title: The diversity of mutations and clinical outcomes for ELANE-associated neutropenia.
abstract: OBJECTIVE
  Mutations in the gene for neutrophil elastase, ELANE, cause cyclic neutropenia (CyN) and severe congenital neutropenia (SCN). This study summarized data from the Severe Chronic Neutropenia International Registry (SCNIR) on genotype-phenotype relationships of ELANE mutations to important clinical outcomes. We also summarize findings for ELANE mutations not observed in SCNIR patients.
  
  
  RESULTS
  There were 307 SCNIR patients with 104 distinctive ELANE mutations who were followed longitudinally for up to 27 years. The ELANE mutations were diverse; there were 65 single amino acid substitutions; 61 of these mutations (94%) were 'probably' or 'possibly damaging' by PolyPhen-2 analysis, and one of the 'benign' mutations was associated with two cases of acute myeloid leukemia (AML). All frame-shift mutations (19/19) were associated with the SCN. The pattern of mutations in the SCN versus CyN was significantly different (P < 10), but some mutations were observed in both groups (overlapping mutations). The cumulative incidence of severe adverse events, that is, myelodysplasia, AML, stem cell transplantation, or deaths was significantly greater for patients with SCN versus those with CyN or overlapping mutations. Specific mutations (i.e. G214R or C151Y) had a high risk for evolution to AML.
  
  
  CONCLUSIONS
  Sequencing is useful for predicting outcomes of ELANE-associated neutropenia.
authors.affiliation: aDepartment of Medicine, University of Washington, Seattle, USA bDepartment of Molecular Hematopoiesis, Kinderklinik, MedizinischeHochschule, Hannover cInternal Medicine II, University Hospital, Tübingen, Tübingen, Germany dDepartment of Medicine, University of Washington, Severe Chronic Neutropenia International Registry, Seattle ePediatric Hematology Oncology, University of Michigan, Ann Arbor fPediatric Hematology Oncology, Saint Joseph's Children's Hospital, Paterson gDepartments of Pediatrics and Cancer Biology, University of Massachusetts Medical School, Worcester hPediatric Hematology/Oncology, Fred Hutchinson Cancer Research Center, Seattle iBiostatistics Branch, National Cancer Institute at the National Institutes of Health, Division of Cancer Epidemiology & Genetics, Bethesda jDivision of Oncology, Washington University, St Louis, USA *Vahagn Makaryan and Cornelia Zeidler contributed equally to the writing of this article.
authors.forename: Vahagn
authors.initials: V
authors.lastname: Makaryan
authors.forename: Cornelia
authors.initials: C
authors.lastname: Zeidler
authors.forename: Audrey Anna
authors.initials: AA
authors.lastname: Bolyard
authors.forename: Julia
authors.initials: J
authors.lastname: Skokowa
authors.forename: Elin
authors.initials: E
authors.lastname: Rodger
authors.forename: Merideth L
authors.initials: ML
authors.lastname: Kelley
authors.forename: Laurence A
authors.initials: LA
authors.lastname: Boxer
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Bonilla
authors.forename: Peter E
authors.initials: PE
authors.lastname: Newburger
authors.forename: Akiko
authors.initials: A
authors.lastname: Shimamura
authors.forename: Bin
authors.initials: B
authors.lastname: Zhu
authors.forename: Philip S
authors.initials: PS
authors.lastname: Rosenberg
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Link
authors.forename: Karl
authors.initials: K
authors.lastname: Welte
authors.forename: David C
authors.initials: DC
authors.lastname: Dale
mesh_terms: D000818:Animals; D030342:Genetic Diseases, Inborn / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology / Q000235:genetics; D019272:Leukocyte Elastase / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009503:Neutropenia / Q000201:enzymology / Q000235:genetics*
chemical_list: D019272:Leukocyte Elastase