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Familial Episodic Pain Type 2 Syndrome via the SCN10A 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
11639 SCN10A 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
11639SCN10A81479 81479,81479 $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.

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

  • Kym Bliven, PhD

Clinical Features and Genetics

Clinical Features

Familial episodic pain syndrome type 2 (FEPS2) is an adult small fiber neuropathy that is characterized by paroxysmal pain involving the distal lower extremities (Faber et al. 2012; Huang et al. 2013). This disorder initially presents as a sudden and intense burning or stabbing pain in the feet that is generally caused by heat, cold, chemicals, or certain surfaces. The pain may also be continuous or evoked by a particular stimulus (Themistocleous et al. 2014). This clinical presentation is caused by a decrease in the number of intraepidermal nerve fibers in the distal region of the leg (Bakkers et al. 2010; Laedermann et al. 2013; Ramachandra et al. 2013). Other features of FEPS2 include allodynia (hypersensitivity to touch) and hyperalgesia (elevated response to a pain stimulus). Certain individuals with FEPS2 may also develop pruritic responses (Themistocleous et al. 2014). FEPS2 episodes can be relieved by warmth, although the affected areas may develop red discoloration. Assessment of nerve conduction of the affected extremities generally shows normal properties, although quantitative testing of sensory capacities of both feet, and in rare cases hands, usually indicates abnormal thresholds for warm and cold temperatures (Hovaguimian & Gibbons 2011). Mutations in two other genes, TRPA1 on chromosome 8q13.3 (Faber et al. 2012) and SCN11A on chromosome 3p22.2 (Zhang et al. 2013) may also cause FEPS.   

Genetics

FEPS2 is an autosomal dominant neurologic disorder caused by heterozygous missense mutations involving the voltage-gated sodium channel type X, alpha subunit (SCN10A) gene (Faber et al. 2012). Voltage-gated sodium channels serve as integral membrane components that play a major role in the generation of the initial action potential of nerve cells. These channels consist of a large alpha subunit that directly interacts with several smaller beta protein subunits (Zhao et al. 2011). Although a wide range of voltage-gated sodium channels exist, each type can be differentiated according to their primary structure, protein kinetics, as well as sensitivity to the tetrodotoxin (TTX) neurotoxin (Rajamani et al. 2008). Sodium channels that are relatively resistant to TTX generally accumulate within the area where nerve injury has occurred, thus resulting in chronic pain (Gold et al. 2003). 

The SCN10A gene maps to chromosome 3p22.2, consists of 27 exons, and encodes a TTX-resistant sodium channel, Nav1.8, which is required in maintaining the excitability of epidermal neurons when skin is exposed to cool temperatures and in other functions of the peripheral sensory nervous system (Abrahamsen et al. 2008). SCN10A has also been implicated in the development of cardiac pain and dysrhythmia, possibly serving gap junction proteins and functioning in cardiac innervation and conduction (Facer et al. 2011; Ritchie et al. 2013; Verkerk et al. 2012; van den Boogaard et al. 2014), as well as in lingual nerve neuromas (Bird et al. 2013). About 30 causative variants have been reported in the SCN10A gene, the great majority of which are missense variants (Faber et al. 2012; Savio-Galimberti et al. 2014).

Clinical Sensitivity - Sequencing with CNV PGxome

In a study involving 104 patients presenting with idiopathic peripheral neuropathic pain, 9 cases were determined to harbor a causative sequence variant in the SCN10A gene (Faber et al. 2012). In another report, one patient who tested negative for causative variants in the SCN9A gene was determined to carry a causative variant in the SCN10A gene (Huang et al. 2013).

Testing Strategy

This test provides full coverage of all coding exons of the SCN10A 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

The ideal SCN10A test candidates have a family history of FEPS along with a positive skin biopsy result for small fiber neuropathy, which includes a decreased density of intradermal nerve fibers and complete epidermal denervation (Devigili et al. 2008; Latronico et al. 2013; Shipton 2013).

