| Domain | Curated finding | Evidence scope | Suggested ontology/identifier |
|---|---|---|---|
| Disease identity | Immunodeficiency 18 is a Mendelian inborn error of immunity caused by biallelic loss-of-function of **CD3E**, typically presenting as **T−B+NK+ severe combined immunodeficiency (SCID)**. (pqac-00000000, pqac-00000035, pqac-00000023) | Human disease-level resources + primary human cases | MONDO:0014278; OMIM phenotype: 615615 |
| Gene | Causal gene: **CD3E** (CD3 epsilon subunit of T-cell receptor complex); Open Targets links CD3E to immunodeficiency 18. (pqac-00000000) | Curated disease-target association + literature-backed evidence | CD3E; Ensembl: ENSG00000198851 |
| Inheritance | Inheritance is **autosomal recessive**; early reports showed affected children from consanguineous families and unaffected heterozygous relatives. (pqac-00000035, pqac-00000036) | Primary human families | HP:0000007 Autosomal recessive inheritance |
| Core immunophenotype | Typical immune phenotype is **absence or near-absence of peripheral T cells** with preserved/elevated **B cells** and present **NK cells**: T−B+NK+. Low/absent IgA and low IgG after maternal IgG wanes are reported. (pqac-00000035, pqac-00000034, pqac-00000023) | Primary human cases | HP:0005403 Absence of T cells; HP:0002841 Hypogammaglobulinemia; SCID phenotype |
| Key infectious/clinical phenotypes | Reported manifestations include early-onset diarrhea, pneumonitis/pneumonia, oral/perineal candidiasis, CMV/adenovirus/EBV infections, failure to thrive, and lymphopenia. (pqac-00000037, pqac-00000035, pqac-00000001) | Primary human cases | HP:0002014 Diarrhea; HP:0006532 Oral candidiasis; HP:0006538 Recurrent pneumonia; HP:0001875 Neutropenia not core/optional; HP:0001888 Lymphopenia; HP:0001508 Failure to thrive |
| Representative variant 1 | **c.128_129del** in exon 5 (legacy description: “homozygous 2-bp deletion at nucleotide 128”) causes frameshift with downstream premature stop; associated with complete CD3ε deficiency in family I. (pqac-00000034, pqac-00000037) | Primary human molecular report | CD3E loss-of-function variant |
| Representative variant 2 | **c.49+1G>C** (NM_000733.3), homozygous donor splice-site variant in intron 2; abolishes exon 2 including the start codon and is functionally a **null mutation**. (pqac-00000038, pqac-00000039, pqac-00000041, pqac-00000042) | Primary human molecular + post-transplant follow-up | CD3E splice donor LoF |
| Representative variant 3 | **c.269T>A, p.Leu90Ter**, a novel nonsense variant, was reported in an Egyptian T-B+ SCID patient. (pqac-00000028, pqac-00000029) | Cohort report; limited single-patient detail in available text | CD3E nonsense LoF |
| Turkish variant note | A **novel pathogenic CD3E frameshift** was reported in Turkish patients, but the exact HGVS was not available in the retrieved full text; do **not** invent nomenclature. (pqac-00000030, pqac-00000033, pqac-00000031) | Secondary mention within cohort literature | CD3E pathogenic frameshift, HGVS unavailable here |
| Mechanism | Biallelic CD3E LoF impairs assembly/signaling of the **pre-TCR/TCR-CD3 complex**, leading to failed thymocyte development and profound deficiency of αβ and γδ T cells; human stage of block is inferred for complete CD3E loss from mouse and related human data. (pqac-00000006, pqac-00000009, pqac-00000012, pqac-00000037) | Human + mouse; some human-stage detail inferred | GO:0042110 T cell activation; GO:0045058 T cell selection; CL:0000084 T cell; UBERON:0002370 thymus |
| Diagnosis | Diagnosis rests on **TREC-based newborn screening**, confirmatory lymphocyte subsets (CD3/CD4/CD8, B, NK), naïve/memory T-cell phenotyping, proliferation testing, maternal engraftment studies, and molecular testing (panel/WES/WGS). **SCID-wide extrapolation.** (pqac-00000025, pqac-00000023, pqac-00000014, pqac-00000015) | SCID-wide consensus/guideline extrapolation, not CD3E-specific validation | PIDTC 2022 SCID definitions; TREC screening workflow |
| Treatment | Definitive therapy is **hematopoietic stem cell transplantation (HSCT)**. One CD3E-deficient patient had long-term survival after haploidentical SCT with split chimerism but later required **IVIG** for humoral deficiency; early historical cases often died pre/post-transplant. **No CD3E-specific gene therapy found.** (pqac-00000038, pqac-00000039, pqac-00000041, pqac-00000037) | Primary CD3E cases + SCID practice context | NCIT: Hematopoietic Stem Cell Transplantation; Intravenous Immune Globulin |
| Prognosis | Untreated SCID is often fatal in infancy; for SCID broadly, outcomes are best with diagnosis by newborn screening and HSCT before 3.5 months and before active infection. Historical CD3E cases had high mortality, but long-term survival after SCT is possible. **SCID-wide extrapolation for timing/survival rates.** (pqac-00000014, pqac-00000018, pqac-00000026, pqac-00000039) | Mixed: primary CD3E + SCID-wide outcomes | Prognostic factors: age at HSCT; infection status |
| Prevention/supportive care | While awaiting definitive therapy: protective isolation, TMP-SMX for PCP prophylaxis after 30 days, IVIG, avoidance of live vaccines and unirradiated blood products, CMV risk mitigation, palivizumab seasonally. **SCID-wide extrapolation.** (pqac-00000023, pqac-00000014, pqac-00000018) | SCID-wide management guidance | NCIT/clinical terms: prophylaxis, immunoglobulin replacement |
| Mouse model | **Cd3e-null mice** show early thymocyte developmental arrest at the **CD44low CD25+ DN3** stage, supporting the causal role of CD3ε in pre-TCR signaling and thymocyte progression. (pqac-00000009, pqac-00000013, pqac-00000008) | Model organism evidence | Mouse Cd3e knockout; GO:0070231 T cell apoptotic process (context-dependent); CL:0000791 thymocyte |
| Major gaps | Extremely few published human cases; no robust CD3E-specific prevalence/incidence estimates, penetrance data, natural-history cohorts, validated biomarker studies, or interventional trials specific to CD3E deficiency. Many management statements are extrapolated from broader SCID literature. (pqac-00000021, pqac-00000022, pqac-00000014, pqac-00000015) | Evidence-gap statement | Rare-disease evidence limitation |


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