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Hereditary Motor and Sensory Neuropathy IIB (HMSN2B) via the RAB7A 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
8871 RAB7A 81405 81405,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
8871RAB7A81405 81405(x1), 81479(x1) $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. If the Sanger option is selected, CNV detection may be ordered through Test #600.

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

Hereditary motor and sensory neuropathy IIB (HMSN2B), also known as axonal Charcot-Marie-Tooth disease type 2B (CMT2B), pertains to a form of ulcero-mutilating peripheral sensory neuropathy that develops during later stages in life (Verhoeven et al. 2003; Rotthier et al. 2009). The clinical and electrophysiological features of nerve conduction in HMSN2B are generally similar to those observed in Charcot-Marie-Tooth disease type 1 (CMT1), although onset occurs early in life (Neves and Kok 2011). The neuropathic symptoms of HMSN2B overlap with diabetes mellitus or exposures to toxic substances (Xiao and Bennett 2012; Kwon et al. 2013; Chiu et al. 2014; Peltier et al. 2014). CMT2B is diagnosed using a combination of medical history and clinical findings from physical and electrodiagnostic examinations (Verhoeven et al. 2013). The age of onset of HMSN2B is between 15 to 30 years; the most common features include sensory loss involving the distal parts of the body, which in turn result in the development of calluses and ulcers in the foot (Murphy et al. 2012). These ulcers, which typically occur during adolescence, do not heal with usual topical treatments, thus eventually resulting in the need to amputate one to a few digits of the foot. On the other hand, the lack of treatment of these ulcers may also lead to osteomyelitis and autoamputation (Taniguchi et al. 2013). After 3 to 4 decades, progressive painful swelling and deformity occurs in the other leg; however, the clinical severity of HMSN2B is variable (Kawaguchi et al. 2012; Ribiere et al. 2012). Some individuals who do not develop callus or ulcers instead notice deformities involving the feet, which include pes cavus and pes planus, as well as hammertoes.

Other clinical features of HMSN2B include mild scoliosis, loss of reflexes in the ankles, decreased sensation in the distal regions of the toes, lateral-gaze nystagmus, and degeneration of the cerebellum as detected by magnetic resonance imaging (MRI) (van Paassen et al. 2014). A stabbing pain may also occur in the ulcerated foot. Examination of motor skills and muscular strength, including coordination and muscle tone and power often show normal values. Tests on nerve conduction and sural nerve biopsy often indicate chronic sensory axonal neuropathy presenting with degeneration of the axons and pronounced regeneration (BasuRay et al. 2010; Cherry et al 2013; Cogil et al. 2013). The absence of changes in motor skills and the stabbing pain are also characteristics of hereditary sensory and autonomic neuropathy type 1 (HSAN1). The occurrence of nystagmus together with cerebellar atrophy is indicative of central nervous system involvement.

Genetics

HMSN2B is an autosomal dominant peripheral sensory neuropathy that is caused by heterozygous mutations in the RAB7A gene, which encodes for a GTP-binding protein located in specific intracellular compartments such as late endosomes and plays a major role in vesicular transport (Verhoeven et al. 2003; Klein et al. 2005; Cherry et al. 2013; BasuRay et al. 2013; Mousa et al. 2013). The RAB7A gene consists of six exons and encodes a 207-amino acid protein that has been evolutionarily conserved in the murine, canine, and human species (Machiewicz & Wyroba 2009). The RAB7A gene has been mapped to chromosomal band 3q21.3 (Kwon et al. 1995).

Inherited neuropathies involving the peripheral nervous system often show significant clinical as well as genetic heterogeneity (Lee & Choi 2006; Montenegro et al. 2011; Davidson et al. 2012). HMSN2B is mainly characterized by pronounced sensory loss, but may be complicated by microbial infections, arthropathy, and even amputations (Caillet et al. 2011; Murphy et al. 2012). A total of 5 causative sequence missense variants in the RAB7A gene have been reported to date. The variants c.385C>T (p.Leu129Phe) and c.484G>A (p.Val162Met) have been reported to be most common (Verhoeven et al. 2003; Holden et al. 2004; Meggouh et al. 2006; Rotthier et al. 2009).

Clinical Sensitivity - Sequencing with CNV PGxome

In a study involving 24 unrelated patients diagnosed with hereditary sensory neuropathy or presenting with ulcero-mutilating CMT phenotype, three patients were observed to carry pathogenic sequence variants in the RAB7A gene (Verhoeven et al. 2003). In another study consisting of 100 unrelated patients with hereditary ulcero-mutilating and sensory neuropathies, seven patients were identified to harbor causative sequence variants in the RAB7A gene (Rotthier et al. 2009).