Gene

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

Disease

Name Inheritance OMIM ID
Episodic Pain Syndrome, Familial, 2 AD 615551

Citations

  • Abrahamsen B, Zhao J, Asante CO, Cendan CM, Marsh S, Martinez-Barbera JP, Nassar MA, Dickenson AH, Wood JN. 2008. The cell and molecular basis of mechanical, cold, and inflammatory pain. Science 321: 702-705.  PubMed ID: 18669863
  • Bakkers M, Faber CG, Drent M, Hermans MC, van Nes SI, Lauria G, De Baets M, Merkies IS. 2010. Pain and autonomic dysfunction in patients with sarcoidosis and small fibre neuropathy. Journal of Neurology 257: 2086-2090. PubMed ID: 20644950
  • Bird EV, Christmas CR, Loescher AR, Smith KG, Robinson PP, Black JA, Waxman SG, Boissonade FM. 2013. Correlation of Nav1.8 and Nav1.9 sodium channel expression with neuropathic pain in human subjects with lingual nerve neuromas. Molecular Pain 9:52. PubMed ID: 24144460
  • Devigili G, Tugnoli V, Penza P, Camozzi F, Lombardi R, Melli G, Broglio L, Granieri E, Lauria G. 2008. The diagnostic criteria for small fibre neuropathy: From symptoms to neuropathology. Brain 131(Pt 7): 1912-1925.  PubMed ID: 18524793
  • Faber CG, Lauria G, Merkies IS, Cheng X, Han C, Ahn HS, Persson AK, Hoeijmakers JG, Gerrits MM, Pierro T, Lombardi R, Kapetis D, Dib-Hajj SD, Waxman SG. 2012. Gain-of-function Nav1.8 mutations in painful neuropathy. Proceedings of the National Academy of Sciences USA 109: 19444-19449. PubMed ID: 23115331
  • Facer P, Punjabi PP, Abrari A, Kaba RA, Severs NJ, Chambers J, Kooner JS, Anand P. 2011. Localisation of SCN10A gene product Na(v)1.8 and novel pain-related ion channels in human heart. International Heart Journal 52: 146-152.  PubMed ID: 21646736
  • Gold MS, Weinreich D, Kim CS, Wang R, Treanor J, Porreca F, Lai J. 2003. Redistribution of Na(V)1.8 in uninjured axons enables neuropathic pain. Journal of Neuroscience 23: 158-166. PubMed ID: 12514212
  • Hovaguimian A, Gibbons CH. 2011. Diagnosis and treatment of pain in small-fiber neuropathy. Current Pain and Headache Reports 15: 193-200. PubMed ID: 21286866
  • Huang J, Yang Y, Zhao P, Gerrits MM, Hoeijmakers JG, Bekelaar K, Merkies IS, Faber CG, Dib-Hajj SD, Waxman SG. 2013. Small-fiber neuropathy Nav1.8 mutation shifts activation to hyperpolarized potentials and increases excitability of dorsal root ganglion neurons. Journal of Neuroscience 33: 14087-14097. PubMed ID: 23986244
  • Laedermann CJ, Cachemaille M, Kirschmann G, Pertin M, Gosselin RD, Chang I, Albesa M, Towne C, Schneider BL, Kellenberger S, Abriel H, Decosterd I. 2013. Dysregulation of voltage-gated sodium channels by ubiquitin ligase NEDD4-2 in neuropathic pain. Journal of Clinical Investigation 123:3002-3013. PubMed ID: 23778145
  • Latronico N, Filosto M, Fagoni N, Gheza L, Guarneri B, Todeschini A, Lombardi R, Padovani A, Lauria G. 2013. Small nerve fiber pathology in critical illness. PLoS One 8: e75696.  PubMed ID: 24098716
  • Rajamani S, Shryock JC, Belardinelli L. 2008. Block of tetrodotoxin-sensitive, Na(V)1.7 and tetrodotoxin-resistant, Na(V)1.8, Na+ channels by ranolazine. Channels (Austin) 2: 449-460. PubMed ID: 19077543
  • Ramachandra R, McGrew SY, Baxter JC, Howard JR, Elmslie KS. 2013. NaV1.8 channels are expressed in large, as well as small, diameter sensory afferent neurons. Channels (Austin) 7: 34-37. PubMed ID: 23064159
  • Ritchie MD, Denny JC, Zuvich RL, Crawford DC, Schildcrout JS, Bastarache L, Ramirez AH, Mosley JD, Pulley JM, Basford MA, Bradford Y, Rasmussen LV, Pathak J, Chute CG, Kullo IJ, McCarty CA, Chisholm RL, Kho AN, Carlson CS, Larson EB, Jarvik GP, Sotoodehnia N; Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) QRS Group, Manolio TA, Li R, Masys DR, Haines JL, Roden DM. 2013. Genome- and phenome-wide analyses of cardiac conduction identifies markers of arrhythmia risk. Circulation 127: 1377-1385. PubMed ID: 23463857
  • Savio-Galimberti E, Weeke P, Muhammad R, Blair M, Ansari S, Short L, Atack TC, Kor K, Vanoye CG, Olesen MS, LuCamp, Yang T, George AL Jr, Roden DM, Darbar D. 2014. SCN10A/Nav1.8 modulation of peak and late sodium currents in patients with early onset atrial fibrillation. Cardiovascular Research 104: 355-363. PubMed ID: 25053638
  • Shipton EA. 2013. Skin matters: Identifying pain mechanisms and predicting treatment outcomes. Neurology Research International 2013: 329364. PubMed ID: 23766902
  • Themistocleous AC, Ramirez JD, Serra J, Bennett DL. 2014. The clinical approach to small fibre neuropathy and painful channelopathy. Practical Neurology 0: 1-12. PubMed ID: 24778270
  • van den Boogaard M, Smemo S, Burnicka-Turek O, Arnolds DE, van de Werken HJ, Klous P, McKean D, Muehlschlegel JD, Moosmann J, Toka O, Yang XH, Koopmann TT, Adriaens ME, Bezzina CR, de Laat W, Seidman C, Seidman JG, Christoffels VM, Nobrega MA, Barnett P, Moskowitz IP. 2014. A common genetic variant within SCN10A modulates cardiac SCN5A expression. Journal of Clinical Investigation 124: 1844-1852. PubMed ID: 24642470
  • Verkerk AO, Remme CA, Schumacher CA, Scicluna BP, Wolswinkel R, de Jonge B, Bezzina CR, Veldkamp MW. 2012. Functional Nav1.8 channels in intracardiac neurons: the link between SCN10A and cardiac electrophysiology. Circulation Research 111: 333-343. PubMed ID: 22723301
  • Zhang XY, Wen J, Yang W, Wang C, Gao L, Zheng LH, Wang T, Ran K, Li Y, Li X, Xu M, Luo J, Feng S, Ma X, Ma H, Chai Z, Zhou Z, Yao J, Zhang X, Liu JY. 2013. Gain-of-function mutations in SCN11A cause familial episodic Pain. American Journal of Human Genetics 93: 957–966. PubMed ID: 24207120
  • Zhao J, O'Leary ME, Chahine M.Regulation of Nav1.6 and Nav1.8 peripheral nerve Na+ channels by auxiliary β-subunits. 2011. Journal of Neurophysiolpgy 106: 608-619. PubMed ID: 21562192

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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STAT and Prenatal Test Options are not available with Patient Plus.

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