Test Catalog

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.

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.


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 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

An interpretive report will be provided.

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.


We strongly recommend 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 polymorphisms in PCR primer binding regions may lead to false negative results.


This test does not assess 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, 72:257-268

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

Special Instructions Library of PDFs including pertinent information and forms related to the test