Severe Congenital Neutropenia and Neutrophilia via the CSF3R Gene

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
774 CSF3R$990.00 81479 Add to Order
Targeted Testing

For ordering targeted known variants, please proceed to our Targeted Variants landing page.

Turnaround Time

The great majority of tests are completed within 18 days.

Clinical Sensitivity

Variants in the CSF3R gene have been reported as the primary cause of disease in only a handful of SCN patients, but CSF3R variants have been reported in 70% to 80% of SCN patients who develop MDS / AML (Dong et al. 1995; Germeshausen et al. 2007; Beekman et al. 2012; Skokowa et al. 2012).

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 CSF3R$690.00 81479 Add to Order
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Over 100

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Turnaround Time

The great majority of tests are completed within 28 days.

Clinical Sensitivity

Reports of large deletions / duplications in the CSF3R gene are rare.

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Clinical Features

Severe Congenital Neutropenia (SCN) is a disorder of neutrophil production with varying symptoms and modes of inheritance. SCN is characterized by absolute neutrophil counts (ANC) consistently below 500/microL and severe systemic bacterial infections beginning in early infancy (Boxer and Newburger 2007). Other symptoms include recurrent fevers, sinusitis, gingivitis and other soft tissue infections. A hallmark of SCN is bone marrow maturation arrest; neutrophils differentiate only to the promyelocyte/myelocyte stage (Kostman 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. 2004; Freedman et al. 2000). SCN is a premalignant condition, and patients are at an elevated risk of developing myelodysplastic syndrome (MDS) and acute myeloblastic leukemia (AML). The risk of developing a malignancy increases upon G-CSF treatment (Gilman et al. 1970; Freedman et al. 2000; Rosenberg et al. 2006). The cumulative incidence of leukemia in SCN patients is ~ 22% after 15 years of G-CSF treatment (Rosenberg et al. 2010). In contrast to neutropenia, neutrophilia is characterized by an increase in neutrophils and is generally defined as an absolute neutrophil count greater than 7700/microL.


Causative variants in the ELANE gene, consisting primarily of missense variants, are associated with 35%-63% of SCN cases (Rosenberg et al. 2006; Bellanne-Chantelot et al. 2004) and are inherited in an autosomal dominant manner. Pathogenic variants in the GFI1 gene have also been identified in a small fraction of patients with autosomal dominant SCN (Person et al. 2003). GATA2 gene variants are also inherited in an autosomal dominant manner and are associated with neutropenia, MonoMac syndrome, and frequent evolution to MDS/AML (Pasquet et al. 2013). Autosomal recessive forms of SCN have been linked to variants in the HAX1 (Klein et al. 2007)G6PC3 (Boztug et al. 2009), CSF3R (Dong et al. 1995; Triot et al. 2014), and VPS45 (Stepensky et al. 2013) genes, and X-linked SCN has been attributed to variants in the WAS gene (Ancliff et al. 2006). In one recent study, a genetic basis of SCN was not identified in approximately 40% of the cases analyzed (Xia et al. 2009). These data suggest that additional genetic causes of SCN have yet to be discovered and that testing for other disorders with neutropenia as a common symptom, e.g. Hermansky-Pudlak syndrome type 2 (HPS2) and Chediak-Higashi syndrome (CHS), should also be considered. The mechanism of neutropenia is due, at least in some cases, to increased apoptosis of myeloid cells. Gene defects in ELANE and G6PC3 are associated with increased endoplasmic reticulum stress and the unfolded protein response (Xia and Link 2008; Klein 2011), whereas deficiencies of the mitochondrial protein HAX1 cause apoptosis through disruption of mitochondrial membrane potential (Klein 2011).

In contrast to other forms of SCN, inherited biallelic missense / nonsense variants, and small deletions in CSF3R were shown recently to be direct causes of SCN in patients who had full myeloid cell maturation in bone marrow, but displayed peripheral neutropenia (Triot et al. 2014). The CSF3R gene encodes the cell-surface granulocyte colony stimulating factor (G-CSF) receptor (G-CSFR). G-CSF stimulates myeloid precursor proliferation, differentiation, and survival through G-CSFR. The cytoplasmic portion of G-CSFR employs activation of Janus kinase and other downstream signaling pathways that lead to transcriptional changes that impact directly cell proliferation, differentiation and survival (Liongue et al. 2009). Though the mechanism is not clearly defined, it is believed that variants within this region of G-CSFR can shift the balance between these processes which may cause SCN and the leukemic events often seen with SCN (Germeshausen et al. 2007; Beekman et al. 2012).

