Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) Panel

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy Genes Gene CPT Codes Copy CPT Codes
10359 ANG 81403,81479 Order Options and Pricing
ANXA11 81479,81479
APP 81406,81479
ARHGEF28 81479,81479
ATXN2 81179,81479
C9orf72 81479,81479
CFAP410 81479,81479
CHCHD10 81479,81479
CHMP2B 81479,81479
DAO 81479,81479
DCTN1 81479,81479
ERBB4 81479,81479
FIG4 81406,81479
FUS 81406,81479
GRN 81406,81479
HNRNPA1 81479,81479
HNRNPA2B1 81479,81479
ITM2B 81479,81479
KIF5A 81479,81479
MAPT 81406,81479
MATR3 81479,81479
MOBP 81479,81479
NEFH 81479,81479
NEK1 81479,81479
OPTN 81406,81479
PFN1 81479,81479
PSEN1 81405,81479
PSEN2 81406,81479
SETX 81406,81479
SOD1 81404,81479
SQSTM1 81479,81479
TAF15 81479,81479
TARDBP 81405,81479
TBK1 81479,81479
TREM2 81479,81479
TUBA4A 81479,81479
UBQLN2 81479,81479
UNC13A 81479,81479
VAPB 81479,81479
VCP 81479,81479
Test Code Test Copy Genes Panel CPT Code Gene CPT Codes Copy CPT Code Base Price
10359Genes x (40)81479 81179, 81403, 81404, 81405, 81406, 81479 $930 Order Options and Pricing

Pricing Comments

C9orf72 hexanucleotide repeat expansion will be performed first as this is the most common cause of ALS and FTD. If C9orf72 testing is negative then the sequencing panel and ATXN2 repeat expansion testing will be performed. Results for the C9orf72ATXN2, and sequencing panel test will be reported separately. Concurrent testing is available upon request. C9ORF72 and ATXN2 repeat expansions are available separately if needed.

We are happy to accommodate requests for testing single genes in this panel or a subset of these genes. The price will remain the list price. If desired, free reflex testing to remaining genes on panel is available. Alternatively, a single gene or subset of genes can also be ordered via our PGxome Custom Panel tool.

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

For Reflex to PGxome pricing click here.

Turnaround Time

C9orf72 assays completed within 12 days on average. Reflexive panels are completed within an additional 18 days on average.

Once a specimen has started the testing process in our lab, the most accurate prediction of TAT will be displayed in the myPrevent portal as an Estimated Report Date (ERD) range. We calculate the ERD for each specimen as testing progresses; therefore the ERD range may differ from our published average TAT. View 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

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 rapid 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 of age for familial cases and 65 years of age 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; Siddique and Siddique. 2019. PubMed ID: 20301623).

The most common ALS 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.

Frontotemporal dementia (FTD) is a clinically heterogeneous syndrome due to the progressive degeneration and atrophy of various regions of the frontal and temporal lobes of the brain. Symptoms are variable with average age of onset in the sixth decade of life; although earlier and later onsets have been documented (Neary et al. 1998. PubMed ID: 9855500; Snowden et al. 2002. PubMed ID: 11823324; Bruni et al. 2007. PubMed ID: 17620546). The annual incidence of FTD is 3-4 per 100,000 (Onyike and Diehl-Schmid. 2013. PubMed ID: 23611343).

Two major forms of FTD, the behavioral-variant (FTD-bv) and the primary progressive aphasia (PPA), are recognized based on the site of onset of degeneration and the associated symptoms. FTD-bv comprises about half of FTD cases with the degenerative process beginning in the frontal lobes and resulting in personality changes and deterioration of social conducts. Most common behavioral changes are: disinhibition, apathy, deterioration of executive function, obsessive thoughts, compulsive behavior, and neglect of personal hygiene (Rascovsky et al. 2011. PubMed ID: 21810890). PPA is a language disorder that is further divided into two sub-forms: progressive nonfluent PPA and semantic variant PPA. Nonfluent PPA is characterized by difficulty in verbal communications, word retrieval, and speech distortion. Reading, writing and spelling are also affected; while memory is relatively preserved. Semantic variant PPA is characterized by the progressive impairment of word comprehension, object and face recognition, and loss of semantic memory. Reading and writing skills are relatively preserved (Gustafson. 1993. PubMed ID: 8401782).

Genetics

About 10% of ALS cases and 30-50% of FTD cases are inherited. In most of these families, ALS and/or FTD is inherited in an autosomal dominant manner with age-dependent penetrance. In rare families, the disease is transmitted in an autosomal recessive or dominant X-linked pattern via the UBQLN2 gene. About 90% of patients with ALS are sporadic cases (SALS) with no known affected relatives. The C9orf72, SOD1, FUS, and TARDBP gene account for 35%, 15%, 3% and 4% of European familial ALS (FALS) cases. In Asian FALS patients, pathogenic variants in the C9orf72, SOD1, FUS, TARDBP genes account for 2%, 30%, 6% and 1.5% cases (Zou et al. 2017. PubMed ID: 28057713).  

