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Amyotrophic Lateral Sclerosis via the OPTN Gene

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

Sequencing

Test Code TestIndividual Gene PriceCPT Code Copy CPT Codes
156 OPTN$830.00 81406 Add to Order
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 18 days.

Clinical Sensitivity
OPTN mutations account for up to 1.2% of AD-ALS and 3.5% of SALS cases of European descent (Del Bo, R. et al. J Neurol Neurosurg Psychiatry 82(11):1239-1243, 2011). 

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Deletion/Duplication Testing via aCGH

Test Code TestIndividual Gene PriceCPT Code Copy CPT Codes
600 OPTN$690.00 81479 Add to Order
Pricing Comment

# of Genes Ordered

Total Price

1

$690

2

$730

3

$770

4-10

$840

11-30

$1,290

31-100

$1,670

Over 100

Call for quote

Turnaround Time

The great majority of tests are completed within 28 days.

Clinical Sensitivity
Large pathogenic deletions in the OPTN gene have been reported in Japanese ALS cases (Maruyama, H. et al. Nature 465(7295):223-226, 2010; Iida, A. et al. Neurobiol Aging 33(8):1843.e19-24, 2012;  Iida, A. et al. J Neurol Neurosurg Psychiatry 83(2):233-235, 2012). However, the proportion of patients with such deletions is unknown at this time.

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Clinical Features
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by a selective loss of motor neurons in the motor cortex, brain steam, and spinal cord (Tandan, R. and Bradley, W.G. Ann Neurol 18(3):271-280, 1985). The dysfunction and loss of these neurons results in rapid progressive muscle weakness, atrophy and ultimately paralysis of limb, bulbar and respiratory muscles. The mean age of onset of symptoms is about 55 years of age; most cases begin between 40 and 70 years of age. The annual incidence of ALS is 1-2 per 100,000 (Cleveland, D.W. and Rothstein, J.D. Nat Rev Neurosci 2(11):806-819, 2001).

The most common symptoms include twitching and cramping of muscles of the hands and feet, loss of motor control in the hands and arms, weakness and fatigue, tripping and falling. Symptoms usually begin with asymmetric involvement of the muscles. As the disease progresses, symptoms may include difficulty in talking, breathing and swallowing, shortness of breath, and paralysis.

Cognitive impairment has not been initially associated with ALS. However, frontotemporal dementia (FTD) has been reported in several cases. Dementia has been documented in patients with ALS from different ethnic groups and affects both males and females (Wikström, J. et al. Arch Neurol 39(11):681-683, 1982; Lipton, A.M. et al. Acta Neuropathol 108(5):379-385, 2004; Mitsuyama, Y. and Inoue, T. Neuropathology 29(6):649-654, 2009).
Genetics
About 10% of ALS cases are familial (Emery, A.E. and Holloway, S. Adv Neurol 36:139-147, 1982). In most of these families, ALS is inherited in an autosomal dominant manner (AD-ALS) and is age-dependent with high penetrance. In rare families, the disease is transmitted in an autosomal recessive or dominant X-linked pattern.

About 90% of patients with ALS are sporadic cases (SALS) with no known affected relatives. It is unclear how many of the apparently sporadic cases are inherited with low penetrance. The clinical presentations of familial ALS (FALS) and sporadic ALS (SALS) are similar. However, the onset of symptoms in FALS is usually earlier compared to that of SALS (Kinsley and Siddique. GeneReviews, 2012).

Autosomal Dominant ALS (AD-ALS) is a clinically and genetically heterogeneous disorder that affects all ethnic groups. At least twelve genetic loci have been reported. Several genes have been identified and include C9orf72, SOD1, FUS, TARDBP, ANG and OPTN.

Over 20 different pathogenic variants in the OPTN gene have been reported in patients with ALS including AD-ALS, SALS and AR-ALS.  Initially, both recessive and dominant OPTN mutations were found in Japanese cases of ALS  (Maruyama, H. et al. Nature 465(7295):223-226, 2010). Subsequently, dominant mutations were found in European cases including Italian (Del Bo, R. et al. J Neurol Neurosurg Psychiatry 82(11):1239-1243, 2011), Danish (Tümer, Z. et al. Neurobiol Aging 33(1):208.e1-5, 2012), and Canadian (Belzil, W. et al.  Neurobiol Aging 32(3):555.e13-4, 2011).  Although most mutations are missense, other types were also reported including nonsense, splicing, small deletions or insertions, indels, and large deletions.

OPTN mutations account for up to 1.2% of AD-ALS and 3.5% of SALS cases of European descent (Del Bo, R. et al., 2011). To date, recessive mutations were reported in Japanese cases only (Maruyama, H. et al., 2010; Iida, A. et al. Neurobiol Aging 33(8):1843.e19-24, 2012;  Iida, A. et al. J Neurol Neurosurg Psychiatry 83(2):233-235, 2012). 

