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Test Catalog

Test ID: SCNGP    
Congenital Neutropenia, Primary Immunodeficiency Disorder Panel (18 genes), Next-Generation Sequencing, Varies

Useful For Suggests clinical disorders or settings where the test may be helpful

Providing a comprehensive genetic evaluation for patients with a personal or family history suggestive of congenital neutropenia, cyclic neutropenia, or other primary immunodeficiency disorder (PIDD) presenting with significant neutropenia

 

Establishing a diagnosis and, in some cases, allowing for appropriate management and surveillance for disease features based on the gene involved

 

Identifying variants within genes known to be associated with PIDD characterized by significant neutropenia allowing for predictive testing of at-risk family members

Genetics Test Information Provides information that may help with selection of the correct genetic test or proper submission of the test request

This test includes next-generation sequencing and supplemental Sanger sequencing to test for variants in the AP3B1(HP2), CSF3R, CXCR4, ELANE(ELA2), G6PC3, GATA2, GFI1, HAX1, LAMTOR2(MAPBPIP), RAC2, SBDS, SLC37A4, TAZ, USB1(C16ORF57), VPS13B(COH1), VPS45, WAS, and WIPF1 genes.

 

Identification of a pathogenic variant may assist with prognosis, clinical management, familial screening, and genetic counseling.

Testing Algorithm Delineates situations when tests are added to the initial order. This includes reflex and additional tests.

For skin biopsy or cultured fibroblast specimens, fibroblast culture and cryopreservation testing will be performed at an additional charge. If viable cells are not obtained, the client will be notified.

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

Severe congenital neutropenia is a primary immunodeficiency disorder (PIDD) that is characterized by severe and recurrent bacterial infections, such as otitis media, bronchitis, pneumonia, osteomyelitis, and cellulitis, typically with the absence of pus at the infected site. Susceptibility to fungal infections may also be observed. Neutropenia may be an isolated finding or may be part of a syndrome. This panel includes genes associated with neutropenia as a major presenting feature; other panels may be more appropriate when neutropenia is identified but not as the main finding.

 

Pathogenic variants in ELANE, which encodes neutrophil elastase, can result in severe congenital neutropenia type 1 (SCN1) or cyclic neutropenia. SCN1 often presents immediately with omphalitis, while diarrhea, pneumonia, and deep abscesses affecting the liver, lungs, or subcutaneous tissues are noted within the first year. Patients are at risk for development of myelodysplastic syndrome or acute myelogenous leukemia, presumably due to acquired mutations in CSF3R (which may also be identified in the presence of congenital neutropenia due to variants in genes other than ELANE, see below). Biallelic mutations in CSF3R have also been recently reported to be associated with severe congenital neutropenia. Cyclic neutropenia typically presents in the first year of life with 3-week-long oscillations in cell counts along with intervals of fever, oral ulcerations, and ulcerations; between intervals, patients are generally healthy. Unlike SCN1, cyclic neutropenia is not associated with risk of malignancy. Both SCN1 and cyclic neutropenia are inherited in an autosomal dominant pattern from an affected parent, although de novo variants have been identified. Studies have demonstrated pathogenic variants in ELANE in nearly 100% of cases with well-documented classical cyclic neutropenia, while in some cases with atypical presentations (ie, oscillations that are not 3 weeks) a variant in ELANE is not identified. ELANE variants are identified in 38% to 80% of cases of congenital neutropenia, depending on the criteria used to identify patients. Although there is some overlap, generally, variants at the active site of neutrophil elastase result in cyclic neutropenia, while variants that prevent normal folding or packaging of the enzyme cause congenital neutropenia.

