Test Id : C9ORF
C9orf72 Hexanucleotide Repeat, Molecular Analysis, Varies
Useful For
Suggests clinical disorders or settings where the test may be helpful
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
Testing Algorithm
Delineates situations when tests are added to the initial order. This includes reflex and additional tests.
For more information see Inherited Motor Neuron Disease and Dementia Testing Algorithm
Method Name
A short description of the method used to perform the test
Polymerase Chain Reaction (PCR)
NY State Available
Indicates the status of NY State approval and if the test is orderable for NY State clients.
Reporting Name
Lists a shorter or abbreviated version of the Published Name for a test
Aliases
Lists additional common names for a test, as an aid in searching
Hexanucleotide repeat expansion
ALS
FTD
C9OR
c9ALS/FTD
G4C2 Expansion
Frontotemporal dementia
Testing Algorithm
Delineates situations when tests are added to the initial order. This includes reflex and additional tests.
For more information see Inherited Motor Neuron Disease and Dementia Testing Algorithm
Specimen Type
Describes the specimen type validated for testing
Varies
Specimen Required
Defines the optimal specimen required to perform the test and the preferred volume to complete testing
Patient Preparation: A previous bone marrow transplant from an allogeneic donor will interfere with testing. For instructions for testing patients who have received a bone marrow transplant, call 800-533-1710.
Submit only 1 of the following specimens:
Specimen Type: Whole blood
Container/Tube: Lavender top (EDTA) or yellow top (ACD)
Specimen Volume: 3 mL
Collection Instructions:
1. Invert several times to mix blood.
2. Send whole blood specimen in original tube. Do not aliquot.
Specimen Stability Information: Ambient (preferred) 4 days/Refrigerated 4 days/Frozen 4 days
Additional Information:
1. Specimens are preferred to be received within 4 days of collection. Extraction will be attempted for specimens received after 4 days, and DNA yield will be evaluated to determine if testing may proceed.
2. To ensure minimum volume and concentration of DNA is met, the requested volume must be submitted. Testing may be canceled if DNA requirements are inadequate.
Specimen Type: Cord blood
Container/Tube: Lavender top (EDTA) or yellow top (ACD)
Specimen Volume: 3 mL
Collection Instructions:
1. Invert several times to mix blood.
2. Send cord blood specimen in original tube. Do not aliquot.
Specimen Stability Information: Ambient (preferred) 4 days/Refrigerated 4 days/Frozen 4 days
Additional Information:
1. Specimens are preferred to be received within 4 days of collection. Extraction will be attempted for specimens received after 4 days, and DNA yield will be evaluated to determine if testing may proceed.
2. To ensure minimum volume and concentration of DNA is met, the requested volume must be submitted. Testing may be canceled if DNA requirements are inadequate.
3. While a properly collected cord blood sample may not be at risk for maternal cell contamination, unanticipated complications may occur during collection. Therefore, maternal cell contamination studies are recommended to ensure the test results reflect that of the patient tested and are available at an additional charge. Order MATCC / Maternal Cell Contamination, Molecular Analysis, Varies on the maternal specimen.
Specimen Type: Extracted DNA
Container/Tube:
Preferred: Screw Cap Micro Tube, 2 mL with skirted conical base
Acceptable: Matrix tube, 1 mL
Collection Instructions:
1. The preferred volume is at least 100 mcL at a concentration of 75 ng/mcL.
2. Include concentration and volume on tube.
Specimen Stability Information: Frozen (preferred) 1 year/Ambient/Refrigerated
Additional Information: DNA must be extracted in a CLIA-certified laboratory or equivalent and must be extracted from a specimen type listed as acceptable for this test (including applicable anticoagulants). Our laboratory has experience with Chemagic, Puregene, Autopure, MagnaPure, and EZ1 extraction platforms and cannot guarantee that all extraction methods are compatible with this test. If testing fails, one repeat will be attempted, and if unsuccessful, the test will be reported as failed and a charge will be applied. If applicable, specific gene regions that were unable to be interrogated due to DNA quality will be noted in the report.
Special Instructions
Library of PDFs including pertinent information and forms related to the test
Forms
1. New York Clients-Informed consent is required. Document on the request form or electronic order that a copy is on file. The following documents are available:
-Informed Consent for Genetic Testing (T576)
-Informed Consent for Genetic Testing (Spanish) (T826)
2. Molecular Genetics: Neurology Patient Information
3. If not ordering electronically, complete, print, and send a Neurology Specialty Testing Client Test Request (T732) with the specimen.
