• Test code: 03503
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit

Invitae Amyotrophic Lateral Sclerosis Panel

Test description

The Invitae Amyotrophic Lateral Sclerosis Panel analyzes up to 20 genes associated with amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease involving loss of upper and lower motor neurons. The genes on the Invitae ALS Panel were curated based on the available evidence to date in order to provide analysis for a number of newly characterized ALS genes along with well-known genetic causes of ALS, with the exception of the C9orf72 gene, which is not included in this panel and is thought to be the most common genetic cause of both ALS and frontotemporal dementia (FTD). C9orf72 hexanucleotide repeat expansion testing is considered first-line genetic testing for individuals with a personal and/or family history of ALS and/or FTD. The Invitae ALS Panel should only be considered in individuals who have already had C9orf72 testing.

Individuals with a clinical diagnosis of ALS, especially those with a family history of ALS and/or dementia, may benefit from diagnostic genetic testing. Identification of the molecular basis of ALS in an affected individual may help to confirm a suspected diagnosis, provide anticipatory guidance, determine which relatives may be at risk, and/or promote enrollment in clinical trials.

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Primary panel (16 genes)


Add-on Preliminary-evidence Genes for Amyotrophic Lateral Sclerosis (4 genes)

The CHMP2B, MATR3, SIGMAR1, and SQSTM1 genes currently have preliminary evidence for a clinical association with ALS. Some clinicians may wish to include genes which do not currently have a definitive clinical association, but which may prove to be clinically significant in the future. These genes can be added at no additional charge. Visit our Preliminary-evidence genes page to learn more.


Alternative tests to consider

For a broader analysis of the genetics of hereditary dementia and ALS:

Clinicians may also consider the Invitae Hereditary Parkinson’s Disease and Parkinsonism panel for individuals with a personal or family history of Parkinson’s disease or parkinsonian features.

Amyotrophic lateral sclerosis (ALS) disease is a rapidly progressive neurodegenerative disease involving the loss of motor neurons within the motor cortex, brainstem, and spinal cord. The majority of individuals with ALS present with twitching and cramping of muscles in the hands and feet, loss of motor control in the hands and arms, weakness and fatigue, and/or tripping and falling. Symptoms usually begin with asymmetric involvement of the muscles. As the disease progresses, symptoms may include difficulty talking, breathing and swallowing, shortness of breath, and paralysis. However, some individuals have bulbar onset ALS, which presents with difficulty talking and/or swallowing. As the disorder progresses, additional components of the nervous system become involved, resulting in spasticity, weakness, muscle wasting, brisk deep tendon reflexes and eventually respiratory failure. Age of symptom onset is variable, but typically occurs in the 40s or 50s. An estimated 10% of individuals with ALS are classified as having familial ALS (FALS) based on the presence of two or more affected individuals in a family. An estimated 68% of familial ALS and 11% of sporadic ALS is thought to be hereditary. A number of genes associated with ALS can also cause FTD, and some individuals may develop features of both disorders. FTD may co-occur in up to 14% of individuals with ALS.

GeneInheritanceAssociated neurological disordersClinical sensitivity
Autosomal dominantAutosomal recessiveX-linked
ALS2 Juvenile ALS; Juvenile primary lateral sclerosis; Infantile-onset ascending hereditary spastic paraplegia Rare
CHCHD10 FTDALS2; Spinal muscular atrophy; Mitochondrial myopathy Rare
CHMP2B* ALS17; FTD3 Unknown
DCTN1 Perry Syndrome, which may present with features of ALS and/or FTD ~100% of Perry Syndrome, rare cause of isolated ALS/FTD
FUS ALS6 ~4% of familial ALS and approximately 1% of sporadic ALS with or without FTD
KIF5A ALS25 Unknown
MATR3* ALS21; Vocal cord and pharyngeal dysfunction with distal myopathy Unknown
OPTN ALS12 <1% of familial and sporadic ALS
PFN1 ALS18 Rare
SETX Spinocerebellar ataxia (SCAR1); ALS4 Unknown
SIGMAR1* ALS16; Distal spinal muscular atrophy (DSMA2) Unknown
SOD1 ALS1 ~12% of familial ALS and ~1-2% of sporadic ALS
SPG11 Hereditary spastic paraplegia with features of juvenile-onset ALS 21% of all recessive hereditary spastic paraplegia, unknown for isolated ALS
SQSTM1* FTDALS3; Paget disease of bone Unknown
TARDBP ALS10; FTD with TDP43 inclusions ~4% of familial ALS and ~1% of sporadic ALS with or without FTD
TBK1 FTDALS4 1-4% of hereditary FTD and/or ALS
TFG Hereditary motor and sensory neuropathy, Okinawa type (HMSNO) Rare
VAPB Finkel type Spinal Muscular Atrophy Rare
VCP Inclusion Body Myopathy with Paget Disease of Bone and/or Frontotemporal Dementia (IBMPFD); ALS14 ~100% of individuals who meet diagnostic criteria for IBMPFD; ~1-2% of familial ALS with or without FTD

*Preliminary-evidence gene

The clinical sensitivity of this panel is dependent on the patient’s true clinical diagnosis, which can often only be accurately determined upon autopsy. For each gene, the table in the Clinical Description section above shows the percentage of clinical cases in which a pathogenic variant is expected. For some genes, the incidence is rare and the clinical sensitivity is unknown. The sensitivity of this test also depends on age of onset and family history.

