Hereditary Sensory and Autonomic Neuropathy Type V (HSAN5) via the NGF Gene
Summary and Pricing 
Test Method
Exome Sequencing with CNV Detection
| Test Code | Test Copy Genes | Test CPT Code | Gene CPT Codes Copy CPT Code | Base Price | |
|---|---|---|---|---|---|
| 9105 | NGF | 81479 | 81479,81479 | $990 | 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 platform).
Click here for costs to reflex to whole PGnome (if original test is on PGnome Sequencing platform).
The Sanger Sequencing method for this test is NY State approved.
For Sanger Sequencing click here.Turnaround Time
3 weeks on average for standard orders or 2 weeks 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.
Clinical Features and Genetics
Clinical Features
Most individuals with HSAN5 show a selective loss or inability to perceive pain and changes in temperatures that affect the extremities (Koike et al. 2010). These main symptoms generally occur during childhood. The results of nerve conduction tests of individuals with HSAN5 are usually normal (An et al. 2008). Histological biopsies often show normal unmyelinated fibers, although the sural nerve displays a significant reduction in the number of small myelinated fibers (Luigetti et al. 2011). Individuals with HSAN5 usually respond to tactile stimuli, exhibit normal tendon reflexes, as well as normal motor and sensory nerve conductions. Symptoms of HSAN5 include self-mutilation of the fingers, lips, and tongue; the autonomic system may also be slightly involved, which could be observed in the form of skin blotching, reduced sweating, and episodic spikes in body temperature (Illigens & Gibbons 2009).
Nerve conduction velocities are generally normal in individuals with HSAN5; however, tibial nerve stimulation does not result in a somatosensory evoked response that can be detected over the spine. Nerve biopsies of HSAN5 patients usually show the absence of small, myelinated afferent fibers, together with a slight decrease in the density of unmyelinated fibers (Flor-de-Lima et al. 2013). In contrast to hereditary sensory and autonomic neuropathy type IV (HSAN4), both mental and the majority of neurological responses of individuals with HSAN5 are not affected.
Genetics
HSAN5 is an autosomal recessive pain disorder that often results in accidental to fatal injuries and self-mutilating activities due to a significant decrease in the sensation for pain (Capsoni et al. 2011). HSAN5 is caused by mutations in the nerve grown factor (NGF) gene, which has been mapped to chromosomal region 1p13.2 (Garson et al. 1987). The NGF gene consists of 3 exons and encodes the nerve growth factor protein, which is mainly involved in the control of growth and differentiation of sympathetic and a few sensory nerves (Darby et al. 1985). The NGF protein promotes the regeneration of damaged sensory axons, thus indicating its selective effect on the peripheral and central nervous systems (Harrington et al. 2004). To date, only six causative sequence variants have been documented in the NGF gene, which include 3 missense substitutions, two small insertions/deletions, and one large deletion (Einarsdottir et al. 2004; Rotthier et al. 2009; Capsoni et al. 2011; Carvalho et al. 2011; Davidson et al. 2012).
Clinical Sensitivity - Sequencing with CNV PGxome
In a study involving 140 patients with hereditary sensory and autonomic neuropathy (HSAN), two patients harbored causative variants in the NGF gene (Davidson et al. 2012). Otherwise, the majority of the reports describing pathogenic variants in the NGF gene involve a single affected patient (Fitzgibbon et al. 2009) or a multigenerational family with 2 to 3 affected members (Einarsdottir et al. 2004; Minde et al. 2006).
Testing Strategy
This test provides full coverage of all coding exons of the NGF 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 NGF test candidate should have sensory and autonomic neuropathy type 5, which involves the fingers, lips, and tongue, as well as autonomic system abnormalities such as skin blotching, reduced sweating, and episodic spikes in body temperature (Illigens & Gibbons 2009). The ideal test candidate should have previously undergone a sural nerve assessment that displays a significant reduction in the number of small myelinated fibers (Luigetti et al. 2010; Tavakoli et al. 2011). This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in NGF.
The ideal NGF test candidate should have sensory and autonomic neuropathy type 5, which involves the fingers, lips, and tongue, as well as autonomic system abnormalities such as skin blotching, reduced sweating, and episodic spikes in body temperature (Illigens & Gibbons 2009). The ideal test candidate should have previously undergone a sural nerve assessment that displays a significant reduction in the number of small myelinated fibers (Luigetti et al. 2010; Tavakoli et al. 2011). This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in NGF.
