dependent signaling. The two branches (dominant-negative alleles and somatic reversion) explain the disease's variable expressivity and its diagnostic subtleties.
| PMID | Title (abbrev.) | Evidence type | Role |
|---|---|---|---|
| 16672702 | Inherited and somatic CD3ζ mutations (Rieux-Laucat, NEJM 2006) | Human clinical | Founding IMD25 case; germline Q70X + somatic reversion |
| 17170122 | T–B+NK+ SCID from complete CD3ζ deficiency (Roberts 2007) | Human clinical + in vitro | Defines mechanism: no protein, failed TCR assembly |
| 38992472 | Nonsense CD247 mutations show dominant-negative features (Briones 2024) | In vitro (Jurkat) | ITAM dosage; dominant-negative alleles; carrier CD3 halving |
| 28743717 | Recovery of CD247 expression / spontaneous repair | Human + molecular | Reversion + compensating mutation mechanisms |
| 27555457 | Primary T-cell immunodeficiency with revertant mosaicism in CD247 | Human clinical | Documents functional somatic mosaicism |
| 42416786 | Newborn screening reduces survival disparities in SCID (PIDTC) | Human cohort (n=796) | Early diagnosis → reduced infection at HCT, better survival |
| 42079620 | SCID newborn screening in Catalonia | Population screening | SCID incidence 1:46,753; excellent outcomes with early Rx |
| 41459527 | NBS for SCID in Ukraine | Population screening | Incidence ~1:49,800–57,000; 85.7% HCT survival |
| 41727503 | Russia TREC/KREC NBS (2.3M newborns) | Population screening | Severe T/B ID prevalence 1:12,298 |
| 41441645 | BCGitis/BCGosis mechanisms | Review | Live-vaccine hazard; screening prevents fatal BCGosis |
| 24515816 | Haploidentical HCT in CD3ε-SCID | Human clinical | CD3-chain SCID curable by HCT; late humoral decline |
| 18482219 | HCT in CD3γ deficiency with IBD | Human clinical | CD3-chain SCID HCT; IBD resolution |
| 17291425 | CD3-TCR complex expression anomalies & immunodeficiencies | Review | Human–mouse differences among CD3 chains |
| 17606633 | Syk/ZAP-70 in early thymocyte development | Mouse | Downstream ITAM/ZAP-70 signaling context |
| 41727494 | VAPP in SCID (case report) | Human clinical | Live-vaccine hazard where NBS absent |
Report compiled from an autonomous multi-iteration investigation (8 confirmed findings, 27 papers reviewed). Evidence types are distinguished as human clinical, in vitro, model organism, and population-screening data. All mechanistic and clinical claims are cited to primary literature by PMID.