Severe Congenital Neutropenia and Cyclic Neutropenia via the ELANE Gene

Severe congenital neutropenia (SCN) comprises a heterogeneous group of disorders of myelopoiesis with varying symptoms and patterns of inheritance. SCN is characterized by absolute neutrophil counts (ANC) consistently below 500/µl and severe systemic bacterial infections beginning in early infancy (Boxer and Newburger. Pediatr Blood Cancer 49:609-614, 2007). Patients typically have recurrent fevers and develop sinusitis, gingivitis, and other soft tissue infections. SCN and cyclic neutropenia share the same symptoms; however, with cyclic neutropenia ANCs rise and fall with a periodicity of ~ 21-days. A hallmark of SCN is bone marrow "maturation arrest;" neutrophils differentiate only to the promyelocyte/myelocyte stage (Kostman. Acta Paediatr Scand 64:362-368, 1975). About 95% of patients respond to treatment with recombinant granulocyte-colony stimulating factor (G-CSF) with an increase in ANC (Bellanne-Chantelot et al. Blood 103:4119-4125, 2004; Freedman et al. Blood 96:429-436, 2000); however, treated patients are still at risk of sepsis (Donini et al. Blood 109:4716-4723, 2007). SCN is a premalignant condition; patients are at an elevated risk of developing myelodysplastic syndrome and acute myeloblastic leukemia (MDS/AML). The risk of developing a malignancy increases upon G-CSF treatment (Gilman et al. Blood 36:576-585, 1970; Freedman et al. Blood 96:429-436, 2000; Rosenberg et al. Blood 107:4628-4635, 2006). In contrast to patients with SCN, MDS/AML have not been diagnosed in patients with cyclic or idiopathic neutropenia.

It is estimated that approximately 35%-63% of patients with neutropenia have heterozygous variants in the ELANE gene (OMIM 130130) (Rosenberg et al. Blood 107:4628-4635, 2006; Bellanne-Chantelot et al Blood 103:4119-4125, 2004). Causative variants are primarily missense and nonsense variants. ELANE encodes neutrophil elastase, a serine protease that cleaves cellular and extracellular proteins and is expressed exclusively in neutrophils and monocytes. Recent reports suggest that mutated elastase in the ER triggers the unfolded protein response in neutrophils causing apoptosis and neutropenia (Ward and Dale Curr Opin Hematol 16:9-13, 2009). In comparison to other neutropenia-related genes, variants in ELANE correlate with a more severe expression of the disease, particularly in cases of congenital neutropenia (Bellanne-Chantelot et al. Blood 103:4119-4125, 2004).

ELANE variants are the most common cause of SCN and the only known cause of cyclic neutropenia.

This test provides full coverage of all coding exons of the ELANE gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).