In addition, acquired variants in CSF3R are strongly correlated to leukemic transformation seen with SCN (Germeshausen et al. 2007; Beekman et al. 2012; Skokowa et al. 2012; Dong et al. 1994; Dong et al. 1995; Tidow et al. 1997). Current data indicate CSF3R variants are not sufficient for development of leukemic transformation, but have been reported in 70% to 80% of SCN patients that developed AML or MDS (Dong et al. 1995; Germeshausen et al. 2007; Beekman et al. 2012; Skokowa et al. 2012). Variants in the CSF3R gene associated with progression to leukemia are located in the carboxy-terminal, intracellular portion of the G-CSFR protein and involve primarily truncating / loss of function changes that lead to enhanced proliferation, resistance to apoptosis, and increased cell survival (Germeshausen et al. 2007; McLemore et al. 1998; Hunter et al. 2000). In addition, an activating CSF3R gene variant defined as Thr617Asn has been reported in patients with neutrophilia (Plo et al. 2009).

Testing Strategy

This test involves bidirectional DNA Sanger sequencing of all coding exons in the three transcripts of the CSF3R gene listed below plus ~20 bp of flanking non-coding DNA on either side of each exon. We will also sequence any single exon (Test #100) or pair of exons (Test #200) in family members of patients with known mutations or to confirm research results.

Indications for Test

Patients with recurring bacterial infections, a family history of SCN, or neutropenia unrelated to other known syndromes (e.g. Chediak-Higashi Syndrome, Hermansky Pudlak Syndrome, or Griscelli Syndrome) and who have evidence of full myeloid cell maturation in bone marrow.


Official Gene Symbol OMIM ID
CSF3R 138971
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Name Inheritance OMIM ID
Hereditary Neutrophilia 162830

