A C9orf72 genetic test looks for an abnormal expansion of the six-letter DNA sequence GGGGCC in the C9orf72 gene. This expansion is an important inherited cause of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and the combined ALS-FTD syndrome. The test can help confirm a genetic diagnosis in someone with symptoms, clarify risk for adult relatives, and guide family planning. It cannot predict whether an unaffected carrier will develop ALS, FTD, both conditions, or neither, and it cannot reliably predict age at onset or severity. Testing also requires a specialized repeat-expansion method. Ordinary gene sequencing and many exome or genome tests may not detect the expansion unless the laboratory specifically analyzes C9orf72. Because a positive result can affect several generations and may reveal uncertain future health risks, pretest counseling is especially valuable. The most useful interpretation combines the laboratory result with symptoms, neurologic findings, family history, ancestry, and the exact method used.
- The test measures: the number and pattern of GGGGCC repeats in C9orf72, not a routine single-letter gene variant.
- A pathogenic expansion supports C9orf72-related ALS, FTD, or ALS-FTD: it does not determine which condition will occur or when.
- A negative result does not rule out inherited ALS or FTD: other genes and testing methods may still be appropriate.
- Predictive testing is generally reserved for informed adults: testing healthy children usually offers no childhood medical benefit.
- No fasting is needed: most laboratories use blood, although saliva or another specimen may sometimes be accepted.
Table of Contents
- What the C9orf72 Test Detects
- Who May Benefit From Testing
- How the Test Is Performed
- Understanding C9orf72 Results
- Symptoms and Disease Spectrum
- Inheritance, Penetrance, and Family Risk
- What to Do After Results
- Limits, Costs, and Questions to Ask
What the C9orf72 Test Detects
The clinically important C9orf72 change is a hexanucleotide repeat expansion. “Hexanucleotide” means a six-DNA-letter unit; in this case, GGGGCC, also written G4C2. Most people carry a relatively small number of these repeats. In affected families, one copy of the gene may contain dozens, hundreds, or thousands of repeated units.
The expansion sits in a noncoding region near the beginning of C9orf72. It does not work like a typical spelling change that alters one amino acid in a protein. Instead, the expanded DNA can disrupt normal C9orf72 activity and produce toxic RNA and abnormal dipeptide-repeat proteins. These effects contribute to degeneration of motor neurons and frontal and temporal brain networks.
C9orf72 expansions connect two disorders that were once viewed as largely separate:
- ALS damages upper and lower motor neurons, causing progressive weakness, muscle wasting, stiffness, speech or swallowing problems, and eventually impaired breathing.
- FTD damages brain regions involved in behavior, judgment, executive skills, personality, and language.
- ALS-FTD includes clinically meaningful features of both conditions.
The expansion is a major genetic cause of familial ALS and familial FTD, especially in people with European ancestry. Its frequency varies considerably across populations, so ancestry can influence the prior chance of finding it. Family history remains useful, but a person can have a C9orf72 expansion even when no relative is known to have ALS or dementia. Small families, early deaths, adoption, inaccurate diagnoses, and age-dependent expression can hide an inherited pattern.
This is a targeted repeat expansion test. It is not equivalent to ordinary C9orf72 sequencing. A report that says “C9orf72 sequencing was negative” may not answer whether the GGGGCC expansion was assessed.
Who May Benefit From Testing
C9orf72 testing may be offered in both diagnostic and predictive settings, but the questions are different.
Testing a person with symptoms
A neurologist may consider the test for someone with ALS, FTD, both syndromes, or a less typical neurodegenerative presentation. Testing is especially informative when the family history includes motor neuron disease, early personality or behavioral change, progressive language difficulty, unexplained dementia, or psychiatric symptoms followed by neurologic decline.
Many specialists now discuss genetic testing with people diagnosed with ALS even without an obvious family history. A broader ALS panel may include C9orf72 expansion analysis plus genes such as SOD1, TARDBP, FUS, and TBK1. For FTD, testing may include C9orf72 along with MAPT, GRN, and other dementia genes. The correct order varies by phenotype, family history, and local practice.
A positive result can:
- establish a molecular explanation for the illness;
- prevent repeated searches for another inherited cause;
- clarify risk for adult relatives;
- support eligibility screening for gene-specific studies;
- guide reproductive discussions; and
- help clinicians anticipate possible motor, cognitive, behavioral, psychiatric, swallowing, and respiratory needs.
