Understanding the Genetics of FTD

A guide for people living with FTD and their families

Acknowledgements

The authors wish to acknowledge the following centers and associations which contributed to the creation of this content:

The University of Pennsylvania Center for Neurodegenerative Disease Research
The University of Pennsylvania Frontotemporal Degeneration Center
The Association for Frontotemporal Degeneration

We also thank the individuals with FTD and their families who have contributed to advancing the science of FTD genetics.

The information provided within the Understanding the Genetics of FTD webpage is based on information available at the time, but this is rapidly evolving research. Changes to this content may be made.

The information provided within the Understanding the Genetics of FTD webpage is designed for educational purposes only and is not rendering medical advice or professional services. The information provided throughout this webpage should not be used for diagnosing or treating a health problem or a disease. It is not a substitute for professional care. If you have or suspect you may have a health problem, you should consult your healthcare provider. If you have a medical emergency, dial 911.

No part of this publication may be reproduced without permission from the Trustees of the University of Pennsylvania.

Frontotemporal Degeneration

Frontotemporal degeneration (FTD) is one of the most common forms of dementia in individuals under the age of 65 years but can occur across a wide range of ages, from roughly 20-89 years of age. Symptoms of FTD are caused by the progressive loss of brain cells (neurons), mainly in the frontal and temporal regions of the brain, although other regions can be affected in some individuals. The frontal lobes of the brain are involved in many functions, including personality, behavior, planning, reasoning, judgement, impulse control, and motor functions. The temporal lobes of the brain are involved in communication, memory, and behavior.

Despite many years of research, it is still not known what triggers the process of neurodegeneration (neuron cell death) in the brains of people who develop FTD. However, clues are gleaned from the presence of particular protein accumulations inside the affected neurons and other brain cells. In a subset of people, the root cause of those protein accumulations can be found in the individual’s genetic code.

Symptoms

FTD is predominantly characterized by progressive decline in behavior and/or language. However, FTD can also impact movement and motor function. The average age of onset is in the mid-50s to 60s. The clinical presentations of FTD can include:

Behavior: changes in personality, loss of empathy, apathy, inappropriate social behavior, and poor judgment
Communication: difficulty understanding and finding words, and/or problems planning and producing speech
Executive: difficulty with planning, judgement and working memory
Movement: decreased movement, muscle rigidity, parkinsonism (tremor, problems with gait and balance
Motor: muscle weakness, muscle loss, twitches (fasciculations)

Pathology

For any neurodegenerative condition, the final and definite diagnosis is currently made after death by doing a brain autopsy. The autopsy will evaluate the location and the severity of brain tissue loss (degeneration) and will include detailed microscopic analysis to detect the types of abnormal protein accumulations in the brain. In FTD, an autopsy can usually distinguish between two main types of pathology.

One group is characterized by clusters of tau protein. Tau plays an important role in the structure and function of a healthy neuron, but in some forms of FTD, the tau protein begins to stick to itself and accumulates, eventually forming large clumps. These clumps are called “inclusions.”

The second group is characterized by inclusions of a protein known as TDP-43. TDP-43 normally helps regulate how genetic information is processed within cells, and aggregates/inclusions of TDP-43 protein are observed in roughly half of people diagnosed with FTD. It is also found at autopsy in the brains and spinal cord of most people diagnosed with amyotrophic lateral sclerosis (ALS). Finding TDP-43 pathology in people diagnosed with FTD and people diagnosed with ALS was an early clue that FTD and ALS are related. This shared protein pathology led to the identification of several genes that can cause either or both conditions.

A small percentage of people with FTD are found to have inclusions made of other proteins, such as FUS (fused in sarcoma) or annexin A11 protein, as the characteristic finding at autopsy.

In most people with FTD, the autopsy findings will pinpoint one of these proteins as the primary finding, but sometimes, especially in older people, there may be an accumulation of more than one type of protein (“co-pathology”). This can include proteins that are associated with other neurodegenerative conditions, such as Alzheimer disease. Research is currently focused on understanding why and how these proteins accumulate, in hopes that the answer will lead to the development of FTD-specific therapies.

