Periodic Fever Syndromes Panel

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy Genes Gene CPT Codes Copy CPT Codes
10315 CARD14 81479,81479 Order Options and Pricing
ELANE 81479,81479
IL36RN 81479,81479
LPIN2 81479,81479
MEFV 81404,81479
MVK 81479,81479
NLRP12 81479,81479
NLRP3 81479,81479
NOD2 81479,81479
PSMB8 81479,81479
PSTPIP1 81479,81479
TNFAIP3 81479,81479
TNFRSF1A 81479,81479
Test Code Test Copy Genes Panel CPT Code Gene CPT Codes Copy CPT Code Base Price
10315Genes x (13)81479 81404, 81479 $890 Order Options and Pricing

Pricing Comments

We are happy to accommodate requests for testing single genes in this panel or a subset of these genes. The price will remain the list price. If desired, free reflex testing to remaining genes on panel is available. Alternatively, a single gene or subset of genes can also be ordered via our PGxome Custom Panel tool.

A 25% additional charge will be applied to STAT orders. View STAT turnaround times here.

For Reflex to PGxome pricing click here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

Turnaround Time

18 days on average

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

Periodic Fever Syndromes (PFS) (also known as monogenic autoinflammatory syndromes) is a collective group of disorders highlighted by recurrent fever and inflammatory episodes. Fever episodes can range from hours up to ~ 2 weeks with recurrences ranging from several bouts per month to a few per year. PFS frequently involve inflammation of the skin, serous membranes, joints, lymph nodes, gastrointestinal tract, and nervous system. Onset of PFS occurs during the first year of life or early childhood with only familial mediterranean fever (FMF) and tumor necrosis factor receptor-associated periodic syndrome having cases of adult onset described. In severe cases, development of amyloidosis may occur. PFS are caused by aberrant inflammasome activation leading to heightened interleukin 1 levels and innate immune dysregulation. Differential diagnosis of individual PFS is important for employing appropriate therapeutics such as colchicine to treat FMF or antibiotics for cyclic neutropenia. PFS may mirror other immune dysfunction disorders such as cyclic neutropenia and SCID due to recurrent fever bouts, but unlike those disorders, bouts are not a result of recurrent infections (Caso et al. 2013; Touitou et al. 2013).

Disorders tested in this PFS panel include familial mediterranean fever/FMF, familial cold autoinflammatory syndrome/FCAS, muckle-wells syndrome/MWS, chronic infantile neurological cutaneous articular syndrome/CINCA, tumor necrosis factor receptor-associated periodic syndrome/TRAPS, mevalonate kinase deficiency/MKD, NLRP12 associated autoinflammatory disorder, pyogenic arthritis pyoderma gangrenosum and cystic acne syndrome/PAPA, Majeed syndrome, cyclic neutropenia, pediatric granulomatous arthritis/PGA, CANDLE syndrome, DITRA syndrome, CARD14 mediated psoriasis/CAMPS, and TNFAIP3-mediated early onset autoinflammatory disease (Sanchez et al. 2013).

Genetics

Autosomal dominant PFS disorders include TRAPS (TNFRSF1A), FACS (NLRP3), MWS (NLRP3), CINCA (NLRP3), NLRP12 associated autoinflammatory disorder (NLRP12), PAPA (PSTPIP1), CAMPS (CARD14), TNFAIP3-mediated early onset inflammatory disease, PGA (NOD2), and cyclic neutropenia (ELANE). Autosomal recessive PFS disorders include FMF (MEFV), MKD (MVK), CANDLE (PSMB8), DITRA (IL36RN) and majeed syndrome (LPIN2) (Caso et al. 2013; Sanchez et al. 2013).

See individual test descriptions for additional information on the molecular biology of each gene product.

Testing Strategy

This panel provides 100% coverage of all coding exons of the genes 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 coverage as ≥20X NGS reads or Sanger sequencing.

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).

