Warts, Hypogammaglobulinemia, Infections, and Myelokathexis (WHIM) Syndrome via the CXCR4 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
8809 CXCR4 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
8809CXCR481479 81479(x2) $890 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. If the Sanger option is selected, CNV detection may be ordered through Test #600.

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 backbone).

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

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

For Sanger Sequencing click here.

Turnaround Time

18 days on average for standard orders or 13 days 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.

EMAIL CONTACTS

Genetic Counselors

Geneticist

  • Megan Piazza, PhD, FACMG

Clinical Features and Genetics

Clinical Features

WHIM Syndrome is a rare immunodeficiency disorder characterized by recurrent early childhood bacterial infections and recalcitrant warts. Recurrent infections often include pneumonias, sinusitis, cellulitis, urinary tract infection, thrombophlebitis, omphalitis, osteomyelitis, deep soft tissue abscesses and skin infections. In some cases, recurrent pneumonias may lead to severe bronchiectasis. Immunodeficiency is characterized by neutropenia, B cell lymphopenia, and hypogammaglobulinemia typically involving IgG, but also involving IgM. T lymphocyte levels and function appear normal (Kawai and Malech 2009). Patients are effectively treated with granulocyte colony stimulating factor (G-CSF), plerixafor and administration of intravenous gamma globulin to limit recurrent infections (Dale et al 2011; Badolato et al 2004; McDermott et al. 2014). Clinical diagnosis of WHIM may be difficult as some patients only exhibit a subset of expected features of the disorder. Thus, molecular testing is often useful for confirmation of a clinical diagnosis and to aid in the treatment and management of WHIM syndrome (Kawai and Malech 2009).

Genetics

WHIM Syndrome is inherited in an autosomal dominant manner and is caused by mutations within the CXCR4 gene. Nonsense and frameshift mutations leading to truncation of the c-terminal tail of the CXCR4 chemokine receptor account for nearly all causative mutations to date. Commonly found mutations include c.1000 C>T resulting in p.R334X and c.1006 G>T resulting in p.G336X (Hernandez et al 2003; Gulino et al 2004). Common WHIM mutations have been found somatically within the CXCR4 gene in >25% of patients with Waldenström macroglobulinemia, a type of B-cell malignancy which results in resistance to ibrutinib therapy (Hunter et al. 2014; Cao et al. 2014). Gross deletions or duplications of the CXCR4 gene have not been reported. The CXCR4 gene encodes for the CXCR4 chemokine receptor, which binds its cogent ligand, CXCL12, to facilitate chemotactic migration. Upon ligand binding, G-protein receptor kinases interact with the intracellular c-terminal tail to drive signal transduction required for motility (Kawai and Malech 2009).

Clinical Sensitivity - Sequencing with CNV PGxome

Pathogenic mutations in the CXCR4 gene have been found in 24 of 26 cases of patients with WHIM by DNA sequencing (Kawai and Malech 2009). Analytical sensitivity should be high because all mutations reported are detectable by this method.

Testing Strategy

This test provides full coverage of all coding exons of the CXCR4 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

Candidates for this test are patients exhibiting recurrent infections and clinical symptoms consistent with WHIM Syndrome. Patients with a family history for WHIM syndrome are the strongest candidates for testing.

Gene

Official Gene Symbol OMIM ID
CXCR4 162643
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Citations

  • Badolato R, Fontana S, Notarangelo LD, Savoldi G. 2004. Congenital neutropenia: advances in diagnosis and treatment. Curr Opin Allergy Clin Immunol 4: 513–521. PubMed ID: 15640692
  • Cao Y, Hunter ZR, Liu X, Xu L, Yang G, Chen J, Patterson CJ, Tsakmaklis N, Kanan S, Rodig S, Castillo JJ, Treon SP. 2014. The WHIM-like CXCR4(S338X) somatic mutation activates AKT and ERK, and promotes resistance to ibrutinib and other agents used in the treatment of Waldenstrom’s Macroglobulinemia. Leukemia. PubMed ID: 24912431
  • Dale DC, Bolyard AA, Kelley ML, Westrup EC, Makaryan V, Aprikyan A, Wood B, Hsu FJ. 2011. The CXCR4 antagonist plerixafor is a potential therapy for myelokathexis, WHIM syndrome. Blood 118: 4963–4966. PubMed ID: 21835955
  • Gulino AV, Moratto D, Sozzani S, Cavadini P, Otero K, Tassone L, Imberti L, Pirovano S, Notarangelo LD, Soresina R, Mazzolari E, Nelson DL, et al. 2004. Altered leukocyte response to CXCL12 in patients with warts hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome. Blood 104: 444–452. PubMed ID: 15026312
  • Hernandez PA, Gorlin RJ, Lukens JN, Taniuchi S, Bohinjec J, Francois F, Klotman ME, Diaz GA. 2003. Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease. Nat. Genet. 34: 70–74. PubMed ID: 12692554
  • Hunter ZR, Xu L, Yang G, Zhou Y, Liu X, Cao Y, Manning RJ, Tripsas C, Patterson CJ, Sheehy P, Treon SP. 2014. The genomic landscape of Waldenstrom macroglobulinemia is characterized by highly recurring MYD88 and WHIM-like CXCR4 mutations, and small somatic deletions associated with B-cell lymphomagenesis. Blood 123: 1637–1646. PubMed ID: 24366360
  • Kawai T, Malech HL. 2009. WHIM syndrome: congenital immune deficiency disease. Curr. Opin. Hematol. 16: 20–26. PubMed ID: 19057201
  • McDermott DH, Liu Q, Ulrick J, Kwatemaa N, Anaya-O’Brien S, Penzak SR, Filho JO, Priel DAL, Kelly C, Garofalo M, Littel P, Marquesen MM, et al. 2011. The CXCR4 antagonist plerixafor corrects panleukopenia in patients with WHIM syndrome. Blood 118: 4957–4962. PubMed ID: 21890643

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.
  • 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


Specimen Types

Specimen Requirements and Shipping Details

PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

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ORDER OPTIONS

View Ordering Instructions

1) Select Test Method (Backbone)


1) Select Test Type


2) Select Additional Test Options

STAT and Prenatal Test Options are not available with Patient Plus.

No Additional Test Options are available for this test.

Note: acceptable specimen types are whole blood and DNA from whole blood only.
Total Price: $
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