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Amyotrophic Lateral Sclerosis and Frontotemporal Dementia via the CHMP2B 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
3487 CHMP2B 81479 81479,81479 $990 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
3487CHMP2B81479 81479,81479 $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 stem, and spinal cord (Tandan et al. 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 and Rothstein 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.

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; Snowden et al. 2002; Bruni et al. 2007). The annual incidence of FTD is 3-4 per 100,000 (Onyike and Diehl-Schmid 2013).

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).

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 et al. 1993).

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; Lipton et al. 2004; Mitsuyama and Inoue, 2009).

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 patients (Phukan et al. 2012).

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

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; Ferrari et al. 2011).

Genetics

About 10% of ALS cases are familial (Emery and Holloway 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 2015)

Autosomal Dominant ALS (AD-ALS) is a clinically and genetically heterogeneous disorder that affects all ethnic groups. Several genes have been implicated in the disease including CHMP2B (Parkinson et al. 2006).

To date, 8 different heterozygous pathogenic variants distributed along the entire coding region of the CHMP2B gene have been identified in patients with ALS. They are all of the missense type (Cox et al. 2010; van Blitterswijk et al. 2012).

FTD is inherited in about 40% of cases (Rosso et al. 2003). 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; Le Ber et al. 2007). To date, 4 different heterozygous pathogenic variants in the CHMP2B gene have been identified in patients with FTD. Two of these are truncating and the other two are missense variants (Skibinski al. 2005; van der Zee et al. 2008).

No pathogenic large copy number variations have been reported in the CHMP2B gene.

CHMP2B encodes a component of an endosomal sorting complex that is involved in degradation of surface receptor proteins and formation of endocytic multivesicular bodies (Tsang et al. 2006). Results obtained from functional studies suggest that accumulation of mutant CHMP2B proteins on endosomes prevent their interactions with lysosomes (Urwin et al. 2010).

In addition to CHMP2B, several other genes have been implicated in ALS, ALF/FTD and FTD (Robberecht and Philips 2013; Kinsley and Siddique 2015).

Clinical Sensitivity - Sequencing with CNV PG-Select

Pathogenic variants in the CHMP2B gene account for ~ 1.3% of patients affected with FTD (van der Zee et al. 2008) and ~ 1% of patients affected with ALS (Cox et al. 2010).

Testing Strategy

This test provides full coverage of all coding exons of the CHMP2B 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 ALS, FTD or ALS-FTD.

Gene

Official Gene Symbol OMIM ID
CHMP2B 609512
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Citations

  • Bruni A.C. et al. 2007. Neurology. 69: 140-7. PubMed ID: 17620546
  • Cleveland D.W., Rothstein J.D. 2001. Nature Reviews. Neuroscience. 2: 806-19. PubMed ID: 11715057
  • Cox L.E. et al. 2010. Plos One. 5: e9872. PubMed ID: 20352044
  • Cruts M. et al. 2006. Nature. 442: 920-4. PubMed ID: 16862115
  • Emery A.E., Holloway S. 1982. Advances in Neurology. 36: 139-47. PubMed ID: 7180680
  • Ferrari R. et al. 2011. Current Alzheimer Research. 8: 273-94. PubMed ID: 21222600
  • Gustafson L. 1993. Dementia. 4: 143-8. PubMed ID: 8401782
  • 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
  • Le Ber I. et al. 2007. Human Mutation. 28: 846-55. PubMed ID: 17436289
  • Lipton A.M. et al. 2004. Acta Neuropathologica. 108: 379-85. PubMed ID: 15351890
  • Lomen-Hoerth C. et al. 2003. Neurology. 60: 1094-7. PubMed ID: 12682312
  • Mitsuyama Y., Inoue T. 2009. Neuropathology. 29: 649-54. PubMed ID: 19780984
  • Morita M. et al. 2006. Neurology. 66: 839-44. PubMed ID: 16421333
  • Neary D. et al. 1998. Neurology. 51: 1546-54. PubMed ID: 9855500
  • Onyike C.U., Diehl-Schmid J. 2013. International Review of Psychiatry. 25: 130-7. PubMed ID: 23611343
  • Parkinson N. et al. 2006. Neurology. 67: 1074-7 PubMed ID: 16807408
  • Phukan J. et al. 2012. Journal of Neurology, Neurosurgery, and Psychiatry. 83: 102-8. PubMed ID: 21836033
  • Rascovsky K. et al. 2011. Brain. 134: 2456-77. PubMed ID: 21810890
  • Robberecht W., Philips T. 2013. Nature Reviews. Neuroscience. 14: 248-64. PubMed ID: 23463272
  • Rosso S.M. et al. 2003. Brain. 126: 2016-22. PubMed ID: 12876142
  • Skibinski G. et al. 2005. Nature Genetics. 37: 806-8. PubMed ID: 16041373
  • Snowden J.S. et al. 2002. The British Journal of Psychiatry. 180: 140-3. PubMed ID: 11823324
  • Tandan R., Bradley W.G. 1985. Annals of Neurology. 18: 271-80. PubMed ID: 4051456
  • Tsang H.T. et al. 2006. Genomics. 88: 333-46. PubMed ID: 16730941
  • Urwin H. et al. 2010. Human Molecular Genetics. 19: 2228-38. PubMed ID: 20223751
  • van Blitterswijk M. et al. 2012. Plos One. 7: e48983. PubMed ID: 23155438
  • van der Zee J. et al. 2008. Human Molecular Genetics. 17: 313-22. PubMed ID: 17956895
  • Wikström J. et al. 1982. Archives of Neurology. 39: 681-3. PubMed ID: 7125994

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