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Amyotrophic Lateral Sclerosis (ALS)/Motor Neuron Disease via the SOD1 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
8949 SOD1 81404 81404,81479 $640 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
8949SOD181404 81404,81479 $640 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.

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

  • Luke Drury, PhD

Clinical Features and Genetics

Clinical Features

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by motor neuron impairment in the cortex, brain stem, and spinal cord (Hardiman et al. 2017. PubMed ID: 28980624). The dysfunction and loss of these neurons results in progressive muscle weakness, atrophy and ultimately paralysis of limb, bulbar and respiratory muscles. About 50% of patients also develop cognitive and behavioral impairment and another 13% develop frontotemporal dementia (van Es et al. 2017. PubMed ID: 28552366). The mean age of symptom onset is 55 years for familial cases and 65 years for sporadic cases; most cases begin between 40 and 70 years of age. The annual incidence of ALS is 2-3 per 100,000 (van Es et al. 2017. PubMed ID: 28552366; Brown and Al-Chalabi. 2017. PubMed ID: 28700839).

ALS has a heterogeneous clinical presentation with variable disease progression timelines. Classic ALS presentation occurs in ~70% of cases with 66% of cases presenting with spinal neurodegenerative primarily affecting lower leg and upper arm motor neurons, and 33% of cases presenting with bulbar involvement resulting in dysarthria and/or dysphagia. 5-15% of ALS cases patients present with bulbar or spinal neurodegeneration and dementia; 5% present with bulbar only features without spreading to other regions; and 10% present with only with lower motor neuron involvement (van Es et al. 2017. PubMed ID: 28552366).

10% of ALS cases are familial (fALS) and 90% are sporadic cases (sALS) with no known affected relatives (Emery and Holloway 1982. PubMed ID: 7180680). The clinical presentations of fALS and sALS are similar, however, the onset of symptoms in fALS is usually earlier compared to that of sALS (van Es et al. 2017. PubMed ID: 28552366; Brown and Al-Chalabi. 2017. PubMed ID: 28700839). Genetic testing is helpful in better understanding ALS disease progression as certain pathogenic variants are associated with earlier or late onset and/or fast or slow progressing disease. Genetic testing is also helpful in the differential diagnosis of ALS from other neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, spinocerebellar ataxia and some forms of Charcot Marie Tooth Disease.  

Genetics

SOD1-mediated ALS is primarily inherited in an autosomal dominant manner via missense changes found throughout the protein. HUGO nomenclature differs from the literature with the initial methionine amino acid not being counted. For example the p.Ala5Val variant is commonly referred to as p.A4V. A Scandinavian founder variant, p.Asp91Ala has been shown to result in autosomal recessiveSOD1-mediated ALS and is found in 1.2% of Finnish Europeans (Andersen et al. 1995. PubMed ID: 7647793; gnomAD.org). Age of onset can occur as early as ~25 years of age with the average being ~50 years of age. Different missense changes can result in very different ages of onset. For example, p.Gly38Arg has an average age of onset of ~25 years compared to ~60 years for the p.Asp134Ala variant. Disease duration is also dependent upon the specific missense change with variants such as p.Ala5Val being found in fast progressers compared to p.Gly42Asp found in slow progressors (Bali et al. 2016. PubMed ID: 27261500). Loss of function variants have also been reported in a limited number of ALS cases (Andersen. 2003. PubMed ID: 14506936). Copy number alterations have not been reported in the SOD1 gene. Incomplete penetrance has been observed (Turner et al. 2013. PubMed ID: 23415570). De novo variants have been reported in a few cases.

Several different mouse models expressing different SOD1 missense changes have been developed (Alrafiah 2018. PubMed ID: 30150420). SOD1 mutation dosage dependent phenomena have been described in several ALS mouse models. For example, high transgene expression of the p.Gly93Ala variant results in earlier ALS development compared to low expression, suggesting dosage dependent phenomena in mouse models of ALS. In mice expressing the SOD1 p.Ala4Val variant, disease onset is not pathogenic until late in life. In humans, the p.Ala4Val variant is associated with highly aggressive ALS (Joyce et al. PubMed ID: 21706386). Overall many mouse models have overlap with ALS presentation but fail to closely mirror clinical course.

SOD1 encodes the superoxide dismutase 1 protein which functions to reduce free superoxide radicals. SOD1 was the first gene associated with ALS (Rosen et al. 1993. PubMed ID: 8446170. Pathogenic variants in the SOD1 gene are responsible for ~15% of familial European ALS and ~30% of familial Asian ALS cases. For sporadic cases, SOD1 causative variants are found in ~1.5% of European and Asians. Pathogenic variants in SOD1 are the most frequent genetic cause of ALS in Asians and second most frequent cause in Europeans (Zou et al. 2017. PubMed ID: 28057713). SOD1 has been cited as a conditional gene for growth of human tissue culture cells (Online Gene Essentiality, ogee.medgenius.info).

A homozygous SOD1 loss of function variant, c.335dupG (p.Cys112Trpfs*11), has been reported in an infant with progressive spastic tetraparesis within the first year of life (Andersen et al. 2019. PubMed ID: 31314961).

Clinical Sensitivity - Sequencing with CNV PG-Select

In a large meta-analysis from 111 ALS studies, causative pathogenic variants were identified in ~55% of Europeans and 40% of Asians with fALS. For sALS cases, causative variants were identified in ~8% of Europeans and 3% of Asians. The mutation spectrum was also different between the populations. In European fALS patients, C9orf72 repeat expansions were found in about a third of cases and SOD1 variants in ~15%. In Asian fALS patients, SOD1 variants were found in a third of cases compared to 2% with C9orf72 repeat expansions (Zou et al. 2017. PubMed ID: 28057713). Analytical sensitivity is >99% as all reported pathogenic variants in the SOD1 gene are detectable by sequencing.

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 SOD1 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.

Indications for Test

Candidates for testing typically present with upper and lower motor neuron impairment with other diagnoses excluded via imaging and neurophysiological examinations. Diagnosis can be difficult as sites of symptom onset and disease progression can be variable. Other screening tools used for ALS include the ALS-Brief Cognitive Assessement (ALS-BCA), El Escorial criteria, the ALS Cognitive Behavioral Screen (ALS-CBS) and the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) (van Es et al. 2017. PubMed ID: 28552366). This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in SOD1.

Gene

Official Gene Symbol OMIM ID
SOD1 147450
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Amyotrophic Lateral Sclerosis Type 1 AR, AD 105400

Citations

  • Alrafiah 2018. PubMed ID: 30150420
  • Andersen et al. 1995. PubMed ID: 7647793
  • Andersen et al. 2019. PubMed ID: 31314961
  • Andersen. 2003. PubMed ID: 14506936
  • Bali et al. 2016. PubMed ID: 27261500
  • Brown and Al-Chalabi. 2017. PubMed ID: 28700839
  • Emery and Holloway 1982. PubMed ID: 7180680
  • Genome Aggregation Database.
  • Hardiman et al. 2017. PubMed ID: 28980624
  • Joyce et al. PubMed ID: 21706386
  • Online Gene Essentiality, ogee.medgenius.info.
  • Rosen et al. 1993. PubMed ID: 8446170
  • Turner et al. 2013. PubMed ID: 23415570
  • van Es et al. 2017. PubMed ID: 28552366
  • Zou et al. 2017. PubMed ID: 28057713

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

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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.
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