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Spinocerebellar Ataxia Type 17 via the TBP CAG/CAA Repeat Expansion

Summary and Pricing

Test Method

Combination Of Repeat-Primed PCR and Fluorescent Fragment-Length Assay
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
6059 TBP 81344 81344 $250 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
6059TBP81344 81344 $250 Order Options and Pricing

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

Turnaround Time

12 days on average for standard orders or 8 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

  • McKenna Kyriss, PhD

Clinical Features and Genetics

Clinical Features

Spinocerebellar ataxia type 17 (SCA17) is a progressive neurodegenerative disorder characterized by variable atrophy of the cerebellum, cerebrum and brain stem. Clinically, patients typically present with ataxia, parkinsonism, cognitive impairment and/or psychiatric symptoms. As the disease progresses, additional symptoms may be observed, including involuntary movements, facial dyskinesia, limb chorea, dystonia, parkinsonism, dementia, and pyramidal signs (Maltecca et al. 2003. PubMed ID: 14638975; Toyoshima et al. 2012. PubMed ID: 20301611). The mean age of onset for SCA17 is approximately 35 years, but has been reported to range from 3 to 75 years (Toyoshima et al. 2012. PubMed ID: 20301611). Clinically, features can resemble those in other types of hereditary ataxias, as well as Huntington disease. For this reason, SCA17 is sometimes referred to as Huntington disease-like type 4 (HDL4) (Toyoshima et al. 2012. PubMed ID: 20301611). There is currently no known cure for SCA17, and medical management focuses on treatment of clinical manifestations of the disease (Toyoshima et al. 2012. PubMed ID: 20301611). Life expectancy is approximately 20 years after the onset of symptoms (Yang et al. 2016. PubMed ID: 28032013).

Genetics

SCA17 is an autosomal dominant disorder. The exact prevalence of SCA17 is unknown; however, it is apparently quite rare as fewer than 100 individuals have been reported worldwide (Toyoshima et al. 2012. PubMed ID: 20301611). SCA17 is caused by expansion of a CAG/CAA repeat within the third exon of the TBP gene, which encodes a polyglutamine tract beginning at amino acid residue 58. The structure of the repeat is as follows, with both CAA and CAG encoding the amino acid glutamine:

(CAG)3 (CAA)3 (CAG)x CAA CAG CAA (CAG)y CAA CAG.

A normal repeat allele is considered to be between 25 to 40 total glutamine repeats, while 49 or more repeats is considered a fully penetrant pathogenic allele. The largest pathogenic repeat reported to date is 66 repeats (Maltecca et al. 2003. PubMed ID: 14638975). Patients with a fully penetrant pathogenic allele are expected to develop symptoms by the age of 50 (Toyoshima et al. 2012. PubMed ID: 20301611). There is some disagreement regarding the effect of mid-range repeat sizes (41 through 48 repeats), although the current consensus is that 41 to 48 repeats may be causative, but exhibit reduced penetrance. Penetrance is estimated at ~50% for 41 through 44 repeats, and greater than 80% for 45 through 48 repeats (Tremolizzo et al. 2011. PubMed ID: 21710129; Toyoshima et al. 2012. PubMed ID: 20301611; Shin et al. 2015. PubMed ID: 26267067; Choubtum et al. 2015. PubMed ID: 26374734). A general genotype-phenotype correlation has been observed between the size of the polyglutamine repeat and the age of onset and severity of disease, with larger repeats associated with earlier onset and more severe presentation (Maltecca et al. 2003. PubMed ID: 14638975; Toyoshima et al. 2012. PubMed ID: 20301611). In homozygous individuals, the age of onset is similar to that observed in heterozygotes, but the disease course has been reported to be more severe and rapidly progressive (Toyoshima et al. 2012. PubMed ID: 20301611).

In most patients reported to date, the CAA CAG CAA interruption is present within the repeat region. The occurrence of this interruption is associated with stable inheritance of the repeat size between generations (Toyoshima et al. 2012. PubMed ID: 20301611). However, in some patients the CAA CAG CAA interruption is absent. In those patients, genetic anticipation has been observed, with a progressively larger repeat size observed in each generation (Maltecca et al. 2003. PubMed ID: 14638975). Please note that with our test methodology, we are not able to determine whether or not the CAA CAG CAA interruption is present.

