ELANE related neutropenia disorders include cyclic neutropenia (CyN) and severe congenital neutropenia (SCN). Cyclic neutropenia is usually diagnosed within the first year of life based on oscillation of neutrophils and fever with approximately 21 day periodicity. Congenital neutropenia is generally diagnosed right after birth and my present with omphalitis. Individuals with ELANE-related neutropenia are at risk of developing myelodysplasia syndrome (MDS) or acute myelogenous leukemia (AML). It is inherited in an autosomal dominant manner. Most reported pathogenic variants are missense, splicing defects, small in-frame deletions, frameshift deletions or premature stop codons with dominant negative effect. Full gene deletions leading to haploinsufficiency do not cause neutropenia (PMID: 31427279). At least 100 pathogenic variants have been reported in over 100 individuals from more than 40 families. This curation includes both familial and de novo missense, small deletion and splicing variants in individuals with CyN or SCN from 4 studies (PMID: 11001877, 10581030, 10581030 and 20803142). Three studies (PMID: 15657182, 31176364 and 28754797) were evaluated encompassing biochemical function, protein interaction, functional alteration from patients cells with different variants, and cell models expressing different variants further confirm the gene and disease validity. In summary, ELANE is definitively associated with CyN and SCN. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.
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