Neutrophil elastase gene (ELANE) mutations are responsible for the majority of 
cases of severe congenital neutropenia (CN) and cyclic neutropenia (CyN). We 
screened CN (n = 395) or CyN (n = 92) patients for ELANE mutations and 
investigated the impact of mutations on mRNA expression, protein expression, and 
activity. We found 116 different mutations in 162 (41%) CN patients and 26 in 51 
(55%) CyN patients, 69 of them were novel. CyN-associated mutations were 
predicted to be more benign than CN-associated mutations, but the mutation 
severity largely overlapped. The frequency of acquired CSF3R mutations, 
malignant transformation, and the need for hematopoietic stem cell 
transplantation was significantly higher in CN patients with ELANE mutation than 
in ELANE mutation negative patients. Cellular elastase activity was reduced in 
neutrophils from CN/CyN patients, irrespective of the mutation status. In CN, 
enzymatic activity was significantly lower in patients with ELANE mutations 
compared with those with wild-type ELANE. Despite differences in the spectrum of 
mutations in CN or CyN, type or localization of mutation only partially 
determine the clinical phenotype. Specific ELANE mutations have limited 
predictive value for leukemogenesis; the risk for leukemia was correlated with 
disease severity rather than with occurrence of an ELANE mutation.