 

In addition to variants in ELANE, severe congenital neutropenia, where the predominant finding is neutropenia, can be inherited as a result of pathogenic variants in other genes. Dominant variants in GFI1 (encoding growth factor independent 1) result in severe congenital neutropenia type 2 (SCN2). Pathogenic variants in G6PC3 (encoding glucose-6-phosphate 3), which are inherited in an autosomal recessive manner, can result in a phenotypic spectrum from isolated/nonsyndromic severe congenital neutropenia to classic G6PC3 deficiency (severe neutropenia along with cardiovascular and urogenital abnormalities) to severe G6PC3 deficiency (also known as Dursun syndrome, which includes features of classic G6PC3 deficiency along with severe lymphopenia, primary pulmonary hypertension, thymic hypoplasia, among other features). Kostmann disease or severe congenital neutropenia type 3 (SCN3) is due to recessive inheritance of pathogenic variants in HAX1 (which encodes HCLS1-associated protein X-1) and may result in seizures and developmental delay in addition to neutropenia. Along with neutropenia, variants in VPS45 inherited in an autosomal recessive manner (also known as severe congenital neutropenia type 5 [SNC5]) are associated with neutrophil dysfunction, bone marrow fibrosis, and nephromegaly due to renal extramedullary hematopoiesis. While loss-of-function variants in WAS, which is located on the X chromosome, cause Wiskott-Aldrich syndrome (characterized by thrombocytopenia, eczema, and recurrent infections), gain-of-function variants affecting the autoinhibitory structure of the protein, have been associated with congenital neutropenia, along with variable lymphopenia, decreased lymphocyte proliferation, and impaired phagocyte activity. Pathogenic variants in WIPF1 can present with similar findings to Wiskott-Aldrich syndrome.

 

Severe neutropenia may also be present as part of a multisystem disorder. Barth syndrome, due to pathogenic variants in TAZ, which is located on the X-chromosome, is characterized by neutropenia, cardio- and skeletal myopathy, growth delay, and distinctive facial features. Biallelic variants in C16orf57 manifest as poikiloderma with neutropenia; the neutropenia may be cyclical. In Cohen syndrome, an autosomal recessive disorder due to variants in COH1 (also known as VPS13B), neutropenia is accompanied by hypotonia, developmental delays, microcephaly, failure to thrive in infancy, truncal obesity in adolescent years, ophthalmologic findings, joint hypermobility, a cheerful disposition, and characteristic facial features. Glycogen storage disease type I (GSDI), caused by biallelic pathogenic variants in either G6PC or SLC37A4, when untreated can result in chronic neutropenia and impaired neutrophil and monocyte function, as well as the characteristic findings that include accumulation of glycogen and fat in the liver and kidneys. Pathogenic variants in LAMTOR2/MAPBPIP have been shown to result in neutropenia, decreased cytotoxic activity of CD8+ T-cells, short stature, and hypopigmented skin. Persistent or intermittent neutropenia is often a presenting feature of Shwachman-Diamond syndrome (SDS), which is also characterized by exocrine pancreatic dysfunction (with malabsorption, malnutrition, and growth failure), bone abnormalities, and hematologic abnormalities (single- or multilineage cytopenias along with predisposition to myelodysplastic syndrome and acute myelogenous leukemia). SDS is an autosomal recessive disorder due to pathogenic variants in SBDS. Warts, hypogammaglobulinemia, immunodeficiency, and myelokathexis (WHIM) syndrome is characterized by neutropenia in addition to hypogammaglobulinemia, and susceptibility to human papillomavirus. It is due to autosomal dominant pathogenic variants in CXCR4. Although most forms of Hermansky-Pudlak syndrome do not include significant neutropenia, type 2 caused by variants in AP3B1 can be associated with persistent neutropenia and increased infections in addition to the typical findings of tyrosinase-positive oculocutaneous albinism, platelet storage pool deficiency, pulmonary fibrosis, and granulomatous colitis. Few patients with RAC2 pathogenic variants have been identified, but neutrophil dysfunction appears to be a feature, though CD11b expression and specific granule release appear to be preserved. Both individuals with dominant and individuals with recessive inheritance have been identified, with and without additional associated phenotypic findings.

 

GATA-binding protein (GATA2) deficiency demonstrates a wide spectrum of clinical presentations, including neutropenia. Most variants appear to arise de novo (spontaneously) and are then transmitted in an autosomal dominant manner. If the clinical phenotype strongly suggests GATA2 deficiency, this gene is available as a stand-alone test (see GATA2 / GATA-Binding Protein 2 (GATA2), Full Gene, Next-Generation Sequencing, Varies). This panel does not evaluate for somatic (acquired) ASXL1 mutations associated with GATA2 deficiency.