Treatments

There is currently no way to prevent, slow down disease progression, or cure FTD. However, physicians may find medications used in other neurologic or psychiatric conditions to help manage some of the symptoms. Non-pharmacological supports for people with FTD and family members, such as behavioral management strategies with structured activities, are also an important part of management of FTD. In addition, treatments that are used in similar disorders, such as speech and/or physical therapy, may be recommended.

Types of FTD

FTD & Genetics

Genetics plays an important role in helping to better understand FTD. Even before genetic causes of FTD were first identified, doctors recognized that in some families, there was a history of multiple family members all being affected by symptoms consistent with FTD. In some families, some individuals may be affected by FTD symptoms while other individuals may have symptoms consistent with related conditions including ALS and Parkinson disease. Families that have participated in genetic research provided the first insights into understanding the hereditary forms of FTD, related conditions like ALS and Parkinson disease, and their potential overlap. Most people with FTD, ~60%, have no family history of FTD or a related condition (e.g., ALS or Parkinson disease), indicating the genetic risk is low. Nevertheless, genetics plays a pivotal role in understanding the mechanisms that cause FTD and provides a target for developing treatment. Thus, it is important to understand the basic science behind why and how genes influence a person’s risk for FTD.

Genetics 101

Our DNA is stored in almost every cell of our body. A DNA chain is made up of individual units called nucleotides (an alphabet of 4 letters). DNA chains are then packaged into larger units called chromosomes. Typically, individuals have a total of 46 chromosomes. Chromosomes come in pairs, and in each pair, one chromosome comes from the father and the other from the mother. The first 22 pairs of chromosomes are the same in males and females (known as autosomes), whereas the 23rd pair determines our sex (males, XY and females, XX).

Genes are specific segments of DNA that carry the instructions for making proteins. The instructions are made up of a unique string of nucleotides that the cell knows how to read and translate into proteins. Proteins are molecules made of amino acid building blocks. Proteins are used by the body for maintaining its structure and function. Because our cells have two copies of every autosomal chromosome, this means we have two copies of each gene. There are many different genes present on each chromosome. Both the sequence of the DNA and the number of copies on each specific gene are important in maintaining normal function of the human body.

A variant (also called mutation) is a difference in the DNA sequence; in other words, there is spelling mistake or typo in the instructions to make a protein. Some variants do not cause any problems for the gene’s instructions. However, some variants are called “pathogenic,” meaning disease-causing, because they disrupt the gene’s function. The gene’s function can be altered in a variety of ways, such as not being able to make enough of the protein it codes for, or not making a version of the protein that the body can use appropriately.

There are many different types of genetic variants. For example, a variant can occur because one or more nucleotides that encode (spell) the gene is either changed, inserted, or deleted. In some cases, the insertions and deletions can be large, even involving the whole gene. In another type of variant, a region of DNA that normally has a small number of a repeated sequence is abnormally expanded to have too many repeats, therefore affecting the gene’s function.

The sequence of DNA in any individual is determined using a variety of methods collectively called “molecular biology.” Not every variant identified in the DNA is necessarily a disease-causing variant. Some identified DNA variants are not harmful, they are just benign variations in the genetic code. These benign variations are called polymorphisms, and they are what make each of us look and behave differently. Sometimes a variation in the DNA sequence is identified that is extremely rare or has never been seen before, so it can’t be classified as being harmful (pathogenic) or normal (benign polymorphism). There are tools and rules that researchers and health care providers can use to evaluate these variations, but even so, sometimes a clear answer is not possible. In these cases, the changes are “indeterminate” and are often referred to as variants of uncertain significance (VUS). When a test result is uncertain, more work is needed to help determine whether that variant will have an impact. Studying additional family members can sometimes be helpful.

Mutations are Genetics Spelling Mistakes (originally pg7).png

When a gene is spelled correctly, the body can read the DNA letters in groups of three, like how we group letters to form words and sentences. If the gene is written correctly, the body can read the instructions.

A variant (also called a mutation) changes that type or order of DNA letters. In the example below, one of the DNA letters changed. This changes the word, and thus the instructions change as well.

Genes & Family History

Most people with FTD (about 60%) have no known family history of FTD or related disorders such as ALS or Parkinson disease. This can be called an “apparently sporadic” family history. When a person with FTD has no known family history, we usually cannot pinpoint a specific genetic cause for their diagnosis. However, among people with FTD without known family history, roughly 5-10% do have a genetic cause (e.g. a pathogenic variant) for their FTD.

