Severe Congenital Neutropenia Panel

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy Genes Gene CPT Codes Copy CPT Codes
10257 AP3B1 81479,81479 Order Options and Pricing
CSF3R 81479,81479
CXCR4 81479,81479
DNAJC21 81479,81479
ELANE 81479,81479
G6PC3 81479,81479
GATA1 81479,81479
GATA2 81479,81479
GFI1 81479,81479
HAX1 81479,81479
JAGN1 81479,81479
LAMTOR2 81479,81479
LYST 81479,81479
RAB27A 81479,81479
RAC2 81479,81479
SBDS 81479,81479
SLC37A4 81406,81479
SMARCD2 81479,81479
TAFAZZIN 81406,81479
USB1 81479,81479
VPS13B 81408,81407
VPS45 81479,81479
WAS 81406,81479
WDR1 81479,81479
WIPF1 81479,81479
Test Code Test Copy Genes Panel CPT Code Gene CPT Codes Copy CPT Code Base Price
10257Genes x (25)81479 81406, 81407, 81408, 81479 $890 Order Options and Pricing

Pricing Comments

We are happy to accommodate requests for testing single genes in this panel or a subset of these genes. The price will remain the list price. If desired, free reflex testing to remaining genes on panel is available. Alternatively, a single gene or subset of genes can also be ordered via our PGxome Custom Panel tool.

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

For Reflex to PGxome pricing click here.

Turnaround Time

18 days on average for standard orders or 14 days on average for STAT orders.

Once a specimen has started the testing process in our lab, the most accurate prediction of TAT will be displayed in the myPrevent portal as an Estimated Report Date (ERD) range. We calculate the ERD for each specimen as testing progresses; therefore the ERD range may differ from our published average TAT. View more about turnaround times here.

Targeted Testing

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

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

A defect in neutrophil function or a decrease in the number of neutrophils can lead to serious immunodeficiencies, recurrent infections, and in some cases lead to an increased risk for hematologic malignancies. 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. PubMed ID: 17584878). Other symptoms include recurrent fevers, sinusitis, gingivitis and other soft tissue infections. A common feature of SCN is bone marrow maturation arrest; neutrophils differentiate only to the promyelocyte/myelocyte stage (Kostman. 1975. PubMed ID: 1130195). 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. PubMed ID: 14962902; Freedman et al. 2000. PubMed ID: 10887102).

Some forms of neutropenia are also associated with an elevated risk of developing myelodysplastic syndrome (MDS) and acute myeloblastic leukemia (AML). The risk of developing a malignancy has been shown to increase due to G-CSF treatment (Gilman et al. 1970. PubMed ID: 4319697; Freedman et al. 2000. PubMed ID: 10887102; Rosenberg et al. 2006. PubMed ID: 16497969), and the cumulative incidence of leukemia in SCN patients is ~ 22% after 15 years of G-CSF treatment (Rosenberg et al. 2010. PubMed ID: 20456363).

Disorders of neutrophil function may involve decreased granule production or diminished granule content, abnormal neutrophil morphologies, secretion defects, and are characterized by many of the same clinical features as disorders due to a lack of neutrophil production (Kuhns et al. 2016. PubMed ID: 27557945; Ambruso et al. 2000. PubMed ID: 10758162).

Genetics

Disorders of neutrophil number and function are clinically and genetically heterogeneous and are found in syndromic and non-syndromic forms. The following is a list of genes associated with some of the more frequently occurring forms of neutrophil disorders.

Autosomal Dominant Disorders

ELANE – Causative variants in the ELANE gene, consisting primarily of missense variants, are associated with cyclic neutropenia and with 35%-63% of SCN cases (Rosenberg et al. 2006. PubMed ID: 16497969; Bellanne-Chantelot et al. 2004. PubMed ID: 14962902).

GFI1 Dominant negative, missense pathogenic variants in the GFI1 gene have been identified in a small fraction of patients with autosomal dominant SCN (Person et al. 2003. PubMed ID: 12778173).

GATA2 – Variants in GATA2 are associated with several disorders including neutropenia, primary lymphedema, MonoMac syndrome, and predisposition to Myelodyplastic syndrome (MDS) and acute myeloid leukemia (AML) (Pasquet et al. 2013. PubMed ID: 23223431).

