Harmonizing TREC Thresholds in Newborn Screening for SCID: Insights From Russian Validation Cohort

Newborn screening (NBS) for severe combined immunodeficiency (SCID) relies on the measurement of T-cell receptor excision circle (TREC) for early diagnosis and intervention. However, considerable variation in TREC cutoff values across countries and testing platforms poses challenges for standardization and optimal screening performance. This study aimed to refine the TREC cutoff values in a large Russian pilot NBS cohort comprising 202,908 newborns, with a primary focus on improving SCID detection sensitivity.

A retrospective analysis of 202,908 newborns from a pilot NBS project assessed TREC and KREC levels. Confirmed PID diagnoses were compared with TREC measurements in a group of 66 false-positive cases. The optimal TREC cutoff was established using ROC analysis, with validation across patients with SCID, 22q11.2 deletion syndrome (22q11.2DS), and syndromic forms of PID from an extended validation cohort of PID patients from the Dmitry Rogachev National Medical Research Center.

Receiver operating characteristic (ROC) analysis based on true-positive cases identified an optimal TREC cutoff of 150 copies/10⁵ cells. Values between 150-200 copies/10⁵ cells were found to identify high-risk newborns who require closer monitoring. This threshold was validated in an independent cohort, reducing missed SCID cases while improving the detection of 22q11.2 deletion syndrome and other syndromic primary immunodeficiencies (PIDs). Notably, elevated TREC levels in some SCID patients reflected "leaky" SCID phenotypes, which nonetheless required curative intervention. Additionally, syndromic PIDs and cases of transient idiopathic lymphopenia (TIL) were also more accurately identified, enabling timely clinical management.

These findings emphasize the need for broader evaluation of TREC cutoff values across diverse assay systems to improve the effectiveness, comparability, and global harmonization of NBS programs.