Approximately 40% of individuals with FTD have a family history that includes at least one other relative who also has or had a neurodegenerative condition. When there is a family history of FTD or other neurodegenerative conditions, the likelihood of identifying a genetic cause depends on how many other relatives are affected, how closely related the affected relatives are, and the specifics of the relatives’ diagnoses (such as what condition(s) they had, and how old they were when symptoms began). The likelihood of finding a genetic cause can range from about 10% to 65% depending on the family history details. It is important to note that not all individuals with a family history of neurodegenerative condition will have an identifiable genetic cause. This could be because the responsible gene has not yet been identified, the genetic variant causing FTD is difficult to detect with existing testing technology, or because the person’s FTD is not actually caused by a gene variant.

Overall, in about 20% of all people with FTD, a genetic cause can be identified as the likely cause of the condition. The specific genes that have been associated with FTD are discussed in detail in the next section. The frequency of the different genetic forms of FTD differs across populations, and is influenced by ancestry, family history, and the specific type of FTD (see table “Types of FTD.”) Clinically, both inherited and apparently sporadic FTD exhibit the same symptoms, which makes evaluation of the family history the most sensitive tool for determining the likelihood of a genetic cause.

People with a genetic form of FTD can lack family history for several reasons. Usually, pathogenic variants that cause FTD are inherited from a parent, but sometimes they occur new in a person at conception (de novo), and therefore a family history would not be expected. Some genetic variants increase the risk of developing FTD but do not always cause FTD; when this type of variant is present in a family, it could seem like there is no family history if people had not developed FTD (see “penetrance”). FTD is also hard to diagnose, and it is possible that family members may not have made it to the right clinical team to get the right diagnosis. This is particularly relevant in former generations where family members may have been evaluated prior to modern definitions of FTD. Even if an FTD diagnosis is made, sometimes family members will not share this information with their relatives. In some families, individuals may have been affected by related conditions (e.g., ALS, Parkinson disease) and the connection between FTD and these conditions was not well understood. Increasing awareness and understanding the biology of FTD will reduce this uncertainty for current and future generations. In some families, there is not much information known about relatives’ health. This can be because the person comes from a small family, has family members who died at a young age due to other causes, is adopted, or is otherwise not in touch with their biological family members. However, despite these potential sources of variability in family history, most genetic causes of FTD are found in those with a known family history of neurodegenerative conditions.

As seen in the pie chart image, families that include a history of multiple relatives with FTD and/or ALS are the most likely to have an underlying genetic cause, while persons with apparently sporadic or unknown family histories are the least likely. There are also families that fall in the middle. This could be that there is at least one relative who has a related neurodegenerative condition like Alzheimer or Parkinson disease, but not a clear-cut family history of FTD or ALS in close relatives. There could also be relatives diagnosed with psychiatric illness later in life, raising concern for missed FTD diagnoses. In short, the greater the family history of FTD or an associated condition like ALS, the more likely that genetics is playing a role.

Many descriptive terms are used in medical settings to discuss family history. Because these terms are often used interchangeably, it can be confusing to understand each term’s meaning and why the distinctions matter. For example, the term “hereditary” indicates that a trait or condition can be directly transmitted between parent and offspring. “Familial” denotes that there is a possibility of a genetic cause due to apparent clustering of affected individuals in a family. This may occur by chance or due to a gene variant (hereditary cause). When a genetic counselor evaluates a person’s family history and draws a pedigree, they look for patterns of neurodegenerative conditions in the family.

Inheritance Patterns in Genetic FTD

A classic pattern of genetic inheritance is called autosomal dominant. “Autosomal” refers to the first 22 pairs of chromosomes, which are identical in both males and females. Therefore, both sexes have an equal chance of being affected if a pathogenic variant is present on a gene in an autosomal chromosome. “Dominant” inheritance means that only one copy of a gene has to have a pathogenic variant to cause a condition. Typically, the copy of the gene with the pathogenic variant is inherited from a parent, and most individuals with an autosomal dominant condition will have a family history of the condition. A child of a person with an autosomal dominant variant has a 50% chance of inheriting the copy of the gene with the variant and a 50% chance of inheriting the copy of the gene without the variant.