RAC2 – Variants in RAC2 were reported in an infant with neutrophil defects including decreased chemotaxis, polarization, azurophilic granule secretion, and superoxide anion production (Ambruso et al. 2000. PubMed ID: 10758162). The patient also showed leukocytosis and neutrophilia.

X-linked Disorders

WAS – Variants are associated with disorders of platelet numbers such as Wiskott-Aldrich syndrome (WAS) and X-linked thrombocytopenia (Lemahieu et al. 1999. PubMed ID: 10447259). WAS is also characterized by eczema and immunodeficiency. Activating variants in WAS have also been associated with disorders of neutrophil numbers including X-linked neutropenia (Ancliff et al. 2006. PubMed ID: 16804117)

TAZ – Variants in TAZ are associated with Barth syndrome – an X-linked multisystem disorder characterized by dilated cardiomyopathy, feeding problems, growth retardation, neutropenia and organic aciduria (Steward et al. 2010. PubMed ID: 20812380).

GATA1 – Variants are associated with anemia, neutropenia, thrombocytopenia and megakaryoblastic leukemia with or without Down syndrome (Hollanda et al. 2006. PubMed ID: 16783379; Sankaran et al. 2012. PubMed ID: 22706301; Hitzler et al. 2003. PubMed ID: 12586620)

CXCR4 – Variants are associated with WHIM syndrome which is a rare immunodeficiency disorder characterized by neutropenia, B cell lymphopenia, hypogammaglobulinemia and by recalcitrant warts (Kawai and Malech. 2009. PubMed ID: 19057201).

Autosomal Recessive Disorders

HAX1 – Kostmann Disease (Kostmann. 1956. PubMed ID: 13326376) is characterized by neutropenia accompanied by neurological symptoms including cognitive dysfunction and epilepsy (Klein et al. 2007. PubMed ID: 17187068; Germeshausen et al. 2008. PubMed ID: 18337561).

G6PC3 – Variants in G6PC3 are associated with severe SCN accompanied by developmental defects such as structural heart defects, urogenital abnormalities, and venous angiectasia of the trunk and extremities (Boztug et al. 2009. PubMed ID: 19118303). Other clinical characteristics may include inflammatory bowel disease, monocytosis, lymphopenia, and anemia (Begin et al. 2013. PubMed ID: 23180359; Dursun et al. 2009. PubMed ID: 19011569).

CSF3R – Inherited biallelic missense/nonsense variants, and small deletions in CSF3R were shown 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. PubMed ID: 24753537). Variants in CSF3R are strongly correlated to leukemic transformation seen with SCN (Germeshausen et al. 2007. PubMed ID: 16985178).

VPS45 – Missense variants in the VPS45 gene have been reported in patients with severe neutrophil deficiencies, bone marrow fibrosis, nephromegaly, and in some cases neurologic abnormalities such as developmental delay, cortical blindness, hearing loss and thin corpus callosum on MRI (Vilboux et al. 2013 PubMed ID: 23738510; Stepensky et al. 2013. PubMed ID: 23599270).

WIPF1 – Homozygous, nonsense variants in the WIPF1 gene have been reported in patients with an autosomal recessive form of Wiskott-Aldrich syndrome (WAS) (Wiskott-Aldrich syndrome 2) (Lanzi et al. 2012. PubMed ID: 22231303; Al-Mousa et al. 2017. PubMed ID: 27742395). Like WAS, patients with WIPF1 gene variants had thrombocytopenia, eczema and immunodeficiencies.

VPS13B – Cohen syndrome is characterized by developmental delay, early onset myopia, joint laxity, characteristic facies (Hennies et al. 2004. PubMed ID: 15154116). Some patients also display microcephaly, neutropenia, and retinopathy (Hennies et al. 2004. PubMed ID: 15154116; Seifert et al. 2006. PubMed ID: 16648375).

USB1 (C16ORF57) – Patients with variants in USB1 are reported to have poikiloderma with neutropenia or neutrophil functional defects (Volpi et al. 2010. PubMed ID: 20004881; Mostefai et al. 2008. PubMed ID: 18925663). Additional characteristics of the disease may include pachyonychia, keratoderma, short stature, and fragile carious teeth.

SLC37A4 – Glycogen Storage Disease Type Ib (GSDIb) is characterized by fasting hypoglycemia, massive hepatomegaly, and hyperlactatemia. In addition, patients with GSDIb may also display neutropenia with abnormal monocytes leading to frequent bacterial and fungal infections. Type Ib patients may also have oral and intestinal mucosal ulcerations and inflammatory intestinal disease suggestive of Crohn’s disease (Veiga-da-Cunha et.al. 1998. PubMed ID: 9758626).

