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Test ID: C9ORF C9orf72 Hexanucleotide Repeat, Molecular Analysis

Useful For

Molecular confirmation of clinically suspected cases of c9FTD/ALS, frontotemporal dementia (FTD), or amyotrophic lateral sclerosis (ALS)

 

Presymptomatic testing for individuals with a family history of c9FTD/ALS and a documented expansion in the C9orf72 gene

Method Name

Polymerase Chain Reaction (PCR)

Reporting Name

C9orf72, Molecular Analysis

Specimen Type

Varies


Shipping Instructions


Specimen preferred to arrive within 96 hours of collection.



Specimen Required


Patient Preparation: A previous bone marrow transplant from an allogenic donor will interfere with testing. Call Mayo Medical Laboratories for instructions for testing patients who have received a bone marrow transplant.

Specimen Type: Whole blood

Container/Tube:

Preferred: Lavender top (EDTA) or yellow top (ACD)

Acceptable: Any anticoagulant

Specimen Volume: 3 mL

Collection Instructions:

1. Invert several times to mix blood.

2. Send specimen in original tube.


Specimen Minimum Volume

1 mL

Specimen Stability Information

Specimen Type Temperature Time
Varies Ambient (preferred)
  Frozen 
  Refrigerated 

Clinical Information

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting the upper and lower motor neurons. The disease is characterized by progressive spasticity, muscle wasting and paralysis, typically leading to death from respiratory failure.

 

Frontotemporal dementia (FTD) is a dementia syndrome that predominantly involves the frontal and temporal lobes of the brain. Clinical presentation is variable and includes progressive changes in behavior and personality and language disturbances. Affected individuals may also exhibit extrapyramidal signs.

 

ALS and FTD are now thought to represent an overlapping spectrum of disease. Recent literature has found that approximately 40% of familial ALS, 25% of familial FTD, and 90% of familial ALS/FTD cases have a large hexanucleotide repeat (GGGGCC) expansion in a noncoding region of C9orf72. At lower frequency, C9orf72 hexanucleotide repeat expansions have also been observed in individuals with sporadic ALS, FTD, and ALS/FTD. The vast majority of individuals affected with a C9orf72-related disorder (c9ALS, c9FTD, or c9ALS/FTD) have hexanucleotide repeat expansions in the hundreds to thousands, while unaffected individuals have repeat sizes less than 20. The significance of repeat sizes between 20 and 100 repeats is currently unclear as both healthy controls and individuals with ALS and/or FTD phenotypes have been reported with repeat sizes in this range.

Reference Values

Normal alleles (reference):<20 GGGGCC repeats

Indeterminate alleles: 20-100 GGGGCC repeats

Pathogenic alleles: >100* GGGGCC repeats

 

*The exact cutoff for pathogenicity is currently undefined. Although additional studies are needed to confirm if 100 repeats is the cutoff for pathogenicity, most individuals affected with a C9orf72-related disorder have C9orf72 hexanucleotide repeat expansions with hundreds to thousands of repeats.

 

An interpretive report will be provided.

Interpretation

An interpretive report will be provided.

Clinical Reference

1. DeJesus-Hernandez M, Mackenzie IR, Boeve BF, et al: Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 2011;72(2):245-256

2. Renton AE, Majounie E, Waite A, et al: A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 2011, 72:257-268

3. Gijselinck I, Van Langenhove T, van der Zee J, et al: A C9orf72 promoter repeat expansion in a Flanders-Belgian cohort with disorders of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum: a gene identification study. Lancet Neuron 2012;11(1):54-65

4. Majounie E, Renton AE, Mok K, et al: Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study. Lancet Neurol 2012 Apr;11(4):323-330

5. Boeve BF, Boylan KB, Graff-Radford NR, et al: Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72. Brain 2012;135(Pt 3):765-783

6. van Blitterswijk M, DeJesus-Hernandez M, Niemantsverdriet E, et al: Association between repeat sizes and clinical and pathological characteristics in carriers of C9ORF72 repeat expansions (Xpansize-72): a cross-sectional cohort study. Lancet Neurol 2013 Oct;12(10):978-988

7. Nordin A, Akimoto C, Wuolikainen A, et al: Extensive size variability of the GGGGCC expansion in C9orf72 in both neuronal and non-neuronal tissues in 18 patients with ALS or FTD. Hum Mol Genet 2015 Jun 1;24(11):3133-3142

8. Xi Z, van Blitterswijk M, Zhang M, et al: Jump from pre-mutation to pathologic expansion in C9orf72. Am J Hum Genet 2015 Jun 4;96(6):962-970

9. Gami P, Murray C, Schottlaender L, et al: A 30-unit hexanucleotide repeat expansion in C9orf72 induces

pathological lesions with dipeptide-repeat proteins and RNA foci, but not TDP-43 inclusions and clinical disease. Acta Neuropathol 2015 Oct;130(4):599-601

10. Ng ASL, Tan EK: Intermediate C9orf72 alleles in neurological disorders: does size really matter? J Med Genet 2017 Sep;54(9):591-597

11. Nordin A, Akimoto C, Wuolikainen A, et al: Sequence variations in C9orf72 downstream of the hexanucleotide repeat region and its effect on repeat-primed PCR interpretation: a large multinational screening study. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. Amyotroph Lateral Scler Frontotemporal Degener 2017 May;18(3-4):256-264

12. Van Mossevelde S, van der Zee J, Cruts M, et al: Relationship between C9orf72 repeat size and clinical phenotype. Curr Opin Genet Dev 2017;44:117-124

Day(s) and Time(s) Performed

Tuesday; 10 a.m.

Analytic Time

5 days

Test Classification

This test was developed and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. This test has not been cleared or approved by the U.S. Food and Drug Administration.

CPT Code Information

81479

 

LOINC Code Information

Test ID Test Order Name Order LOINC Value
C9ORF C9orf72, Molecular Analysis In Process

 

Result ID Test Result Name Result LOINC Value
52852 Result Summary 50397-9
52853 Result 77635-1
52854 Interpretation 69047-9
52855 Reason for Referral 42349-1
52856 Specimen 31208-2
55158 Method 49549-9
52857 Source 31208-2
52858 Released By No LOINC Needed

Forms

1. New York Clients-Informed consent is required. Please document on the request form or electronic order that a copy is on file. An Informed Consent for Genetic Testing (T576) is available in Special Instructions.

2. Molecular Genetics: Neurology Patient Information in Special Instructions

3. If not ordering electronically, complete, print, and send a Neurology Specialty Testing Client Test Request (T732) with the specimen (http://www.mayomedicallaboratories.com/it-mmfiles/neurology-request-form.pdf

Mayo Medical Laboratories | Genetics and Pharmacogenomics Catalog Additional Information:

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