Gene
| Official Gene Symbol | OMIM ID |
|---|---|
| NGF | 162030 |
| Inheritance | Abbreviation |
|---|---|
| Autosomal Dominant | AD |
| Autosomal Recessive | AR |
| X-Linked | XL |
| Mitochondrial | MT |
Disease
| Name | Inheritance | OMIM ID |
|---|---|---|
| Neuropathy, Hereditary Sensory And Autonomic, Type V | 608654 |
Related Test
| Name |
|---|
| Chronic Joint Pain and Dysfunction via the MMP13 Gene |
Citations
- An JY, Park MS, Kim JS, Shon YM, Lee SJ, Kim YI, Lee KS, Kim BJ. 2008. Comparison of diabetic neuropathy symptom score and medial plantar sensory nerve conduction studies in diabetic patients showing normal routine nerve conduction studies. Internal Medicine 47(15): 1395-1398. PubMed ID: 18670144
- Capsoni S, Covaceuszach S, Marinelli S, Ceci M, Bernardo A, Minghetti L, Ugolini G, Pavone F, Cattaneo A. 2011. Taking pain out of NGF: a "painless" NGF mutant, linked to hereditary sensory autonomic neuropathy type V, with full neurotrophic activity. PLoS One 6: e17321. PubMed ID: 21387003
- Capsoni S, Covaceuszach S, Marinelli S, Ceci M, Bernardo A, Minghetti L, Ugolini G, Pavone F, Cattaneo A. 2011. Taking pain out of NGF: a "painless" NGF mutant, linked to hereditary sensory autonomic neuropathy type V, with full neurotrophic activity. PLoS One 6: e17321. PubMed ID: 21387003
- Carvalho OP, Thornton GK, Hertecant J, Houlden H, Nicholas AK, Cox JJ, Rielly M, Al-Gazali L, Woods CG. 2011. A novel NGF mutation clarifies the molecular mechanism and extends the phenotypic spectrum of the HSAN5 neuropathy. Journal of Medical Genetics 48: 131-135. PubMed ID: 20978020
- Darby JK, Feder J, Selby M, Riccardi V, Ferrell R, Siao D, Goslin K, Rutter W, Shooter EM, Cavalli-Sforza LL. 1985. A discordant sibship analysis between beta-NGF and neurofibromatosis. American Journal of Human Genetics 37: 52-59. PubMed ID: 2983544
- Davidson G, Murphy S, Polke J, Laura M, Salih M, Muntoni F, Blake J, Brandner S, Davies N, Horvath R, Price S, Donaghy M, Roberts M, Foulds N, Ramdharry G, Soler D, Lunn M, Manji H, Davis M, Houlden H, Reilly M. 2012. Frequency of mutations in the genes associated with hereditary sensory and autonomic neuropathy in a UK cohort. Journal of Neurology 259(8): 1673-1685. PubMed ID: 22302274
- Davidson G, Murphy S, Polke J, Laura M, Salih M, Muntoni F, Blake J, Brandner S, Davies N, Horvath R, Price S, Donaghy M, Roberts M, Foulds N, Ramdharry G, Soler D, Lunn M, Manji H, Davis M, Houlden H, Reilly M. 2012. Frequency of mutations in the genes associated with hereditary sensory and autonomic neuropathy in a UK cohort. Journal of Neurology 259: 1673-1685. PubMed ID: 22302274
- Einarsdottir E, Carlsson A, Minde J, Toolanen G, Svensson O, Solders G, Holmgren G, Holmberg D, Holmberg M. 2004. A mutation in the nerve growth factor beta gene (NGFB) causes loss of pain perception. Human Molecular Genetics 13(8): 799-805. PubMed ID: 14976160
- Einarsdottir E, Carlsson A, Minde J, Toolanen G, Svensson O, Solders G, Holmgren G, Holmberg D, Holmberg M. 2004. A mutation in the nerve growth factor beta gene (NGFB) causes loss of pain perception. Human Molecular Genetics 13: 799-805. PubMed ID: 14976160
- Fitzgibbon GJ, Kingston H, Needham M, Gaunt L. 2009. Haploinsufficiency of the nerve growth factor beta gene in a 1p13 deleted female child with an insensitivity to pain. Developmental Medicine and Child Neurology 51(10): 833-837. PubMed ID: 19183217