SBDS – Shwachman-Diamond Syndrome (SDS) is characterized by exocrine pancreatic dysfunction, bone marrow failure and skeletal abnormalities (Dall’Oca et al. 2012. PubMed ID: 22201042). Hematologic abnormalities include neutropenia, thrombocytopenia, anemia or pancytopenia (Myers. 2014 PubMed ID: 20301722). A diagnosis of SDS is also associated with an elevated risk of myleodysplasia syndrome (MDS), and acute myelogenous leukemia (AML) (Burroughs et al. 2009. PubMed ID: 19327581).

RAB27A – Griscelli syndrome 2(GS2) is characterized by partial albinism and Hemophagocytic Lymphohistiocytosis (HLH) which involves uncontrolled activation and proliferation of T cells and macrophages that cause organ failure. Common symptoms of HLH include fever, hepatosplenomegaly, pancytopenia, attenuated or absent NK cell function, and hemophagocytosis (Henter et al. 2007. PubMed ID: 16937360).

LYST – Chediak-Higashi Syndrome (CHS) is characterized by partial albinism, bleeding diathesis, nystagmus, neutropenia, and other immunodeficiencies causing recurrent infections (Chediak. 1952. PubMed ID: 13004553; Higashi. 1954. PubMed ID: 13169161; Karim et al. 2002. PubMed ID: 11857544).

LAMTOR2 – Members of a Mennonite family with a homozygous LAMTOR2 regulatory variant were reported to have neutropenia with short stature, hypopigmented skin, coarse facial features and pulmonary infections (Bohn et al. 2007. PubMed ID: 17195838).

JAGN1 – Several families were identified which had a history of autosomal recessive neutropenia due to variants in the JAGN1 gene (neutropenia, severe congenital 6; Boztug et al. 2014. PubMed ID: 25129144). Bone marrow biopsies showed granulocyte maturational arrest and electron microscopy showed almost a complete absence of granules in neutrophils.

SMARCD2 – Patients from three different pedigrees with neutropenia, granule deficiencies, myelodysplasia with excess blasts, and mild-to-moderate developmental delay and dysmorphic features were found to have loss of function variants in the SMARCD2 gene (Witzel et al. 2017. PubMed ID: 28369036).

WDR1 – Four children from three families were found to have recurrent infections accompanied by mild neutropenia, severe skin and mucosal ulcerations and stomatitis (Kuhns et al. 2016. PubMed ID: 27557945). Functional studies showed that variants in the WDR1 protein alter cytoskeleton organization causing abnormal neutrophil morphology and neutrophil dysfunction.

DNAJC21 – Variants in the DNAJC21 gene are associated with bone marrow failure and have been reported to cause Shwachman-Diamond syndrome (SDS) (Dhanraj et al. 2017. PubMed ID: 28062395). SDS is characterized by exocrine pancreatic dysfunction, bone marrow failure and skeletal abnormalities (Dall’Oca et al. 2012. PubMed ID: 22201042). Hematologic abnormalities include neutropenia, thrombocytopenia, anemia or pancytopenia and an elevated risk of myleodysplasia syndrome (MDS), and acute myelogenous leukemia (AML) (Myers. 2014. PubMed ID: 20301722; Burroughs et al. 2009. PubMed ID: 19327581).

AP3B1 – Hermansky-Pudlak Syndrome 2 (HPS2) is characterized by tyrosinase-positive oculocutaneous albinism, significant reduction in visual acuity, nystagmus, and bleeding diathesis (Hermansky and Pudlak. 1959. PubMed ID: 13618373). Patients with HPS2 are also likely to develop congenital neutropenia and infections (Jung et al. 2006. PubMed ID: 16537806). Similar characteristics are found with the related Chediak-Higashi Syndrome (CHS).

Missense, nonsense, splicing variants, and small insertions/deletions are the primary types of variants reported for the genes in this panel. Large, multi-exon and whole gene deletions associated with neutropenia are not as frequent as other types of variants, but have been reported in all but the following genes in this panel: DNAJC21, SMARCD2, JAGN1, LAMTOR2, USB1, WIPF1, VPS45, GATA1, RAC2.

