Congenital neutropenia, CSF3R, Cyclic neutropenia, ELANE, HAX1, Neutrophil elastase, Next Gen Sequencing Test, SBDS, Severe congenital neutropenia, WAS, WIPF1, X-linked severe congenital neutropenia, X-linked thrombocytopenia, NextGen Sequencing Test
Genes analyzed: AK2, AP3B1, AP3D1, CD40LG, CEBPE, CLPB, CSF3R, CXCR2, CXCR4, DNAJC21, EFL1, ELANE, G6PC3, GATA2, GFI1, GINS1, HAX1, JAGN1, LYST, RAC2, SBDS, SLC37A4, SMARCD2, SRP54, TAZ(TAFAZZIN), USB1, VPS13B, VPS45, WAS, and WIPF1
Providing a genetic evaluation for patients with a personal or family history suggestive of severe congenital neutropenia and/or cyclic neutropenia.
Establishing a diagnosis of an inherited congenital neutropenia and, in some cases, allowing for appropriate management and surveillance for disease features based on the gene involved.
Identification of a disease-causing variant may assist with diagnosis, prognosis, clinical management, recurrence risk assessment, familial screening, and genetic counseling for severe congenital neutropenia and cyclic neutropenia.
Patient Preparation: A previous bone marrow transplant from an allogenic donor will interfere with testing. Call 800-533-1710 for instructions for testing patients who have received a bone marrow transplant.
Specimen preferred to arrive within 96 hours of collection.
Whole Blood Collection Instructions:
1. Invert several times to mix blood.
2. Send whole blood specimen in original tube. Do not aliquot.
Skin Biopsy Collection:
Additional Information: A separate culture charge will be assessed under CULFB / Fibroblast Culture for Biochemical or Molecular Testing. An additional 3 to 4 weeks is required to culture fibroblasts before genetic testing can occur.
All specimens will be evaluated at Mayo Clinic Laboratories for test suitability.
Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Misinterpretation of results may occur if the information provided is inaccurate or incomplete.
If testing was performed because of a clinically significant family history, it is often useful to first test an affected family member. Detection of a reportable variant in an affected family member would allow for more informative testing of at-risk individuals.
To discuss the availability of additional testing options or for assistance in the interpretation of these results, contact Mayo Clinic Laboratories genetic counselors at 800-533-1710.
Next-generation sequencing may not detect all types of genomic variants. In rare cases, false-negative or false-positive results may occur. The depth of coverage may be variable for some target regions; assay performance below the minimum acceptable criteria or for failed regions will be noted. Given these limitations, negative results do not rule out the diagnosis of a genetic disorder. If a specific clinical disorder is suspected, evaluation by alternative methods can be considered.
There may be regions of genes that cannot be effectively evaluated by sequencing or deletion and duplication analysis as a result of technical limitations of the assay, including regions of homology, high guanine-cytosine (GC) content, and repetitive sequences. Confirmation of select reportable variants will be performed by alternate methodologies based on internal laboratory criteria.
This test is validated to detect 95% of deletions up to 75 base pairs (bp) and insertions up to 47 bp. Deletions-insertions (delins) of 40 or more bp, including mobile element insertions, may be less reliably detected than smaller delins.
This analysis targets single and multi-exon deletions/duplications; however, in some instances, single exon resolution cannot be achieved due to isolated reduction in sequence coverage or inherent genomic complexity. Balanced structural rearrangements (such as translocations and inversions) may not be detected.
This test is not designed to detect low levels of mosaicism or to differentiate between somatic and germline variants. If there is a possibility that any detected variant is somatic, additional testing may be necessary to clarify the significance of results.
Genes may be added or removed based on updated clinical relevance. Refer to the Targeted Genes and Methodology Details for Severe Congenital and Cyclic Neutropenia Gene Panel for the most up to date list of genes included in this test. For detailed information regarding gene specific performance and technical limitations, see Method Description or contact a laboratory genetic counselor.
If the patient has had an allogeneic hematopoietic stem cell transplant or a recent non-leukoreduced blood transfusion, results may be inaccurate due to the presence of donor DNA. Call Mayo Clinic Laboratories for instructions for testing patients who have received a bone marrow transplant.
Reclassification of Variants:
Currently, it is not standard practice for the laboratory to systematically review previously classified variants on a regular basis. The laboratory encourages health care providers to contact the laboratory at any time to learn how the classification of a particular variant may have changed over time. Due to broadening genetic knowledge, it is possible that the laboratory may discover new information of relevance to the patient. Should that occur, the laboratory may issue an amended report.
