Nationwide TREC/KREC-based newborn screening and clinical outcomes in Japan

Large-scale real-world data on T-cell receptor excision circle (TREC)- and κ-deleting recombination excision circle (KREC)-based newborn screening for inborn errors of immunity remain limited. In this nationwide cohort, we evaluated Japan's program (2020-2025), including 1,380,634 newborns. Of 869 referred infants (0.06%), 40 were diagnosed, including 15 with severe combined immunodeficiency (SCID), 16 with X-linked agammaglobulinemia or other agammaglobulinemias, and nine with severe T cell lymphopenia. After a median follow-up of 18 mo, overall survival was 98%. All infants with SCID survived; 14 underwent hematopoietic cell transplantation with sustained engraftment. Referral rates were 0.04% for TREC and 0.03% for KREC. Repeat sampling was associated with lower referral rates (0.05 vs. 0.56%). Referral rates varied across assay kits and laboratory practices, reflecting interlaboratory heterogeneity in a decentralized screening system. The transition from self-paid to public funding increased coverage from 77.1 to 97.7%. These findings support TREC/KREC-based screening and highlight the need for standardized algorithms and sustained public funding for equitable nationwide implementation.