Related Test

Severe Congenital Neutropenia Sequencing Panel


Genetic Counselors
  • Ancliff PJ, Blundell MP, Cory GO, Calle Y, Worth A, Kempski H, Burns S, Jones GE, Sinclair J, Kinnon C, Hann IM, Gale RE, Linch DC, Thrasher AJ. 2006. Two novel activating mutations in the Wiskott-Aldrich syndrome protein result in congenital neutropenia. Blood 108: 2182–2189. PubMed ID: 16804117
  • Beekman R, Valkhof MG, Sanders MA, Strien PMH van, Haanstra JR, Broeders L, Geertsma-Kleinekoort WM, Veerman AJP, Valk PJM, Verhaak RG, Löwenberg B, Touw IP. 2012. Sequential gain of mutations in severe congenital neutropenia progressing to acute myeloid leukemia. Blood 119: 5071–5077. PubMed ID: 22371884
  • Bellanne-Chantelot C. 2004. Mutations in the ELA2 gene correlate with more severe expression of neutropenia: a study of 81 patients from the French Neutropenia Register. Blood 103: 4119–4125. PubMed ID: 14962902
  • Boxer LA, Newburger PE. 2007. A molecular classification of congenital neutropenia syndromes. Pediatric Blood & Cancer 49: 609–614. PubMed ID: 17584878
  • Boztug K, Appaswamy G, Ashikov A, Schäffer AA, Salzer U, Diestelhorst J, Germeshausen M, Brandes G, Lee-Gossler J, Noyan F. 2009. A syndrome with congenital neutropenia and mutations in G6PC3. New England Journal of Medicine 360: 32–43. PubMed ID: 19118303
  • Dong F, Brynes RK, Tidow N, Welte K, Löwenberg B, Touw IP. 1995. Mutations in the gene for the granulocyte colony-stimulating–factor receptor in patients with acute myeloid leukemia preceded by severe congenital neutropenia. New England Journal of Medicine 333: 487–493. PubMed ID: 7542747
  • Dong F, Hoefsloot LH, Schelen AM, Broeders CA, Meijer Y, Veerman AJ, Touw IP, Löwenberg B. 1994. Identification of a nonsense mutation in the granulocyte-colony-stimulating factor receptor in severe congenital neutropenia. Proc Natl Acad Sci U S A 91: 4480–4484. PubMed ID: 7514305
  • Freedman MH, Bonilla MA, Fier C, Bolyard AA, Scarlata D, Boxer LA, Brown S, Cham B, Kannourakis G, Kinsey SE. 2000. Myelodysplasia syndrome and acute myeloid leukemia in patients with congenital neutropenia receiving G-CSF therapy. Blood 96: 429–436. PubMed ID: 10887102
  • Germeshausen M, Ballmaier M, Welte K. 2007. Incidence of CSF3R mutations in severe congenital neutropenia and relevance for leukemogenesis: results of a long-term survey. Blood 109: 93–99. PubMed ID: 16985178
  • Gilman PA, Jackson DP, Guild HG. 1970. Congenital agranulocytosis: prolonged survival and terminal acute leukemia. Blood 36: 576–585. PubMed ID: 4319697
  • Hunter MG, Avalos BR. 2000. Granulocyte colony-stimulating factor receptor mutations in severe congenital neutropenia transforming to acute myelogenous leukemia confer resistance to apoptosis and enhance cell survival. Blood 95: 2132–2137. PubMed ID: 10706885
  • Klein C. 2011. Genetic defects in severe congenital neutropenia: emerging insights into life and death of human neutrophil granulocytes. Annu. Rev. Immunol. 29: 399–413. PubMed ID: 21219176
  • Kostman R. 1975. Infantile genetic agranulocytosis. A review with presentation of ten new cases. Acta Paediatr Scand 64: 362–368. PubMed ID: 1130195
  • Liongue C, Wright C, Russell AP, Ward AC. 2009. Granulocyte colony-stimulating factor receptor: Stimulating granulopoiesis and much more. The International Journal of Biochemistry & Cell Biology 41: 2372–2375. PubMed ID: 19699815
  • McLemore ML, Poursine-Laurent J, Link DC. 1998. Increased granulocyte colony-stimulating factor responsiveness but normal resting granulopoiesis in mice carrying a targeted granulocyte colony-stimulating factor receptor mutation derived from a patient with severe congenital neutropenia. Journal of Clinical Investigation 102: 483. PubMed ID: 9691084
  • Pasquet M, Bellanné-Chantelot C, Tavitian S, Prade N, Beaupain B, LaRochelle O, Petit A, Rohrlich P, Ferrand C, Den Neste E Van, Poirel HA, Lamy T, Ouachée-Chardin M, Mansat-De Mas V, Corre J, Récher C, Plat G, Bachelerie F, Donadieu J, Delabesse E. 2013. High frequency of GATA2 mutations in patients with mild chronic neutropenia evolving to MonoMac syndrome, myelodysplasia, and acute myeloid leukemia. Blood 121: 822–829. PubMed ID: 23223431
  • Person RE, Li F-Q, Duan Z, Benson KF, Wechsler J, Papadaki HA, Eliopoulos G, Kaufman C, Bertolone SJ, Nakamoto B, Papayannopoulou T, Grimes HL, Horwitz M. 2003. Mutations in proto-oncogene GFI1 cause human neutropenia and target ELA2. Nat. Genet. 34: 308–312. PubMed ID: 12778173
  • Plo I, Zhang Y, Couédic J-PL, Nakatake M, Boulet J-M, Itaya M, Smith SO, Debili N, Constantinescu SN, Vainchenker W, Louache F, Botton S de. 2009. An activating mutation in the CSF3R gene induces a hereditary chronic neutrophilia. J Exp Med 206: 1701–1707. PubMed ID: 19620628
  • Rosenberg PS, Zeidler C, Bolyard AA, Alter BP, Bonilla MA, Boxer LA, Dror Y, Kinsey S, Link DC, Newburger PE, Shimamura A, Welte K, Dale DC. 2010. Stable Long-Term Risk of Leukaemia in Patients with Severe Congenital Neutropenia Maintained on G-CSF Therapy. Br J Haematol 150: 196-199. PubMed ID: 20456363
  • Rosenberg PS. 2006. The incidence of leukemia and mortality from sepsis in patients with severe congenital neutropenia receiving long-term G-CSF therapy. Blood 107: 4628–4635. PubMed ID: 16497969
  • Skokowa J, Steinemann D, Katsman-Kuipers JE, Zeidler C, Klimenkova O, Klimiankou M, Ãœnalan M, Kandabarau S, Makaryan V, Beekman R, Behrens K, Stocking C, et al. 2014. Cooperativity of RUNX1 and CSF3R mutations in severe congenital neutropenia: a unique pathway in myeloid leukemogenesis. Blood 123: 2229–2237. PubMed ID: 24523240
  • Stepensky P, Saada A, Cowan M, Tabib A, Fischer U, Berkun Y, Saleh H, Simanovsky N, Kogot-Levin A, Weintraub M, Ganaiem H, Shaag A, Zenvirt S, Borkhardt A, Elpeleg O, Bryant NJ, Mevorach D. 2013. The Thr224Asn mutation in the VPS45 gene is associated with the congenital neutropenia and primary myelofibrosis of infancy. Blood 121: 5078–5087. PubMed ID: 23599270
  • Tidow N, Pilz C, Teichmann B, Müller-Brechlin A, Germeshausen M, Kasper B, Rauprich P, Sykora K-W, Welte K. 1997. Clinical relevance of point mutations in the cytoplasmic domain of the granulocyte colony-stimulating factor receptor gene in patients with severe congenital neutropenia. Blood 89: 2369–2375. PubMed ID: 9116280
  • Triot A, Järvinen PM, Arostegui JI, Murugan D, Kohistani N, Díaz JLD, Racek T, PuchaÅ‚ka J, Gertz EM, Schäffer AA, Kotlarz D, Pfeifer D, et al. 2014. Inherited biallelic CSF3R mutations in severe congenital neutropenia. Blood 123: 3811–3817. PubMed ID: 24753537
  • Xia J, Bolyard AA, Rodger E, Stein S, Aprikyan AA, Dale DC, Link DC. 2009. Prevalence of mutations in ELANE , GFI1 , HAX1 , SBDS , WAS and G6PC3 in patients with severe congenital neutropenia. British Journal of Haematology 147: 535–542. PubMed ID: 19775295
  • Xia J, Link DC. 2008. Severe congenital neutropenia and the unfolded protein response. Curr. Opin. Hematol. 15: 1–7. PubMed ID: 18043239
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Bi-Directional Sanger Sequencing

