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Severe Congenital Neutropenia via the VPS45 Gene

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
VPS45 81479 81479,81479 $990
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
11799VPS4581479 81479,81479 $990 Order Options and Pricing

Pricing Comments

Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based tests. However, if full gene Sanger sequencing is desired for STAT turnaround time, insurance, or other reasons, please see link below for Test Code, pricing, and turnaround time information.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

Click here for costs to reflex to whole PGxome (if original test is on PGxome Sequencing platform).

Click here for costs to reflex to whole PGnome (if original test is on PGnome Sequencing platform).

The Sanger Sequencing method for this test is NY State approved.

For Sanger Sequencing click here.

Turnaround Time

3 weeks on average for standard orders or 2 weeks on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.


Genetic Counselors


  • Siwu Peng, PhD

Clinical Features and Genetics

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/ul 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).


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), and VPS45 (Stepensky et al. 2013) genes. 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). To date, only two missense variants in the VPS45 gene have been reported as causes of autosomal recessive neutropenia: p.Thr224Asn and p.Glu238Lys (Stepensky et al. 2013; Vilboux et al. 2013). Patients with these variants had severe neutrophil deficiencies, bone marrow fibrosis, nephromegaly, and in some cases neurologic abnormalities manifested as developmental delay, cortical blindness, hearing loss and thin corpus callosum on MRI (Vilboux et al. 2013).

Clinical Sensitivity - Sequencing with CNV PGxome

Causative variants in the ELANE gene are associated with 35%-63% of Severe Congenital Neutropenia (SCN) cases (Rosenberg et al. 2006; Bellanne-Chantelot et al. 2004) and are inherited in an autosomal dominant manner. Causative variants in the VPS45 gene have been identified in only a few families and are a rare cause of autosomal recessive SCN (Stepensky et al. 2013; Vilboux et al. 2013).

Testing Strategy

This test provides full coverage of all coding exons of the VPS45 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).

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). This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in VPS45.


Official Gene Symbol OMIM ID
VPS45 610035
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


  • 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
  • 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
  • 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
  • Gilman PA, Jackson DP, Guild HG. 1970. Congenital agranulocytosis: prolonged survival and terminal acute leukemia. Blood 36: 576–585. PubMed ID: 4319697
  • 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
  • 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
  • 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
  • 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
  • Vilboux T, Lev A, Malicdan MCV, Simon AJ, Järvinen P, Racek T, Puchalka J, Sood R, Carrington B, Bishop K, Mullikin J, Huizing M, Garty BZ, Eyal E, Wolach B, Gavrieli R, Toren A, Soudack M, Atawneh OM, Babushkin T, Schiby G, Cullinane A, Avivi C, Polak-Charcon S, Barshack I, Amariglio N, Rechavi G, van der Werff ten Bosch J, Anikster Y, Klein C, Gahl WA, Somech R. 2013. A Congenital Neutrophil Defect Syndrome Associated with Mutations in VPS45. New England Journal of Medicine 369: 54–65. PubMed ID: 23738510
  • 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


Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

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.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

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.

For Requisition Forms, visit our Forms page

If ordering a Duo or Trio test, the proband and all comparator samples are required to initiate testing. If we do not receive all required samples for the test ordered within 21 days, we will convert the order to the most effective testing strategy with the samples available. Prior authorization and/or billing in place may be impacted by a change in test code.

Specimen Types

Specimen Requirements and Shipping Details

PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

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