ImmunologyTier 1Medical Sciences concept

T-cell receptor excision circles (TRECs) and SCID screening

Core concept

TRECs are a by-product of V(D)J recombination in the thymus
- During TCR alpha rearrangement, the intervening delta locus is excised as a circular episome - the signal joint TREC (sjTREC)
- Episomal, not replicated at mitosis -> diluted with every subsequent division
- -> TREC count measures RECENT THYMIC EMIGRANTS, i.e. new naive T-cell output, not total T-cell number
Measured by quantitative PCR on the dried blood spot - the same Guthrie card already collected
- Low or absent TRECs -> T-cell lymphopenia -> SCID until proven otherwise
- KRECs (kappa-deleting recombination excision circles) are the B-cell equivalent, screening for agammaglobulinaemia
Rationale for screening: SCID is a paediatric emergency, >90% survival if transplanted before 3.5 months and before any infection, versus poor survival once infection is established

V(D)J recombination - what the screen is actually testing

RAG1/RAG2 cut at recombination signal sequences; Artemis, DNA-PKcs, ligase IV, Cernunnos repair the ends; TdT adds junctional nucleotides
Required for both immunoglobulin and TCR gene rearrangement
*RAG1/RAG2 deficiency -> T-B-NK+ SCID - NK cells are spared because their receptors (KIR, NCR) are germline-encoded and do not need V(D)J recombination*
- Hypomorphic RAG mutations -> Omenn syndrome - oligoclonal autoreactive T cells, erythroderma, alopecia, lymphadenopathy, eosinophilia, high IgE

SCID phenotypes by lineage

Genotype	Gene	Phenotype
T- B+ NK-	IL2RG (common gamma chain), X-linked - the commonest (~40%); JAK3 (AR)	Cytokine receptor signalling
T- B+ NK+	IL7RA	T-cell survival
T- B- NK+	RAG1/RAG2, Artemis (DCLRE1C), LIG4	V(D)J recombination (Artemis and LIG4 add radiosensitivity)
T- B- NK-	ADA (adenosine deaminase)	Toxic metabolite accumulation; also causes deafness, skeletal and neurological abnormality
Variable	PNP, ZAP70, CD3 chains, coronin-1A	-

Causes of a low TREC other than SCID

Prematurity (thymic immaturity - usually normalises)
Syndromic T-cell lymphopenia - 22q11.2 deletion (DiGeorge), trisomy 21, CHARGE, ataxia-telangiectasia, Jacobsen
Secondary loss - congenital heart disease with thymectomy at cardiac surgery, chylothorax/third-space loss, gastroschisis, neonatal leukaemia, maternal immunosuppression
A low TREC is a screening flag, not a diagnosis - it must be confirmed with lymphocyte subsets and naive/memory phenotyping

Immediate actions on a positive newborn screen - before the diagnosis is even confirmed
- NO LIVE VACCINES - rotavirus (given at 6 weeks in Australia), BCG, MMR, varicella
- Irradiated, CMV-negative, leucodepleted cellular blood products only - transfusion-associated GVHD is fatal in SCID
- Isolate; start cotrimoxazole PJP prophylaxis, antifungal prophylaxis and immunoglobulin replacement
- Avoid breastfeeding if the mother is CMV-positive; urgent immunology referral
Confirmatory testing - flow cytometry (CD3/CD4/CD8/CD19/CD16-56), naive (CD45RA+CD62L+) vs memory T cells, lymphocyte proliferation to mitogens, maternal engraftment studies, genetic panel
Definitive treatment
- Allogeneic HSCT - the earlier the better; a matched sibling is ideal, but haploidentical parental grafts are used
- Gene therapy established for ADA-SCID and used for X-SCID; PEG-ADA enzyme replacement as a bridge
- Thymus transplantation for complete DiGeorge (a defect of the thymic stroma, not the stem cell - HSCT does not fix it)
TREC screening is implemented across Australian jurisdictions as part of newborn bloodspot screening; it also incidentally detects 22q11 deletion and other causes of T-cell lymphopenia

3 more sections, plus exam facts

Premium unlocks every note across every specialty, and the full exam fact library behind it.