Clinical Sensitivity - Sequencing with CNV PGxome

Analytical sensitivity for detection of causative variants in the MEFV, MVK, NLRP3, NLRP12, TNFRSF1A, LPIN2, ELANE, and PSTPIP1 is >95% as gross deletions have not been reported. Clinical sensitivity is variable. In patients diagnosed with familial mediterranean fever, an identifiable pathogenic variant in the MEFV gene was found in 70-80% of cases (Aksentijevich et al. 1999). In patients with biochemical evidence of impaired mevalonate kinase activity and suspected Hyper-IgD syndrome or mevalonic aciduria, causative variants in the MVK gene were found ~95% of cases (Mandey et al. 2006; Bader-Meunier et al. 2011). In tumor necrosis factor receptor-associated periodic syndrome patients, causative variants in the TNFRSF1A gene are found in 40-50% of familial and ~5% of sporadic cases (Aksentijevich et al. 2001; Dode et al. 2002). Causative variants in NLRP3 have been identified in >85% of patients with familial cold autoinflammatory syndrome and ~60% of patients with chronic infantile neurological cutaneous articular syndrome (Aksentijevich et al. 2007; Aksentijevich et al. 2002). Clinical sensitivity for detection of ELANE causative variants in patients with cyclic neutropenia varies with two reports finding causative variants in 31 of 81 and 21 of 24 patients respectively (Dale et al. 2000; Bellanne-Chantelot et al. 2004). 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) form of PGA (Rosé et. al. 2009)

Clinical sensitivity cannot be estimated for pyogenic arthritis pyoderma gangrenosum and cystic acne syndrome, Majeed syndrome, CANDLE, DITRA, TNFAIP3-mediated early onset autoinflammatory disease, CAMPS and NLRP12-associated autoinflammatory disorder because only a small number of cases have been reported.

Thus far, no gross deletions or duplications have been reported in the ELANE, CARD14, NOD2, PSMB8, NLRP3, NLRP12, PSTPIP1, LPIN2, TNFRSF1A, IL36RN, or MEFV genes (Human Gene Mutation Database). A gross deletion involving exon 1 of TNFAIP3 has been reported in one patient with Sjögren's syndrome (Nocturne et al. 2013). Deletions in the MVK gene have been reported in three cases, but account for less than 5% of all cases of mevalonate kinase deficiency (Takada et. al. 2003; Cuisset et. al. 2001; Zhang et. al. 2015).

Indications for Test

Candidates present with periodic/episodic fevers without an underlying infection typically within the first few years of life. Attacks are short and recurrent with spontaneous remission. Cyclic Neutropenia mirrors many features of other PFS, but is triggered by underlying infection. Fever episodes often present with elevated serum amyloid A, elevated erythrocyte sedimentation rate, and leukocytosis (Caso et al. 2013; Touitou et al. 2013).

Genes

Official Gene Symbol OMIM ID
CARD14 607211
ELANE 130130
IL36RN 605507
LPIN2 605519
MEFV 608107
MVK 251170
NLRP12 609648
NLRP3 606416
NOD2 605956
PSMB8 177046
PSTPIP1 606347
TNFAIP3 191163
TNFRSF1A 191190
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Test

Name
PGxome®

Citations

  • Aksentijevich I. et al. 1999. The American Journal of Human Genetics. 64: 949–962. PubMed ID: 10090880
  • Aksentijevich I. et al. 2001. American Journal of Human Genetics. 69: 301-14. PubMed ID: 11443543
  • Aksentijevich I. et al. 2002. Arthritis and Rheumatism. 46: 3340-8. PubMed ID: 12483741
  • Aksentijevich I. et al. 2007. Arthritis and Rheumatism. 56: 1273-85. PubMed ID: 17393462
  • Bader-Meunier B. et al. 2011. Pediatrics. 128: e152-e159. PubMed ID: 21708801
  • Bellanne-Chantelot C. 2004. Blood. 103: 4119-25. PubMed ID: 14962902
  • Caso F. et al. 2013. International Journal of Rheumatology. 2013: 513782. PubMed ID: 24282415
  • Cuisset L. et al. 2001. European Journal of Human Genetics. 9: 260-6. PubMed ID: 11313769
  • Dale David C. et al. 2000. Blood. 96: 2317–22. PubMed ID: 11001877
  • Dodé C. et al. 2002. Nephrology, Dialysis, Transplantation. 17: 1212-7. PubMed ID: 12105243
  • Human Gene Mutation Database (Bio-base).
  • Mandey Saskia H.L. et al. 2006. Human Mutation. 27: 796-802. PubMed ID: 16835861
  • Nocturne G. et al. 2013. Blood. 122: 4068-76. PubMed ID: 24159176
  • Rosé 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
  • Takada K. et al. 2003. Arthritis and Rheumatism. 48: 2645-51. PubMed ID: 13130485
  • Touitou I. et al. 2013. Orphanet Journal of Rare Diseases. 8: 162. PubMed ID: 24131530
  • Zhang Z. et al. 2015. Elife. 4: e06322. PubMed ID: 26202976

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.

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

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