TNF-Receptor Associated Periodic Syndrome (TRAPS) via the TNFRSF1A Gene

Summary and Pricing

Test Method

Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
8609 TNFRSF1A 81479 81479,81479 $640 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
8609TNFRSF1A81479 81479 $640 Order Options and Pricing

Pricing Comments

This test is also offered via our exome backbone with CNV detection (click here). The exome-based test may be higher priced, but permits reflex to the entire exome or to any other set of clinically relevant genes.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

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

TNF-Receptor Associated Periodic Syndrome (TRAPS), originally known as Familial Hibernian Fever, is the second most common inherited recurrent fever syndrome affecting about one in a million people. TRAPS periodic fevers can range in length (a few days to a few months) and frequency (monthly to every few years). Episodes are usually 1-3 weeks in length and atypical of other periodic fever syndromes including Familial Mediterranean Fever (FMF, Test #1555), Familial cold autoinflammatory syndromes (Test #1638) and Muckle-wells syndrome (Test#1638) where duration of attacks last around three days (Kastner 2005). Additional symptoms co-occurring with fever include muscle pain, limb rashes, periorbital edema, joint pain, and vasculitis. Amyloidosis develops in 15-20% of patients and can lead to renal failure. Symptom onset can occur either spontaneously or after minor triggers including local injury, infection, stress, exercise, and hormonal change. TRAPS primarily occurs in early childhood but can begin later in life (Cantarini et al. 2012). Unlike patients with FMF, patients with TRAPS are unresponsive to treatment with colchicine but may be treated with corticosteroids or etanercept (Kusuhara et al. 2012). Adult-onset TRAPS may be phenotypically similar to FMF in terms of duration of fever episodes, therefore genetic testing is helpful for confirming diagnosis and selecting appropriate treatments (Cantarini et al. 2012; Shinar et al. 2012).

Genetics

TRAPS is inherited in an autosomal dominant manner with variable penetrance through mutations in the TNFRSF1A gene. TNFRSF1A encodes the tumor necrosis factor alpha (TNFα) receptor, predominantly found on the surface of immune cells and involved in inflammation, T-cell activation, and B-cell homeostasis. Four cysteine-rich subdomains reside extracellular at the N-terminal end of the protein (Cantarini et al 2012; Kastner 2005). About 50% of causative missense mutations involve cysteine residues and disrupt intramolecular disulphide bonds critical for maintaining receptor structure. Causative missense mutations either introducing or removing proline residues affecting TNFRSF1A secondary structure have been reported (http://fmf.igh.cnrs.fr/ISSAID/infevers; Sarrauste et al 2003). These types of mutations are associated with higher disease penetrance and lead to improper folding of the receptor, intracellular retention, and irresponsiveness to extracellular TNFα (Lobito et al. 2006; Lewis et al. 2012). Two non-structural variants with low disease penetrance, c.362G>A, p.Arg92Gln and c.254C>T, p.Pro46Leu, have been found in 1-5% of the general population (Aksentijevich et al. 2001; Rebelo et al. 2006; Ravet et al 2006). Splice site mutations and small deletions in the TNFRSF1A gene have been found in a few cases (Churchman et al 2007; Aksentijevich et al 2001). Disease pathogenesis is unclear, but is hypothesized to be due to hypersensitization to other innate stimuli such as lipopolysaccharide resulting in excessive pro-inflammatory responses (Simon et al. 2010; Turner et al. 2012).

Clinical Sensitivity - Sequencing with CNV PG-Select

Clinical sensitivity is predicted to be about 40-50% in familial TRAPS cases. Spontaneous TRAPS or TRAPS-like individuals have identifiable mutations in the TNFRSF1A gene in ~5% of cases (Aganna et al. 2003; Aksentijevich et al. 2001). Analytical sensitivity should be very high as all documented mutations are detectable by Sanger sequencing.

Testing Strategy

This test provides full coverage of all coding exons of the TNFRSF1A gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

Indications for Test

Diagnosis of TRAPS should be considered when periodic fevers co-occur with muscle pain, abdominal pain and limb rashes in the absence of infection or autoimmune disease. Apart from periodic fever episodes, no secondary symptoms are found 100% of the time with fever onset, thereby making diagnosis difficult. Unresponsiveness to colchicine treatment during periodic fevers is also indicative of TRAPS. Genetic testing confirms the diagnosis of TRAPS (Cantarini et al 2012).

