Newborn screening (NBS) with kappa-deleting recombination excision circles (KRECs) is primarily used to detect B cell lymphopenia and agammaglobulinemia as markers of inborn errors of immunity (IEIs). However, reduced B cell output on KREC testing may also represent an early sentinel of hematological disorders. Brazil currently implements NBS with both T cell receptor excision circles (TRECs) and KRECs, providing a unique opportunity to characterize disorders uncovered by isolated KREC abnormalities.
To describe the Brazilian experience using KREC-based NBS, identifying hematologic disorders, and to highlight the role of KRECs as an early marker of diseases affecting B cell production.
We conducted a prospective review of newborns referred to a Brazilian reference center following abnormal KREC results on NBS. Clinical, immunologic, and hematologic data were collected (complete blood counts, immunophenotyping, immunoglobulin levels, and bone marrow aspirate). After confirmation of B cell lymphopenia, patients underwent panel-based genetic testing. Final diagnoses and time from NBS referral to etiologic definition were recorded.
Among infants referred for abnormal KRECs, distinct hematologic conditions were identified: 10 G6PD mutations (7/10 G6PD c.[202G>A(;)376A>G]), one GATA2 deficiency (GATA2 c.1348G>A; KREC 1copy/µL), one Shwachman–Diamond syndrome [SBDS c.258+2T>C(intron), c.184A>T; KREC 47copies/µL], and one juvenile myelomonocytic leukemia (NRAS c.35G>A; KRECs 6 copies/µL). In all cases, abnormal KRECs were the first abnormal finding and preceded clinical manifestations, as the confirmed B cell lymphopenia guided early hematologic assessment and subsequent genetic testing, establishing the final diagnosis. The KREC abnormality expedited diagnostic evaluation, facilitated recognition of the associated conditions, and guided early multidisciplinary follow-up with immunology and hematology when indicated. These diagnoses would likely have been substantially delayed in the absence of a KREC-based screening abnormality.
The Brazilian experience illustrates that KREC-based NBS can function as a powerful entry point not only to agammaglobulinemia but also to hematologic disorders that impair B cell lymphopoiesis, including bone marrow failure syndromes and myeloid neoplasms. The association between low KRECs and G6PD variants in our cohort is under investigation to clarify links with B cell impairment. Integrating KRECs into NBS programs and strengthening immunology–hematology collaboration can expand the impact of NBS beyond classical B cell IEIs, enabling earlier diagnosis.