Of note, based on current data, the OPTN gene does not appear to be involved in FTD or ALS-FTD.

Prior to their involvement with ALS, OPTN mutations have been reported in patients with primary open-angle glaucoma and ataxia (POAG) (Rezaie, T. et al. Science 295(5557):1077-1079, 2002).

The OTPN gene encodes optineurin protein, which has several roles including transcription activation and membrane trafficking.
Testing Strategy
This test involves bidirectional DNA sequencing of all coding exons and splice sites of the OTPN gene. The full coding sequence of each exon plus ~ 20 bp of flanking DNA on either side are sequenced. We will also sequence any single exon (Test #100) or pair of exons (Test #200) in family members of patients with known mutations or to confirm research results.
Indications for Test
Patients with symptoms suggestive of AD-ALS,  SALS, or AR-ALS and no mutations in the genes most commonly associated with ALS (See Amyotrophic Lateral Sclerosis Sanger Sequencing Panel, Test #155).

Gene

Official Gene Symbol OMIM ID
OPTN 602432
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Tests

Name
Amyotrophic lateral sclerosis (ALS) via the hnRNPA1 Gene
Amyotrophic Lateral Sclerosis / Motor Neuron Disease via the FUS Gene
Amyotrophic Lateral Sclerosis / Motor Neuron Disease via the PFN1 Gene
Amyotrophic Lateral Sclerosis / Motor Neuron Disease via the SOD1 Gene
Amyotrophic Lateral Sclerosis / Motor Neuron Disease via the TARDBP Gene
Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Sequencing Panel
Amyotrophic Lateral Sclerosis via the ANG Gene
Amyotrophic Lateral Sclerosis via the C9orf72 Gene Hexanucleotide Repeat Expansion
Glaucoma Sequencing Panel

CONTACTS

Genetic Counselors
Geneticist
Citations
  • Belzil, W. et al. (2011). "Analysis of OPTN as a causative gene for amyotrophic lateral sclerosis." Neurobiol Aging 32(3):555.e13-14. PubMed ID: 21074290
  • Cleveland, D.W. and Rothstein, J.D. (2001). "From Charcot to Lou Gehrig: deciphering selective motor neuron death in ALS." Nat Rev Neurosci 2(11): 806-819. PubMed ID: 11715057
  • Del Bo, R. et al. (2011). "Novel optineurin mutations in patients with familial and sporadic amyotrophic lateral sclerosis." J Neurol Neurosurg Psychiatry 82(11):1239-1243. PubMed ID: 21613650
  • Emery A.E., Holloway S. 1982. Advances in Neurology. 36: 139-47. PubMed ID: 7180680
  • Iida A, Hosono N, Sano M, Kamei T, Oshima S, Tokuda T, Kubo M, Nakamura Y, Ikegawa S. 2012. Optineurin mutations in Japanese amyotrophic lateral sclerosis. J. Neurol. Neurosurg. Psychiatr. 83: 233–235. PubMed ID: 21217154
  • Iida A, Hosono N, Sano M, Kamei T, Oshima S, Tokuda T, Nakajima M, Kubo M, Nakamura Y, Ikegawa S. 2012. Novel deletion mutations of OPTN in amyotrophic lateral sclerosis in Japanese. Neurobiology of Aging 33: 1843.e19–1843.e24. PubMed ID: 22402017
  • Kinsley L, Siddique T. 2015 Amyotrophic Lateral Sclerosis Overview. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong C-T, and Stephens K, editors. GeneReviews™, Seattle (WA): University of Washington, Seattle. PubMed ID: 20301623
  • Lipton, A.M. et al. (2004). "Frontotemporal lobar degeneration with motor neuron disease-type inclusions predominates in 76 cases of frontotemporal degeneration". Acta Neuropathol 108(5):379-385. PubMed ID: 15351890
  • Maruyama H, Morino H, Ito H, Izumi Y, Kato H, Watanabe Y, Kinoshita Y, Kamada M, Nodera H, Suzuki H, Komure O, Matsuura S,Kobatake K, Morimoto N, Abe K, Suzuki N, Aoki M, Kawata A, Hirai T, Kato T, Ogasawara K, Hirano A, Takumi T, Kusaka H, Hagiwara K, Kaji R, Kawakami H. 2010. Mutations of optineurin in amyotrophic lateral sclerosis. Nature 465: 223–226. PubMed ID: 20428114
  • Mitsuyama, Y. and Inoue, T. (2009). "Clinical entity of frontotemporal dementia with motor neuron disease". Neuropathology 29(6):649-654. PubMed ID: 19780984
  • Rezaie T, Child A, Hitchings R, Brice G, Miller L, Coca-Prados M, Héon E, Krupin T, Ritch R, Kreutzer D, Crick RP, Sarfarazi M. 2002. Adult-onset primary open-angle glaucoma caused by mutations in optineurin. Science 295: 1077–1079. PubMed ID: 11834836
  • Tümer, Z. et al. (2012). "Novel heterozygous nonsense mutation of the OPTN gene segregating in a Danish family with ALS." Neurobiol Aging 33(1):208.e1-5. PubMed ID: 21852022
  • Tandan, R. and Bradley, WG. (1985). "Amyotrophic lateral sclerosis: Part 1. Clinical features, pathology, and ethical issues in management." Ann Neurol 18(3): 271-280. PubMed ID: 4051456
  • Wikström J. et al. (1982). "Classic amyotrophic lateral sclerosis with dementia". Arch Neurol 39(11):681-683 PubMed ID: 7125994
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TEST METHODS