Specimen Minimum Volume
Defines the amount of sample necessary to provide a clinically relevant result as determined by the testing laboratory. The minimum volume is sufficient for one attempt at testing.
See Specimen Required
Reject Due To
Identifies specimen types and conditions that may cause the specimen to be rejected
Specimen Stability Information
Provides a description of the temperatures required to transport a specimen to the performing laboratory, alternate acceptable temperatures are also included
| Specimen Type | Temperature | Time | Special Container |
|---|---|---|---|
| Varies | Varies | ||
Useful For
Suggests clinical disorders or settings where the test may be helpful
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
Testing Algorithm
Delineates situations when tests are added to the initial order. This includes reflex and additional tests.
For more information see Inherited Motor Neuron Disease and Dementia Testing Algorithm
Clinical Information
Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
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.
Amyotrophic lateral sclerosis 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 or FTD phenotypes have been reported with repeat sizes in this range.
Reference Values
Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
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
Provides information to assist in interpretation of the test results
The interpretive report includes an overview of the findings as well as the associated clinical significance.
Cautions
Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
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 the 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 the methylation status of the C9orf72 gene.
Clinical Reference
Recommendations for in-depth reading of a clinical nature
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(2):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;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;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;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;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;130(4):599-601
10. Ng ASL, Tan EK. Intermediate C9orf72 alleles in neurological disorders: does size really matter? J Med Genet. 2017;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. Amyotroph Lateral Scler Frontotemporal Degener. 2017;18(3-4):256-264
12. Van Mossevelde S, van der Zee J, Cruts M, Van Broeckhoven. Relationship between C9orf72 repeat size and clinical phenotype. Curr Opin Genet Dev. 2017;44:117-124
13. Breevoort S, Gibson S, Figueroa K, Bromberg M, Pulst S. Expanding clinical spectrum of C9ORF72-related disorders and promising therapeutic strategies. A review. Neurol Genet. 2022;8(3):e670. 24;8(5):e200028
Method Description
Describes how the test is performed and provides a method-specific reference
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)
PDF Report
Indicates whether the report includes an additional document with charts, images or other enriched information
Day(s) Performed
Outlines the days the test is performed. This field reflects the day that the sample must be in the testing laboratory to begin the testing process and includes any specimen preparation and processing time before the test is performed. Some tests are listed as continuously performed, which means that assays are performed multiple times during the day.
Varies
Report Available
The interval of time (receipt of sample at Mayo Clinic Laboratories to results available) taking into account standard setup days and weekends. The first day is the time that it typically takes for a result to be available. The last day is the time it might take, accounting for any necessary repeated testing.
Specimen Retention Time
Outlines the length of time after testing that a specimen is kept in the laboratory before it is discarded
Performing Laboratory Location
Indicates the location of the laboratory that performs the test
Fees :
Several factors determine the fee charged to perform a test. Contact your U.S. or International Regional Manager for information about establishing a fee schedule or to learn more about resources to optimize test selection.
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Test Classification
Provides information regarding the medical device classification for laboratory test kits and reagents. Tests may be classified as cleared or approved by the US Food and Drug Administration (FDA) and used per manufacturer instructions, or as products that do not undergo full FDA review and approval, and are then labeled as an Analyte Specific Reagent (ASR) product.
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
Provides guidance in determining the appropriate Current Procedural Terminology (CPT) code(s) information for each test or profile. The listed CPT codes reflect Mayo Clinic Laboratories interpretation of CPT coding requirements. It is the responsibility of each laboratory to determine correct CPT codes to use for billing.
CPT codes are provided by the performing laboratory.
CPT codes are provided by the performing laboratory.
81479
LOINC® Information
Provides guidance in determining the Logical Observation Identifiers Names and Codes (LOINC) values for the order and results codes of this test. LOINC values are provided by the performing laboratory.
| Test Id | Test Order Name | Order LOINC Value |
|---|---|---|
| C9ORF | C9orf72, Molecular Analysis | 81846-8 |
| Result Id | Test Result Name |
Result LOINC Value
Applies only to results expressed in units of measure originally reported by the performing laboratory. These values do not apply to results that are converted to other units of measure.
|
|---|---|---|
| 52852 | Result Summary | 50397-9 |
| 52853 | Result | 77635-1 |
| 52854 | Interpretation | 69047-9 |
| 52855 | Reason for Referral | 42349-1 |
| 52856 | Specimen | 31208-2 |
| 52857 | Source | 31208-2 |
| 52858 | Released By | 18771-6 |
| 55158 | Method | 85069-3 |