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FTD and Genetic Testing: Understanding the Genes, the Spectrum of Disease, and Why Research Matters

Aug 25
6 min read

Frontotemporal dementia (FTD) is often described as a single disease, but it is better understood as a family of neurodegenerative disorders that can affect behavior, personality, language, movement, and cognition. For some families, genetics plays a major role. For others, there is no identifiable genetic cause.

Understanding the connection between FTD and genetics can help families make informed decisions about genetic testing, better understand patterns of disease within a family, and perhaps most importantly help researchers uncover new causes and treatments.


The Genetic Side of FTD

Approximately one-third of FTD cases are thought to have a significant inherited component, although estimates vary depending on how family history is defined. The majority of clearly genetic FTD is associated with changes in one of three major genes: C9orf72, GRN, and MAPT.


C9orf72

The C9orf72 gene is particularly important because changes in this gene can be associated with both FTD and amyotrophic lateral sclerosis (ALS).

A person with a C9orf72 expansion may develop FTD, ALS, both FTD and ALS, or in some families other neurological or psychiatric symptoms. Importantly, researchers cannot currently predict exactly which symptoms a carrier will develop or when they will begin.


This means that a family carrying a C9orf72 expansion may appear very different from one generation to another. One relative might develop behavioral changes associated with FTD, another might develop ALS, while another could develop a combination of cognitive, behavioral, and motor symptoms.


GRN

The GRN gene provides instructions for making progranulin, a protein involved in several important cellular processes. Disease-causing GRN variants can lead to FTD, most commonly behavioral-variant FTD, but the presentation can vary considerably. Different members of the same family may develop different symptoms and may develop them at different ages. Some individuals with GRN-related disease can also develop parkinsonism.


MAPT

The MAPT gene is responsible for producing the tau protein, which plays an important role in maintaining neurons. Certain MAPT variants can cause abnormal tau accumulation and lead to frontotemporal degeneration. MAPT-related disease often presents as behavioral-variant FTD, although the exact symptoms and age of onset can vary. MAPT is unusual in that an individual who inherits a disease-causing variant is expected to develop a frontotemporal disorder, but the precise age of onset and the exact symptoms generally cannot be predicted.


Other Genes Are Also Involved

FTD genetics extends well beyond C9orf72, GRN, and MAPT.

Researchers have identified additional genes associated with familial FTD and FTD-ALS, including VCP, CHMP2B, TARDBP, FUS, SQSTM1, TBK1, TIA1, CHCHD10, OPTN, CCNF, and UBQLN2, among others. Some of these are extremely rare and have been identified in only a small number of families.


This growing list demonstrates something important: FTD is genetically diverse. There is not one "FTD gene."


FTD Can Exist on a Spectrum

One of the most important things to understand about genetic FTD is that a gene does not always produce one specific diagnosis.

Instead, some genetic variants can produce a spectrum of neurological disease.


That spectrum can include:

  • Behavioral-variant frontotemporal dementia (bvFTD)

  • Primary progressive aphasia (PPA), including language-predominant forms

  • FTD with ALS

  • ALS

  • Parkinsonism or other movement symptoms

  • Corticobasal syndrome or related movement presentations

  • Progressive supranuclear palsy-like presentations in some families

  • Psychiatric symptoms in some genetic families


For example, C9orf72 can be associated with FTD, ALS, or both. Other genes can also sit at the intersection between FTD and ALS. This helps explain why two relatives carrying the same genetic variant may not look exactly alike. One person may primarily experience changes in personality and behavior, while another may develop language difficulties or motor symptoms.


A genetic diagnosis can explain a family connection without necessarily predicting the exact disease that an individual will experience.


What Does It Mean to Be a Genetic Carrier?

When people hear the word "carrier," they sometimes assume it means that a person has a 50% chance of developing disease. That is not necessarily how FTD genetics works.


Many of the major inherited FTD variants are autosomal dominant. In these families, a person who carries a disease-causing variant can have a significant risk of developing disease and can potentially pass the variant to each biological child.

However, the actual risk and clinical implications depend on the specific gene and variant.


Even within the same family, people can experience:

  • Different ages of onset

  • Different symptoms

  • Different disease courses

  • Different combinations of cognitive, behavioral, language, and motor symptoms


For this reason, genetic testing results should ideally be discussed with a genetic counselor or healthcare professional familiar with FTD rather than interpreted on their own.