Test Procedure

Nomenclature for sequence variants was from the Human Genome Variation Society (  As required, DNA is extracted from the patient specimen.  PCR is used to amplify the indicated exons plus additional flanking non-coding sequence.  After cleaning of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit.  Products are resolved by electrophoresis on an ABI 3730xl capillary sequencer.  In most cases, sequencing is performed in both forward and reverse directions; in some cases, sequencing is performed twice in either the forward or reverse directions.  In nearly all cases, the full coding region of each exon as well as 20 bases of non-coding DNA flanking the exon are sequenced.

Analytical Validity

As of March 2016, we compared 17.37 Mb of Sanger DNA sequence generated at PreventionGenetics to NextGen sequence generated in other labs. We detected only 4 errors in our Sanger sequences, and these were all due to allele dropout during PCR. For Proficiency Testing, both external and internal, in the 12 years of our lab operation we have Sanger sequenced roughly 8,800 PCR amplicons. Only one error has been identified, and this was due to sequence analysis error.

Our Sanger sequencing is capable of detecting virtually all nucleotide substitutions within the PCR amplicons. Similarly, we detect essentially all heterozygous or homozygous deletions within the amplicons. Homozygous deletions which overlap one or more PCR primer annealing sites are detectable as PCR failure. Heterozygous deletions which overlap one or more PCR primer annealing sites are usually not detected (see Analytical Limitations). All heterozygous insertions within the amplicons up to about 100 nucleotides in length appear to be detectable. Larger heterozygous insertions may not be detected. All homozygous insertions within the amplicons up to about 300 nucleotides in length appear to be detectable. Larger homozygous insertions may masquerade as homozygous deletions (PCR failure).

Analytical Limitations

In exons where our sequencing did not reveal any variation between the two alleles, we cannot be certain that we were able to PCR amplify both of the patient’s alleles. Occasionally, a patient may carry an allele which does not amplify, due for example to a deletion or a large insertion. In these cases, the report contains no information about the second allele.

Similarly, our sequencing tests have almost no power to detect duplications, triplications, etc. of the gene sequences.

In most cases, only the indicated exons and roughly 20 bp of flanking non-coding sequence on each side are analyzed. Test reports contain little or no information about other portions of the gene, including many regulatory regions.

In nearly all cases, we are unable to determine the phase of sequence variants. In particular, when we find two likely causative mutations for recessive disorders, we cannot be certain that the mutations are on different alleles.