Evaluation and categorization of variants are performed using published American College of Medical Genetics and Genomics and the Association for Molecular Pathology recommendations as a guideline.(7) Other gene-specific guidelines may also be considered. Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance. Variants classified as benign or likely benign are not reported.
Multiple in silico evaluation tools may be used to assist in the interpretation of these results. The accuracy of predictions made by in silico evaluation tools is highly dependent upon the data available for a given gene, and periodic updates to these tools may cause predictions to change over time. Results from in silico evaluation tools are interpreted with caution and professional clinical judgment.
Rarely, incidental or secondary findings may implicate another predisposition or presence of active disease. These findings will be carefully reviewed to determine whether they will be reported.
Inherited congenital neutropenia refers to a subset of primary immunodeficiencies impacting neutrophil maturation and function. The severity of the clinical manifestations in these disorders typically reflects the degree of neutropenia. Most cases of neutropenia are due to acquired (non-genetic) causes. Severe congenital neutropenia (SCN) is characterized by chronically low neutrophil count and recurrent, often life-threatening infections beginning in the first few months of life. Some individuals with SCN may also have an increased risk for myelodysplastic syndrome or acute myelogenous leukemia.(1-3) Cyclic neutropenia (CN) is characterized by periods of severe neutropenia and infections that last 3 to 5 days and recur at regular intervals.(1-5) Individuals with SCN or CN may also exhibit recurrent fevers, sinusitis, gingivitis, cellulitis, oral ulcers, colonic ulcers, and other manifestations of chronic infections.(1-5) Bone marrow biopsy on affected individuals may show arrest in myelopoiesis at the promyelocyte/myelocyte stage.(1-3)
The prevalence of inherited severe congenital neutropenia and cyclic neutropenia is estimated to range from 1:500,000 to 1:100,000 live births.(1-5) The genetic etiology of inherited congenital neutropenia is most commonly due to disease-causing variants in genes that play a role in neutrophil differentiation.(1) Inheritance can be autosomal recessive, autosomal dominant, or X-linked.
The most common causes of isolated congenital neutropenia are disease-causing variants in the ELANE and HAX1 genes, which encode neutrophil elastase and HCLS1(hematopoietic cell-specific Lyn substrate)-associated protein X-1, respectively. Autosomal dominant ELANE-related neutropenia is the most common cause of congenital neutropenia in children and may present with oral/colonic ulcers, recurrent upper and lower respiratory infections, and various infections of the soft tissue.(2,4,6) In addition, most cases of cyclic neutropenia are due to disease-causing variants in ELANE. Autosomal recessive Kostmann disease, caused by variants in the HAX1 gene, is the second most common cause of congenital neutropenia in children and presents similarly to ELANE-related neutropenia.(2,4,6) X-linked WAS-related disorders lead to a spectrum of congenital neutropenia phenotypes including Wiskott-Aldrich syndrome and X-linked congenital neutropenia.(5,6) Isolated severe congenital neutropenia may more rarely be due to disease-causing variants in several additional genes including CSF3R, CXCR2, GFI1 and WIPF1.(1,6)
Severe neutropenia may also be present as part of a multisystem disorder.(1) This panel assesses for many conditions in which neutropenia is seen in conjunction with extra-hematologic features, including but not limited to:
-Shwachman-Diamond syndrome, an autosomal dominant condition due to disease-causing variants in the SBDS gene, is also characterized by exocrine pancreatic dysfunction, bone abnormalities, and hematologic abnormalities.
-GATA2-deficieny (monocytopenia and mycobacterial infection [MonoMAC] syndrome), an autosomal dominant condition due to disease-causing variants in the GATA2 gene, demonstrates a wide spectrum of clinical presentations ranging from mild chronic neutropenia with monocytopenia to Emberger syndrome and predisposition to acute myeloid malignancy.
-Barth syndrome, an X-linked condition due to disease-causing variants in the TAZ gene, is also characterized cardiomyopathy, skeletal myopathy, growth delay, and distinctive facial features.
-Cohen syndrome, an autosomal recessive condition due to disease-causing variants in the VSP13B gene, is also characterized by hypotonia, developmental delays, microcephaly, failure to thrive in infancy, truncal obesity, ophthalmologic findings, joint hypermobility, a cheerful disposition, and characteristic facial features.
-WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome, an autosomal dominant condition caused by variants in the CXCR4 gene, is also characterized by hypogammaglobulinemia and susceptibility to human papillomavirus.
An interpretive report will be provided
All detected variants are evaluated according to American College of Medical Genetics and Genomics recommendations.(7) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.