Dentatorubral-Pallidoluysian Atrophy (DRPLA) via the ATN1 CAG 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
5999 ATN1 81177 81177 $250 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
5999ATN181177 $250 Order Options and Pricing

A 25% additional charge will be applied to STAT orders. View STAT turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

Turnaround Time

12 days on average

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare progressive neurodegenerative disorder characterized by myoclonus, epilepsy, cerebellar ataxia, choreoathetosis, psychiatric disturbances, and intellectual deterioration or dementia (Veneziano and Frontali. 2016. PubMed ID: 20301664). DRPLA is caused by expansion of a CAG repeat encoding a poly glutamine (Poly-Q) tract in exon 6 on the ATN1 gene. DRPLA is also known as Naito-Oyanagi disease after the researchers that first characterized this disorder in Japan (Kanazawa et al. 1998. PubMed ID: 9933295). It is also referred to Haw River Syndrome after an extended African American kindred from the Haw River area in rural North Carolina (Burke et al. 1994. PubMed ID: 7951323). DRPLA is enriched in in the Japanese population, with an estimated prevalence of 2 to 7 cases per million individuals (Carroll et al. 2018. PubMed ID: 30410817). Outside of Japan, the exact prevalence of DRPLA is presently unknown.

DRPLA displays phenotypic variability as disease severity increases and age of onset decreases with increasing CAG repeat size. Onset varies from early infancy (<1 year) through to the seventh decade with a mean onset of 30 years (Veneziano and Frontali. 2016. PubMed ID: 20301664). Disease duration ranges from 0 to 35 years with an average length of 8 years. Death may occur between 18 to 80 years of age with an average of 49 years. Individuals affected before 20 years of age typically present with ataxia, myoclonus, epilepsy, and progressive intellectual deterioration, while those affected after 20 years of age typically present with ataxia, choreoathetosis, dementia, and psychiatric disturbances (Veneziano and Frontali. 2016. PubMed ID: 20301664). In some cases, brain neuroimaging may reveal progressive cerebellar and brain stem atrophy (Tsuji et al. 2012. PubMed ID: 21827919). Treatment is limited to managing individual symptoms such as antiepileptic drugs, psychotropic medications, and riluzole and rehabilitation therapy for epilepsy, psychiatric manifestations, and ataxia, respectively (Veneziano and Frontali. 2016. PubMed ID: 20301664). The clinical features and presentation of DRLPA displays overlap with hereditary ataxias and Huntington disease (Brusco et al. 2004. PubMed ID: 15148151; Veneziano and Frontali. 2016. PubMed ID: 20301664). Genetic testing may aide in establishing a differential diagnosis. Genetic testing may also assist reproductive planning.

Genetics

DRLPA is inherited in an autosomal dominant manner. It is caused by a CAG repeat expansion in the ATN1 gene that occurs in exon six and encodes a polglutamine tract beginning at residue 488. Repeat copy numbers can be categorized into three categories: 6-35 CAG repeats are normal alleles, 36-47 CAG repeats are mutable normal alleles, and ≥ 48 CAG repeats are full penetrance pathogenic alleles (Veneziano and Frontali. 2016. PubMed ID: 20301664). Mutable normal alleles are unstable and may expand upon transmission to subsequent generations. Although not typically associated with symptoms, a limited number of cases with a mild DRPLA phenotype and repeat lengths in the mutable normal allele range have been reported (Carroll et al. 2018. PubMed ID: 30410817). The mutable and pathogenic CAG repeats are known to exhibit anticipation as the repeat expands upon transmission to successive generations with earlier age of onset and more severe course of disease. Expansion of the CAG repeat is typically associated with paternal transmission, but may occur with maternal transmission in rare instances (Nagafuchi et al. 1994. PubMed ID: 8136826; Veneziano and Frontali. 2016. PubMed ID: 20301664).

