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Episodic Pain Syndrome Panel

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy Genes Gene CPT Codes Copy CPT Codes
10123 SCN10A 81479,81479 Order Options and Pricing
SCN11A 81479,81479
SCN9A 81479,81479
Test Code Test Copy Genes Panel CPT Code Gene CPT Codes Copy CPT Code Base Price
10123Genes x (3)81479 81479(x6) $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 Custom Panel tool.

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).

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

  • Kym Bliven, PhD

Clinical Features and Genetics

Clinical Features

The Familial Episodic Pain Syndromes (FEPSs) are small fiber neuropathies characterized by intense, episodic inflammatory pain in specific regions of the body (Faber et al. 2012; Bennett and Woods, 2014). Currently, there are three recognized subtypes of this disorder (FEPS I-III).

FEPS type I is generally confined to the upper body, including the thorax and arms (Kremeyer et al. 2010). Attacks initially present in infancy and are often triggered by fasting in combination with other physical stressors, such as illness, cold temperature, and fatigue. Other symptoms may include breathing difficulties, tachycardia, sweating, pallor, and peribuccal cyanosis.

FEPS type II typically involves the distal lower extremities, although at least two patients have also reported hand pain (Faber et al. 2012; Han et al. 2014). Individuals may also present with allodynia, hyperalgesia, and/or red discoloration of the feet. While only a few patients with FEPS II have been described to date, onset of this disorder appears to occur in adulthood, and attacks may be triggered by stimuli such as cold temperature or intense physical exercise.

Finally, the pain associated with FEPS type III is primarily concentrated in the distal lower extremities, occasionally arising in the joints of fingers and arms (Zhang et al. 2013). Other symptoms may include numbness and tingling, skin discoloration, dry eyes and mouth, hyperhidrosis, orthostatic dizziness, palpitations, and/or hot flushes (Huang et al. 2014). In contrast to FEPS types I and II, age of onset of FEPS type III appears to be highly variable, although severity of the disorder may diminish with age (Zhang et al. 2013; Huang et al. 2014).

The symptoms of FEPS also overlap with those of other episodic pain syndromes, such as SCN9A-associated paroxysmal extreme pain disorder, primary erythermalgia, and small fiber neuropathy (Emery et al. 2015).

Paroxysmal extreme pain disorder (PEPD) is characterized by episodes of extreme pain that is generally confined to proximal regions of the body, including the rectum, eye, and mandible. Additionally, individuals may present with inflammation, excess secretions from the eyes or nose, and/or tonic attacks with apnea and bradycardia (Bennett and Woods 2014). Episodes may occur at birth or shortly after, and can be triggered by certain types of provoking stimuli, such as yawning, eating, or defecation (Fertleman et al. 2006).

The predominant symptom of primary erythermalgia is an episodic burning sensation in the hands and feet, often accompanied by redness and swelling (Bennett and Woods 2014). An increase in temperature further aggravates these symptoms, while a decrease in temperature provides relief. In contrast, while SCN9A-associated small fiber neuropathy is also characterized by a painful burning sensation in the lower extremities, patients are unaffected by alterations in temperature (Faber et al. 2012).

Genetics

The episodic pain syndromes are autosomal dominant diseases caused by gain-of-function variants that result in either enhanced activation of cation channels or impairment of cation channel deactivation (Bennet and Woods 2014; Emery et al. 2015). Our Episodic Pain Syndrome NextGen Panel currently includes the genes SCN9A, SCN10A, and SCN11A. Sequencing of TRPA1, which is associated with Familial Episodic Pain Syndrome (FEPS) Type I, is not available at this time.

SCN9A: The SCN9A gene encodes the alpha subunit of a type IX voltage-gated sodium channel, also referred to as Nav1.7 (Faber et al. 2012). Over 60 pathogenic variants have been reported in SCN9A to date (http://www.hgmd.cf.ac.uk/). Heterozygous gain-of-function missense variants in this gene may cause one of several pain disorders, including erythermalgia, small fiber neuropathy, and paroxysmal extreme pain disorder (Faber et al. 2012; Michiels et al. 2005; Fertleman et al. 2006). In contrast, loss-of-function variants in SCN9A may result in congenital indifference to pain, an autosomal recessive disease (Cox et al. 2006).

