Sodium Channel, Voltage-Gated, Type IX, Alpha Subunit Disorders via the SCN9A Gene

Small fiber neuropathy (OMIM 133020) is a relatively common adult onset disorder characterized by burning, neuropathic pain and autonomic symptoms of orthostatic dizziness, palpitations, dry eyes, and dry mouth (Faber et al. Ann Neurol 71:26-39, 2012). Nerve biopsies of affected individuals show that the intraepidermal density of small diameter nerve fibers is reduced. A minority of the eight Dutch patients reported by Faber et al. reported significant gastrointestinal symptoms while most of this cohort experienced persistence of the pain or burning over several years to involve the hands, mouth, or body.

Primary erythermalgia (OMIM 133020) is characterized by neuropathic pain of the feet and lower legs described by patients as a moderate to severe burning sensation. Affected areas feel warm and appear red and swollen. Symptoms are provoked by exercise, standing, and exposure to heat and humidity (Michiels et al. Arch Neurol 62:1587-1590, 2005). Onset can occur anywhere from childhood to adulthood. The frequency and severity of episodes increase with age. Variable levels of pain relief may be achieved by cooling affected areas and use of pain medications (Herskovitz et al. Neurology 43:621-622, 1993).

Familial febrile seizures, type 3B (OMIM 613863) and generalized epilepsy with febrile seizures-plus, type 7 (OMIM 613863, GEFS+, type 7) are related disorders of childhood-onset febrile seizures. Whereas familial febrile seizures, type 3B resolves in early childhood, the GEFS+, type 7 phenotype progresses to febrile and afebrile seizures and, in some patients, epilepsy (Singh et al. PLoS Genet 5:e1000649, 2009; Singh et al. Ann Neurol 45: 75-81, 1999).

Paroxysmal extreme pain disorder (OMIM 167400) is characterized by pain and autonomic dysfunction (Fertleman et al. Neuron 52:767-774, 2006). Four types of stimuli cause painful episodes in affected individuals: 1) the birth process induces pain crisis as evidenced by red and stiff affected newborns; 2) defecation in infants and young children triggers rectal pain; 3) provoked or, more commonly lack of a stimulus, leads to ocular pain; 4) yawning or eating triggers mandibular pain. This disorder is distinct in that pain, which is extreme, is restricted to the rectal, ocular, and mandibular areas. Skin flushing, syncope, excess secretions from the eyes and nose are presenting autonomic symptoms. Episodes of pain in this disorder may decrease with age, however they do not resolve completely.

Channelopathy-associated insensitivity to pain (OMIM 243000) is characterized by congenital inability to perceive any form of pain, but with normal sensory perception of touch, pressure, tickle, and temperature (Cox et al. Nature 444:894-898, 2006). The first molecularly confirmed cases were from Northern Pakistan, however, confirmed cases from many different nationalities have subsequently been reported (Goldberg et al. Clin Genet 71: 311-319, 2007). In one study, patients were found to also lack the ability to smell (Weiss et al. Nature 472: 186-190, 2011).

Heterozygous gain-of-function missense mutations in SCN9A cause primary erythermalgia, small fiber neuropathy, familial febrile seizures, type 3B, generalized epilepsy with febrile seizures-plus, type 7, and paroxysmal extreme pain disorder. Channelopathy-associated insensitivity to pain is inherited as an autosomal recessive disorder. All mutations reported to date in this recessive disorder result in loss of function via premature stop codons or frame-shifts and protein truncations.

Analytical sensitivity may be high because all SCN9A mutations reported to date are expected to be detected by direct sequencing of genomic DNA. Clinical sensitivity is problematic to predict due to genetic heterogeneity of these disorders and the dearth of documented cases.

This test provides full coverage of all coding exons of the SCN9A gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.