Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Panel

Summary and Pricing

Test Method

Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
Test Code Test Copy GenesGene CPT Codes Copy CPT Codes
1965 ANG81403,81479 Add to Order
ANXA1181479,81479
ARHGEF2881479,81479
C9orf7281479,81479
CDH1381479,81479
CHMP2B81479,81479
FUS81406,81479
GRN81406,81479
HNRNPA181479,81479
HNRNPA2B181479,81479
KIF5A81479,81479
MAPT81406,81479
OPTN81406,81479
PFN181479,81479
PSEN181405,81479
PSEN281406,81479
SETX81406,81479
SOD181404,81479
SQSTM181479,81479
TARDBP81405,81479
TBK181479,81479
TREM281479,81479
UBQLN281479,81479
VAPB81479,81479
VCP81479,81479
Test Code Test Copy Genes Total Price Panel CPT Code Gene CPT Codes Copy CPT Code STAT
1965 Genes x (25) $890 81479 81403, 81404, 81405, 81406, 81479 Add to Order

Pricing Comments

$250 for C9orf72 repeat expansion only (see test # 151).

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.

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

A 25% additional charge will be applied to STAT orders. View STAT turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

Turnaround Time

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

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics of ALS & FTD

Clinical Features

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by a selective loss of motor neurons in the motor cortex, brain stem, and spinal cord (Tandan and Bradley. 1985. PubMed ID: 4051456). 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 and Rothstein. 2001. PubMed ID: 11715057).

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), previously referred to as Pick’s disease, 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 insidious and begin usually during the fourth and sixth decades 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, 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.

In FTD-bv, the degenerative process begins in the frontal lobes and results 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).

In PPA, the degenerative process begins in the temporal lobes. PPA is a language disorder that is further divided into two sub-forms: progressive non-fluent aphasia (PNFA) and semantic dementia (SD). PNFA is characterized by difficulty in verbal communications, word retrieval, and speech distortion. Reading, writing and spelling are also affected; while memory is relatively preserved. SD 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).

Cognitive impairment was not 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 et al. 1982. PubMed ID: 7125994; Lipton et al. 2004. PubMed ID: 15351890; Mitsuyama and Inoue. 2009. PubMed ID: 19780984).

A more recent prospective study showed that FTD occurred in up to 14% of patients with ALS. Furthermore, cognitive impairment was detected in more than 40% of ALS patients (Phukan et al. 2012. PubMed ID: 21836033).

Definite ALS has been reported in patients with a clinical diagnosis of FTD (Lomen-Hoerth et al. 2003. PubMed ID: 12682312).

In addition to pure ALS and pure FTD, a combination of ALS and FTD clinical features have been reported in both sporadic and familial cases (Morita et al. 2006. PubMed ID: 16421333; Ferrari et al. 2011. PubMed ID: 21222600).

Genetics

About 10% of ALS cases are familial (Emery and Holloway. 1982. PubMed ID: 7180680). 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 2015. PubMed ID: 20301623).

Autosomal Dominant ALS (AD-ALS) is a clinically and genetically heterogeneous disorder that affects all ethnic groups. The following genes have been implicated in the disease: ANG, ARHGEF28, ANXA11, C9orf72, CDH3, CDH13, CHMP2B, FUS, GRN, HNRNPA1, HNRNP2B1, KIF5A, OPTN, PFN1, SOD1, SETX, SQSTM1, VAPB, VCP, PSEN1, TARDBP, TBK1, and UBQLN2.

FTD is inherited in about 40% of cases (Rosso et al. 2003. PubMed ID: 12876142). In these families, the disease is inherited in an autosomal dominant manner. The remaining cases appear to be simplex with no known affected relatives. Similar to ALS, it is unclear how many of the apparently sporadic cases of FTD are inherited with low penetrance (Cruts et al. 2006. PubMed ID: 16862115; Le Ber et al. 2007. PubMed ID: 17436289). FTD is genetically heterogeneous. Several genes have been implicated in the disorder: C9orf72, CHMP2B, FUS, GRN, SQSTM1, MAPT, PSEN1, PSEN2, TARDBP, TREM2 and UBQLN2.

The C9ORF72, GRN, and SQSTM1 genes have been implicated in patients with a combination of ALS and FTD (ALS-FTD).

Overall, the vast majority of pathogenic variants are missense. Few truncating variants were reported in SOD1, FUS, OPTN, CHMP2B, SQSTM1, ARHGEF28, GRN, PSEN1, PSEN2 and TREM2. Large pathogenic deletions appear to be rare. They were reported only in four genes: OPTN, GRN, MAPT and PSEN1 (Iida et al. 2012. PubMed ID: 22402017; Maruyama et al. 2010. PubMed ID: 20428114; Pickering-Brown et al. 2006. PubMed ID: 17071927; Rohrer et al. 2013. PubMed ID: 23904625; Rovelet-Lecrux et al. 2009. PubMed ID: 19263483; Evin et al. 2002. PubMed ID: 11997713).