An expansion of a GGGGCC hexanucleotide repeat in a non-coding region of the C9orf72 gene is the most common inherited cause of ALS and FTD (Renton et al. 2011. PubMed ID: 21944779; DeJesus-Hernandez et al. 2011. PubMed ID: 21944778). Alleles with less than 25 repeats are usually considered normal (Majounie et al. 2012. PubMed ID: 22406228; van der Zee et al. 2013. PubMed ID: 23111906). Alleles with more than 30 repeats are considered pathogenic (Renton et al. 2011. PubMed ID: 21944779). This expanded repeat accounts for up to 40% of FALS cases and 7% of SALS cases (Byrne et al. 2012. PubMed ID: 22305801). The GGGGCC hexanucleotide repeat expansion was reported in patients with ALS, ALS-FTD or FTD (Siddique and Siddique. 2019. PubMed ID: 20301623).

ATXN2 expansions of the exon 1 poly-glutamine track ranging from 29-32 CAG repeats have also been associated with an increased risk for development of ALS (Van Damme et al. 2011. PubMed ID: 21562247). While expansions >32 repeats are typically associated with Spinocerebellar Ataxia 2 (SCA2), patients with ALS and with >32 repeats have been reported (Sproviero et al. 2017. PubMed ID: 28017481; Ross et al. 2011. PubMed ID: 21610160). For example, ALS was reported in a family with one affected individual being homozygous for 33 repeats and a second affected individual being compound heterozygous for 31 and 33 repeats (Van Damme et al. 2011. PubMed ID: 21562247). Penetrance is incomplete for individuals with 29-32 repeats.

FTDs are inherited in 30-50% of cases in an autosomal dominant manner with pathogenic variants in C9orf72, MAPT and GRN accounting for about 30%, 15% and 25% of cases respectively. An expansion of a GGGGCC hexanucleotide repeat in an intron 1 non-coding region of the C9orf72 gene is the most common inherited cause of FTD. 

See individual gene summaries for more information about molecular biology of gene products and spectra of pathogenic variants.

Clinical Sensitivity - Sequencing with CNV PGxome

This NGS panel will detect pathogenic variants in at least 68% of patients with FALS and 11% of SALS. Pathogenic variants in the C9orf72 (40%), SOD1 (1-50%), FUS (1-5%), and TARDBP (1-5%) genes account for the majority of FALS cases. In SALS C9orf72 and SOD1 account for 7% and 1-2% of cases respectively (van Es et al. 2017. PubMed ID: 28552366; Robberecht and Philips. 2013. PubMed ID: 23463272). Pathogenic variants in the ANG, SQSTM1, PFN1, UBQLN2, OPTN, VCP, and VAPB genes account for less <1% of FALS cases. Clinical sensitivity for the C21orf2, CHCHD10, CHMP2B, DAO, DCTN1, ERBB4, FIG4, HNRNPA1, HNRNPA2B1, KIF5A, MATR3, MOBP, NEFH, NEK1, SCFD1, SETX, TAF15, TBK1, TUBA4A, and UNC13A genes is currently unknown due to the limited number of cases reported to date, but is expected to be low (Robberecht and Philips. 2013. PubMed ID: 23463272; Brown and Al-Chalabi. 2017. PubMed ID: 28700839).

In familial FTD, pathogenic variants are identified in up to 65% of cases with C9orf72, MAPT, and GRN accounting for about three-fourths of these cases (Goldman and Van Deerlin et al. 2018. PubMed ID: 29971646). The majority of genes in this panel have no or very few large deletions/duplications.

Testing Strategy

C9orf72 hexanucleotide repeat expansion will be performed first as this is the most common cause of ALS and FTD. If C9orf72 testing is negative then the sequencing panel and ATXN2 repeat expansion testing will be performed. Results for the C9orf72, ATXN2, and sequencing panel test will be reported separately. Concurrent testing is available upon request.

Both the C9orf72 and ATXN2 repeat expansion tests each utilize four unique gene specific assays: (1) a repeat primed PCR assay with the locus specific primer 5’ (upstream) of the repeat region (2) a repeat primed PCR assay with the locus specific primer 3’ (downstream) of the repeat region and two unique fluorescent fragment length assays. C9orf72 and ATXN2 are not included in the sequencing panel.

The sequencing panel typically provides 99.0% coverage of all coding exons of the genes listed plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing.

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).

Indications for Test

Patients with ALS 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), the ALS Cognitive Behavioral Scressn (ALS-CBS) and the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) (van Es et al. 2017. PubMed ID: 28552366).

The International Behavioral Variant FTD Criteria Consortium (FTDC) defines diagnosis for bvFTD as patients that present with three of the six clinical features: disinhibition, apathy, loss of sympathy, compulsive behaviors, hyperorality, and/or dysexecutive neuropsychologic profile.  Diagnosis for PPA includes language deficits as the primary cause of impaired living and aphasia being most prominent at symptom onset.

