Pediatric Granulomatous Arthritis via the NOD2 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
11521 NOD2 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
11521NOD281479 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.

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

Pediatric Granulomatous Arthritis (PGA) is an autoinflammatory syndrome due to pathogenic variants in the NOD2 gene and is hallmarked by granulomatous inflammation of eyes, joints, and skin. Chronic arthritis occurs within the first decade of life. Joint inflammation occurs in all cases of PGA and starts with minimal swelling in wrists, knees, and elbows but progresses to flexion contractures in fingers. Uveitis occurs in about 80% of cases with patients developing bilateral panuveitis. Progressive inflammation can also results in cataract, glaucoma, and synechiae. In some cases, fever, central neuropathy, arteritis, and granulomatous involvement of visceral organs has been reported. There are two different forms of PGA with identical phenotypes, Blau Syndrome and Early Onset Sarcoidosis, which represent familial and sporadic forms respectively (Rosé et. al. 2009; Ikeda et al. 2014; Sanchez et al. 2013).

Pathogenic variants in the NOD2 gene have also been reported in patients with increased risk for Crohn’s disease. In a study of 612 patients with Crohn’s disease, 50% of patients carried at least one pathogenic variant in the NOD2 gene. Patients with two pathogenic variants in the NOD2 gene had earlier onset of disease (16 years vs. 19 years of age). However, NOD2 variants are not the sole cause of this complex disease with both environmental and other genetic factors playing roles in onset (Lesage et al. 2002). Testing for the NOD2 pathogenic variants for Crohn’s disease is not recommended at this time.

Genetics

PGA is inherited in an autosomal dominant manner through pathogenic variants in the NOD2 gene. Missense gain of function variants, primarily in exon 4 of the NOD2 gene, have been reported in all PGA cases to date with the p.Arg334Gln and p.Arg334Trp variants being found in greater than half of cases (Rosé et. al. 2009; Miceli-Richard et al. 2001; Ikeda et al. 2014). The NOD2 protein is involved in innate immune responses to bacterial infections and initiates pro-inflammatory responses. In patients with PGA, heightened NOD2 pro-inflammatory responses result in disease (Kanazawa et al. 2005).

Several polymorphisms in the NOD2 gene have been associated with susceptibility to Crohn’s disease. In particular the p.Arg702Trp, p.Gly908Arg, and c.3019dupC variants have been found more frequently in patients with Crohn’s disease (Lesage et al. 2002). However, these variants are also commonly found with minor allele frequencies as high as of 4.5%, 1.5% and 2% in certain populations (exac.broadinstitute.org). This indicates that these variants have low penetrance for disease. To date, pathogenic variants in the NOD2 gene are non-overlapping between individuals with PGA and susceptibility to Crohn’s.

Clinical Sensitivity - Sequencing with CNV PGxome

In an international registry for pediatric granulomatous diseases, 75 individuals were assessed for pathogenic variants in the NOD2 gene. In this cohort, 45 symptomatic patients had a pathogenic variant in the NOD2 gene. Of these 45 individuals, 22 were familial (Blau syndrome) and 23 were sporadic (Early Onset Sarcoidosis) (Rosé et. al. 2009). Analytical sensitivity should >99% as all reported variants in the NOD2 gene are detectable by sequencing.

Testing Strategy

This test provides full coverage of all coding exons of the NOD2 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

Laboratory findings consistent with Blau syndrome include persistently elevated leukocyte and platelet counts, increased erythrocyte sedimentation rate, and increased C-reactive protein. Patient symptoms for PGA include a classic triad occurring within the first decade of life: chronic uveitis, arthritis, and dermatitis (Sanchez et al. 2013).

Gene

Official Gene Symbol OMIM ID
NOD2 605956
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Citations

  • Ikeda K. et al. 2014. Arthritis Research & Therapy. 16: R89. PubMed ID: 24713464
  • Kanazawa N. et al. 2005. Blood. 105: 1195-7. PubMed ID: 15459013
  • Lesage S. et al. 2002. American Journal of Human Genetics. 70: 845-57. PubMed ID: 11875755
  • Miceli-Richard C. et al. 2001. Nature Genetics. 29: 19-20. PubMed ID: 11528384
  • Rosé C.D. et. al. 2009. Arthritis Rheum. 2009. 60: 1797-803 PubMed ID: 19479837
  • Sanchez G.A. et al. 2013. Rheumatic Diseases Clinics of North America. 39: 701-34. PubMed ID: 24182851

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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