The diversity of mutations and clinical outcomes for ELANE-associated neutropenia

Abstract

Purpose of review: 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.

Recent findings: 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.

Summary: Sequencing is useful for predicting outcomes of ELANE-associated neutropenia.

FIGURE 1

ELANE mutations in cyclic and congenital neutropenia. Linear representation of ELANE – five exons and four introns showing location and types of mutations observed in 307 patients. Mutations seen in SCN are listed above the gene map, and those seen in CyN are listed below. Mutations seen in both SCN and CyN are indicated in bold. Mutations with MDS/AML cases reported are italicized and the superscripts indicate the number of patients with that mutation who developed MDS/AML. AML, acute myeloid leukemia; CyN, cyclic neutropenia; MDS, myelodysplasia; SCN, severe congenital neutropenia.

FIGURE 2

Associations between ELANE mutations and severe bacterial infections in patients with cyclic neutropenia (CyN) and severe congenital neutropenia (SCN) prior to any treatment with G-CSF therapy. (a) Percentage with a positive history of mouth ulcers (mo+) versus negative history (mo−); (b) history of pneumonia by disease association of mutation (pn+) versus negative (pn−); (c) history of deep-tissue abscess, positive (ab+) versus negative (ab−) amongst patients with mutations unique to CyN, overlapping mutations, and mutations unique to SCN. The number of patients is shown above each bar. The overlapping mutations are those listed in Fig. 1. P values are from permutation test with random assignment of genotype within families.

FIGURE 3

Probability of adverse events in SCN vs. CyN and in SCN patients with unique vs. overlapping mutations. Cumulative incidence [cumulative proportion of patients experiencing a major event acute myeloid leukemia (AML) or myelodysplasia (MDS), hematopoietic stem cell transplantation, or death] (a) for patients with a diagnosis of cyclic neutropenia (CyN) or congenital neutropenia (SCN), or (b) by disease association of mutations in patients with SCN. Shaded areas represent 95% point-wise confidence bands. AML, acute myeloid leukemia; G-CSF, granulocyte colony-stimulating factor; MDS, myelodysplasia.

FIGURE 4

Associations between ELANE mutations and phenotype in patients with severe congenital neutropenia (SCN) maintained on long-term G-CSF therapy. Left-hand panels: box-plots of dose versus (a) mutation position or (b) specific mutation. Central mark shows the median, whereas notches show 95% confidence limits for the median. Edges of boxes show 25th and 75th percentiles. Whiskers extend by 1.5 times the inter-quartile range. Dots show values for individual patients. Right-hand panels: cumulative incidence (cumulative proportion of patients experiencing MDS/AML, transplant, or death) versus years on G-CSF therapy by (c) mutation position or (d) specific mutation. Kaplan–Meier curves show grouped data for clarity. Shaded areas represent 95% point-wise confidence bands. AML, acute myeloid leukemia; G-CSF, granulocyte colony-stimulating factor; MDS, myelodysplasia.