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Amyotrophic Lateral Sclerosis via the ANG Gene

Summary and Pricing

Test Method

Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
9225 ANG 81403 81403,81479 $990 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
9225ANG81403 81403,81479 $990 Order Options and Pricing

Pricing Comments

This test is also offered via our exome backbone with CNV detection (click here). The exome-based test may be higher priced, but permits reflex to the entire exome or to any other set of clinically relevant genes.

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

Testing run on PG-Select capture probes does not include exome-wide CNV analysis. Reflex is available to PGxome or an exome-based panel, or you can use this gene list to create a custom panel (click here).

Click here for costs to reflex to whole PGxome.

Turnaround Time

3 weeks on average for standard orders or 2 weeks 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

  • Sali Farhan, PhD

Clinical Features and Genetics

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.

Pathogenic variants in the ANG gene have been reported in both AD-FALS and SALS cases (Greenway, M.J. et al. Nat Genet 38(4):411-413, 2006; Paubel, A. et al. Arch Neurol 65(10):1333-1336, 2008; Gellera, C. et al. Neurogenetics 9(1):33-40, 2008). To date, about 25 different causative variants have been reported in ALS patients. Except for one nonsense variant, (c.338G>A, p.W113*) (Lattante, S. et al. Neurology 79(1):66-72, 2012), all of these variants are of the missense type.

ANG mutations appear to be a rare cause of ALS. They account for up to 2.3% of AD-ALS cases and 1% of SALS (Gellera, C. et al., 2008).

Although ANG pathogenic variants have been mostly detected in patients of Irish and Scottish decent, they have been reported in other populations. Specifically, the variant (c.122A>T, p.K41I) has been reported in various populations and appears to be the most common pathogenic ANG variant (Greenway, M.J. et al., 2006). This variant was also reported in all affected members of a Dutch family with a history of ALS. In this family, one of the affected individuals presented with ALS and later developed FTD, while the other affected members had ALS without FTD (van Es, M.A. et al. Neurology 72(3):287-288, 2009).

The ANG gene encodes the angiogenin protein. Mutations in the ANG gene identified in patients with ALS were associated with loss of angiogenic activity (Wu, D. et al. Ann Neurol 62(6):609-617, 2007).

Clinical Sensitivity - Sequencing with CNV PG-Select

ANG mutations account for up to 2.3% of AD-ALS cases and 1% of SALS (Gellera, C. et al. Neurogenetics 9(1):33-40, 2008).

Thus far, no large deletions or duplications have been reported in the ANG gene (Human Gene Mutation Database).

Testing Strategy

This test provides full coverage of all coding exons of the ANG gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

Indications for Test

Patients with symptoms suggestive of AD-ALS or sporadic ALS with or without FTD , and no mutations in the remaining ALS-associated genes.

Gene

Official Gene Symbol OMIM ID
ANG 105850
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Amyotrophic Lateral Sclerosis Type 9 611895

Citations

  • 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
  • Emery A.E., Holloway S. 1982. Advances in Neurology. 36: 139-47. PubMed ID: 7180680
  • Gellera, C. et al. (2008). "Identification of new ANG gene mutations in a large cohort of Italian patients with amyotrophic lateral sclerosis." Neurogenetics 9(1): 33-40. PubMed ID: 18087731
  • Greenway, M. J., et.al. (2006). "ANG mutations segregate with familial and 'sporadic' amyotrophic lateral sclerosis." Nat Genet 38(4): 411-413. PubMed ID: 16501576
  • Human Gene Mutation Database (Bio-base).
  • 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
  • Lattante, S. et al. (2012). "Contribution of major amyotrophic lateral sclerosis genes to the etiology of sporadic disease." Neurology 79(1):66-72. PubMed ID: 22722621
  • 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
  • Mitsuyama, Y. and Inoue, T. (2009). "Clinical entity of frontotemporal dementia with motor neuron disease". Neuropathology 29(6):649-654. PubMed ID: 19780984
  • Paubel, A. et.al. (2008). "Mutations of the ANG gene in French patients with sporadic amyotrophic lateral sclerosis." Arch Neurol 65(10): 1333-6. PubMed ID: 18852347
  • 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
  • van Es, M.A. et al. (2009). "A case of ALS-FTD in a large FALS pedigree with a K17I ANG mutation." Neurology 72(3):287-288. PubMed ID: 19153377
  • Wikström, J. et al. (1982). "Classic amyotrophic lateral sclerosis with dementia". Arch Neurol 39(11):681-683. PubMed ID: 7125994
  • Wu, D., et.al. (2007). "Angiogenin loss-of-function mutations in amyotrophic lateral sclerosis." Ann Neurol 62(6): 609-617. PubMed ID: 17886298

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

If ordering a Duo or Trio test, the proband and all comparator samples are required to initiate testing. If we do not receive all required samples for the test ordered within 21 days, we will convert the order to the most effective testing strategy with the samples available. Prior authorization and/or billing in place may be impacted by a change in test code.


Specimen Types

Specimen Requirements and Shipping Details

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STAT and Prenatal Test Options are not available with Patient Plus.

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Note: acceptable specimen types are whole blood and DNA from whole blood only.
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