This diagram shows all the possible inheritance combinations for a couple in which one parent has a genetic variant. Each time the parent with the genetic variant has a child, there is a 50% chance of passing on the copy of the gene with the variant, and a 50% chance of passing on the copy without a variant. The chances are equal for males and females.

Currently, the majority of proven genetic causes of FTD follow the pattern of autosomal dominant inheritance. It is believed that there are likely other factors, both genetic and environmental, that influence an individual’s risk of developing FTD. There may be genes or specific variants that do not directly cause FTD but rather increase susceptibility. This type of genetic finding is referred to as a risk factor. It is also likely that a combination of both genetic and environmental factors can influence the risk of FTD; this is often referred to as multifactorial inheritance. Research is underway to determine other risk factors that play a role in the development of FTD.

Another type of inheritance pattern that has been described in FTD is X-linked. In X-linked inheritance, there is a variant in a gene on the X chromosome. Typically, women have two X chromosomes, and men have one X and one Y. Because men typically only have one copy of the X chromosome and therefore only one copy of the X-chromosome genes, men are more likely to be affected by X-linked disorders, though sometimes women may have symptoms.

Penetrance in Genetic FTD

Penetrance is an important concept to review to better understand the genetics of FTD. It is a term used to refer to the likelihood that a genetic variant will cause FTD or related disorders. It refers to the proportion of individuals with a genetic variant who will develop symptoms of the condition. Complete penetrance occurs when every individual with a particular gene variant develops symptoms. Incomplete or “reduced” penetrance occurs when some individuals with a particular genetic variant develop symptoms of the condition, while others with the variant do not develop symptoms.

Sometimes the term “age-dependent penetrance” is used in FTD. This means that, for an individual with a genetic variant, the likelihood of symptom onset increases with age. Even though the genetic variant is something the person is born with, it does not cause them to develop symptoms until adulthood.

For many reasons, penetrance can be difficult to accurately determine. For example, sometimes one gene variant can cause a wide range of symptoms, such as symptoms of FTD or related conditions like ALS. This can make it difficult to assess what counts as developing symptoms. Additionally, sometimes variants can be rare, with limited data to help better understand penetrance.

Penetrance refers to the proportion of individuals with a genetic variant who will develop symptoms of the condition. Complete penetrance occurs when every individual with a genetic variant develops symptoms of the condition. Incomplete or “reduced” penetrance occurs when some individuals with a genetic variant develop symptoms of the condition while others do not.

Genes & Family History (originally pg8).png

Autosomal Dominant Inheritance (originally pg 9).png

The Concept of Penetrance (originally pg13).png

Genes Associated with FTD

All the genes described in this section can cause genetic FTD. All the genetic forms of FTD described follow the autosomal dominant pattern of inheritance except for UBQLN2, which follows the X-linked pattern of inheritance. While this list describes some of the more common known genes associated with FTD, new gene contributions are still being discovered.

C9orf72 – Found on Chromosome 9

In 2011, after many years of research, the Chromosome 9 open reading frame 72 gene (C9orf72) was identified as causing both FTD and ALS. The function of the C9orf72 protein is not yet understood. Individuals with the C9orf72 variant have abnormal accumulations of the TDP-43 protein in affected neurons.
The variant in C9orf72 is an expansion, meaning a section of DNA which normally is repeated several times has an increased number of repeats. The section of DNA is referred to as a hexanucleotide repeat, which means that 6 (hexa) units of DNA (nucleotides) are repeated, causing an expansion in the gene that negatively impacts the gene’s ability to create a functional protein. The expansion is sometimes called “G4C2.”
While TDP-43 inclusions are the main pathology associated with C9orf72 forms of FTD/ALS, there are also additional brain pathologies found including accumulations of RNA (a molecule that carries instructions from DNA to make proteins) and translated protein from the expanded portion in the C9orf72 gene.
The C9orf72 variant can cause FTD, ALS, or a combination of both FTD and ALS. Research is ongoing to better understand how this gene variant can lead to two different types of clinical symptoms.
The C9orf72 expansion is believed to be the most common genetic cause of hereditary FTD in people of European descent. A C9orf72 pathogenic expansion is found in up to 10% of people with FTD without known family history, and in ~30% of people with familial FTD.
- A wide range of symptoms, disease progression, and age of onset are seen both between families and within the same family.
  - Average age of onset is 58.2 years (range 20-91 years), with average illness duration of 6 years
  - Symptoms can include those related to behavior, language, and muscle/motor neuron
  - Other presentations may include Parkinsonian symptoms or psychiatric symptoms
Our understanding of the penetrance of C9orf72 is evolving. While initial estimates suggested that about 50% of people developed symptoms by age 50 and nearly 100% by age 80, recent studies have found penetrance may be lower than initially estimated. Indeed, C9orf72 penetrance may depend on other factors, such as family history and/or genetic modifiers. Though we have more to learn about penetrance for C9orf72, what is clear is that not everyone with an expansion will develop symptoms.