With few exceptions, pathogenic variants in the genes included in this panel are inherited with an autosomal dominant manner or occurr de novo. The exceptions are:

One single variant, p.Asp90Ala, in SOD1 was reported at the homozygous state in patients with ALS (Andersen et al. 1995. PubMed ID: 7647793).

Recessive variants in OPTN were reported in Japanese cases (Maruyama et al. 2010. PubMed ID: 20428114; Iida et al. 2012. PubMed ID: 22402017).

UBQLN2-Related ALS and FTD are inherited in an X-linked dominant manner with reduced penetrance in females. The age of onset appears to be earlier in males with no difference in the duration of the disease (Deng et al. 2011. PubMed ID: 21857683).

See individual gene test descriptions for information on molecular biology of gene products.

Testing Strategy

Because a pathogenic expansion of the GGGGCC hexanucleotide repeat in a non-coding region of C9orf72 has been reported as the most common genetic cause of ALS, FTD, and ALS-FTD (Renton et al. 2011. PubMed ID: 21944779; DeJesus-Hernandez et al. 2011. PubMed ID: 21944778; Byrne et al. 2012. PubMed ID: 22305801), we will first screen the patients’ DNA for the presence or absence of this expansion. When we find a pathogenic expansion, we stop testing. When there is no evidence for the pathogenic expansion, we sequence all coding exons of the genes listed using Next Generation Sequencing (NGS).

The repeat-primed PCR test is used as a screening method for the presence or absence of a pathogenic GGGGCC hexanucleotide repeat expansion located in the first intron of C9orf72. Of note, this test is not designed to determine the number of GGGGCC repeats in alleles carrying the pathogenic expansion (Warner et al. 1996. PubMed ID: 9004136; Renton et al. 2011. PubMed ID: 21944779).

This panel provides 100% coverage of all coding exons of the genes listed, plus ~10 bases of flanking noncoding DNA. We define coverage as ≥20X NGS reads or Sanger sequencing.

Clinical Sensitivity - Sequencing and CNV

This NGS panel will detect pathogenic variants in at least 68% of patients with familial ALS and 11% of apparently sporadic cases of ALS (Renton et al. 2014. PubMed ID: 24369373). This panel will also detect pathogenic variants in up to 65% of patients with familial FTD. The following Table indicates sensitivity by gene and by phenotype.

Sensitivity corresponds to the percentage of all genotyped patients with a clinical diagnosis and a positive family history of either ALS or FTD. For genes with rare pathogenic variants, the numbers of reported simplex cases are listed.

Gene ALS Reference FTD Reference
C9ORF72 40% Robberecht and Philips. 2013. PubMed ID: 23463272 25% Majounie et al. 2012. PubMed ID: 22406228
SOD1 20% Robberecht and Philips. 2013. PubMed ID: 23463272 NA NA
TARDBP 1-5% Robberecht and Philips. 2013. PubMed ID: 23463272 One case Borroni et al. 2010. PubMed: 20645878
FUS 1-5% Robberecht and Philips. 2013. PubMed ID: 23463272 One case Van Langenhove et al. 2010. PubMed ID: 20124201
TBK1 3.60% van der Zee et al. 2017. PubMed ID: 28008748 1.70% Gijselinck et al. 2015. PubMed ID: 26581300
SETX 2% Couthouis et al. 2014. PubMed ID: 25299611 NA NA
ANXA11 1% Smith et al. 2017. PubMed ID: 28469040 NA NA
ANG <1% Robberecht and Philips. 2013. PubMed ID: 23463272 NA NA
OPTN <1% Robberecht and Philips. 2013. PubMed ID: 23463272 NA NA
CHMP2B 4 cases Ferrari et al. 2012. PubMed ID: 22459598 5 cases HGMD
VCP <1% Robberecht and Philips. 2013. PubMed ID: 23463272 NA NA
VAPB <1% Robberecht and Philips. 2013. PubMed ID: 23463272 NA NA
UBQLN2 1.20% Synofzik et al. 2012. PubMed ID: 22892309 2.2 Synofzik et al. 2012. PubMed ID: 22892309
PFN1 1-2% Wu et al. 2012. PubMed ID: 22801503 NA NA
SQSTM1 3% Rubino et al. 2012. PubMed ID: 22972638 3% Rubino et al. 2012. PubMed ID: 22972638
ARHGEF28 3 cases

Droppelmann et al. 2013. PubMed ID: 23286752

Ma et al. 2014. PubMed ID: 24712971

NA NA
CDH13 3 cases

Couthouis et al. 2014. PubMed ID: 25299611

Daoud et al. 2011. PubMed ID: 21220648

NA NA
GRN One case Sleegers et al. 2008. PubMed ID: 18184915 >20% Baker et al. 2006. PubMed ID: 16862116
HNRNPA1 2 Families Kim et al. 2013. PubMed ID: 23455423 NA NA
HNRNPA2B1 One case Couthouis et al. 2014. PubMed ID: 25299611 NA NA
MAPT NA NA Up to 20% Rademakers et al. 2012. PubMed ID: 22732773
PSEN1 2 cases Rademakers et al. 2012. PubMed ID: 22732773 10 cases HGMD
PSEN2 NA NA One case Ferrari et al. 2012. PubMed ID: 22459598
TREM2 NA NA 2 cases HGMD
KIF5A 0.5% Brenner et al. 2018. PubMed ID: 29342275 NA NA

Indications for Test

Patients with symptoms suggestive of ALS, FTD and ALS-FTD.

