Autosomal Recessive Hyper IgE Syndrome via the DOCK8 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
11257 DOCK8 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
11257DOCK881479 81479 $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

Clinical Features and Genetics

Clinical Features

Hyper-IgE Syndrome (HIES), also known as Job’s syndrome and Buckley’s syndrome, is characterized by a triad of symptoms including recurrent staphylococcal abscesses, recurrent airway infections, and increased immunoglobin E (>2000 U/ml) in serum (Szczawinska-Poplonyk et al 2011). Patients with autosomal recessive HIES (AR-HIES) are also more susceptible to food allergies, hemolytic anemia, vasculitis, and have a higher frequency of neurological complications including encephalitis, and vascular brain lesions. Connective tissue and bone abnormalities are typically not observed in AR-HIES (Engelhardt et al 2015). Genetic testing is helpful in the differential diagnosis of HIES subtypes and from other similar disorders including Omenn Syndrome, common variable immunodeficiency, atopic dermatitis, chronic granulomatous disease, and aspergillosis.

Genetics

AR-HIES is primarily due to pathogenic variants in the DOCK8 gene. There have been two reported cases of AR-HIES due to pathogenic variants in the TYK2 gene. In a study of 64 patients with DOCK8 deficiency, gross deletions encompassing one or more exons, small insertions/deletions, nonsense and splice site variants accounted for 68%, 6%, 14% and 12% of causative variants respectively. Only 3 causative missense variants have been reported to date (Sanal et al. 2012; Zhang et al. 2009; Jing et al. 2014; Engelhardt et al. 2015). In one case, a patient with AR-HIES also presented with mental retardation due to a balanced translocation of the DOCK8 gene with the X chromosome (Griggs et al. 2008). The DOCK8 gene encodes a guanine nucleotide exchange factor and interacts with Rho GTPase to regulate its function. In B-cells, DOCK8 functions as an adapter in Toll-like receptor/MyD88 signaling to drive proliferation and differentiation (Jabara et al. 2012).

Clinical Sensitivity - Sequencing with CNV PGxome

In a study of 60 families with 82 patients with AR-HIES, pathogenic variants in the DOCK8 gene were found in 78% of cases. Of those patients, gross deletions ranging from a single exon to the whole gene were found in 32 of 64 patients (Engelhardt et al. 2015). Analytical sensitivity is therefore about ~50% for detection of pathogenic mutations in the DOCK8 gene by sequencing.

Testing Strategy

This test provides full coverage of all coding exons of the DOCK8 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 showing IgE levels higher than 2000 U/ml, recurrent lung infections, and staphylococcal abscesses (Szczawinska-Poplonyk et al 2011). Other laboratory findings often include candidiasis, eczema, eosinophilia, decreased T and B cell counts, low serum IgM and variable IgG antibody responses (Zhang et al. 2009). This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in DOCK8.

Gene

Official Gene Symbol OMIM ID
DOCK8 611432
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Citations

  • Engelhardt KR, Gertz ME, Keles S, Schäffer AA, Sigmund EC, Glocker C, Saghafi S, Pourpak Z, Ceja R, Sassi A, Graham LE, Massaad MJ, Mellouli F, Ben-Mustapha I, Khemiri M, Kilic SS, Etzioni A, Freeman AF, Thiel J4, Schulze I, Al-Herz W, Metin A, Sanal Ö, Tezcan I, Yeganeh M, Niehues T, Dueckers G, Weinspach S, Patiroglu T, Unal E, Dasouki M, Yilmaz M, Genel F, Aytekin C, Kutukculer N, Somer A, Kilic M, Reisli I, Camcioglu Y, Gennery AR, Cant AJ, Jones A, Gaspar BH, Arkwright PD, Pietrogrande MC, Baz Z, Al-Tamemi S, Lougaris V, Lefranc G, Megarbane A, Boutros J, Galal N, Bejaoui M, Barbouche MR, Geha RS, Chatila TA, Grimbacher B. 2015. The extended clinical phenotype of 64 patients with dedicator of cytokinesis 8 deficiency. Journal of Allergy and Clinical Immunology. PubMed ID: 25724123
  • Griggs BL, Ladd S, Saul RA, DuPont BR, Srivastava AK. 2008. Dedicator of cytokinesis 8 is disrupted in two patients with mental retardation and developmental disabilities. Genomics 91: 195–202. PubMed ID: 18060736
  • Jabara HH, McDonald DR, Janssen E, Massaad MJ, Ramesh N, Borzutzky A, Rauter I, Benson H, Schneider L, Baxi S, Recher M, Notarangelo LD, Wakim R, Dbaibo G, Dasouki M, Al-Herz W, Barlan I, Baris S, Kutukculer N, Ochs HD, Plebani A, Kanariou M, Lefranc G, Reisli I, Fitzgerald KA, Golenbock D, Manis J, Keles S, Ceja R, Chatila TA, Geha RS. 2012. DOCK8 functions as an adaptor that links TLR-MyD88 signaling to B cell activation. Nature Immunology 13: 612–620. PubMed ID: 22581261
  • Jing H, Zhang Q, Zhang Y, Hill BJ, Dove CG, Gelfand EW, Atkinson TP, Uzel G, Matthews HF, Mustillo PJ, Lewis DB, Kavadas FD, Hanson IC, Kumar AR, Geha RS, Douek DC, Holland SM, Freeman AF, Su HC. 2014. Somatic reversion in dedicator of cytokinesis 8 immunodeficiency modulates disease phenotype. Journal of Allergy and Clinical Immunology 133: 1667–1675. PubMed ID: 24797421
  • Sanal O, Jing H, Ozgur T, Ayvaz D, Strauss-Albee DM, Ersoy-Evans S, Tezcan I, Turkkani G, Matthews HF, Haliloglu G, Yuce A, Yalcin B, Gokoz O, Oguz KK, Su HC. 2012. Additional Diverse Findings Expand the Clinical Presentation of DOCK8 Deficiency. Journal of Clinical Immunology 32: 698–708. PubMed ID: 22476911
  • Szczawinska-Poplonyk A, Kycler Z, Pietrucha B, Heropolitanska-Pliszka E, Breborowicz A, Gerreth K. 2011. The hyperimmunoglobulin E syndrome--clinical manifestation diversity in primary immune deficiency. Orphanet J Rare Dis 6: 76. PubMed ID: 22085750
  • Zhang Q, Davis JC, Lamborn IT, Freeman AF, Jing H, Favreau AJ, Matthews HF, Davis J, Turner ML, Uzel G, Holland SM, Su HC. 2009. Combined Immunodeficiency Associated with DOCK8 Mutations. New England Journal of Medicine 361: 2046–2055. PubMed ID: 19776401

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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