Testing Strategy

This test provides full coverage of all coding exons of the RAB7A 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 RAB7A test candidates should either have a family history of peripheral sensory neuropathy involving the lower extremities including atrophy of the feet and muscles or a profound decrease in sensitivity involving lower limbs (Neves & Kok 2011; Ribiere et al. 2012). The ideal test candidate should have previously undergone a sural nerve biopsy indicating a significantly lower immunostaining density for the Rab-interacting protein (RILP; OMIM 607848) (Spinosa et al. 2008).

Gene

Official Gene Symbol OMIM ID
RAB7A 602298
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Charcot-Marie-Tooth Disease Type 2B AD 600882

Citations

  • BasuRay S, Mukherjee S, Romero EG, Seaman MN, Wandinger-Ness A. 2013. Rab7 mutants associated with Charcot-Marie-Tooth disease cause delayed growth factor receptor transport and altered endosomal and nuclear signaling. Journal of Biological Chemistry 288: 1135-1149. PubMed ID: 23188822
  • Caillet M, Janvier K, Pelchen-Matthews A, Delcroix-Genête D, Camus G, Marsh M, Berlioz-Torrent C. 2011. Rab7A is required for efficient production of infectious HIV-1. PLoS Pathogens 7: e1002347.  PubMed ID: 22072966
  • Cherry S, Jin EJ, Ozel MN, Lu Z, Agi E, Wang D, Jung WH, Epstein D, Meinertzhagen IA, Chan CC, Hiesinger PR. 2013. Charcot-Marie-Tooth 2B mutations in rab7 cause dosage-dependent neurodegeneration due to partial loss of function. Elife 2: e01064. PubMed ID: 24327558
  • Chiu HY, Hsu HY, Kuo LC, Su FC, Yu HI, Hua SC, Lu CH. 2014. How the impact of median neuropathy on sensorimotor control capability of hands for diabetes: an achievable assessment from functional perspectives. PLoS One 9: e94452. PubMed ID: 24722361
  • Cogli L, Progida C, Thomas CL, Spencer-Dene B, Donno C, Schiavo G, Bucci C. 2013. Charcot-Marie-Tooth type 2B disease-causing RAB7A mutant proteins show altered interaction with the neuronal intermediate filament peripherin. Acta Neuropathologica 125: 257-272. PubMed ID: 23179371
  • 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
  • Houlden H, King RH, Muddle JR, Warner TT, Reilly MM, Orrell RW, Ginsberg L. 2004. A novel RAB7 mutation associated with ulcero-mutilating neuropathy. Annals of Neurology 56(4): 586-590. PubMed ID: 15455439
  • Kawaguchi N, Suzuki N, Tateyama M, Takai Y, Misu T, Nakashima I, Itoyama Y, Aoki M. 2012. Two cases of elderly-onset hereditary neuropathy with liability to pressure palsy manifesting bilateral peroneal nerve palsies. Case Reports in Neurology 4: 149-155. PubMed ID: 23185166
  • Klein CJ, Wu Y, Kruckeberg KE, Hebbring SJ, Anderson SA, Cunningham JM, Dyck PJ, Klein DM, Thibodeau SN, Dyck PJ. 2005. SPTLC1 and RAB7 mutation analysis in dominantly inherited and idiopathic sensory neuropathies. Journal of Neurology, Neurosurgery and Psychiatry 76: 1022-1024. PubMed ID: 15965219
  • Kwon JM, Elliott JL, Yee WC, Ivanovich J, Scavarda NJ, Moolsintong PJ, Goodfellow PJ. 1995. Assignment of a second Charcot-Marie-Tooth type II locus to chromosome 3q. American Journal of Human Genetics 57: 853-858. PubMed ID: 7573046
  • Kwon MJ, Kim J, Shin H, Jeong SR, Kang YM, Choi JY, Hwang DH, Kim BG. 2013. Contribution of macrophages to enhanced regenerative capacity of dorsal root ganglia sensory neurons by conditioning injury. Journal of Neuroscience 33: 15095-15108. PubMed ID: 24048840
