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Hereditary Spastic Paraplegia (HSP) via the ENTPD1 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
13055 ENTPD1 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
13055ENTPD181479 81479(x2) $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.

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

  • Greg Fischer, PhD

Clinical Features and Genetics

Clinical Features

Hereditary spastic paraplegia (HSP) is a group of clinically and genetically diverse diseases, characterized by bilateral lower extremity spasticity (rigid muscles) and weakness (Fink. 2014. PubMed ID: 25192507; Hensiek et al. 2015. PubMed ID: 25480570; Hedera et al. 2018. PubMed ID: 20301682). HSP is classified as “pure” or “uncomplicated” when symptoms are confined to lower extremity spasticity and weakness and hypertonic urinary bladder. In contrast, HSP is classified as “complex” or “complicated” if the impairments in the lower limbs are also accompanied by other systemic or neurologic abnormalities such as seizures, ataxia, intellectual disability, dementia, peripheral neuropathy, and vision and hearing impairment (Fink. 2014. PubMed ID: 25192507; Hedera et al. 2018. PubMed ID: 20301682). The incidence of all forms of HSP is estimated to be less than one in 10,000 individuals or 0.01% (Hensiek et al. 2015. PubMed ID: 25480570).

Symptoms of the disease may begin at any age, with early onset HSP starting in early childhood and often resembling spastic diplegic cerebral palsy and late onset HSP beginning later in childhood or early adulthood (Fink. 2014. PubMed ID: 25192507; Hedera et al. 2018. PubMed ID:  20301682). In addition to variation in the age of onset, the severity and rate of progression are highly variable among different subtypes of complex HSPs, and even within a specific subtype (Tesson et al. 2015. PubMed ID: 25758904).

Advantages of genetic testing for HSP include confirmation of diagnosis, identification of other health risks associated with complicated HSP, allowing for targeted testing of other family members, and assistance with reproductive planning (Hedera et al. 2018. PubMed ID: 20301682).

Genetics

To date, more than 90 genetic loci and over 70 genes have been shown to be involved in HSP (Tesson et al. 2015. PubMed ID: 25758904; de Souza et al. 2017. PubMed ID: 27271711). HSP may be inherited in an autosomal dominant (AD) (75% to 80% of cases), autosomal recessive (AR) manner (25% to 30%);  or X-linked (XL) (1% to 2%) manner (Hensiek et al. 2015. PubMed ID: 25480570; Hedera et al. 2018. PubMed ID:  20301682). The genotype-phenotype correlation is poor, and some genes are associated with both complex and pure HSP (Fink. 2013. PubMed ID: 23897027).

Biallelic variants in ENTPD1 have been reported in autosomal recessive spastic paraplegia type 64 (SPG64), which is an early-onset complex form of HSP. To our knowledge, no de novo variants have been reported in patients with SPG64 and all reported variants have been found in single patients or families. Variants reported to date include missense and nonsense variants (Novarino et al. 2014. PubMed ID: 24482476; Travaglini et al. 2018. PubMed ID: 29691679; Mamelona et al. 2019. PubMed ID: 30652007). To our knowledge, no large deletions or duplications have been reported in patients with SPG64; however, given the small number of patients reported to date, we cannot rule out the possibility that copy number variants could be clinically important. 

The ENTPD1 gene encodes ectonucleoside triphosphate diphosphohydrolase 1 (ENTPDase-1), a membrane protein that catalyzes dephosphorylation of extra-cellular nucleotides that are involved in the regulation of purinergic neurotransmission. ENTPDase-1 is comprised of two small cytoplasmic domains at the N- and C-termini and a large extra-cellular domain that spans amino acids 38 to 478 and includes the catalytic site (Mamelona et al. 2019. PubMed ID: 30652007). To date, all variants associated with SPG64 have been reported to occur in the extra-cellular domain of the protein (Novarino et al. 2014. PubMed ID: 24482476; Travaglini et al. 2018. PubMed ID: 29691679; Mamelona et al. 2019. PubMed ID: 30652007). ENTPD1 has been cited as a nonessential gene for growth of human tissue culture cells (Online Gene Essentiality, ogee.medgenius.info).

Clinical Sensitivity - Sequencing with CNV PGxome

To date, only a handful of families with SPG64 have been reported, indicating that the disorder is a rare form of HSP (Novarino et al. 2014. PubMed ID: 24482476; Travaglini et al. 2018. PubMed ID: 29691679; Mamelona et al. 2019. PubMed ID: 30652007).

Testing Strategy

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the ENTPD1 gene plus 10 bases flanking noncoding DNA in all available transcripts in addition to 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 symptoms consistent with autosomal recessive early onset complex spastic paraplegia are candidates for this test. Targeted testing is indicated for family members of patients who have known pathogenic variants in ENTPD1. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in ENTPD1. Finally, prenatal diagnosis may be considered in families with known disease-causing variants in ENTPD1

Gene

Official Gene Symbol OMIM ID
ENTPD1 601752
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Spastic Paraplegia 64 AR 615683

Citations

  • de Souza et al. 2017. PubMed ID: 27271711
  • Fink. 2013. PubMed ID: 23897027
  • Fink. 2014. PubMed ID: 25192507
  • Hedera. 2018. PubMed ID: 20301682
  • Hensiek et al. 2015. PubMed ID: 25480570
  • Mamelona et al. 2019. PubMed ID: 30652007
  • Novarino et al. 2014. PubMed ID: 24482476
  • Online Gene Essentiality,
  • Tesson et al. 2015. PubMed ID: 25758904
  • Travaglini et al. 2018. PubMed ID: 29691679

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

Disease Resources

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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.
Total Price: $
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