The result does not replace a clinical diagnosis. Weakness still requires neurologic examination, electrodiagnostic testing, and evaluation for treatable mimics. Behavioral or language changes require cognitive assessment and, often, brain imaging. Genetics explains cause; it does not measure current disease stage.
Testing an adult relative without symptoms
An unaffected adult whose family has a confirmed expansion may choose presymptomatic genetic testing. This is a personal decision rather than an automatic medical step. Some people want information for life planning or family building. Others prefer not to learn an uncertain adult-onset risk when prevention remains limited.
Predictive testing is most accurate after the expansion has been documented in an affected relative. Testing an unaffected person first can create a difficult negative result: it may mean the person did not inherit C9orf72, or it may mean the family’s illness is caused by another gene that has not yet been identified.
Healthy children are generally not tested for an adult-onset C9orf72 expansion because the result usually does not change childhood care and removes the child’s future choice about knowing. Testing may be reconsidered if a minor develops relevant symptoms or if a specialist identifies a direct medical reason.
How the Test Is Performed
C9orf72 testing usually begins with a blood sample. No fasting or medication change is required. A laboratory extracts DNA and applies methods designed for repeat expansions.
Repeat-primed PCR
Repeat-primed polymerase chain reaction, often abbreviated RP-PCR, is commonly used to detect the characteristic pattern produced by an expanded GGGGCC repeat. It can show that an expansion is present even when the laboratory cannot count every repeat. The report may describe a “sawtooth” or stutter pattern rather than provide an exact expansion size.
A separate flanking PCR may measure shorter alleles that fall within the amplifiable range. When two normal-sized alleles are visible, the laboratory may confidently report no expansion. When only one allele appears, the person could truly have two alleles of the same size, or a very large second allele may have failed to amplify. RP-PCR helps resolve that uncertainty.
Confirmation and sizing
Some laboratories use Southern blotting, long-read sequencing, or another validated method to confirm a large expansion or estimate its size. Exact sizing is technically difficult because pathogenic alleles can be extremely long and unstable. Repeat length may also differ among blood cells and between blood and brain tissue, a phenomenon called somatic mosaicism.
For that reason, a result such as “more than 145 repeats” or “expanded allele detected” can be medically sufficient. A very precise-looking blood repeat count should not be treated as a forecast of age at onset, phenotype, or rate of progression.
Standard whole-exome sequencing generally does not capture this noncoding repeat, and routine short-read sequencing may not size it reliably. Some newer genome-analysis pipelines can flag repeat expansions, but detection depends on the platform, software, validation, and reporting policy. The test order should explicitly state C9orf72 GGGGCC repeat expansion analysis.
Before testing, ask the laboratory or clinician:
- Does the assay detect both short and very large expansions?
- Does it report a laboratory-specific normal, uncertain, and pathogenic range?
- How are borderline results confirmed?
- Can the laboratory distinguish two equal normal alleles from one visible allele plus a hidden expansion?
- Is deletion, duplication, or sequence analysis included, or only repeat analysis?
These details matter because a broad genetic panel may include C9orf72 by name while using a method that does not fully evaluate its repeat expansion.
Understanding C9orf72 Results
Reports vary among laboratories. The laboratory’s validated categories and method notes take priority over a universal cutoff.
| Result category | Usual meaning | Common next step |
|---|---|---|
| Pathogenic expansion detected | Supports C9orf72-related ALS, FTD, or ALS-FTD in a symptomatic person; indicates inherited susceptibility in an unaffected adult | Genetic counseling, phenotype-based care, and discussion of adult family testing |
| No expansion detected | Makes C9orf72-related disease less likely but does not exclude ALS, FTD, or another genetic cause | Review assay coverage and consider a broader panel or other diagnostic workup |
| Intermediate or uncertain repeat size | Clinical significance is unclear and may depend on repeat structure, mosaicism, family segregation, and laboratory thresholds | Confirm the result, review relatives’ results and symptoms, and avoid predictive conclusions |
| Indeterminate or technically limited | The sample or method did not provide a definitive answer | Repeat testing or use a complementary validated method |
Positive or pathogenic expansion
In someone with compatible symptoms, a pathogenic expansion establishes a C9orf72-related diagnosis. The result explains the inherited molecular cause but does not say whether the clinical label should be ALS, FTD, or ALS-FTD; clinicians determine that from the examination and disease course.
In an unaffected adult, the same finding means the person has a substantially increased lifetime chance of developing a disorder within the C9orf72 spectrum. It is not a diagnosis of active disease. Penetrance rises with age, yet some carriers remain unaffected into older age. The result cannot provide an individual countdown.
