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Spastic Paraplegia 11 via the SPG11 Gene

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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TEST METHODS

Sequencing

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
4333 SPG11$1590.00 81407 Add to Order
Pricing Comment

Our most cost-effective testing approach is NextGen sequencing with Sanger sequencing supplemented as needed to ensure sufficient coverage and to confirm NextGen calls that are pathogenic, likely pathogenic or of uncertain significance. If, however, full gene Sanger sequencing only is desired (for purposes of insurance billing or STAT turnaround time for example), please see link below for Test Code, pricing, and turnaround time information.

For Sanger Sequencing click here.
Targeted Testing

For ordering targeted known variants, please proceed to our Targeted Variants landing page.

Turnaround Time

The great majority of tests are completed within 28 days.

Clinical Sensitivity

SPG11 accounts for approximately 21% of all autosomal recessive (AR) hereditary spastic paraplegia (HSP) (Stevanin et al. 2008b). For patients with early-onset and cognitive impairments associated with thin corpus callosum (TCC), pathogenic variants in SPG11 may account for up to 59% of cases (Stevanin et al. 2008b; Denora et al. 2009). 

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Clinical Features

Spastic paraplegia 11 (SPG11) is a type of hereditary spastic paraplegia (HSP) and is characterized by progressive spasticity and weakness of the lower limbs (Stevanin et al. 2008a). Most SPG11 cases are complex, i.e., the spastic paraparesis are associated with other features, such as cognitive impairments, thin corpus callosum (TCC), white and grey matter abnormalities (Stevanin et al. 2008b; Franca et al. 2012). Onset is typically early (age 1-31 years) and most SPG11 patients become wheelchair users 10-20 years after disease onset (Stevanin et al. 2008a).

Although cognitive impairments and TCC serve as phenotype predictors of SPG11, these features may also be present in other HSP patients with a different genetic basis. In addition, pathogenic variants in SPG11 can also cause Charcot-Marie-Tooth disease type 2X (Montecchiani et al. 2016) and juvenile Amyotrophic Lateral Sclerosis type 5 (ALS5) (Orlacchio et al. 2010), different neurological disorders with overlapping features. Molecular genetic testing is very useful in a precise diagnosis of this type of disease.

Genetics

SPG11 is inherited as an autosomal recessive (AR) disorder and it is known to be the most common type of AR-HSP. SPG11 (also known as KIAA1840) is the only gene in which pathogenic variants cause SPG11 (Stevanin et al. 2007). The SPG11 gene encodes spatacsin (for spasticity with thin or atrophied corpus callosum syndrome protein), a protein expressed throughout the nervous system. The function of spatacsin is not well understood, but a recent study suggests that it may play roles in axonal maintenance and intracellular protein trafficking (Perez-Branguli et al. 2014). To date, with the exception of a few (<10) missense variants reported, all the identified pathogenic variants (>150) in SPG11 are either nonsense or deletions/duplications leading to a frameshift, strongly suggesting a loss-of-function mechanism (Human Gene Mutation Database).

Testing Strategy

For this NextGen test, the full coding regions plus ~20 bp of non-coding DNA flanking each exon are sequenced for the gene listed below. Sequencing is accomplished by capturing specific regions with an optimized solution-based hybridization kit, followed by massively parallel sequencing of the captured DNA fragments. Additional Sanger sequencing is performed for any regions not captured or with insufficient number of sequence reads. All pathogenic, likely pathogenic, or variants of uncertain significance are confirmed by Sanger sequencing.

Since this test is performed using exome capture probes, a reflex to exome sequencing may be ordered. The price of the exome reflex is $990.

Indications for Test

Candidates for this test are patients showing features consistent with AR-HSP and family members of patients who have known SPG11-HSP mutations.

Gene

Official Gene Symbol OMIM ID
SPG11 610844
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Spastic Paraplegia 11 AR 604360

Related Tests

Name
Complex Hereditary Spastic Paraplegia Sequencing Panel
Hereditary Spastic Paraplegia Comprehensive Sequencing Panel
Pure Hereditary Spastic Paraplegia Sequencing Panel

CONTACTS

Genetic Counselors
Geneticist
Citations
  • Denora P.S. et al. 2009. Human Mutation. 30: E500-19. PubMed ID: 19105190
  • França M.C. Jr. et al. 2012. Journal of Neurology, Neurosurgery, and Psychiatry. 83: 828-33. PubMed ID: 22696581
  • Human Gene Mutation Database (HGMD).
  • Montecchiani C. et al. 2016. Brain : a Journal of Neurology. 139: 73-85. PubMed ID: 26556829
  • Orlacchio A. et al. 2010. Brain : a Journal of Neurology. 133: 591-8. PubMed ID: 20110243
  • Pérez-Brangulí F. et al. 2014. Human Molecular Genetics. 23: 4859-74. PubMed ID: 24794856
  • Stevanin G et al. 2008a. Spastic Paraplegic 11. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews™, Seattle (WA): University of Washington, Seattle. PubMed ID: 20301389
  • Stevanin G. et al. 2007. Nature Genetics. 39: 366-72. PubMed ID: 17322883
  • Stevanin G. et al. 2008b. Brain : a Journal of Neurology. 131: 772-84. PubMed ID: 18079167
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TEST METHODS

