Glucose-6-phosphate dehydrogenase (G6PD) provides the main cellular source of NADPH through the pentose phosphate pathway, supporting antioxidant defenses and metabolic programs required for hematopoietic development. In leukocytes, NADPH is essential for maintaining redox balance during proliferation and differentiation, including in B cell ontogeny. Whether impaired NADPH generation could mechanistically contribute to low kappa-deleting recombination excision circles (KRECs) and early B cell lymphopenia in newborn screening remains unexplored.
To describe the relevance of KREC levels in Brazilian newborn screening (NBS), focusing on how impaired redox metabolism due to G6PD deficiency can contribute to severe B cell lymphopenia detected by KRECs.
From 2021 to 2025, the São Paulo, Brazil, NBS program screened nearly 500,000 infants. Those with abnormal results (750 neonates) were referred to our center. After confirmation of B cell lymphopenia (B cell counts below 100 cells/mm3 or 2%), patients underwent panel-based genetic testing.
Among infants referred for abnormal KRECs, we identified 66 patients with severe B cell lymphopenia, accounting for 9% of all B cell lymphopenias. Of these 66 neonates, a panel-based genetic testing was performed in 44 patients. Surprisingly, we identified 10 patients (27%) harboring three different G6PD mutations: 7/10 G6PD c.[202G>A(;)376A>G] (4 females, 3 males), a complex allele in hemizygosity, which can cause mild symptoms even in female carriers; 2/10 G6PD c.376A>G (1 homozygous female and 1 hemizygous male); and 1 male with hemizygous G6PD c.949G>A. Of these G6PD patients, 4 have no other genetically defined cause to date. The other 6 patients are under evaluation of heterozygous variants of uncertain significance (VUS) in IGLL1, CR2, IRF4, TRNT1, KMT2D, and PARN. These findings support the hypothesis that reduced enzymatic activity may affect early B cell development and result in lower KREC levels at birth.
The potential correlation between G6PD deficiency and severe B cell lymphopenia observed in NBS aligns with emerging biological evidence. To our knowledge, no prior study has specifically assessed the relationship between G6PD status and KREC-defined B cell lymphopenia in NBS programs. Investigating this potential correlation may clarify whether G6PD deficiency acts as a contributing factor or a disease modifier in the interpretation of B cell lymphopenia in KREC-based NBS for IEI.