Negative result
A negative targeted test means the laboratory did not find a detectable pathogenic expansion. It does not rule out non-genetic disease, variants in other genes, structural variants, or a C9orf72 expansion that the particular method could not resolve. Review the test name and technical section before assuming all C9orf72-related changes were excluded.
For a symptomatic person, a clinician may recommend a multigene panel, deletion/duplication analysis, or whole-genome sequencing with appropriate repeat-expansion capability. For a relative, a negative result is most reassuring when the family’s exact pathogenic expansion was already confirmed and the laboratory performed targeted familial testing.
Intermediate or uncertain result
Older references sometimes describe approximate bands such as 2–24 repeats as normal, 25–60 as uncertain, and more than 60 as pathogenic. These ranges are useful background, not a substitute for the reporting laboratory’s validated criteria. Interruptions within the repeat, technical limits, and tissue mosaicism complicate interpretation.
An uncertain result should not be used alone to diagnose disease, predict future illness, test children, or make irreversible reproductive decisions. The laboratory may recommend confirmation, parental or relative studies, or updated interpretation as evidence improves. This situation is different from a conventional variant of uncertain significance, but the same caution applies: uncertainty is not proof of disease.
Symptoms and Disease Spectrum
C9orf72 expansions produce a wide clinical spectrum, even within one family. One relative may develop ALS, another behavioral-variant FTD, and another a combination. Age at onset is often in mid-to-late adulthood, but reported ages span several decades.
ALS-related signs may include:
- focal hand, arm, leg, neck, or breathing-muscle weakness;
- muscle twitching, cramps, or visible wasting;
- stiffness, slowed movement, overactive reflexes, or spasticity;
- slurred speech or a weak voice;
- choking, prolonged meals, or unintended weight loss; and
- shortness of breath when lying flat, morning headaches, or disturbed sleep.
FTD-related signs may appear before obvious memory loss. They can include loss of judgment, apathy, disinhibition, reduced empathy, rigid routines, compulsive behavior, changes in food preference, or progressive language impairment. Hallucinations, delusions, anxiety, or other psychiatric features can be unusually prominent in some C9orf72 carriers. These symptoms may initially resemble a primary psychiatric disorder, Alzheimer disease, Parkinson disease, or another dementia.
A genetic result should therefore prompt a broad clinical view rather than a narrow symptom checklist. Someone diagnosed with ALS may benefit from screening for executive, behavioral, or language changes. Someone diagnosed with FTD may need periodic review for weakness, swallowing difficulty, muscle twitching, stiffness, and breathing symptoms.
Urgent assessment is warranted for rapidly worsening shortness of breath, choking with inability to clear the airway, repeated aspiration, sudden inability to walk safely, suicidal thoughts, severe agitation, or behavior that places the person or others in immediate danger. The genetic test itself is not an emergency test; acute symptoms require clinical care regardless of whether results are available.
Inheritance, Penetrance, and Family Risk
A pathogenic C9orf72 expansion usually follows an autosomal dominant inheritance pattern. A carrier has one expanded copy and one non-expanded copy. Each biological child has a 50% chance of inheriting the expanded copy, regardless of sex. The same 50% probability applies independently to every pregnancy.
Inheritance and disease are not identical. Penetrance describes the proportion of carriers who develop clinical symptoms. C9orf72 penetrance is age dependent and incomplete: risk generally rises with age, but an expansion does not guarantee symptoms by a specific birthday. Estimates drawn from affected families can overstate risk for a newly identified carrier because families enter studies precisely because several people became ill.
The result also has limited power to predict:
- ALS versus FTD versus a combined syndrome;
- behavioral, language, motor, or psychiatric presentation;
- age at onset;
- speed of progression; or
- lifespan after symptoms begin.
Researchers have investigated whether larger expansions cause earlier or more severe disease. In routine blood testing, repeat size is too unstable and technically uncertain to support that conclusion for an individual. Claims of genetic “anticipation,” meaning earlier onset in later generations, remain difficult to prove because families are subject to recall bias, changing diagnosis, and imperfect repeat sizing.
A genetic counselor can draw a three-generation family history and identify who should be tested first. Once a pathogenic expansion is confirmed, adult relatives can pursue a targeted familial test rather than repeating an unnecessarily broad workup.
Family-building options may include natural conception without testing, prenatal diagnosis, use of donor eggs or sperm, adoption, or in vitro fertilization with preimplantation genetic testing. These choices involve personal values, cost, access, and the uncertainty of age-dependent disease. A genetics and reproductive-medicine team can explain what testing can establish without implying that one option is preferred.