Why Genetic Testing Matters

Genetic testing can be an emotional and deeply personal decision. There is no single right answer for every person or family. But genetic testing can provide important information.


For someone already diagnosed with FTD, identifying a genetic cause may help explain why the disease has appeared across generations. For relatives who are considering testing, it can provide information about whether they carry a known familial variant.


Genetic information can also become increasingly important as treatments are developed. Researchers are actively studying genetic forms of FTD and developing therapies that target specific disease mechanisms. Knowing the genetic cause can help determine whether someone may qualify for certain clinical trials or research studies.


For families considering testing, genetic counseling before and after testing is strongly worth considering. Testing can affect not only the individual being tested but also parents, siblings, children, and extended family members.


Genetic Testing Is Also About Research

Genetic testing isn't only about finding answers for one family.

It can help researchers answer much bigger questions:

  • Why does one person develop FTD at 45 while another develops symptoms at 65?

  • Why does one person with a particular mutation develop FTD while another develops ALS?

  • Why do two people with the same genetic variant have different symptoms?

  • What causes the disease to begin in the first place?


Research involving families with known genetic variants has already transformed our understanding of FTD. The discovery of C9orf72, for example, revealed an important genetic connection between FTD and ALS and opened new avenues for understanding both diseases.


Research programs such as the ALLFTD consortium study people with known FTD-associated mutations as well as people with FTD syndromes who do not have a known mutation. This allows researchers to study both genetic and apparently non-genetic forms of the disease.


Genetic research can ultimately lead to better biomarkers, earlier diagnosis, more accurate disease prediction, and treatments designed around specific disease mechanisms.


A Negative Genetic Test Does Not Mean "Nothing Is There"

This is perhaps one of the most important messages for families.

A negative genetic test does not necessarily mean that FTD is not genetic.

Researchers have identified many genes associated with FTD, but they have not identified every genetic cause.


Some families have very strong histories of FTD, ALS, or related neurological disease but do not have a mutation that current clinical testing can identify. The AFTD specifically notes that additional FTD-causing genes are likely still waiting to be discovered.


There are several possible explanations for a negative result. The responsible gene may not yet have been discovered. A particular type of genetic change may not be detected by the test that was performed. Or the disease may involve a combination of genetic, biological, and environmental factors that scientists do not yet fully understand.


In other words:

"We didn't find a gene" is not always the same as "there is no genetic cause."


For families with a strong history of FTD or ALS and negative testing, researchers may recommend options such as DNA banking or participation in research studies so that samples can potentially be studied again as scientific knowledge advances.


The Future of FTD Genetics

FTD research is moving quickly. Scientists are continuing to identify genes, understand how genetic variants damage brain cells, discover biomarkers, and develop treatments aimed at specific disease pathways. Genetic research has already shown that diseases once thought to be separate can share biological mechanisms.


But there is still much we do not know.


There are undoubtedly people living with FTD today whose genetic cause has not yet been identified. Their families are an important part of the future of FTD research. Every genetic test, every research participant, every donated biological sample, and every carefully documented family history can add another piece to the puzzle.


Moving Forward Together

For families affected by FTD, genetic testing can bring answers but it can also bring difficult questions. It should be approached thoughtfully, with appropriate genetic counseling and an understanding of what current testing can and cannot tell us.


The most important thing to remember is that FTD genetics is bigger than any single gene.


C9orf72, GRN, and MAPT account for the majority of known genetic FTD, but many other genes can be involved. Genetic variants can produce a spectrum ranging from FTD to ALS, movement disorders, and overlapping neurological symptoms. And there are almost certainly additional genetic causes that science has not discovered yet.


For that reason, genetic testing is not simply about looking backward and asking, "Why did this happen to my family?" It is also about looking forward and asking:

"What can we learn from our family that might help the next family?"


That is where genetic testing and research come together and where there is real hope for a future in which FTD can be diagnosed earlier, understood more completely, and ultimately treated or prevented.




This article is intended for educational purposes and is not a substitute for personalized medical or genetic advice. Anyone considering FTD genetic testing should consider speaking with a qualified genetic counselor or clinician familiar with FTD.


 
 

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