Genetics of FTD

People with FTD and their families often worry if FTD is hereditary, particularly if one or more additional family members have received a diagnosis of FTD or another neurodegenerative disorder, such as ALS or Alzheimer’s disease.

Is FTD inherited? In at least half of affected individuals, the answer is “no” – their FTD is said to be sporadic, meaning that none of their relatives are known to have FTD. However, approximately 40% of affected individuals with FTD do have a family history that includes at least one other relative diagnosed with a neurodegenerative disease. Their FTD is described as familial.

What genes are commonly mutated in FTD?

Genes are segments of the DNA that contain “recipes” for making the proteins that carry out the functions needed to keep the cell alive. Mutations are changes in the DNA sequence of a gene. Like typos in a cookbook recipe, mutations lead to errors in the instructions for making the protein encoded by the mutated gene.

Hereditary FTD is caused by harmful gene mutations that affect proteins essential to the normal functioning and survival of brain cells. Researchers have identified three genes that account for the majority of mutation-associated hereditary FTD cases:

C9orf72

  • Most common genetic mutation in hereditary FTD and ALS
  • Mutations disrupt the regulation and function of RNA, which creates a template from genes for use in protein synthesis
  • Leads to abnormal accumulation of TDP-43 protein

GRN Progranulin

  • Mutations reduce levels of progranulin, which is involved in cell survival and regulating inflammation
  • Leads to abnormal accumulation of TDP-43 protein

MAPT Microtubule-associated protein tau

  • Mutations disrupt structure and function of tau protein, which assembles and stabilizes the cell’s internal structure
  • Leads to abnormal accumulation of tau protein

Mutations in other genes have also been described but are much rarer than the three mentioned above. They include VCP, CHMP2B, FUS, and TARDBP.

A very small percentage of people with sporadic FTD (less than 10%) have a mutation in a known FTD gene. Meanwhile, an estimated 10-15% of people with familial FTD have a similar mutation.

Are some gene mutations more likely to occur in particular FTD disorders?

In general, there is not a one-to-one correspondence between the familial type of a specific FTD disorder and a specific gene. For example, mutations in MAPT, GRN and C9orf72 are all found in people diagnosed with bvFTD. The C9orf72 mutation is more common in people diagnosed with FTD-ALS.

My partner has an FTD-causing gene mutation, but I do not have this mutation or any family history of FTD. What is the risk to our children?

Each child of a couple in which one parent is unaffected and one carries an FTD mutation has a 50% chance of inheriting the mutation.

One of the options that a person with a mutation has as they contemplate planning a family is pre-gestational diagnosis. The process is expensive and may raise ethical concerns for some, but it is one by which an individual can be assured that their offspring will not carry the familial mutation. The process does not require that the individual at risk (the prospective parent) learn their own mutation status. For more information, we would strongly encourage consultation with a genetic counselor.

What should I do if I think FTD may be inherited in my family?

If your family history does raise some concerns, there are some important steps you can take to explore further.

  1. Get informed. The resources listed below provide more information about basic genetic terms and concepts, as well as details of the genetics of FTD. Talk to the neurologist about your concerns.
  2. Talk to other members of your family. Not all relatives will want to pursue this information, so you may need to be sensitive to their wishes. Gathering as much family history is an important step. Ask questions about the early symptoms of any family member affected with FTD or a related disease. Find out the age of onset of symptoms.
  3. Ask for a referral. Ask your neurologist for a referral to a genetic counselor or other healthcare professional experienced in the genetics of adult neurological conditions.
  4. Stay calm. You’ve already taken an important first step by gathering information and exploring your options. Remember that AFTD is here to help and answer your questions.

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Additional Resources

Several AFTD webinars on genetics in FTD are available:

AFTD has worked with the University of Pennsylvania Center for Neurodegenerative Disease Research to publish a booklet called Understanding the Genetics of FTD: A Guide for Patients and Their Families. You can download the booklet here or request a print copy by emailing [email protected].

The National Society of Genetic Counselors (NSGC), the professional organization for genetic counselors, is another resource you can contact to locate a certified genetic counselor in your area.

An excellent introduction to the fundamentals of genetics and genetic disorders is learn.genetics.utah.edu, an online resource developed and maintained by the University of Utah’s Genetic Science Learning Center.

CureVCP is an organization devoting to curing diseases caused by mutations of the VCP protein, including FTD. Visit the CureVCP website for more information.