 

Table 1. Genes included in the Congenital Neutropenia/Neutrophil-Related PID Gene Panel

GENE SYMBOL (ALIAS)

PROTEIN

OMIM

INCIDENCE

INHERITANCE

PHENOTYPE DISORDER

AP3B1

AP-3 complex subunit beta-1 isoform 1

603401

Rare

AR

Hermansky-Pudlak syndrome 2

CSF3R

Granulocyte colony-stimulating factor receptor isoform a precursor

138971

 

AR, acquired

Severe congenital neutropenia

CXCR4

C-X-C chemokine receptor type 4 isoform b

162643

 

AD

Myelokathexis, isolated, WHIM syndrome (AD)

ELANE

Neutrophil elastase preproprotein

130130

 2:1,000,000-3:1,000,000 (SCN); 1:1,000,000 (cyclic neutropenia)

AD

Severe congenital neutropenia (SCN), cyclic neutropenia

G6PC3

Glucose-6-phosphatase 3

611045

 

AR

Dursun syndrome, severe congenital neutropenia (SCN) 4

GATA2

Endothelial transcription factor GATA-2 isoform 1

137295

 

AD

Immunodeficiency 21, Emberger syndrome, susceptibility to acute myeloid leukemia and myelodysplastic syndrome

GFI1

Zinc finger protein Gfi-1

600871

 

AD

Severe congenital neutropenia (SCN) 2(AD), nonimmune chronic idiopathic neutropenia of adults

HAX1

HCLS1-associated protein X-1 isoform a

605998

 

AR

Severe congenital neutropenia (SCN) 3

LAMTOR2 (MAPBPIP)

Ragulator complex protein LAMTOR2 isoform 1

610389

 

AR

Immunodeficiency due to defect in MAPBP-interacting protein

RAC2

ras-Related C3 botulinum toxin substrate 2

602049

 

AD/AR

Neutrophil functional defects

SBDS

Ribosome maturation protein SBDS

607444

 

AR

Shwachman-Diamond syndrome, susceptibility to aplastic anemia

SLC37A4

Ddipeptidyl peptidase 1 isoform a preproprotein

602671

 

AR

Glycogen storage disease Ib and 1c

TAZ

Tafazzin isoform 1

300394

 

XL

Barth syndrome

USB1 (C16ORF57)

U6 snRNA phosphodiesterase isoform 1

613276

Rare

AR

Poikiloderma with neutropenia   

VPS13B (COH1)

Vacuolar protein sorting-associated protein 13B isoform 5

607817

 

AR

Cohen syndrome

VPS45

Vacuolar protein sorting-associated protein 45 isoform 1

610035

 

AR

Severe congenital neutropenia (SCN) 5

WAS

(Gain-of-function mutations)

Wiskott-Aldrich syndrome protein

300392

 

XL (gain of function)

Neutropenia, severe congenital, X-linked, thrombocytopenia, X-linked

WIPF1

WAS/WASL-interacting protein family member 1

602357

 

In progress

Wiskott-Aldrich syndrome 2

AD=autosomal dominant AR=autosomal recessive

XL=X-linked

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

An interpretive report will be provided.

Interpretation Provides information to assist in interpretation of the test results

Evaluation and categorization of variants is performed using the most recent published American College of Medical Genetics and Genomics (ACMG) recommendations as a guideline. Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.

 

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 predictions made by these tools may change over time. Results from in silico evaluation tools should be interpreted with caution and professional clinical judgment.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

The majority of DNA extracted from whole blood is derived from neutrophils. Therefore, blood specimens collected from patients with severe neutropenia may yield limited quantity of DNA that is insufficient for testing. When ordering this test for patients with severe neutropenia, please consider timing the collection when the patient has a higher neutrophil count, submitting an alternate specimen type, or collecting additional blood volume.