It is important to note that pathogenic variants in the C9orf72 gene account for an estimated 40% of familial ALS (and approximately 7% of sporadic ALS in individuals of European ancestry), and this panel should only be considered in those who have already been tested for C9orf72.

ALS can be associated with different inheritance patterns including autosomal dominant, autosomal recessive, and X-linked. Some genes are associated with both autosomal dominant and autosomal recessive inheritance.

ALS is an adult onset condition with variable age of onset, and penetrance can be difficult to calculate for the majority of genetic forms. Penetrance is typically age-dependent. An estimated 90% of individuals with either a SOD1 or FUS mutation will be symptomatic by 70 years of age.

The annual incidence of ALS is estimated to be 4-8 per 100,000 individuals, and an estimated 10% of all cases are hereditary.

A genetic cause for ALS may be suspected in individuals who have:

  • A clinical diagnosis of ALS (with or without frontotemporal dementia), and who have previously been tested for repeat expansion of the C9orf72 gene
  • A clinical diagnosis of early-onset ALS (onset before 50 years of age), especially in those with a family history of ALS or related conditions
  • No personal history of disease (unaffected individuals), but who are known to be at risk for a hereditary form of ALS because of family history

In addition to meeting one of the above criteria, individuals considering genetic testing for hereditary forms of ALS should first receive thorough pre-test genetic counseling from a professional qualified to provide such counseling regarding the implications of testing for neurodegenerative disorders that have no known treatment or cure at this time.

  1. Kiernan, MC, et al. Amyotrophic lateral sclerosis. Lancet. 2011; 377(9769):942-55. PMID: 21296405
  2. Riva, N, et al. Recent advances in amyotrophic lateral sclerosis. J. Neurol. 2016; :None. PMID: 27025851
  3. Miller, RG, et al. Practice parameter update: the care of the patient with amyotrophic lateral sclerosis: multidisciplinary care, symptom management, and cognitive/behavioral impairment (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2009; 73(15):1227-33. PMID: 19822873
  4. Sreedharan, J, et al. TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science. 2008; 319(5870):1668-72. PMID: 18309045
  5. Corrado, L, et al. High frequency of TARDBP gene mutations in Italian patients with amyotrophic lateral sclerosis. Hum. Mutat. 2009; 30(4):688-94. PMID: 19224587
  6. Kabashi, E, et al. TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat. Genet. 2008; 40(5):572-4. PMID: 18372902
  7. Borroni, B, et al. TARDBP mutations in frontotemporal lobar degeneration: frequency, clinical features, and disease course. Rejuvenation Res. 2010; 13(5):509-17. PMID: 20645878
  8. Floris, G, et al. Clinical phenotypes and radiological findings in frontotemporal dementia related to TARDBP mutations. J. Neurol. 2015; 262(2):375-84. PMID: 25408367
  9. Therrien, M, et al. ALS: Recent Developments from Genetics Studies. Curr Neurol Neurosci Rep. 2016; 16(6):59. PMID: 27113253
  10. Kinsley, L, Siddique, T. Amyotrophic Lateral Sclerosis Overview. 2001 Mar 23. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301623
  11. Traynor, BJ, et al. Incidence and prevalence of ALS in Ireland, 1995-1997: a population-based study. Neurology. 1999; 52(3):504-9. PMID: 10025778
  12. Chow, CY, et al. Deleterious variants of FIG4, a phosphoinositide phosphatase, in patients with ALS. Am. J. Hum. Genet. 2009; 84(1):85-8. PMID: 19118816
  13. Orlacchio, A, et al. SPATACSIN mutations cause autosomal recessive juvenile amyotrophic lateral sclerosis. Brain. 2010; 133(Pt 2):591-8. PMID: 20110243
  14. Goldman, JS, et al. Genetic counseling and testing for Alzheimer disease: joint practice guidelines of the American College of Medical Genetics and the National Society of Genetic Counselors. Genet. Med. 2011; 13(6):597-605. PMID: 21577118
  15. Renton, AE, et al. State of play in amyotrophic lateral sclerosis genetics. Nat. Neurosci. 2014; 17(1):17-23. PMID: 24369373
  16. Roggenbuck, J, et al. Genetic testing and genetic counseling for amyotrophic lateral sclerosis: an update for clinicians. Genet. Med. 2016; :None. PMID: 27537704
  17. Brenner, D, et al. Hot-spot KIF5A mutations cause familial ALS. Brain. 2018; :None. PMID: 29342275

Clinical management guidelines for ALS can be found at www.aan.com

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below. In addition, the analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
ALS2 NM_020919.3
CHCHD10 NM_213720.2
CHMP2B NM_014043.3
DCTN1 NM_004082.4
FUS NM_004960.3
KIF5A NM_004984.2
MATR3 NM_199189.2
OPTN NM_021980.4
PFN1 NM_005022.3
SETX NM_015046.5
SIGMAR1 NM_005866.3
SOD1 NM_000454.4
SPG11 NM_025137.3
SQSTM1 NM_003900.4
TARDBP NM_007375.3
TBK1 NM_013254.3
TFG NM_006070.5
UBQLN2 NM_013444.3
VAPB NM_004738.4
VCP NM_007126.3