  • Lee JH, Choi BO. 2006. Charcot-marie-tooth disease: seventeen causative genes. Journal of Clinical Neurology 2: 92-106. PubMed ID: 20396492
  • Mackiewicz P, Wyroba E. 2009. Phylogeny and evolution of Rab7 and Rab9 proteins. BMC Evolutionary Biology 9: 101. PubMed ID: 19442299
  • Meggouh F, Bienfait HM, Weterman MA, de Visser M, Baas F. 2006. Charcot-Marie-Tooth disease due to a de novo mutation of the RAB7 gene. Neurology 67(8): 1476-1478. PubMed ID: 17060578
  • Montenegro G, Powell E, Huang J, Speziani F, Edwards YJ, Beecham G, Hulme W, Siskind C, Vance J, Shy M, Züchner S. 2011. Exome sequencing allows for rapid gene identification in a Charcot-Marie-Tooth family. Annals of Neurology 69: 464-470. PubMed ID: 21254193
  • Mousa SA, Shaqura M, Khalefa BI, Zöllner C, Schaad L, Schneider J, Shippenberg TS, Richter JF, Hellweg R, Shakibaei M, Schäfer M. 2013. Rab7 silencing prevents μ-opioid receptor lysosomal targeting and rescues opioid responsiveness to strengthen diabetic neuropathic pain therapy. Diabetes 62: 1308-1319. PubMed ID: 23230081
  • Murphy SM, Laura M, Fawcett K, Pandraud A, Liu YT, Davidson GL, Rossor AM, Polke JM, Castleman V, Manji H, Lunn MP, Bull K, Ramdharry G, Davis M, Blake JC, Houlden H, Reilly MM. 2012. Charcot-Marie-Tooth disease: frequency of genetic subtypes and guidelines for genetic testing. Journal of Neurology, Neurosurgery and Psychiatry 83: 706-710. PubMed ID: 22577229
  • Neves EL, Kok F. 2011. Clinical and neurophysiological investigation of a large family with dominant Charcot-Marie-Tooth type 2 disease with pyramidal signs. Arquivos de Neuro-Psiquiatria 69: 424-430. PubMed ID: 21755115
  • Peltier A, Goutman SA, Callaghan BC. 2014. Painful diabetic neuropathy. BMJ 348: g1799. PubMed ID: 24803311
  • Ribiere C, Bernardin M, Sacconi S, Delmont E, Fournier-Mehouas M, Rauscent H, Benchortane M, Staccini P, Lantéri-Minet M, Desnuelle C. 2012. Pain assessment in Charcot-Marie-Tooth (CMT) disease. Annals of Physical and Rehabilitation Medicine 55: 160-173. PubMed ID: 22475878
  • 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
  • Spinosa MR, Progida C, De Luca A, Colucci AM, Alifano P, Bucci C. Functional characterization of Rab7 mutant proteins associated with Charcot-Marie-Tooth type 2B disease. Journal of Neuroscience 28: 1640-1648. PubMed ID: 18272684
  • Taniguchi JB, Elui VM, Osório FL, Hallak JE, Crippa JA, Machado-de-Sousa JP, Kebbe LM, Lourenço CM, Scarel-Caminaga RM, Marques W Jr.. 2013. Quality of life in patients with Charcot-Marie-Tooth disease type 1A. Arquivos de Neuro-Psiquiatria 71: 392-396. PubMed ID: 23828533
  • van Paassen B.W. et al. 2014. Orphanet Journal of Rare Diseases. 9: 38. PubMed ID: 24646194
  • Verhoeven K, De Jonghe P, Coen K, Verpoorten N, Auer-Grumbach M, Kwon JM, FitzPatrick D, Schmedding E, De Vriendt E, Jacobs A, Van Gerwen V, Wagner K, Hartung HP, Timmerman V. 2003. Mutations in the small GTP-ase late endosomal protein RAB7 cause Charcot-Marie-Tooth type 2B neuropathy. American Journal of Human Genetics 72(3): 722-727. PubMed ID: 12545426
  • Xiao WH, Bennett GJ. 2012. Effects of mitochondrial poisons on the neuropathic pain produced by the chemotherapeutic agents, paclitaxel and oxaliplatin. Pain 153: 704-709. PubMed ID: 22244441
  •  BasuRay S, Mukherjee S, Romero E, Wilson MC, Wandinger-Ness A. 2010. Rab7 mutants associated with Charcot-Marie-Tooth disease exhibit enhanced NGF-stimulated signaling. PLoS One 5: e15351. PubMed ID: 21151572

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