Exome Sequencing

Test Procedure

For the PGxome we use Next Generation Sequencing (NGS) technologies to cover the coding regions of targeted genes plus ~10 bases of non-coding DNA flanking each exon. As required, genomic DNA is extracted from patient specimens. Patient DNA corresponding to these regions is captured using Agilent Clinical Research Exome hybridization probes. Captured DNA is sequenced using Illumina's Reversible Dye Terminator (RDT) platform NextSeq 500 using 150 by 100 bp paired end reads (Illumina, San Diego, CA, USA). The following quality control metrics are generally achieved: >97% of target bases are covered at >20x, and mean coverage of target bases >120x. Data analysis and interpretation is performed by the internally developed software Titanium-Exome. In brief, the output data from the NextSeq 500 is converted to fastqs by Illumina Bcl2Fastq 1.8.4, and mapped by BWA. Variant calls are made by the GATK Haplotype caller and annotated using in house software and SnpEff. Variants are filtered and annotated using VarSeq (www.goldenhelix.com). Common benign, likely benign, and low quality variants are filtered from analysis. All reported pathogenic, likely pathogenic, and variants of uncertain significance are confirmed by Sanger sequencing.

For Sanger sequencing, polymerase chain reaction (PCR) is used to amplify targeted regions. After purification of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit. PCR products are resolved by electrophoresis on an ABI 3730xl capillary sequencer. In nearly all cases, cycle sequencing is performed separately in both the forward and reverse directions.

Analytical Validity
Analytical Limitations

Interpretation of the test results is limited by the information that is currently available. Better interpretation should be possible in the future as more data and knowledge about human genetics and this specific disorder are accumulated.

When sequencing does not reveal any heterozygous differences from the reference sequence, we cannot be certain that we were able to detect both patient alleles. Occasionally, a patient may carry an allele which does not capture or amplify, due to a large deletion or insertion. In these cases, the report will contain no information about the second allele. Our Sanger and NGS tests (including PGxome) are generally not capable of detecting Copy Number Variants (CNVs).

For technical reasons, the PGxome test is not 100% sensitive. Some exons cannot be efficiently captured, and some genes cannot be accurately sequenced because of the presence of multiple copies in the genome. Therefore, a small fraction of sequence variants relevant to the patient's health will not be detected.

We sequence coding exons for most given transcripts, plus ~10 bp of flanking non-coding DNA for each exon. Unless specifically indicated, test reports contain no information about other portions of the gene, such as regulatory domains, deep intronic regions, uncharacterized alternative exons, chromosomal rearrangements, repeat expansions, epigenetic effects, and mitochondrial genome variants.

In most cases, we are unable to determine the phase of sequence variants. In particular, when we find two likely causative mutations for recessive disorders, we cannot be certain that the mutations are on different alleles.

Our ability to detect minor sequence variants due to somatic mosaicism is limited. Sequence variants that are present in less than 50% of the patient's nucleated cells may not be detected.

Runs of mononucleotide repeats (eg (A)n or (T)n) with n >8 in the reference sequence are generally not analyzed because of strand slippage during amplification.

Unless otherwise indicated, DNA sequence data is obtained from a specific cell-type (usually leukocytes if taken from whole blood). Test reports contain no information about the DNA sequence in other cell-types.

We cannot be certain that the reference sequences are correct.

We have confidence in our ability to track a specimen once it has been received by PreventionGenetics. However, we take no responsibility for any specimen labeling errors that occur before the sample arrives at PreventionGenetics.

A negative finding does not rule out a genetic diagnosis.

Genetic counseling to help to explain test results to the patients and to discuss reproductive options is recommended.

Order Kits

Ordering Options


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.

SPECIMEN TYPES
WHOLE BLOOD

(Delivery accepted Monday - Saturday)

  • Collect 3 ml -5 ml (5 ml preferred) of whole blood in EDTA (purple top tube) or ACD (yellow top tube). For Test #500-DNA Banking only, collect 10 ml -20 ml of whole blood.
  • For small babies, we require a minimum of 1 ml of blood.
  • Only one blood tube is required for multiple tests.
  • Ship blood tubes at room temperature in an insulated container. Do not freeze blood.
  • During hot weather, include a frozen ice pack in the shipping container. Place a paper towel or other thin material between the ice pack and the blood tube.
  • In cold weather, include an unfrozen ice pack in the shipping container as insulation.
  • At room temperature, blood specimen is stable for up to 48 hours.
  • If refrigerated, blood specimen is stable for up to one week.
  • Label the tube with the patient name, date of birth and/or ID number.

DNA

(Delivery accepted Monday - Saturday)

  • Send in screw cap tube at least 5 µg -10 µg of purified DNA at a concentration of at least 20 µg/ml for NGS and Sanger tests and at least 5 µg of purified DNA at a concentration of at least 100 µg/ml for gene-centric aCGH, MLPA, and CMA tests, minimum 2 µg for limited specimens.
  • For requests requiring more than one test, send an additional 5 µg DNA per test ordered when possible.
  • DNA may be shipped at room temperature.
  • Label the tube with the composition of the solute, DNA concentration as well as the patient’s name, date of birth, and/or ID number.
  • We only accept genomic DNA for testing. We do NOT accept products of whole genome amplification reactions or other amplification reactions.

CELL CULTURE

(Delivery preferred Monday - Thursday)

  • PreventionGenetics should be notified in advance of arrival of a cell culture.
  • Culture and send at least two T25 flasks of confluent cells.
  • Some panels may require additional flasks (dependent on size of genes, amount of Sanger sequencing required, etc.). Multiple test requests may also require additional flasks. Please contact us for details.
  • Send specimens in insulated, shatterproof container overnight.
  • Cell cultures may be shipped at room temperature or refrigerated.
  • Label the flasks with the patient name, date of birth, and/or ID number.
  • We strongly recommend maintaining a local back-up culture. We do not culture cells.
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