C9orf72, FTD, and ALS

The genetic change is a repeat expansion

Within C9orf72 is a short sequence of six DNA letters that is normally repeated a limited number of times. In C9orf72-related FTD and ALS, that segment has expanded, sometimes to hundreds or thousands of repeats.

This is not the usual one-letter DNA change that many sequencing panels are designed to find. A laboratory generally needs a targeted repeat-expansion assay. Standard sequence-based panels and exome sequencing can miss a pathogenic C9orf72 expansion unless it is tested separately.

Laboratories may use more than one method to detect or characterize the expansion. Exact sizing can be technically difficult, and the number reported in blood does not reliably predict the age symptoms will begin or the form the disease will take.

One expansion can lead to several clinical syndromes

A person with a pathogenic C9orf72 expansion may develop:

• behavioral-variant FTD, with progressive changes in behavior, judgment, motivation, empathy, or personality;
• primary progressive aphasia, with progressive language difficulty;
• ALS, with weakness, muscle wasting, stiffness, difficulty speaking or swallowing, or breathing problems;
• a combination of FTD and ALS features;
• other movement, cognitive, or psychiatric features in some cases.

The gene does not allow a clinician to predict which of these will appear first. Relatives carrying the same expansion may receive different diagnoses.

C9orf72-related disease is usually associated with abnormal TDP-43 biology in the brain and, in ALS, motor neurons. Several mechanisms may contribute, including toxic effects of the expanded repeat and reduced normal C9orf72 function.

How C9orf72 is inherited

C9orf72-related FTD and ALS is inherited in an autosomal dominant manner. Each child of a person with a pathogenic expansion has a 50 percent chance of inheriting it.

Penetrance is age-related and reduced. Risk rises with age, but not every carrier develops symptoms within a typical lifespan. A positive result cannot establish an exact age of onset.

A family history can include FTD, ALS, unexplained language or behavior change, parkinsonism, or diagnoses that were made before the FTD-ALS spectrum was well recognized. An apparently negative family history does not exclude C9orf72.

What a result can and cannot tell us

In a person with symptoms, a pathogenic expansion can unify what initially looked like separate FTD and ALS diagnoses within a family. It can allow adult relatives to consider targeted testing and may support eligibility for C9orf72-focused research.

The result does not determine whether a carrier will develop FTD, ALS, or both. It does not reliably predict the exact first symptom, onset age, severity, or pace.

An intermediate or uncertain repeat result requires careful laboratory and clinical interpretation. Thresholds, assay limitations, and the possibility of variation among tissues matter.

Who should be tested first

When possible, testing should begin with a relative who has FTD, ALS, or a related symptomatic syndrome. This establishes whether a pathogenic C9orf72 expansion is present in the family.

If the familial expansion is known, an adult relative without symptoms can choose targeted predictive testing. A broad negative sequencing panel is not an adequate substitute if C9orf72 expansion analysis was not performed.

Predictive testing is a personal decision

Predictive testing can clarify whether an adult relative inherited the familial expansion. It cannot tell that person whether FTD or ALS will occur first, when symptoms might begin, or how the illness would progress.

The decision may affect emotional health, family communication, reproductive and financial planning, insurance considerations, and research participation. Genetic counseling provides space to consider both knowing and not knowing.

Testing children for an adult-onset C9orf72 condition is generally avoided when the result would not change care during childhood.

Research and follow-up

C9orf72 is an active area of observational and therapeutic research. Studies are examining how the expansion alters RNA, proteins, cellular recycling, and inflammation, and how disease might be detected before symptoms.

Research testing may use methods or reporting standards that differ from a clinical laboratory. Ask whether a research result requires clinical confirmation before it is used for medical or family decisions.