Our ability to detect minor sequence variants, due for example to somatic mosaicism is limited. Sequence variants that are present in less than 50% of the patient’s nucleated cells may not be detected.

Runs of mononucleotide repeats (eg (A)n or (T)n) with n >8 in the reference sequence are generally not analyzed because of strand slippage during PCR and cycle sequencing.

Unless otherwise indicated, the sequence data that we report are based on DNA isolated from a specific tissue (usually leukocytes). Test reports contain no information about gene sequences in other tissues.

Deletion/Duplication Testing via Array Comparative Genomic Hybridization

Test Procedure

Equal amounts of genomic DNA from the patient and a gender matched reference sample are amplified and labeled with Cy3 and Cy5 dyes, respectively. To prevent any sample cross contamination, a unique sample tracking control is added into each patient sample. Each labeled patient product is then purified, quantified, and combined with the same amount of reference product. The combined sample is loaded onto the designed array and hybridized for at least 22-42 hours at 65°C. Arrays are then washed and scanned immediately with 2.5 µM resolution. Only data for the gene(s) of interest for each patient are extracted and analyzed.

Analytical Validity

PreventionGenetics' high density gene-centric custom designed aCGH enables the detection of relatively small deletions and duplications within a single exon of a given gene or deletions and duplications encompassing the entire gene. PreventionGenetics has established and verified this test's accuracy and precision.

Analytical Limitations

Our dense probe coverage may allow detection of deletions/duplications down to 100 bp; however due to limitations and probe spacing this cannot be guaranteed across all exons of all genes. Therefore, some copy number changes smaller than 100-300 bp within a targeted large exon may not be detected by our array.

This array may not detect deletions and duplications present at low levels of mosaicism or those present in genes that have pseudogene copies or repeats elsewhere in the genome.

aCGH will not detect balanced translocations, inversions, or point mutations that may be responsible for the clinical phenotype.

Breakpoints, if occurring outside the targeted gene, may be hard to define.

The sensitivity of this assay may be reduced when DNA is extracted by an outside laboratory.

Order Kits

Ordering Options

myPrevent - Online Ordering
  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.


(Delivery accepted Monday - Saturday)

  • Collect 3 ml -5 ml (5 ml preferred) of whole blood in EDTA (purple top tube) or ACD (yellow top tube). For Test #500-DNA Banking only, collect 10 ml -20 ml of whole blood.
  • For small babies, we require a minimum of 1 ml of blood.
  • Only one blood tube is required for multiple tests.
  • Ship blood tubes at room temperature in an insulated container. Do not freeze blood.
  • During hot weather, include a frozen ice pack in the shipping container. Place a paper towel or other thin material between the ice pack and the blood tube.
  • In cold weather, include an unfrozen ice pack in the shipping container as insulation.
  • At room temperature, blood specimen is stable for up to 48 hours.
  • If refrigerated, blood specimen is stable for up to one week.
  • Label the tube with the patient name, date of birth and/or ID number.


(Delivery accepted Monday - Saturday)

  • Send in screw cap tube at least 5 µg -10 µg of purified DNA at a concentration of at least 20 µg/ml for NGS and Sanger tests and at least 5 µg of purified DNA at a concentration of at least 100 µg/ml for gene-centric aCGH, MLPA, and CMA tests, minimum 2 µg for limited specimens.
  • For requests requiring more than one test, send an additional 5 µg DNA per test ordered when possible.
  • DNA may be shipped at room temperature.
  • Label the tube with the composition of the solute, DNA concentration as well as the patient’s name, date of birth, and/or ID number.
  • We only accept genomic DNA for testing. We do NOT accept products of whole genome amplification reactions or other amplification reactions.


(Delivery preferred Monday - Thursday)

  • PreventionGenetics should be notified in advance of arrival of a cell culture.
  • Culture and send at least two T25 flasks of confluent cells.
  • Some panels may require additional flasks (dependent on size of genes, amount of Sanger sequencing required, etc.). Multiple test requests may also require additional flasks. Please contact us for details.
  • Send specimens in insulated, shatterproof container overnight.
  • Cell cultures may be shipped at room temperature or refrigerated.
  • Label the flasks with the patient name, date of birth, and/or ID number.
  • We strongly recommend maintaining a local back-up culture. We do not culture cells.
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