Microtubule – Associated Protein Tau (MAPT) – Found on Chromosome 17

MAPT was the first gene associated with genetic FTD, in 1998. MAPT codes for the protein tau and individuals with a pathogenic variant in MAPT have abnormal accumulations of the tau protein in affected neurons.
Pathogenic variants in MAPT account for 5-20% of familial FTD. People who have FTD due to MAPT will most often have a family history of other affected relatives. A pathogenic MAPT variant is found in up to 2% of people with FTD without a known family history.
- A wide range of symptoms, disease progression, and age of onset are seen both between families and within the same family.
  - Pathogenic variants in MAPT are associated with a wide range of FTD subtypes including bvFTD, non-fluent variant PPA, semantic variant PPA, PSP, and CBS. The most common subtype associated with MAPT variants is bvFTD.
  - Average age of onset is 49.5 years (range: 17-82), with an average duration of illness being 9 years.
  - Among the genetic forms of FTD, it appears that MAPT has the tightest correlation for age of onset among family members; in other words, the age of onset of FTD in the family can help predict the age other people in the family may develop FTD, but this is not a perfect estimate.
There have been over 65 MAPT pathogenic variants identified. Most pathogenic variants in the MAPT gene have complete or near complete (>95%) penetrance.

Progranulin (GRN) – Found on Chromosome 17

GRN was discovered as a cause of FTD in 2006 and codes for the protein progranulin. Individuals with a pathogenic variant in GRN have abnormal accumulations of the TDP-43 protein in affected neurons.
Pathogenic variants in GRN account for 5-25% of familial FTD. People who have FTD due to GRN most often have a family history of other affected relatives. A pathogenic GRN variant is found in about 5% of people with FTD without known family history.
- A wide range of symptoms, disease progression, and age of onset are seen both between families and within the same family.
  - Pathogenic variants in GRN are associated with a wide range of clinical syndromes including bvFTD, nonfluent variant PPA, CBS, or a memory problem resembling Alzheimer disease. Moreover, these clinical features of these syndromes can often be found in combination and can evolve over time. The most common subtype associated with GRN variants is bvFTD.
  - Average age of onset is reported as roughly 61years (range: 25-90 years), and average duration of illness is 7 years with a wide range of approximately 3-12 years.
Incomplete or age-dependent penetrance has been reported. About 50% of people with a pathogenic variant in GRN experience symptoms by age 60, and about 90% of people have symptoms by age 70.
There have been studies of genetic modifiers that may influence GRN penetrance. One modifier identified is the TMEM106B gene. Some people have a version of their TMEM106B gene that has a protective effect, such that even if they have a pathogenic variant in GRN, they may not definitely develop FTD. Ongoing research is studying TMEM106B and other genetic variants which could influence the penetrance and clinical expression of GRN.
Scientists have learned that pathogenic variants in GRN cause FTD because GRN is unable to make enough progranulin (the protein GRN produces). This type of mechanism is called “loss of function.” This in turn gives drug developers a target for creating potential therapies. The focus of many GRN-FTD clinical trials is to try to raise progranulin levels in the brain with the hope that this would slow or stop progression of FTD. If these therapies show promising results, additional trials may be run to give the therapeutics to people who know they have a pathogenic variant in GRN but do not yet have symptoms of FTD, in the hopes of preventing or delaying the onset of FTD (i.e. preventative clinical trials).

