Cryopyrin-Associated Periodic Syndromes via the NLRP3 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
11519 NLRP3 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
11519NLRP381479 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.

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

Cryopyrin-Associated Periodic Syndromes (CAPS) include a group of autoinflammatory diseases due to mutations in the NLRP3 gene. CAPS are rare disorders affecting about 1 in 1,000,000 people primarily in North America and Europe (Kastner 2005).

Familial Cold Autoinflammatory Syndrome (FCAS) is characterized by episodes of fever, urticarial-like rash, and joint pain after exposure to cold temperatures. Most patients initially present with rashes at birth or within the first few months of life. This rash is typically seen first on the face or extremities, and may spread to the rest of the body. Joint pain is typically found within hands, knees and ankles. Other symptoms may include conjunctivitis, sweating, drowsiness, headache and nausea. FCAS episodes are variable and may be triggered by exposure to cold temperatures for only a few minutes or an hour or more. Episodes typically last 12 hours, but may persist up to 3 days. Rarely, patients develop amyloidosis later in life.

Neonatal Onset Multisystem Inflammatory Disease (NOMID), also known as Chronic Infantile Neurologic Cutaneous and Arthropathy (CINCA) syndrome, is the most severe form of recurrent fevers due to mutations in the NLRP3 gene. Initial symptoms include rash typically present at birth which persists throughout life. NOMID is characterized by persistent inflammation damaging the nervous system, skin, and joints. Other symptoms include headaches, seizures, chronic meningitis, intellectual disability, loss of hearing, and loss of vision. Persistent joint inflammation often leads to swelling, cartilage overgrowth leading to short stature, prominent forehead, and protruding eyes. Amyloidosis is seen in <2% of patients. Treatment with IL-1 receptor antagonists has been successful in controlling disease (Farasat et al. 2008).

Muckle-Wells syndrome (MWS) is a rare disease characterized by recurrent and self-limited episodes of fever, urticaria, arthralgia, myalgia (Dodé et al. 2002) and conjunctivitis since childhood, which are related to exposure to cold temperatures. Late-onset sensorineural deafness is also observed. Amyloidosis is the main complication and is found in 25% of cases. Two distinct clinical phenotypes are observed: an 'inflammatory phenotype', most commonly seen in patients diagnosed in childhood characterized by relapsing fever and abdominal pain, and an 'organ -disease' phenotype in patients diagnosed during adulthood characterized by fatigue and hearing loss (Kuemmerle-Deschner et al. 2013).

Genetics

FCAS, NOMID, and MWS are all autosomal dominant diseases characterized by mutations in the NLRP3 gene. Nearly all the causative mutations identified to date are missense variants within exon 3, affecting protein-protein interactions and protein secondary structure (Aksentijevich et al. 2007; Jesus et al. 2008). Specific mutations within the NLRP3 gene may not allow distinguishing between FCAS, NOMID or MWS as common missense mutations have been found within these disorders despite clinically different phenotypes. This suggests that additional modifier genes are involved in determining the disease spectrum. Patients with FCAS typically have a family history, while NOMID is often due to de novo mutations within the NLRP3 gene (Aksentijevich et al. 2002; Jesus et al. 2008). The NLRP3 gene encodes a protein called cryopyrin, a NOD-like receptor, which is a component of the inflammasome complex. When triggered by a danger signal, assembly of the inflammasome increases Interleukin 1β production to drive inflammation to fight off infections (Fujisawa et al. 2007).

Clinical Sensitivity - Sequencing with CNV PGxome

Mutations in NLRP3 have been identified in >85% of patients with FACS and ~60% of patients with NOMID (Aksentijevich et al. 2007). Clinical sensitivity for MWS cannot be estimated because only a small number of patients have been reported. Analytical sensitivity should be high because all mutations reported are detectable by sequencing.

Testing Strategy

This test provides full coverage of all coding exons of the NLRP3 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 features consistent with CAPS (high erythrocyte sedimentation rate, c-reactive protein, and serum amyloid A protein levels) and family members of patients who have known NLRP3 mutations. The diagnosis of Muckle-Wells Syndrome (MWS) remains challenging due to the clinical heterogeneity and lack of diagnostic criteria. Individuals with episodes of fever, urticaria, arthralgia, myalgia and conjunctivitis since childhood, abdominal pain and late-onset sensorineural deafness should consider testing for mutations in NLRP3.

Gene

Official Gene Symbol OMIM ID
NLRP3 606416
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Citations

  • Aksentijevich I, D Putnam C, Remmers EF, Mueller JL, Le J, Kolodner RD, Moak Z, Chuang M, Austin F, Goldbach-Mansky R, Hoffman HM, Kastner DL. 2007. The clinical continuum of cryopyrinopathies: novel CIAS1 mutations in North American patients and a new cryopyrin model. Arthritis Rheum. 56: 1273–1285. PubMed ID: 17393462
  • Aksentijevich I, Nowak M, Mallah M, Chae JJ, Watford WT, Hofmann SR, Stein L, Russo R, Goldsmith D, Dent P, Rosenberg HF, Austin F, et al. 2002. De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): a new member of the expanding family of pyrin-associated autoinflammatory diseases. Arthritis Rheum. 46: 3340–3348. PubMed ID: 12483741
  • Dodé C, Dû N Le, Cuisset L, Letourneur F, Berthelot J-M, Vaudour G, Meyrier A, Watts RA, David Scott GI, Nicholls A. 2002. New Mutations of CIAS1 That Are Responsible for Muckle-Wells Syndrome and Familial Cold Urticaria: A Novel Mutation Underlies Both Syndromes. The American Journal of Human Genetics 70: 1498–1506. PubMed ID: 11992256
  • Farasat S, Aksentijevich I, Toro JR. 2008. Autoinflammatory diseases: clinical and genetic advances. Arch. Dermatol. 144: 392–402. PubMed ID: 18347298
  • Fujisawa A, Kambe N, Saito M, Nishikomori R, Tanizaki H, Kanazawa N, Adachi S, Heike T, Sagara J, Suda T, Nakahata T, Miyachi Y. 2007. Disease-associated mutations in CIAS1 induce cathepsin B-dependent rapid cell death of human THP-1 monocytic cells. Blood 109: 2903–2911. PubMed ID: 17164343
  • Jesus AA, Silva CA, Segundo GR, Aksentijevich I, Fujihira E, Watanabe M, Carneiro-Sampaio M, Duarte AJS, Oliveira JB. 2008. Phenotype-genotype analysis of cryopyrin-associated periodic syndromes (CAPS): description of a rare non-exon 3 and a novel CIAS1 missense mutation. J. Clin. Immunol. 28: 134–138. PubMed ID: 18080732
  • Kastner DL. 2005. Hereditary periodic fever syndromes. Hematol. Educ. Program Am. Soc. Hematol. Am. Soc. Hematol. Educ. Program 74–81. PubMed ID: 16304362
  • Kuemmerle-Deschner JB, Samba SD, Tyrell PN, Koné-Paut I, Marie I, Deschner N, Benseler SM. 2013. Challenges in diagnosing Muckle-Wells syndrome: Identifying two distinct phenotypes. Arthritis Care Res (Hoboken). PubMed ID: 24127202

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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