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Test Code C9ORF C9orf72 Hexanucleotide Repeat, Molecular Analysis, Varies

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 800-533-1710 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 Special Container
Varies Ambient (preferred)
  Frozen 
  Refrigerated 

Reject Due To

All specimens will be evaluated at Mayo Clinic Laboratories for test suitability.

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.

Cautions

For predictive testing, it is important to first document the presence of the hexanucleotide repeat expansion in the C9orf72 gene in an affected family member to confirm that the repeat expansion is the underlying mechanism of disease in the family.

 

It is strongly recommended that patients undergoing predictive testing receive genetic counseling both prior to testing and after results are available.

 

Predictive testing of an asymptomatic child is not recommended.

 

Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Errors in our interpretation of results may occur if information given is inaccurate or incomplete.

 

Due to somatic mosaicism, repeat size identified in the peripheral blood specimen may not reflect the repeat size in untested tissues (eg, central nervous system). In addition, a negative result does not rule out the presence of a mutation in the mosaic state that may be present but below the limit of detection of this assay (approximately 5%).

 

Rare sequence variants immediately downstream of the C9orf72 repeat region may interfere with genotype results but are not expected to affect repeat-primed peaks.

 

Rare undocumented variants (ie, polymorphisms) in the polymerase chain reaction primer binding regions may lead to false negative results.

 

This test does not assess methylation status of the C9orf72 gene.

Method Description

A combined amplicon-length and repeat-primed polymerase chain reaction-based assay is utilized to size alleles up to approximately 145 repeats and detect expansions of GGGGCC hexanucleotide repeat region in the C9orf72 gene.(Ida CM, Lundquist PA, Bram E, et al: Evaluation of Single-tube Combined Amplicon-length and Repeat-primed Long-read PCR Assay for Clinical Detection and Characterization of C9orf72 Hexanucleotide Repeat Expansion. Abstract 731. 2017 ACMG Annual Clinical Genetics Meeting. Phoenix, AZ, March 23, 2017.)

Day(s) Performed

Tuesday

Report Available

21 to 28 days

Performing Laboratory

Mayo Clinic Laboratories in Rochester

Test Classification

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

CPT Code Information

81479

 

LOINC Code Information

Test ID Test Order Name Order LOINC Value
C9ORF C9orf72, Molecular Analysis 81846-8

 

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 85069-3
52857 Source 31208-2
52858 Released By 18771-6

Testing Algorithm

For more information see Inherited Motor Neuron Disease and Dementia Testing Algorithm