Bi-Directional Sanger Sequencing

Test Procedure

Nomenclature for sequence variants was from the Human Genome Variation Society (http://www.hgvs.org).  As required, DNA is extracted from the patient specimen.  PCR is used to amplify the indicated exons plus additional flanking non-coding sequence.  After cleaning of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit.  Products are resolved by electrophoresis on an ABI 3730xl capillary sequencer.  In most cases, sequencing is performed in both forward and reverse directions; in some cases, sequencing is performed twice in either the forward or reverse directions.  In nearly all cases, the full coding region of each exon as well as 20 bases of non-coding DNA flanking the exon are sequenced.

Analytical Validity

As of March 2016, we compared 17.37 Mb of Sanger DNA sequence generated at PreventionGenetics to NextGen sequence generated in other labs. We detected only 4 errors in our Sanger sequences, and these were all due to allele dropout during PCR. For Proficiency Testing, both external and internal, in the 12 years of our lab operation we have Sanger sequenced roughly 8,800 PCR amplicons. Only one error has been identified, and this was due to sequence analysis error.

Our Sanger sequencing is capable of detecting virtually all nucleotide substitutions within the PCR amplicons. Similarly, we detect essentially all heterozygous or homozygous deletions within the amplicons. Homozygous deletions which overlap one or more PCR primer annealing sites are detectable as PCR failure. Heterozygous deletions which overlap one or more PCR primer annealing sites are usually not detected (see Analytical Limitations). All heterozygous insertions within the amplicons up to about 100 nucleotides in length appear to be detectable. Larger heterozygous insertions may not be detected. All homozygous insertions within the amplicons up to about 300 nucleotides in length appear to be detectable. Larger homozygous insertions may masquerade as homozygous deletions (PCR failure).

Analytical Limitations

In exons where our sequencing did not reveal any variation between the two alleles, we cannot be certain that we were able to PCR amplify both of the patient’s alleles. Occasionally, a patient may carry an allele which does not amplify, due for example to a deletion or a large insertion. In these cases, the report contains no information about the second allele.

Similarly, our sequencing tests have almost no power to detect duplications, triplications, etc. of the gene sequences.

In most cases, only the indicated exons and roughly 20 bp of flanking non-coding sequence on each side are analyzed. Test reports contain little or no information about other portions of the gene, including many regulatory regions.

In nearly all 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 for example 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 PCR and cycle sequencing.

Unless otherwise indicated, the sequence data that we report are based on DNA isolated from a specific tissue (usually leukocytes). Test reports contain no information about gene sequences in other tissues.

Deletion/Duplication Testing Via Array Comparative Genomic Hybridization

Test Procedure

Equal amounts of genomic DNA from the patient and a gender matched reference sample are amplified and labeled with Cy3 and Cy5 dyes, respectively. To prevent any sample cross contamination, a unique sample tracking control is added into each patient sample. Each labeled patient product is then purified, quantified, and combined with the same amount of reference product. The combined sample is loaded onto the designed array and hybridized for at least 22-42 hours at 65°C. Arrays are then washed and scanned immediately with 2.5 µM resolution. Only data for the gene(s) of interest for each patient are extracted and analyzed.

Analytical Validity

PreventionGenetics' high density gene-centric custom designed aCGH enables the detection of relatively small deletions and duplications within a single exon of a given gene or deletions and duplications encompassing the entire gene. PreventionGenetics has established and verified this test's accuracy and precision.

Analytical Limitations

Our dense probe coverage may allow detection of deletions/duplications down to 100 bp; however due to limitations and probe spacing this cannot be guaranteed across all exons of all genes. Therefore, some copy number changes smaller than 100-300 bp within a targeted large exon may not be detected by our array.

This array may not detect deletions and duplications present at low levels of mosaicism or those present in genes that have pseudogene copies or repeats elsewhere in the genome.

aCGH will not detect balanced translocations, inversions, or point mutations that may be responsible for the clinical phenotype.

Breakpoints, if occurring outside the targeted gene, may be hard to define.

The sensitivity of this assay may be reduced when DNA is extracted by an outside laboratory.

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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