Gene

Official Gene Symbol OMIM ID
TNFRSF1A 191190
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Tests

Name
Familial Hemophagocytic Lymphohistiocytosis (FHL) Panel
Periodic Fever Syndromes Panel

Citations

  • Aganna E, Hammond L, Hawkins PN, Aldea A, McKee SA, Amstel HKP van, Mischung C, Kusuhara K, Saulsbury FT, Lachmann HJ, Bybee A, McDermott EM, et al. 2003. Heterogeneity among patients with tumor necrosis factor receptor-associated periodic syndrome phenotypes. Arthritis Rheum. 48: 2632–2644. PubMed ID: 13130484
  • Aksentijevich I, Galon J, Soares M, Mansfield E, Hull K, Oh HH, Goldbach-Mansky R, Dean J, Athreya B, Reginato AJ, Henrickson M, Pons-Estel B, et al. 2001. The tumor-necrosis-factor receptor-associated periodic syndrome: new mutations in TNFRSF1A, ancestral origins, genotype-phenotype studies, and evidence for further genetic heterogeneity of periodic fevers. Am. J. Hum. Genet. 69: 301–314. PubMed ID: 11443543
  • Cantarini L, Lucherini OM, Muscari I, Frediani B, Galeazzi M, Brizi MG, Simonini G, Cimaz R. 2012. Tumour necrosis factor receptor-associated periodic syndrome (TRAPS): state of the art and future perspectives. Autoimmun Rev 12: 38–43. PubMed ID: 22884554
  • Churchman SM, Church LD, Savic S, Coulthard LR, Hayward B, Nedjai B, Turner MD, Mathews RJ, Baguley E, Hitman GA, Gooi HC, Wood PMD, et al. 2008. A novel TNFRSF1A splice mutation associated with increased nuclear factor kappaB (NF-kappaB) transcription factor activation in patients with tumour necrosis factor receptor associated periodic syndrome (TRAPS). Ann. Rheum. Dis. 67: 1589–1595. PubMed ID: 18086728
  • Kastner DL. 2005. Hereditary periodic fever syndromes. Hematology Am Soc Hematol Educ Program 74–81. PubMed ID: 16304362
  • Kusuhara K, Hoshina T, Saito M, Ishimura M, Inoue H, Horiuchi T, Sato T, Hara T. 2012. Successful treatment of a patient with tumor necrosis factor receptor-associated periodic syndrome using a half-dose of etanercept. Pediatr Int 54: 552–555. PubMed ID: 22830546
  • Lewis AK, Valley CC, Sachs JN. 2012. TNFR1 signaling is associated with backbone conformational changes of receptor dimers consistent with overactivation in the R92Q TRAPS mutant. Biochemistry 51: 6545–6555. PubMed ID: 22799488
  • Lobito AA, Kimberley FC, Muppidi JR, Komarow H, Jackson AJ, Hull KM, Kastner DL, Screaton GR, Siegel RM. 2006. Abnormal disulfide-linked oligomerization results in ER retention and altered signaling by TNFR1 mutants in TNFR1-associated periodic fever syndrome (TRAPS). Blood 108: 1320–1327. PubMed ID: 16684962
  • Ravet N, Rouaghe S, Dodé C, Bienvenu J, Stirnemann J, Lévy P, Delpech M, Grateau G. 2006. Clinical significance of P46L and R92Q substitutions in the tumour necrosis factor superfamily 1A gene. Ann. Rheum. Dis. 65: 1158–1162. PubMed ID: 16569687
  • Rebelo SL, Bainbridge SE, Amel-Kashipaz MR, Radford PM, Powell RJ, Todd I, Tighe PJ. 2006. Modeling of tumor necrosis factor receptor superfamily 1A mutants associated with tumor necrosis factor receptor-associated periodic syndrome indicates misfolding consistent with abnormal function. Arthritis Rheum. 54: 2674–2687. PubMed ID: 16871532
  • Sarrauste de Menthière C, Terrière S, Pugnère D, Ruiz M, Demaille J, Touitou I. 2003. INFEVERS: the Registry for FMF and hereditary inflammatory disorders mutations. Nucleic Acids Res. 31: 282–285. PubMed ID: 12520003
  • Shinar Y, Obici L, Aksentijevich I, Bennetts B, Austrup F, Ceccherini I, Costa JM, Leener A De, Gattorno M, Kania U, Kone-Paut I, Lezer S, et al. 2012. Guidelines for the genetic diagnosis of hereditary recurrent fevers. Ann. Rheum. Dis. 71: 1599–1605. PubMed ID: 22661645
  • Simon A, Park H, Maddipati R, Lobito AA, Bulua AC, Jackson AJ, Chae JJ, Ettinger R, Koning HD de, Cruz AC, Kastner DL, Komarow H, et al. 2010. Concerted action of wild-type and mutant TNF receptors enhances inflammation in TNF receptor 1-associated periodic fever syndrome. Proc. Natl. Acad. Sci. U.S.A. 107: 9801–9806. PubMed ID: 20457915
  • Turner MD, Chaudhry A, Nedjai B. 2012. Tumour necrosis factor receptor trafficking dysfunction opens the TRAPS door to pro-inflammatory cytokine secretion. Biosci. Rep. 32: 105–112. PubMed ID: 22115362

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

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Note: acceptable specimen types are whole blood and DNA from whole blood only.
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