Clinical Sensitivity - Sequencing with CNV PGxome

It is difficult to differentiate Severe Congenital Neutropenia (SCN) from individual syndromic forms of neutropenia (Donadieu et al. 2011. PubMed ID: 21595885) making it challenging to determine the clinical sensitivity of testing. Based upon current literature, variants in the ELANE gene are the most frequent cause of SCN (~ 56%) and six of the genes in this panel (ELANE, G6PC3, GFI1, HAX1, SBDS, WAS) account for a total of about 60% of SCN (Xia et al. 2009. PubMed ID: 19775295; Bellane-Chantelot et al. 2004. PubMed ID: 14962902). Therefore, of the remaining ~ 40% of cases, some cases will remain unknown after testing, whereas some cases may be attributed to variants in the remaining genes in this panel.

Testing Strategy

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 99.3% coverage of all coding exons of the genes 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 coverage as ≥20X NGS reads or Sanger sequencing.

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).

Indications for Test

Patients with recurring bacterial infections, a family history of SCN, or neutropenia unrelated to other known syndromes.

Related Test

Name
PGxome®

Citations

  • Al-Mousa et al. 2017. PubMed ID: 27742395
  • Ambruso et al. 2000. PubMed ID: 10758162
  • Ancliff et al. 2006. PubMed ID: 16804117
  • Begin et al. 2013. PubMed ID: 23180359
  • Bellanné-Chantelot et al. 2004. PubMed ID: 14962902
  • Bohn et al. 2007. PubMed ID: 17195838
  • Boxer and Newburger. 2007. PubMed ID: 17584878
  • Boztug et al. 2009. PubMed ID: 19118303
  • Boztug et al. 2014. PubMed ID: 25129144
  • Burroughs et al. 2009. PubMed ID: 19327581
  • Chediak. 1952. PubMed ID: 13004553
  • Dall’Oca et al. 2012. PubMed ID: 22201042
  • Dhanraj et al. 2017. PubMed ID: 28062395
  • Donadieu et al. 2011. PubMed ID: 21595885
  • Dursun et al. 2009. PubMed ID: 19011569
  • Freedman et al. 2000. PubMed ID: 10887102
  • Germeshausen et al. 2007. PubMed ID: 16985178
  • Germeshausen et al. 2008. PubMed ID: 18337561
  • Gilman et al. 1970. PubMed ID: 4319697
  • Hennies et al. 2004. PubMed ID: 15154116
  • Henter et al. 2007. PubMed ID: 16937360
  • Hermansky and Pudlak. 1959. PubMed ID: 13618373
  • Higashi. 1954. PubMed ID: 13169161
  • Hitzler et al. 2003. PubMed ID: 12586620
  • Hollanda et al. 2006. PubMed ID: 16783379
  • Jung et al. 2006. PubMed ID: 16537806
  • Karim et al. 2002. PubMed ID: 11857544
  • Kawai and Malech. 2009. PubMed ID: 19057201
  • Klein et.al. 2007. PubMed ID: 17187068
  • Kostman. 1975. PubMed ID: 1130195
  • Kostmann. 1956. PubMed ID: 13326376
  • Kuhns et al. 2016. PubMed ID: 27557945
  • Lanzi et al. 2012. PubMed ID: 22231303
  • Lemahieu et al. 1999. PubMed ID: 10447259
  • Mostefai et al. 2008. PubMed ID: 18925663
  • Myers. 2014. PubMed ID: 20301722
  • Pasquet et al. 2013. PubMed ID: 23223431
  • Person et al. 2003. PubMed ID: 12778173
  • Rosenberg et al. 2006. PubMed ID: 16497969
  • Rosenberg et al. 2010. PubMed ID: 20456363
  • Sankaran et al. 2012. PubMed ID: 22706301
  • Seifert et al. 2006. PubMed ID: 16648375
  • Stepensky et al. 2013. PubMed ID: 23599270
  • Steward et al. 2010. PubMed ID: 20812380
  • Triot et al. 2014. PubMed ID: 24753537
  • Veiga-da-Cunha et.al. 1998. PubMed ID: 9758626
  • Vilboux et al. 2013. PubMed ID: 23738510
  • Volpi et al. 2010. PubMed ID: 20004881
  • Witzel et al. 2017. PubMed ID: 28369036
  • Xia et al. 2009. PubMed ID: 19775295

Ordering/Specimens

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.

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  • 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


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