Impact of different genetic mutations on granulocyte development and G-CSF responsiveness in congenital neutropenia

Congenital neutropenia (CN) is a genetic disorder characterized by persistent or intermittent low peripheral neutrophil counts, thus increasing susceptibility to bacterial and fungal infections. Various forms of CN, caused by distinct genetic mutations, exhibit differential responses to granulocyte colony-stimulating factor (G-CSF) therapy, with the underlying mechanisms not fully understood. This study presents an in-depth comparative analysis of clinical and immunological features in five CN patient groups (SCN1, SCN3, CyN, WHIM and SBDS) associated with mutations in ELANE, HAX1, CXCR4 and SBDS genes. Our analysis led to the identification of 11 novel mutations in ELANE and one each in HAX1, CXCR4 and G6PC3 genes. Investigating bone marrow (BM) granulopoiesis and blood absolute neutrophil count (ANC) following G-CSF treatment, we found that SCN1 and SCN3 presented with severe early-stage disruption between the promyelocyte and myelocyte, leading to a poor response to G-CSF. In contrast, CyN, affected at the late PMN stage of neutrophil development, showed a strong G-CSF response. WHIM, displaying normal neutrophil development, responded robustly to G-CSF, while SBDS, with moderate disruption from the early myeloblast stage, exhibited a moderate response. Notably, SCN1 uniquely impeded neutrophil development, while SCN3, CyN, WHIM, and SBDS also affected eosinophils and basophils. Additionally, SCN1, SCN3, and CyN presented with elevated serum immunoglobulins, increased BM plasma cells, and higher APRIL levels. Our study reveals a strong correlation between the stage and severity of granulocyte development disruption and the efficacy of G-CSF therapy.