 

Clinical Correlations:

Some individuals who have involvement of one or more of the genes on the panel may have a variant that is not identified by the methods performed (eg, promoter variants, deep intronic variants). The absence of a variant, therefore, does not eliminate the possibility of disease. Test results should be interpreted in context of clinical findings, family history, and other laboratory data. Misinterpretation of results may occur if the information provided is inaccurate or incomplete.

 

For predictive testing of asymptomatic individuals, it is often useful to first test an affected family member. Identification of a pathogenic variant in an affected individual allows for more informative testing of at-risk individuals.

 

Technical Limitations:

Next-generation sequencing may not detect all types of genetic variants. The variant detection software has lower detection efficiency for insertion/deletion variants as compared to single nucleotide variants. Therefore, small deletions and insertions greater than 8 nucleotides in length may not be detected by this test. Copy Number variations (CNV) are not currently reported for any of the genes on this panel. Additionally, rare polymorphisms may be present that could lead to false-negative or false-positive results. In some cases, DNA variants of undetermined significance may be identified. If results do not match clinical findings, consider alternative methods for analyzing these genes, such as Sanger sequencing or large deletion/duplication analysis. If the patient has had an allogeneic blood or bone marrow transplant or a recent (ie, <6 weeks from time of sample collection) heterologous blood transfusion, results may be inaccurate due to the presence of donor DNA. Call 800-533-1710 for instructions for testing patients who have received a bone marrow transplant.

 

Reclassification of Variants-Policy:

At this time, it is not standard practice for the laboratory to systematically review likely deleterious alterations or variants of uncertain significance that are detected and reported. The laboratory encourages health care providers to contact the laboratory at any time to learn how the status of a particular variant may have changed over time. Consultation with a healthcare provider, or team of healthcare providers, with expertise in genetics and primary immunodeficiencies, is recommended for interpretation of this result.

 

A list of benign and likely benign variants detected is available from the lab upon request.

 

Contact the laboratory if additional information is required regarding the transcript or human genome assembly used for the analysis of results.

Clinical Reference Recommendations for in-depth reading of a clinical nature

1. Picard C, Gaspar HB, Al-Herz W, Bousfina A, et al: International Union of Immunological Societies: 2017 Primary Immunodeficiency Disease Committee Report on Inborn Errors of Immunity, J Clin Immunol. 2018; 38:96-128

2. Donadieu J, Fenneteau O, Beaupain B, et al: Congenital neutropenia: diagnosis, molecular bases and patient management. Orphanet Journal of Rare Diseases. 2011;6:26

3. Boxer LA, Stein S, Buckley D, et al: Strong evidence for autosomal dominant inheritance of severe congenital neutropenia associated with ELA2 mutations. J Pediatr. 2006;148:633-636

4. Beel K, Bandenberghe P: G-CSF receptor (CSF3R) mutations in X-linked neutropenia evolving to acute myeloid leukemia or myelodysplasia. Haematologica. 2009;94(10):1449-1452

5. Klein C: Genetic defects in severe congenital neutropenia: emerging insights into life and death of human neutrophil granulocytes. Ann Rev Immunol. 2011;29:399-413

6. Albert MH, Notarangelo LD, Ochs HD: Clinical spectrum, pathophysiology and treatment of the Wiskott-Aldrich syndrome. Cur Opin Hematol. 2011;18(1):42-48

7. Concolino D, Roversi G, Muzzi GL, et al: Clericuzio-type poikiloderma with neutropenia syndrome in three sibs with mutations in the C16orf57 gene: delineation of the phenotype. Am J Med Genet. 2010;152A(10):2588-2594

8. Bohn G, Allroth A, Brandea G, et al: A novel human primary immunodeficiency syndrome caused by deficiency of endosomal adaptor protein p14. Nature Med. 2007;13(1):38-45

9. Triot A, Jarvinen PM, Arostegui JI, et al: Inherited biallelic CSF3R mutations in severe congenital neutropenia. Blood. 2014;123:3811-3817

10. Bousifiha AA, et al: A phenotypic approach for IUIS PID classification and diagnosis: guidelines for clinicians at the bedside. J Clin Immunol. 2013;Aug;33(6):1078-1087

Special Instructions Library of PDFs including pertinent information and forms related to the test