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Peripheral Neuropathies via the HINT1 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
9141 HINT1 81479 81479,81479 $990 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
9141HINT181479 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. 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 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.

EMAIL CONTACTS

Genetic Counselors

Geneticist

  • Angela Gruber, PhD

Clinical Features and Genetics

Clinical Features

Pathogenic variants in the HINT1 gene cause inherited peripheral neuropathies that range from a strict distal motor neuropathy without sensory involvement to axonal neuropathy with neuromyotonia and mild sensory involvement (Zimon et al. 2012; Zhao et al. 2014). Therefore, some patients are clinically diagnosed as having Charcot Marie Tooth 2 whereas others are diagnosed with distal hereditary motor neuropathy. One defining clinical feature seen in many patients is neuromyotonia. In two different cohort studies around 70% of affected individuals had action myotonia in the hands and/or neuromyotonic discharges on needle EMG (Zimon et al. 2012; Laššuthová et al. 2015). Disease onset is typically in the first or second decade and most patients present with distal weakness in the lower and upper limbs; however, only lower limb involvement has also been observed. There is a predominance of more motor neuron involvement than sensory nerves being affected.

Genetics

HINT1 peripheral neuropathies are inherited in an autosomal recessive manner. The HINT1 gene consists of 3 coding exons and encodes the 126 amino acid histidine triad nucleotide binding protein 1 (HINT1). HINT1 is a ubiquitously expressed homodimeric purine phosphoramidase and also acts as a tumor suppressor that functions in several apoptotic pathways (Zimon et al. 2012). Many of the pathogenic variants lie near the catalytic core and alter substrate binding, protein stability, or catalytic activity. Several of the described missense variants lie in the catalytic active site and abolish enzyme activity (Zimon et al. 2012). Reported pathogenic variants include missense and nonsense variants (Zimon et al. 2012, Zhao et al. 2014, Laššuthová et al. 2015). HINT1 is the fifth most frequent cause of CMT2/HMN in Czech populations with the p.Arg37Pro variant being the most common pathogenic variant in this population (Laššuthová et al. 2015). Carrier frequency of the P.Arg37Pro variant in Czech populations is estimated to be ~1:180 (Laššuthová et al. 2015).

Clinical Sensitivity - Sequencing with CNV PGxome

In the original study describing HINT1 as a causative gene for inherited neuropathies, a large cohort study of individuals suspected of autosomal recessive inherited peripheral neuropathy was performed (Zimon et al. 2012). Thirty-one of 293 (11%) cases were found to have HINT1 pathogenic variants. In 31 patients specifically with axonal neuropathy and neuromyotonia, 21 (68%) were found to have HINT1 pathogenic variants. In an additional study using exome sequencing on patients with a clinical diagnosis of distal hereditary motor neuropathy, two of 12 were found to have HINT1 variants (Zhao et al. 2014). In another large cohort study of Czech patients with either motor neuropathy or motor and sensory neuropathy, 14 of 196 (7%) individuals had pathogenic HINT1 variants (Laššuthová et al. 2015). The estimated carrier frequency in Czech populations for the pathogenic Arg37Pro variant is estimated to be ~1:182. Analytical sensitivity should be almost 100% because all reported pathogenic variants are detectable by sequencing.

Testing Strategy

This test provides full coverage of all coding exons of the HINT1 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

Individuals with clinical symptoms of axonal neuropathy and neuromyotonia or distal hereditary motor neuropathy. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in HINT1.

Gene

Official Gene Symbol OMIM ID
HINT1 601314
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Citations

  • Laššuthová P, Brozková DŠ, Krutová M, Neupauerová J, Haberlová J, Mazanec R, Dvorácková N, Goldenberg Z, Seeman P. 2015. Mutations in HINT1 are one of the most frequent causes of hereditary neuropathy among Czech patients and neuromyotonia is rather an underdiagnosed symptom. Neurogenetics 16: 43–54. PubMed ID: 25342199
  • Zhao H, Race V, Matthijs G, Jonghe P De, Robberecht W, Lambrechts D, Damme P Van. 2014. Exome sequencing reveals HINT1 mutations as a cause of distal hereditary motor neuropathy. Eur. J. Hum. Genet. 22: 847–850. PubMed ID: 24105373
  • Zimon M, Baets J, Almeida-Souza L, Vriendt E De, Nikodinovic J, Parman Y, Battaloglu E, Matur Z, Guergueltcheva V, Tournev I, Auer-Grumbach M, Rijk P De, Petersen BS, Müller T, Fransen E, Van Damme P, Löscher WN, Barisic N, Mitrovic Z, Previtali SC, Topaloglu H, Bernert G, Beleza-Meireles A, Todorovic S, Savic-Pavicevic D, Ishpekova B, Lechner S, Peeters K, Ooms T, Hahn AF, Züchner S, Timmerman V, Van Dijck P, Rasic VM, Janecke AR, De Jonghe P, Jordanova A. 2012. Loss-of-function mutations in HINT1 cause axonal neuropathy with neuromyotonia. Nature Genetics 44: 1080–1083. PubMed ID: 22961002

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

If ordering a Duo or Trio test, the proband and all comparator samples are required to initiate testing. If we do not receive all required samples for the test ordered within 21 days, we will convert the order to the most effective testing strategy with the samples available. Prior authorization and/or billing in place may be impacted by a change in test code.


Specimen Types

Specimen Requirements and Shipping Details

PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

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ORDER OPTIONS

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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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