Some other genes more rarely associated with FTD:

Annexin A11 (ANXA11)
- Pathogenic variants in ANXA11 have been associated with ALS. Several variants have also been reported in people with FTD, PSP, and IBM.
- Pathology is defined by annexin A11 aggregation.
Coiled-coil-helix-coiled-coil-helix domain-containing protein 10 (CHCHD10)
- Pathogenic variants in CHCHD10 are a rare cause of FTD and/or ALS. Some variants in this gene have also been associated with other muscle disorders.
- Pathology is defined by CHCHD10 protein aggregation and variable TDP-43 pathology.
Charged multivesicular body protein 2B (CHMP2B)
- Pathogenic variants in CHMP2B are an extremely rare cause of FTD, only found in a few families world-wide (predominantly Danish and Belgian)
- Average age of symptom onset is 58 years (range 46-65 years)
- Most often associated with ubiquitin proteasome system (UPS) pathology (FTLD-UPS).
Fused in sarcoma (FUS)
- Pathogenic variants in FUS are very rare. These are more commonly associated with hereditary ALS than FTD.
- When a person has FTD due to a pathogenic variant in FUS, they tend to present with bvFTD, be younger at age of onset, and have a more rapidly progressive illness.
- Most often associated with FUS pathological inclusions (FTLD-FUS).
Sequestosome 1 (SQSTM1)
- Pathogenic variants in SQSTM1 are a rare cause of FTD. Some variants in this gene have been associated with Paget disease of bone, as well as ALS, in addition to bvFTD.
- Most often associated with atypical TDP-43 distribution, but can also be associated with multiple protein inclusions including tau, FUS, and alpha-synuclein.
TAR DNA-binding protein (TARDBP)
- Pathogenic variants in TARDBP are very rare. These are more commonly associated with hereditary ALS than FTD but can present with bvFTD with a temporal lobe predominance of atrophy.
- Associated with TDP-43 pathology.
Tank-binding kinase 1 (TBK1)
- Pathogenic variants in TBK1 have been associated with both ALS and FTD.
- It is understood that the mechanism is loss-of-function, similar to GRN, which may inform future approaches for clinical trials.
- Most often associated with TDP-43 pathological inclusions.
Ubiquilin 2 (UBQLN2)
- Pathogenic variants in UBQLN2 are a rare cause of FTD and ALS.
- This genetic form of FTD is associated with X-linked inheritance.
- Most often associated with both TDP-43 and ubiquilin-2 pathological inclusions.
Valosin-containing protein (VCP)
- Pathogenic variants in VCP can cause a wide variety of clinical presentations including FTD, ALS, inclusion body myopathy (IBM), and Paget disease of the bone.
- One specific pathogenic variant in VCP causes a condition called vacuolar tauopathy which is an early-onset, autosomal dominant form of behavioral variant of FTD.
- IBM is characterized by slowly progressive muscle weakness beginning in the teens to early adulthood. About 90% of people with a pathogenic variant in VCP develop weakness, with average age of onset being 45 years.
- Paget disease of the bone is characterized by enlarged and misshapen bones. About 51% of people with a pathogenic variant in VCP have osteolytic bone lesions (areas of bone where normal tissue has been broken down, leading to reduced bone density).
- Pathogenic variants in VCP account for a very small percentage of FTD and are typically found in families with the specific constellation of symptoms as described above. About 32% of people with a pathogenic variant in VCP develop FTD, with average age of onset being 54 years.
- There is a wide range of symptoms, disease progression, and age of onset both between families and among families with a VCP variant. Affected individuals may develop FTD, IBM, Paget disease of the bone or any combination of the three conditions.
- Most often associated with TDP-43 pathological inclusions but in rare instances can be associated with vacuolar tauopathy.

Genetic Counseling

Genetic counselors are healthcare providers who meet with individuals who have a personal and/or family history of a condition that can have a genetic cause. Genetic counselors can discuss available types of genetic tests, the potential benefits and limitations of genetic testing, what types of information can be learned with genetic test results, and what the results could mean for an individual and their family. Genetic counselors review your personal and family medical history to provide a risk assessment, which means they help determine the likelihood that a condition in the family is genetic. Genetic counselors also provide emotional support and resources as people adjust to living with a diagnosis or living at risk for a condition. Having an appointment with a genetic counselor does NOT mean a person has to have genetic testing. Some people know they don’t want to have genetic testing but still find value in talking with a genetic counselor for information and support.

