T-B+ severe combined immunodeficiency due to CD3delta/CD3epsilon/CD3zeta

Summary

T-B+ severe combined immunodeficiency due to CD3delta/CD3epsilon/CD3zeta (MONDO:0015703) is a disease with 3 cohort genes. The dominant Reactome pathway is Translocation of ZAP-70 to Immunological synapse (3 cohort genes).

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Cohort genes: 3
• Phenotypes (HPO): 23

Clinical features

Signs & symptoms

Clinical features (HPO)

23 HPO clinical features (Orphanet curated; top 23 by frequency):

HPO ID	Term	Frequency
HP:0002719	Recurrent infections	Very frequent (80-99%)
HP:0001888	Lymphopenia	Frequent (30-79%)
HP:0001945	Fever	Frequent (30-79%)
HP:0003460	Decreased circulating total IgA	Frequent (30-79%)
HP:0004315	Decreased circulating IgG level	Frequent (30-79%)
HP:0008866	Failure to thrive secondary to recurrent infections	Frequent (30-79%)
HP:0031381	Decreased lymphocyte proliferation in response to mitogen	Frequent (30-79%)
HP:0045080	Decreased proportion of CD3-positive T cells	Frequent (30-79%)
HP:0000388	Otitis media	Occasional (5-29%)
HP:0001019	Erythroderma	Occasional (5-29%)
HP:0001433	Hepatosplenomegaly	Occasional (5-29%)
HP:0001880	Eosinophilia	Occasional (5-29%)
HP:0002014	Diarrhea	Occasional (5-29%)
HP:0002039	Anorexia	Occasional (5-29%)
HP:0002090	Pneumonia	Occasional (5-29%)
HP:0002722	Recurrent abscess formation	Occasional (5-29%)
HP:0004385	Protracted diarrhea	Occasional (5-29%)
HP:0005353	Recurrent herpes	Occasional (5-29%)
HP:0005401	Recurrent candida infections	Occasional (5-29%)
HP:0006532	Recurrent pneumonia	Occasional (5-29%)
HP:0009098	Chronic oral candidiasis	Occasional (5-29%)
HP:0010702	Increased circulating antibody level	Occasional (5-29%)
HP:0012115	Hepatitis	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	T-B+ severe combined immunodeficiency due to CD3delta/CD3epsilon/CD3zeta
Mondo ID	MONDO:0015703
Orphanet	169160
UMLS	C5679578
MedGen	1842819
GARD	0017053
Is cancer (heuristic)	no

Also known as: T-B+ SCID due to CD3delta/CD3epsilon/CD3zeta

Data availability: 3 GenCC gene-disease records.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › immunodeficiency disease › combined immunodeficiency › severe combined immunodeficiency › T-B+ severe combined immunodeficiency › T-B+ severe combined immunodeficiency due to CD3delta/CD3epsilon/CD3zeta

Related subtypes (9): T-B+ severe combined immunodeficiency due to gamma chain deficiency, combined immunodeficiency, X-linked, T-B+ severe combined immunodeficiency due to JAK3 deficiency, immunodeficiency 104, lung fibrosis-immunodeficiency-46,XX gonadal dysgenesis syndrome, severe combined immunodeficiency due to CORO1A deficiency, T-B+ severe combined immunodeficiency due to IL-7Ralpha deficiency, T-B+ severe combined immunodeficiency due to CD45 deficiency, severe combined immunodeficiency due to LAT deficiency

Subtypes (3): immunodeficiency 25, immunodeficiency 18, immunodeficiency 19

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 5 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
CD3E	Definitive	Autosomal recessive	immunodeficiency 18	3
CD247	Strong	Autosomal recessive	immunodeficiency 25	3
CD3D	Strong	Autosomal recessive	immunodeficiency 19	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CD3D	Orphanet:169160	T-B+ severe combined immunodeficiency due to CD3delta/CD3epsilon/CD3zeta
CD3E	Orphanet:169160	T-B+ severe combined immunodeficiency due to CD3delta/CD3epsilon/CD3zeta
CD247	Orphanet:169160	T-B+ severe combined immunodeficiency due to CD3delta/CD3epsilon/CD3zeta
CD247	Orphanet:85408	Rheumatoid factor-negative polyarticular juvenile idiopathic arthritis
CD247	Orphanet:85410	Oligoarticular juvenile idiopathic arthritis

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CD3D	HGNC:1673	ENSG00000167286	P04234	T-cell surface glycoprotein CD3 delta chain	gencc
CD3E	HGNC:1674	ENSG00000198851	P07766	T-cell surface glycoprotein CD3 epsilon chain	gencc
CD247	HGNC:1677	ENSG00000198821	P20963	T-cell surface glycoprotein CD3 zeta chain	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CD3D	T-cell surface glycoprotein CD3 delta chain	Part of the TCR-CD3 complex present on T-lymphocyte cell surface that plays an essential role in adaptive immune response.
CD3E	T-cell surface glycoprotein CD3 epsilon chain	Part of the TCR-CD3 complex present on T-lymphocyte cell surface that plays an essential role in adaptive immune response.
CD247	T-cell surface glycoprotein CD3 zeta chain	Part of the TCR-CD3 complex present on T-lymphocyte cell surface that plays an essential role in adaptive immune response.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Antibody/Immunoglobulin	2	19.5×	0.007
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CD3D	Antibody/Immunoglobulin	yes		Phos_immunorcpt_sig_ITAM, Ig-like_fold, CD3_esu/gsu/dsu
CD3E	Antibody/Immunoglobulin	yes		Phos_immunorcpt_sig_ITAM, Ig_sub2, Ig-like_fold
CD247	Other/Unknown	no		Phos_immunorcpt_sig_ITAM, CD3_zeta/IgE_Fc_rcpt_gamma, T-cell_CD3_zeta

Expression context

Cohort genes with no expression data: 0.

