Abstract
Severe combined immunodeficiency (SCID) is a pediatric emergency in which affected infants appear healthy at birth and are typically diagnosed only after life-threatening infection develops, by which point survival after hematopoietic stem cell transplantation declines substantially. Newborn screening using T-cell receptor excision circles (TRECs), often paired with kappa-deleting recombination excision circles (KRECs), enables presymptomatic detection of SCID and other clinically significant T- and B-cell lymphopenias and has been adopted across much of the United States and Western Europe; however, Baltic and Eastern European programs remain largely absent from the published literature. We report the first two years of Latvia’s nationwide TREC/KREC newborn screening program (1 April 2023–31 March 2025), covering 26,217 newborns (>99% of live births), and examine its interface with Latvia’s universal birth-dose BCG vaccination policy. Screening cutoffs were revised during the study period, reducing recall rates from an initial 4.6%/6.2% (TRECs/KRECs) to an overall 1.06%. Of 14 infants referred for specialist evaluation, none had classical SCID, while 3 (21%) were diagnosed with clinically significant non-SCID T-cell lymphopenia—2 with 22q11.2 deletion (DiGeorge) syndrome and 1 with 11q terminal deletion (Jacobsen) syndrome. TREC values rose progressively with gestational age, whereas KREC values showed the inverse pattern, being highest in the most preterm infants—a divergence with implications for gestational-age-specific cutoff design. These findings demonstrate that population-wide TREC/KREC screening is feasible in a small national program, with diagnostic value beyond SCID to clinically actionable non-SCID lymphopenias and provide the first published experience of nationwide SCID newborn screening from a Baltic country.