Chronic Granulomatous Disease via the CYBB 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
11223 CYBB 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
11223CYBB81479 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

Chronic granulomatous disease (CGD) an inherited immunodeficiency characterized by repeated infections with bacterial and fungal pathogens and formation of granulomas. CGD immunodeficiency is due to an impairment of the NADPH oxidase complex resulting in an inability to generate superoxide in phagocytic cells to lyse pathogens (Song et al. 2011). Common pathogens include Staphylococcus aureus, Pseudomonas species, Candida albicans, Aspergillus species, and Nocardia species. Pneumonia, granuloma formation within gastrointestinal and genitourinary tracts, and failure to thrive are hallmark symptoms of the disorder. In severe cases, granulomas can lead to abscess formation and organ failure. Treatments include long course antimicrobials to ward off infections (Leiding and Holland 2012). Simultaneous administration of antimicrobials and corticosteroids may be used to resolve colitis associated with heightened inflammatory responses to infection (Leiding et al. 2012). Patients with CGD should avoid areas where fungal spores are common such as mulch, gardens, and yard waste. Approximately one in 200,000 newborns in the US are affected with CGD (Winkelstein et al 2000). Genetic testing can aid in differential diagnosis of CGD from other disorders associated with granuloma formation and hyperinflammation such as cystic fibrosis, hyper IgE syndrome, Crohn’s disease, allergic bronchopulmonary aspergillosis, and glucose 6-phosphate dehydrogenase deficiency (Leiding and Holland 2012).

Genetics

CGD is inherited in an X-linked manner through mutations in the CYBB gene. Autosomal recessive forms of CGD also occur through mutations in the CYBA, NCF1, NCF2, and NCF4 genes (Roos and de Boer 2014). Disease onset with individuals with X-linked CGD is ~3 years with mortality occurring in 20% compared to autosomal recessive forms with onset ~7 years and mortality occurring in 8% of cases. The majority of CYBB mutations are truncating with nonsense (30%), deletions (22%) and splice site (19.5%) mutations being causative for CGD (Roos et al 2010; Piirilä et al. 2006). Missense mutations are found in 20% of cases with mutations residing in amino acids 1-309 minimally affecting superoxide production and associated with good prognosis compared to missense mutations in amino acid 310 affecting FAD and NAPDH binding domains and rendering NADPH complex nonfunctional leading to worse prognosis (Leiding and Holland 2012). Insertions, gross deletions, and promoter mutations are present in less than 5% of cases of X-linked CGD. Contiguous gene deletions have been reported to span several genes leading to associations of Kell phenotype/Mcleod syndrome (XK gene), Duchenne muscular dystrophy (DMD gene), and retinitis pigmentosa (RPGR gene) with X-linked CGD (Brown et al. 1996; Watkins et al. 2011). Adult-onset of CGD has been reported in females heterozygous for CYBB mutations and is thought to occur through skewed X-inactivation (Gono et al. 2008; Anderson-Cohen et al. 2003). The CYBB gene encodes the gp91phox subunit of the NADPH oxidase complex. This complex is responsible for transporting electrons from NAPDH to oxygen to generate superoxide within the phagolysosome to facilitate lysis of pathogens in phagocytic cells such as neutrophils and macrophages (Song et al. 2011).

Clinical Sensitivity - Sequencing with CNV PGxome

Mutations in the CYBB gene account for ~70% of cases of CGD (Leiding and Holand 2012; Roos et al. 2010). Analytical sensitivity is >95% for detection of causative mutations within the CYBB gene. Deletions of one or more exons are common and also detectable by Sanger sequencing in males. In females, analytical sensitivity is lower as we are unable to detect large heterozygous deletions by this method. Gross deletions of the CYBB gene have been reported in less than 5% of cases (Roos et al. 2010). Deletions have been reported to span several genes leading to associations of Kell phenotype/Mcleod syndrome (XK gene), Duchenne muscular dystrophy (DMD gene), and retinitis pigmentosa (RPGR gene) with X-linked CGD (Brown et al. 1996; Watkins et al. 2011).