The TBP gene (6q27) contains 7 coding exons and encodes the ubiquitously expressed TATA box-Binding Protein. TBP is a general transcription factor which is involved in transcription by nuclear RNA polymerases (Toyoshima et al. 2012. PubMed ID: 20301611; Yang et al. 2016. PubMed ID: 28032013).

Clinical Sensitivity - Repeat-Primed PCR & Fragment Length

The sensitivity of this test is expected to be ~100% for individuals with known spinocerebellar ataxia type 17, as the disorder is caused solely by expansion of the CAG/CAA repeat within exon 3 of the TBP gene (Toyoshima et al. 2012. PubMed ID: 20301611).

Clinical sensitivity in patients with a diagnosis of spinocerebellar ataxia (SCA) of an unknown genetic etiology is expected to be lower and to vary depending upon the ethnicity of the patient. For example, in a cohort of 225 ataxic individuals from Italy, only ~1% (2 of 225 patients) were found to have pathogenic expansions in TBP (Brusco et al. 2004. PubMed ID: 15148151). However, ~10% of ataxic patients (8 of 82 patients) in a Thai cohort were found to have pathogenic expansions in TBP (Choubtum et al. 2015. PubMed ID: 26374734).

Testing Strategy

A combination of amplicon-length analysis and repeat-primed PCR is used as a screening method for the presence or absence of a pathogenic CAG trinucleotide repeat expansion located in the third exon of TBP (Warner et al. 1996. PubMed ID: 9004136; Toyoshima et al. 2012. PubMed ID: 20301611). Two repeat-primed PCR assays, for the 3’ and 5’ ends of the repeat region, as well as amplicon-length analysis, are all used as described for different disorders (DeJesus-Hernandez et al. 2011. PubMed ID: 21944778; Jama et al. 2013. PubMed ID: 23414820; Cleary et al. 2016. PubMed ID: 27288208). Test controls include DNA samples from individuals known to have a repeat expansion in TBP in either the pathogenic or intermediate size range, as well as healthy individuals.

This test is designed to only detect pathogenic expansions within the CAG/CAA repeat in exon 3 of the TBP gene. With our test methodology, we are unable to determine if the CAA CAG CAA interruption (see Genetics section for additional details) is present.

Indications for Test

Testing should be considered for patients presenting with cerebellar ataxia, involuntary movement, psychiatric symptoms or dementia. This test may also be considered for patients with a family history of spinocerebellar ataxia type 17 (SCA17). As with Huntington disease, predictive testing is not recommended for asymptomatic patients under the age of 18 (to allow for a patient’s own, informed decision) due to the debilitating nature of the disease, lack of treatment options, and the potential psychological issues that may result from either a positive or negative test result (Semaka et al. 2006. PubMed ID: 16965319; Bean and Bayrak-Toydemir. 2014. PubMed ID: 25356969).

Gene

Official Gene Symbol OMIM ID
TBP 600075
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Spinocerebellar Ataxia 17 AD 607136

Citations

  • Bean and Bayrak-Toydemir. 2014. PubMed ID: 25356969
  • Brusco et al. 2004. PubMed ID: 15148151
  • Choubtum et al. 2015. PubMed ID: 26374734
  • Cleary et al. 2016. PubMed ID: 27288208
  • DeJesus-Hernandez et al. 2011. PubMed ID: 21944778
  • Jama et al. 2013. PubMed ID: 23414820
  • Maltecca et al. 2003. PubMed ID: 14638975
  • Semaka et al. 2006. PubMed ID: 16965319
  • Shin et al. 2015. PubMed ID: 26267067
  • Toyoshima et al. 2012. PubMed ID: 20301611
  • Tremolizzo et al. 2011. PubMed ID: 21710129
  • Warner et al. 1996. PubMed ID: 9004136
  • Yang et al. 2016. PubMed ID: 28032013

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

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ORDER OPTIONS

View Ordering Instructions

1) Select Test Method (Backbone)


1) Select Test Type


2) Select Additional Test Options

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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