Diseases

Name Inheritance OMIM ID
Adult Proximal Spinal Muscular Atrophy, Autosomal Dominant AD 182980
Alzheimer Disease, Type 3 AD 607822
Alzheimer Disease, Type 4 AD 606889
Alzheimer's Disease AD 104300
Amyotrophic lateral sclerosis 19 AD 615515
Amyotrophic lateral sclerosis 22 with or without frontotemporal dementia AD 616208
Amyotrophic Lateral Sclerosis Type 10 AD 612069
Amyotrophic Lateral Sclerosis Type 11 AD 612577
Amyotrophic Lateral Sclerosis Type 12 613435
Amyotrophic Lateral Sclerosis Type 14 613954
Amyotrophic Lateral Sclerosis Type 15 XL 300857
Amyotrophic Lateral Sclerosis Type 17 AD 614696
Amyotrophic Lateral Sclerosis Type 18 614808
Amyotrophic Lateral Sclerosis Type 20 AD 615426
Amyotrophic Lateral Sclerosis Type 4 AD 602433
Amyotrophic Lateral Sclerosis Type 6 608030
Amyotrophic Lateral Sclerosis Type 8 AD 608627
Amyotrophic Lateral Sclerosis Type 9 611895
Amyotrophic lateral sclerosis, susceptibility to, 24 AD 617892
Amyotrophic Lateral Sclerosis, Susceptibility to, 25 AD 617921
Amytrophic Lateral Sclerosis 23 AD 617839
Ceroid Lipofuscinosis Neuronal 11 AR 614706
Charcot-Marie-Tooth disease, axonal, type 2CC AD 616924
Charcot-Marie-Tooth Disease, Type 2Y AD 616687
CHMP2B-Related Frontotemporal Dementia AD 600795
Dementia Familial British AD 176500
Dementia, Familial Danish AD 117300
Epithelial-Myoepithelial Carcinoma AD 612237
Frontotemporal Dementia AD 600274
Frontotemporal Dementia And/Or Amyotrophic Lateral Sclerosis AD 105550
Frontotemporal dementia and/or amyotrophic lateral sclerosis 2 AD 615911
Frontotemporal Dementia and/or Amyotrophic Lateral Sclerosis 3 AD 616437
Frontotemporal Dementia and/or Amyotrophic Lateral Sclerosis 4 AD 616439
Frontotemporal Dementia, Ubiquitin-Positive AD 607485
Inclusion Body Myopathy With Early-Onset Paget Disease And Frontotemporal Dementia AD 167320
Inclusion Body Myopathy with Early-Onset Paget Disease with or without Frontotemporal Dementia 2 615422
Inclusion Body Myopathy with Early-Onset Paget Disease without Frontotemporal Dementia 3 AD 615424
Myopathy, Distal, 2 AD 606070
Neuronopathy, Distal Hereditary Motor, Type VIIB AD 607641
Paget Disease of Bone 3 AD 167250
Parkinson-Dementia Syndrome AR 260540
Perry Syndrome AD 168605
Pick's Disease AD 172700
Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 2 AD 618193
Spastic Paraplegia 10 AD 604187
Spinocerebellar Ataxia 2 AD 183090
Spinocerebellar Ataxia Autosomal Recessive 1 AR 606002
Spondylometaphyseal dysplasia, axial AR 602271
Supranuclear Palsy, Progressive, 1 AD 601104

Related Tests

Name
PGxome®
C9orf72 Gene Hexanucleotide Repeat Expansion
Alzheimer Disease, Familial, Panel
Amyotrophic Lateral Sclerosis (ALS) Panel
Dementia Panel
Spinocerebellar Ataxia Type 2 via the ATXN2 CAG Repeat Expansion

Citations

  • Brown and Al-Chalabi. 2017. PubMed ID: 28700839
  • Bruni et al. 2007. PubMed ID: 17620546
  • Byrne et al. 2012. PubMed ID: 22305801
  • DeJesus-Hernandez et al. 2011. PubMed ID: 21944778
  • Goldman and Van Deerlin et al. 2018. PubMed ID: 29971646
  • Gustafson. 1993. PubMed ID: 8401782
  • Hardiman et al. 2017. PubMed ID: 28980624
  • Majounie et al. 2012. PubMed ID: 22406228
  • Neary et al. 1998. PubMed ID: 9855500
  • Onyike and Diehl-Schmid. 2013. PubMed ID: 23611343
  • Rascovsky et al. 2011. PubMed ID: 21810890
  • Renton et al. 2011. PubMed ID: 21944779
  • Robberecht and Philips. 2013. PubMed ID: 23463272
  • Ross et al. 2011. PubMed ID: 21610160
  • Siddique and Siddique. 2019. PubMed ID: 20301623
  • Snowden et al. 2002. PubMed ID: 11823324
  • Sproviero et al. 2017. PubMed ID: 28017481
  • Van Damme et al. 2011. PubMed ID: 21562247
  • van der Zee et al. 2013. PubMed ID: 23111906
  • 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.

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


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