- Flor-de-Lima F, Macedo L, Taipa R, Melo-Pires M, Rodrigues ML. 2013. Hereditary neuropathy with liability to pressure palsy: a recurrent and bilateral foot drop case report. Case Reports in Pediatrics 2013: 230541. PubMed ID: 24251057
- Garson JA, van den Berghe JA, Kemshead JT. 1987. Novel non-isotopic in situ hybridization technique detects small (1 Kb) unique sequences in routinely G-banded human chromosomes: fine mapping of N-myc and beta-NGF genes. Nucleic Acids Research 15: 4761-4770. PubMed ID: 3299258
- Harrington AW, Leiner B, Blechschmitt C, Arevalo JC, Lee R, Mörl K, Meyer M, Hempstead BL, Yoon SO, Giehl KM. 2004. Secreted proNGF is a pathophysiological death-inducing ligand after adult CNS injury. Proceedings of the National Academy of Sciences USA 101: 6226-6230. PubMed ID: 15026568
- Illigens BM, Gibbons CH. 2009. Sweat testing to evaluate autonomic function. Clinical Autonomic Research Journal 19: 79-87. PubMed ID: 18989618
- Illigens BM, Gibbons CH. 2009. Sweat testing to evaluate autonomic function. Clinical Autonomic Research Journal 19: 79-87. PubMed ID: 18989618
- Khaledi M, Rezaei N. 2012. Hereditary and sensory autonomic neuropathies. Iranian Journal of Pediatrics 22: 567-568. PubMed ID: 23431414
- Koike H, Atsuta N, Adachi H, Iijima M, Katsuno M, Yasuda T, Fukada Y, Yasui K, Nakashima K, Horiuchi M, Shiomi K, Fukui K, Takashima S, Morita Y, Kuniyoshi K, Hasegawa Y, Toribe Y, Kajiura M, Takeshita S, Mukai E, Sobue G. 2010. Clinicopathological features of acute autonomic and sensory neuropathy. Brain 133: 2881-2896. PubMed ID: 20736188
- Luigetti M, Madia F, Conte A, Tonali P, Sabatelli M. 2010. Neuropathy with predominant small fiber involvement associated with abnormal anti-MAG titer. Internal Medicine 49(23): 2627-2629. PubMed ID: 21139305
- Luigetti M, Madia F, Conte A, Tonali P, Sabatelli M. 2010. Neuropathy with predominant small fiber involvement associated with abnormal anti-MAG titer. Internal Medicine 49(23): 2627-2629. PubMed ID: 21139305
- Masoudi R, Ioannou MS, Coughlin MD, Pagadala P, Neet KE, Clewes O, Allen SJ, Dawbarn D, Fahnestock M. 2009. Biological activity of nerve growth factor precursor is dependent upon relative levels of its receptors. Journal of Biological Chemistry 284: 18424-18433. PubMed ID: 19389705
- Minde J, Svensson O, Holmberg M, Solders G, Toolanen G. 2006. Orthopedic aspects of familial insensitivity to pain due to a novel nerve growth factor beta mutation. Acta Orthopaedica 77(2): 198-202. PubMed ID: 16752279
- Rotthier A, Baets J, De Vriendt E, Jacobs A, Auer-Grumbach M, Lévy N, Bonello-Palot N, Kilic SS, Weis J, Nascimento A, Swinkels M, Kruyt MC, Jordanova A, De Jonghe P, Timmerman V. 2009. Genes for hereditary sensory and autonomic neuropathies: a genotype-phenotype correlation. Brain 132: 2699-2711. PubMed ID: 19651702
- Tavakoli M, Malik RA. 2011. Corneal confocal microscopy: a novel non-invasive technique to quantify small fibre pathology in peripheral neuropathies. Journal of Visualized Experiments 47: 2194. PubMed ID: 21248693
- Wyatt SL, Spori B, Vizard TN, Davies AM. Selective regulation of nerve growth factor expression in developing cutaneous tissue by early sensory innervation. Neural Development 6: 18. PubMed ID: 21529369
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PGxome (Exome) Sequencing Panel
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