News From the Genetics Lab
New Diagnostic Tests for Congenital Neutropenia: ELA2 and HAX1
Two new molecular diagnostic tests will join the menu of the Diagnostic Center for Heritable Immunodeficiencies (DCHI).
The differential diagnosis of neutropenia is extensive and includes both acquired and inherited diseases. Recent progress in unraveling the underlying genetic defects has resulted in the identification of several genetic mutations that are associated with congenital neutropenia. Congenital forms of neutropenia can be roughly classified into isolated severe congenital neutropenia (SCN) and neutropenia as part of congenital disorders (see reference 1; side-bar). SCN is characterized by peripheral blood neutrophil counts that are consistently below 500/μL, and the so-called maturation arrest in the bone marrow, in which neutrophil differentiation is halted at the promyelocyte/myelocyte stage. The clinical manifestations include omphalitis after birth, recurrent skin and oropharyngeal infections, as well as deep-seated abscesses in liver, lung and subcutaneous tissues, amongst other infections. Individuals with SCN have poor wound healing and have an increased risk of myelodysplastic syndrome (MDS), associated with monosomy 7, and acute myeloid leukemia (AML). Treatment options include prompt and aggressive treatment of infections, injections with granulocyte colonystimulating factor (G-CSF), periodic bone marrow studies to detect MDS, and allogeneic stem cell transplantation (aSCT). A review of the literature (summarized in reference 2) suggests that 38-80% of autosomal dominant cases of SCN are linked to heterozygous ELA2 mutations. ELA2 encodes neutrophil elastase, a serine protease exclusively expressed in neutrophils and monocytes. How ELA2 mutations cause SCN remains unclear. In addition to SCN, ELA2 mutations also cause cyclic neutropenia; defined as neutropenia with counts below 200/μL for 3-5 days at ~ 3-week intervals, while peak neutrophil counts often remain below 2000/μL.
The ELA2 mutation detection rate for cyclic neutropenia is higher than for SCN (~90-100% of cases). Genotype-phenotype relationships appear to indicate that certain mutations are predominantly associated with cyclic neutropenia, with no established risk of evolution into AML, whereas other mutations are more commonly found in SCN. It should be realized that the patterns of mutations in cyclic neutropenia and SCN are distinct when populations are studied, but can overlap when individual patients are evaluated. This suggests that distinguishing between cyclic neutropenia and SCN should be done on the basis of clinical findings and not on the basis of genotype alone. Approximately 50 years after the first description of Kostmann syndrome, mutations in the gene encoding HAX1 were found in the original family. Homozygous mutations in HAX1 are associated (non-overlapping with ELA2) with autosomal recessive cases of SCN. HAX1 encodes a protein critical for maintaining and stabilizing the inner mitochondrial membrane potential and protecting myeloid (progenitor) cells from undergoing apoptosis. As also observed in ELA2 mutations, patients with HAX1 have been shown to acquire somatic mutations in the G-CSF receptor-3 gene (GCSF3R), linked to the process of malignant transformation (reference 4). Genotype-phenotype relationships for HAX1 mutations are becoming apparent. Most patients identified to date are of Middle-Eastern descent, and the vast majority carry a specific mutation (p.Trp44X). Several new mutations have recently been described, associated with the presence of an alternative splice variant (isoform-b) of HAX1, which is also affected by the mutations. Other neutropenia-associated genes include WASP (part of the DCHI menu), while GFI1 (and others) will join the DIL Menu in the near future. Click here for more information about DCHI
| ELA2/HAX1; further reading: |
|---|
- Bohn et al. Curr Opin Rheumatol. 2007;19:644.
- Skokowa et al. Curr Opin Hematol. 2007;14:22.
- Horwitz et al. Nat Genet. 1997;23:433.
- Klein et al. Nat Genet. 2007;39:86.
- Germeshausen et al. Blood. 2008 (Epub ahead of print).
- Germeshausen et al. Blood. 2008;107:4628.
|
