TABLE I.

PIDTC 2022 Definitions for SCID

SCID subtype	Diagnosis requires	Criterion 1	Criterion 2	Criterion 3	Criterion 4
Typical SCID (very low autologous T cells)	Criteria 1 & 2 OR Criteria 1 & 3 OR Criterion 4	Very low T cells (<0.05 × 109/L)*	Pathogenic gene variant(s)†	No alternate explanation for low T-cell count‡ AND, EITHER: Undetectable or low TRECs§ OR <20% of CD4+ T cells have naive cell surface markers ‖	Presence of TME¶
Leaky/atypical SCID (low T cells)	Criteria 1 & 2 & 4 OR Criteria 1 & 3 & 4	Two or more of: Low T-cell number for age (0.05–1.0 × 109/L)# Oligoclonal T cells** Abnormal TRECs OR <20% of CD4+ T cells are naive	Pathogenic gene variant(s)	Reduced proliferation††	Does not have: Other SCID subtype CID with known genotype Thymic disorder Other disorder with low T-cell numbers‡‡
Omenn syndrome	All 4 Criteria	>80% of CD4+ T cells have CD45RO+ memory phenotype	Pathogenic gene variant(s)	Generalized rash AND Absence of TME	Two or more of: Eosinophilia (>0.8 × 109/L) Elevated IgE Abnormal TRECs Lymphadenopathy Hepatomegaly and/or splenomegaly Oligoclonal T cells

^*T-cell subset determination (with naive/memory phenotyping) should be repeated at least once, with the second test used as the criterion value. In patients with an identified pathogenic variant, the interval between tests must be at least 1 wk; however, in patients without an identified pathogenic gene variant, the T-cell number must remain <0.05 × 10⁹/L for at least 8 wk to qualify as typical SCID due to the potential for spontaneous improvement, with a shorter interval only if urgent hematopoietic cell transplant is required before 8 wk.

^†Pathogenic variant(s) identified in a gene whose product is known to be essential for T-cell development (examples in Table III).

^‡Alternate explanations for low T-cell counts include those listed in Criterion 4 of leaky/atypical SCID.

^§Number of TRECs below the normal cutoff, or cycle threshold value above the normal cutoff defined as consistent with SCID by performing laboratory.

^‖Naive T cells should be measured via CD3/CD4/CD45RA, or with additional naive markers.

^¶Best performed by DNA analysis, such as with short tandem repeats, from whole blood or CD3-seperated cells, with any level of detection considered positive. Documented TME classifies patients as typical SCID; TME testing is strongly recommended for patients considered to possibly have leaky/atypical SCID.

^#Low T-cell numbers for age defined as <0.6 × 10⁹/L (any age), <0.8 × 10⁹/L if aged 2–4 y, or <1.0 × 10⁹/L if younger than 2 y.

^**Oligoclonal T cells as defined by laboratory performing testing, eg, <5 peaks in ≥4 T-cell receptor (TCR) Vbeta families on spectratyping, evidence of expansion of ≥2 TCR Vbeta families to >2 × the upper limit of normal for those families, or low Shannon [H] entropy index on high-throughput sequencing of TCR Vbeta variable regions.

^††Reduced proliferation is defined as a proliferative response to PHA, anti-CD3, or anti-CD3/CD28 <50% lower limit of reference range for laboratory.

^‡‡See Table II.