3 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	3
lymph node	2
thymus	2
vermiform appendix	1
blood	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CD3D	221	broad	marker	thymus, granulocyte, lymph node
CD3E	168	broad	marker	granulocyte, vermiform appendix, lymph node
CD247	179	broad	marker	granulocyte, thymus, blood

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CD3D	4,789
CD247	2,417
CD3E	2,267

Intra-cohort edges

A	B	Sources
CD247	CD3D	string_interaction
CD247	CD3E	biogrid_interaction, string_interaction
CD3D	CD3E	intact, string_interaction

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CD3E	P07766	44
CD247	P20963	38
CD3D	P04234	31

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 20. Enrichment computed across 3 evidence-associated genes (3 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Translocation of ZAP-70 to Immunological synapse	3	634.4×	4e-08	CD3D, CD3E, CD247
Phosphorylation of CD3 and TCR zeta chains	3	543.8×	4e-08	CD3D, CD3E, CD247
Co-inhibition by PD-1	3	519.1×	4e-08	CD3D, CD3E, CD247
Generation of second messenger molecules	3	346.1×	1e-07	CD3D, CD3E, CD247
Downstream TCR signaling	3	128.3×	2e-06	CD3D, CD3E, CD247
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	3	87.2×	5e-06	CD3D, CD3E, CD247
TCR signaling	2	331.0×	3e-05	CD3D, CD3E
Regulation of T cell activation by CD28 family	2	282.0×	4e-05	CD3D, CD3E
Nef and signal transduction	1	423.0×	0.005	CD247
FCGR activation	1	292.8×	0.006	CD247
Adaptive Immune System	2	19.9×	0.006	CD3D, CD3E
Role of phospholipids in phagocytosis	1	152.3×	0.011	CD247
FCGR3A-mediated IL10 synthesis	1	97.6×	0.016	CD247
FCGR3A-mediated phagocytosis	1	62.4×	0.021	CD247
Regulation of actin dynamics for phagocytic cup formation	1	61.4×	0.021	CD247
Immune System	2	8.6×	0.021	CD3D, CD3E
Cargo recognition for clathrin-mediated endocytosis	1	34.9×	0.033	CD3D
Clathrin-mediated endocytosis	1	28.4×	0.039	CD3D
Membrane Trafficking	1	12.4×	0.083	CD3D
Vesicle-mediated transport	1	11.6×	0.084	CD3D

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
alpha-beta T cell activation	3	3370.4×	5e-10	CD3D, CD3E, CD247
T cell receptor signaling pathway	3	151.8×	5e-06	CD3D, CD3E, CD247
gamma-delta T cell activation	2	1404.3×	7e-06	CD3E, CD247
positive thymic T cell selection	2	936.2×	1e-05	CD3D, CD3E
adaptive immune response	3	84.3×	1e-05	CD3D, CD3E, CD247
cell surface receptor signaling pathway	3	64.1×	2e-05	CD3D, CD3E, CD247
protein-containing complex assembly	2	75.9×	0.001	CD3E, CD247
T cell anergy	1	1404.3×	0.003	CD3E
positive regulation of T cell anergy	1	936.2×	0.004	CD3E
signal complex assembly	1	702.2×	0.004	CD3E
positive regulation of cell-cell adhesion mediated by integrin	1	702.2×	0.004	CD3E
CD4-positive, alpha-beta T cell proliferation	1	624.1×	0.004	CD3E
Fc-gamma receptor signaling pathway	1	624.1×	0.004	CD247
positive regulation of CD4-positive, alpha-beta T cell proliferation	1	561.7×	0.005	CD3E
negative thymic T cell selection	1	468.1×	0.005	CD3E
positive regulation of protein localization to cell surface	1	255.3×	0.009	CD247
positive regulation of cell-matrix adhesion	1	224.7×	0.009	CD3E
protein complex oligomerization	1	224.7×	0.009	CD247
positive regulation of interleukin-4 production	1	187.2×	0.010	CD3E
positive regulation of interleukin-2 production	1	156.0×	0.011	CD3E
negative regulation of smoothened signaling pathway	1	151.8×	0.011	CD3E
positive regulation of calcium-mediated signaling	1	140.4×	0.012	CD3E
dendrite development	1	130.6×	0.012	CD3E
T cell costimulation	1	124.8×	0.012	CD3E
cerebellum development	1	119.5×	0.012	CD3E
positive regulation of T cell proliferation	1	86.4×	0.015	CD3E
T cell activation	1	86.4×	0.015	CD3E
positive regulation of type II interferon production	1	74.9×	0.017	CD3E
apoptotic signaling pathway	1	74.9×	0.017	CD3E
calcium-mediated signaling	1	61.1×	0.019	CD3E

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 3

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CD3D	0	0
CD3E	0	0
CD247	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	2	CD3D, CD3E
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	CD247

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
CD3D	0	—
CD3E	0	—
CD247	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.