Genes

Official Gene Symbol OMIM ID
ANG 105850
ANXA11 602572
ARHGEF28 612790
C9orf72 614260
CDH13 601364
CHMP2B 609512
FUS 137070
GRN 138945
HNRNPA1 164017
HNRNPA2B1 600124
KIF5A 602821
MAPT 157140
OPTN 602432
PFN1 176610
PSEN1 104311
PSEN2 600759
SETX 608465
SOD1 147450
SQSTM1 601530
TARDBP 605078
TBK1 604834
TREM2 605086
UBQLN2 300264
VAPB 605704
VCP 601023
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Test

Name
PGxome®

Citations

  • Andersen et al. 1995. PubMed ID: 7647793
  • Baker et al. 2006. PubMed ID: 16862116
  • Borroni et al. 2010. PubMed ID: 20645878
  • Brenner et al. 2018. PubMed ID: 29342275
  • Bruni et al. 2007. PubMed ID: 17620546
  • Byrne et al. 2012. PubMed ID: 22305801
  • Cleveland and Rothstein. 2001. PubMed ID: 11715057
  • Couthouis et al. 2014. PubMed ID: 25299611
  • Cruts et al. 2006. PubMed ID: 16862115
  • Daoud et al. 2011. PubMed ID: 21220648
  • DeJesus-Hernandez et al. 2011. PubMed ID: 21944778
  • Deng et al. 2011. PubMed ID: 21857683
  • Droppelmann et al. 2013. PubMed ID: 23286752
  • Emery and Holloway. 1982. PubMed ID: 7180680
  • Evin et al. 2002. PubMed ID: 11997713
  • Ferrari et al. 2011. PubMed ID: 21222600
  • Ferrari et al. 2012. PubMed ID: 22459598
  • Gijselinck et al. 2015. PubMed ID: 26581300
  • Gustafson. 1993. PubMed ID: 8401782
  • Human Gene Mutation Database (Bio-base).
  • Iida et al. 2012. PubMed ID: 22402017
  • Kim et al. 2013. PubMed ID: 23455423
  • Kinsley and Siddique. 2015. PubMed ID: 20301623
  • Le Ber et al. 2007. PubMed ID: 17436289
  • Lipton et al. 2004. PubMed ID: 15351890
  • Lomen-Hoerth et al. 2003. PubMed ID: 12682312
  • Ma et al. 2014. PubMed ID: 24712971
  • Majounie et al. 2012. PubMed ID: 22406228
  • Maruyama et al. 2010. PubMed ID: 20428114
  • Mitsuyama and Inoue. 2009. PubMed ID: 19780984
  • Morita et al. 2006. PubMed ID: 16421333
  • Neary et al. 1998. PubMed ID: 9855500
  • Onyike and Diehl-Schmid. 2013. PubMed ID: 23611343
  • Phukan et al. 2012. PubMed ID: 21836033
  • Pickering-Brown et al. 2006. PubMed ID: 17071927
  • Rademakers et al. 2012. PubMed ID: 22732773
  • Rascovsky et al. 2011. PubMed ID: 21810890
  • Renton et al. 2011. PubMed ID: 21944779
  • Renton et al. 2014. PubMed ID: 24369373
  • Robberecht and Philips. 2013. PubMed ID: 23463272
  • Rohrer et al. 2013. PubMed ID: 23904625
  • Rosso et al. 2003. PubMed ID: 12876142
  • Rovelet-Lecrux et al. 2009. PubMed ID: 19263483
  • Rubino et al. 2012. PubMed ID: 22972638
  • Sleegers et al. 2008. PubMed ID: 18184915
  • Smith et al. 2017. PubMed ID: 28469040
  • Snowden et al. 2002. PubMed ID: 11823324
  • Synofzik et al. 2012. PubMed ID: 22892309
  • Tandan and Bradley. 1985. PubMed ID: 4051456
  • van der Zee. 2017. PubMed ID: 28008748
  • Van Langenhove et al. 2010. PubMed ID: 20124201
  • Warner et al. 1996. PubMed ID: 9004136
  • Wikström et al. 1982. PubMed ID: 7125994
  • Wu et al. 2012. PubMed ID: 22801503

Ordering/Specimens

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.

For Requisition Forms, visit our Forms page


Specimen Types

Specimen Requirements and Shipping Details

loading Loading... ×

Copy Text to Clipboard
×