The ATN1 gene encodes the atrophin-1 protein, a transcriptional corepressor involved in nuclear signaling that is widely expressed in the central nervous system and other tissues (Wang et al. 2008. PubMed ID: 17150957). Although the function of the ATN1 protein is yet to be fully elucidated, animal models provide insight into the pathologic process. Mice with a single 129 CAG repeat allele in the ATN1 gene display a progressive neurodegenerative phenotype similar to juvenile onset DRPLA (Sato et al. 2009. PubMed ID: 19039037). These mice were observed to have progressive brain atrophy that was associated with neuronal intranuclear accumulation of the elongated ATN1 protein (Sato et al. 2009. PubMed ID: 19039037). This protein accumulation leads to the formation of neuronal intranuclear inclusions, atrophy of the perikarya and dendrites, and a decrease in the number and size of dendritic spines, which leads to brain atrophy and neuronal dysfunction without cell death (Saki et al. 2006. PubMed ID: 16891319).

While the ATN1 CAG repeat expansion is exclusively associated with DRPLA, de novo pathogenic missense variants and in-frame insertions in the ATN1 gene are also reported to be associated with autosomal dominant congenital hypotonia, epilepsy, developmental delay, and digital anomalies (Palmer et al. 2019. PubMed ID: 30827498). Please see our Custom Panel tool if you are interested in testing for these additional pathogenic variants.

Testing Strategy

This test consists of a combination of three complementary PCR assays that are used as a screening method for the presence or absence of the CAG trinucleotide repeat expansion located in the sixth exon of the ATN1 gene. These assays include two repeat-primed PCR assays for the 3’ and 5’ ends of the repeat region, as well as a fluorescent fragment-length assay (also known as the flanking assay) (Warner et al. 1996. PubMed ID: 9004136; DeJesus-Hernandez et al. 2011. PubMed ID: 21944778; Renton et al. 2011. PubMed ID: 21944779; Cleary et al. 2016. PubMed ID: 27288208). Allele sizing only includes pure CAG repeats. There are four glutamine residues prior to the poly glutamine CAG expansion (sequence is CAGCAACAGCAA[CAG]N), which are not counted in our allele sizing assays. This is consistent with ATN1 CAG repeat expansion reporting in the literature.

There is a chance that highly expanded alleles (>100) may not be detectable by fragment analysis. However, the repeat primed PCR expansion assays should detect highly expanded alleles.

Clinical Sensitivity - Repeat-Primed PCR & Fragment Length

This test is designed to identify the number of CAG repeats in the two alleles for ATN1. Clinical sensitivity is nearly 100% when a patient presents with symptoms and a familial history of the disease (Veneziano and Frontali. 2016. PubMed ID: 20301664).

Indications for Test

Candidates for this test are patients with clinical features suggestive of DRPLA. This test is also indicated for family members of patients who have the CAG trinucleotide repeat expansion in ATN1.

Gene

Official Gene Symbol OMIM ID
ATN1 607462
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Dentatorubral Pallidoluysian Atrophy AD 125370

Citations

  • Brusco et al. 2004. PubMed ID: 15148151
  • Burke et al. 1994. PubMed ID: 7951323
  • Carroll et al. 2018. PubMed ID: 30410817
  • Cleary et al. 2016. PubMed ID: 27288208
  • DeJesus-Hernadez et al. 2011. PubMed ID: 21944778
  • Kanazawa. 1998. PubMed ID: 9933295
  • Nagafuchi et al. 1994. PubMed ID: 8136826
  • Palmer et al. 2019. PubMed ID: 30827498
  • Renton et al. 2011. PubMed ID: 21944779
  • Sakai et al. 2006. PubMed ID: 16891319
  • Sato et al. 2009. PubMed ID: 19039037
  • Tsuji. 2012. PubMed ID: 21827919
  • Veneziano and Frontali. 2016. PubMed ID: 20301664
  • Wang et al. 2008. PubMed ID: 17150957
  • Warner et al. 1996. PubMed ID: 9004136

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.

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

loading Loading... ×

ORDER OPTIONS

View Ordering Instructions

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.

Total Price: $
×
Copy Text to Clipboard
×