Testing Strategy

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

Oxidative burst test (Nitroblue tetrazolium or dihydrorhodamine) indicating impaired superoxide production, and recurrent fungal and bacterial infections are characteristic of CGD. Protein expression analysis is not a reliable predictor of CGD as missense mutations may render CYBB protein nonfunctional (Kuhns et al. 2010).

Gene

Official Gene Symbol OMIM ID
CYBB 300481
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Granulomatous Disease, Chronic, X-Linked XL 306400

Citations

  • Anderson-Cohen M, Holland SM, Kuhns DB, Fleisher TA, Ding L, Brenner S, Malech HL, Roesler J. 2003. Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial, extremely skewed X chromosome inactivation. Clin. Immunol. 109: 308–317. PubMed ID: 14697745
  • Brown J, Dry KL, Edgar AJ, Pryde FE, Hardwick LJ, Aldred MA, Lester DH, Boyle S, Kaplan J, Dufier JL, Ho MF, Monaco AM, et al. 1996. Analysis of three deletion breakpoints in Xp21.1 and the further localization of RP3. Genomics 37: 200–210. PubMed ID: 8921393
  • Gono T, Yazaki M, Agematsu K, Matsuda M, Yasui K, Yamaura M, Hidaka F, Mizukami T, Nunoi H, Kubota T, Ikeda S-I. 2008. Adult onset X-linked chronic granulomatous disease in a woman patient caused by a de novo mutation in paternal-origin CYBB gene and skewed inactivation of normal maternal X chromosome. Intern. Med. 47: 1053–1056. PubMed ID: 18520120
  • Kuhns DB, Alvord WG, Heller T, Feld JJ, Pike KM, Marciano BE, Uzel G, DeRavin SS, Priel DAL, Soule BP, Zarember KA, Malech HL, et al. 2010. Residual NADPH oxidase and survival in chronic granulomatous disease. N. Engl. J. Med. 363: 2600–2610. PubMed ID: 21190454
  • Leiding JW, Freeman AF, Marciano BE, Anderson VL, Uzel G, Malech HL, DeRavin S, Wilks D, Venkatesan AM, Zerbe CS, Heller T, Holland SM. 2012. Corticosteroid therapy for liver abscess in chronic granulomatous disease. Clin. Infect. Dis. 54: 694–700. PubMed ID: 22157170
  • Leiding JW, Holland SM. 2012. Chronic Granulomatous Disease. In: Pagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews(®), Seattle (WA): University of Washington, Seattle. PubMed ID: 22876374
  • Piirilä H, Väliaho J, Vihinen M. 2006. Immunodeficiency mutation databases (IDbases). Hum. Mutat. 27: 1200–1208. PubMed ID: 17004234
  • Roos D, Boer M de. 2014. Molecular diagnosis of chronic granulomatous disease. Clin. Exp. Immunol. 175: 139–149. PubMed ID: 24016250
  • Roos D, Kuhns DB, Maddalena A, Roesler J, Lopez JA, Ariga T, Avcin T, Boer M de, Bustamante J, Condino-Neto A, Matteo G Di, He J, Hill HR, Holland SM, Kannengiesser C, Köker MY, Kondratenko I, van Leeuwen K, Malech HL, Marodi L, Nunoi H, Stasia MJ, Ventura AM, Witwer CT, Wolach B, Gallin JI. 2010. Hematologically important mutations: X-linked chronic granulomatous disease (third update). Blood Cells Mol. Dis. 45: 246–265. PubMed ID: 20729109
  • Song E. et al. 2011. Clinical and molecular allergy : CMA. 9: 10. PubMed ID: 21624140
  • Watkins CE, Litchfield J, Song E, Jaishankar GB, Misra N, Holla N, Duffourc M, Krishnaswamy G. 2011. Chronic granulomatous disease, the McLeod phenotype and the contiguous gene deletion syndrome-a review. Clin Mol Allergy 9: 13. PubMed ID: 22111908
  • Winkelstein JA, Marino MC, Johnston RB Jr, Boyle J, Curnutte J, Gallin JI, Malech HL, Holland SM, Ochs H, Quie P, Buckley RH, Foster CB, Chanock SJ, Dickler H. 2000. Chronic granulomatous disease. Report on a national registry of 368 patients. Medicine (Baltimore) 79: 155–169. PubMed ID: 10844935

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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