SCN10A: The SCN10A gene encodes the alpha subunit of the type X voltage-gated sodium channel. also referred to as Nav1.8 (Faber et al. 2012). SCN10A gain-of-function missense variants are responsible for FEPS type II. To date, four variants have been reported as causative for SCN10A-associated pain syndromes (Faber et al. 2012; Huang et al. 2013; Han et al. 2014).

SCN11A: The SCN11A gene encodes the alpha subunit of the type XI voltage-gated sodium channel, also referred to as Nav1.9 or NaN (Zhang et al. 2013). SCN11A gain-of-function missense variants are responsible for FEPS type III, and at least six pathogenic variants have been described in this gene (http://www.hgmd.cf.ac.uk/). Additionally, one gain-of-function missense change in SCN11A has been associated with hereditary sensory and autonomic neuropathy type VII (HSAN7), a congenital disorder characterized by the inability to perceive pain (Leipold et al. 2013).

Clinical Sensitivity - Sequencing with CNV PGxome

In a cohort of 104 patients who presented with painful, predominantly small-fiber neuropathy, Faber et al. reported 9 individuals (~8.5%) with pathogenic variants in SCN10A (Faber et al. 2012).

In a separate study of 345 patients who presented with painful peripheral neuropathy and were negative for causative variants in SCN9A or SCN10A, 12 patients (~3.5%) harbored pathogenic variants within the SCN11A gene (Huang et al. 2014).

Clinical sensitivity for the SCN9A-related episodic pain syndromes is difficult to predict due to the absence of large cohort studies and the phenotypic heterogeneity of these disorders. Analytic sensitivity is likely high, however, as all reported pathogenic variants to date are missense changes that are expected to be identified by direct sequencing of genomic DNA.

Testing Strategy

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

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. 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

The ideal test candidates for this Episodic Pain Syndrome panel are individuals who present with recurring episodes of pain and have a family history of FEPS type II, FEPS type III, or any of the SCN9A-related pain disorders.

Genes

Official Gene Symbol OMIM ID
SCN10A 604427
SCN11A 604385
SCN9A 603415
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Test

Name
PGxome®

Citations

  • Bennett D.L and Woods C.G. 2014. The Lancet Neurology. 13:587-99. PubMed ID: 24813307
  • Cox J.J. et al. 2006. Nature. 444: 894-8. PubMed ID: 17167479
  • Emery E.C. et al. 2015. The Journal of Neuroscience : the Official Journal of the Society For Neuroscience. 35:7674-81. PubMed ID: 25995458
  • Faber C.G. et al. 2012. Proceedings of the National Academy of Sciences U S A. 109:19444–9. PubMed ID: 23115331
  • Faber, C. G. et al. (2012). PubMed ID: 21698661
  • Fertleman C.R. et al. 2006. Neuron. 52: 767-74. PubMed ID: 17145499
  • Han C. et al. 2014. Journal of Neurology, Neurosurgery, and Psychiatry. 85:499-505. PubMed ID: 24006052
  • Huang J, Han C, Estacion M, Vasylyev D, Hoeijmakers JG, Gerrits MM, Tyrrell L, Lauria G, Faber CG, Dib-Hajj SD, Merkies IS, Waxman SG, PROPANE Study Group. 2014. Gain-of-function mutations in sodium channel Na(v)1.9 in painful neuropathy. Brain 137: 1627-1642. PubMed ID: 24776970
  • Huang J. et al. 2013. The Journal of Neuroscience : the Official Journal of the Society For Neuroscience. 33:14087-97.  PubMed ID: 23986244
  • Kremeyer B. et al. 2010. Neuron. 66: 671-80. PubMed ID: 20547126
  • Leipold E, Liebmann L, Korenke GC, Heinrich T, Giesselmann S, Baets J, Ebbinghaus M, Goral RO, Stödberg T, Hennings JC, Bergmann M, Altmüller J, Thiele H, Wetzel A, Nürnberg P, Timmerman V, De Jonghe P, Blum R, Schaible HG, Weis J, Heinemann SH, Hübner CA, Kurth I. 2013. A de novo gain-of-function mutation in SCN11A causes loss of pain perception. Nature Genetics 45: 1399-1404. PubMed ID: 24036948
  • Michiels, J. J. et al. (2005).   PubMed ID: 16216943
  • Zhang X.Y. et al. 2013. American Journal of Human Genetics. 93:957-66. PubMed ID: 24207120

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.
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