What to Do After Results
A result becomes useful when it leads to a clear, phenotype-specific plan.
After a positive result in someone with symptoms
Arrange follow-up with a neurologist experienced in ALS, FTD, or both. Care is based on current symptoms, not the repeat count. Depending on the presentation, evaluation may include breathing tests, swallowing and nutrition assessment, speech communication planning, physical and occupational therapy, cognitive testing, behavioral safety review, driving assessment, and caregiver support.
Discuss clinical trials only after confirming eligibility, risks, location, and the study’s purpose. C9orf72-targeted approaches remain an active research area, including strategies aimed at toxic RNA, dipeptide-repeat proteins, and other disease pathways. A positive test may help identify relevant studies, but it does not guarantee access or benefit.
Give the family a copy of the complete report. The exact laboratory, method, and wording will help relatives obtain accurate targeted testing years later. Store the report with other permanent medical records rather than relying on a verbal description such as “the ALS gene was positive.”
After a positive predictive result
An unaffected carrier should not be labeled as having ALS or dementia. A genetics or neurology team can discuss whether a baseline neurologic and cognitive evaluation would be useful. There is no single surveillance schedule proven to prevent C9orf72 disease, so follow-up should reflect the person’s preferences, age, family history, research participation, and access to specialist care.
Emotional responses can include relief from uncertainty, grief, guilt, anger, or heightened attention to normal lapses and muscle sensations. Psychological support is part of responsible predictive testing, not evidence that the person is coping poorly. Decisions about insurance and privacy should be considered before testing because genetic-discrimination protections vary by country and may not cover life, disability, or long-term-care insurance.
After a negative or uncertain result
For a symptomatic person, continue the diagnostic workup. The next test may be an ALS panel, an FTD/dementia panel, or a combined neurologic genetic panel. Laboratory reanalysis may become useful as methods and gene-disease evidence change.
For an unaffected relative, clarify whether the family mutation was known. A true negative for a documented familial expansion usually returns that person’s C9orf72-related risk close to population risk, although it does not eliminate unrelated neurologic disease. An uncertain result requires restraint; relatives should not be assigned carrier status without stronger evidence.
Limits, Costs, and Questions to Ask
C9orf72 testing is powerful because it can find a specific major cause, but its limits are substantial. It cannot diagnose every case of ALS or FTD, measure current neuron loss, predict a carrier’s exact future, or replace clinical assessment. It may also uncover information that relatives did not wish to know.
Cost depends on the country, laboratory, insurance plan, and whether testing is ordered alone or within a panel. Coverage may require a neurologist’s documentation, a family history, or preauthorization. Sponsored testing programs sometimes reduce cost, but patients should ask who pays, which genes are analyzed, whether data may be used for research, and whether confirmatory testing is included.
Before consenting, consider asking:
- Is this diagnostic testing for symptoms, or predictive testing for future risk?
- Has a C9orf72 expansion already been confirmed in an affected relative?
- Does this order use repeat-primed PCR or another validated expansion assay?
- How will a borderline or technically limited result be handled?
- Which other ALS or FTD genes are included, and can the methods detect deletions, duplications, and other repeat expansions?
- Who will explain the result and coordinate follow-up?
- What privacy, insurance, employment, and data-sharing rules apply where I live?
- How could the result affect siblings, children, and reproductive choices?
Genetic counseling before and after testing gives these questions enough time and context. The most responsible plan respects both a person’s right to know and the right not to know, while ensuring that a symptomatic patient is not denied clinically appropriate care because genetic testing is negative or delayed.
References
- Roadmap for C9ORF72 in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis: Report on the C9ORF72 FTD/ALS Summit 2023 (Consensus Report)
- Personalised penetrance estimation for C9orf72-related amyotrophic lateral sclerosis and frontotemporal dementia 2024 (Research Study)
- Design considerations for C9orf72 disease prevention trials 2025 (Review)
- Role of C9orf72 hexanucleotide repeat expansions in ALS/FTD pathogenesis 2024 (Review)
- C9orf72 Frontotemporal Dementia and/or Amyotrophic Lateral Sclerosis 2020 (GeneReviews)
Disclaimer
C9orf72 testing and interpretation should be directed by qualified genetics and neurology professionals. A positive expansion does not predict an individual’s exact diagnosis, age at onset, or disease course, and a negative result does not exclude ALS, FTD, or another inherited neurologic condition. Seek urgent medical care for breathing difficulty, severe swallowing problems, immediate safety concerns, or rapidly worsening neurologic symptoms.