Genetic Testing

Genetic testing for FTD is performed by analyzing a DNA sample for variants in the genes known to cause FTD. This process is like the concept of spell-checking a document, looking for any typos. The DNA is typically obtained from a cheek swab (buccal) sample, saliva (spit kit) sample, or blood sample. Sometimes under certain conditions other sample types, such as tissue from an autopsy, can be used for testing a deceased person.

Clinical genetic testing is available for genes currently known to cause FTD. Typically, a multi-gene panel that includes genes associated with FTD and related disorders (such as ALS and Alzheimer disease) is recommended. If the genetic cause of FTD has already been identified in the family, sometimes targeted testing will be recommended (testing only for the known variant in the family). If genetic testing for the most common causes of FTD does not identify a causal variant, broader testing such as exome or genome sequencing may be offered. These tests evaluate nearly all the genes in the DNA, rather than focusing on the ones known to be linked to FTD. A genetic counselor or other clinician with genetics expertise will determine the most appropriate genetic test(s).

To obtain a clinical genetic test, a clinician such as a genetic counselor or neurologist orders the test from a clinical laboratory that is licensed and certified to provide clinical genetic testing services. The Clinical Laboratory Improvement Amendments (CLIA) establish quality standards for laboratory testing in the United States to ensure accurate and reliable reporting. Laboratories used for clinical genetic testing are CLIA-certified. Testing for a multi-gene panel is usually completed in 2-4 weeks, although for broader testing it may take up to 4 months for results. Most often, insurance companies cover some or all the costs of testing, but policies vary regarding coverage and reimbursement for genetic testing services. Costs of clinical genetic testing can vary from a few hundred dollars for a multi-gene panel to over a thousand dollars for broader tests like exome or genome. The results of the clinical test would be reported back to the provider who ordered the test, so that the results can be disclosed by the provider and recorded in the medical record.

Many FTD centers conduct research studies. Some studies may include genetic testing; however, research testing is not typically aligned with CLIA standards, and policies vary regarding whether results from the research tests would be returned to the individual. When participating in a genetic research study, ask whether results are shared with participants. If results are shared with participants, ask when and how results might be communicated; often research testing takes much longer to complete than clinical testing.

There are sometimes opportunities for people to participate in a sponsored genetic testing program, if one is available. Sponsored testing programs offer genetic counseling and genetic testing at no cost. These programs are sponsored by biopharmaceutical companies or nonprofit entities interested in identifying groups of people who may benefit from their organization’s work. In exchange for no-cost genetic counseling and testing, the sponsor may receive deidentified data for research purposes. The sponsor does not gain access to the person’s identifiable information. It is important that people consider whether they are comfortable with data sharing; each program has different data sharing policies.

As described in the “Genes and Family History” section, family history provides the biggest clue as to whether genetic testing might detect an FTD-causing variant. Typically, the stronger the history of dementia, ALS, and/or movement disorders in other family members, the greater the possibility that there is a genetic variant responsible. Not every individual with a family history of neurodegenerative conditions will have a detectable genetic variant, but it does provide some insight regarding the possibility. There is a much lower likelihood of finding an FTD genetic variant in an apparently sporadic family pedigree; however, sometimes variants are found in people with FTD who do not have a family history suggestive of a hereditary form.

Any person diagnosed with FTD has the option to pursue genetic testing. Although a genetic cause is more likely to be found in those individuals who also have a family history of FTD or other neurodegenerative conditions, all people with FTD should be offered the opportunity to consider genetic testing. For specific questions about genetic testing for FTD, it would be best to speak with a clinician familiar with genetic testing, such as a genetic counselor.

Genetic Testing for Individuals with FTD

If a person with suspected FTD is found to have a pathogenic variant in a gene associated with FTD, this would support the accuracy of the person’s clinical diagnosis. It also answers the question of why a person developed FTD, which can bring answers to those wondering what caused the condition. In some cases, it can provide insight into the expected disease progression, in terms of duration or types of symptoms. For example, a genetic result may inform a person with FTD that they are at increased risk of developing symptoms of ALS if a pathogenic variant is found in a gene also linked to ALS, such as C9orf72. The identification of a genetic cause for FTD would also determine the risk to other family members for inheriting the same genetic variant. At the time of this publication, there is not an FDA approved medication or treatment available that would be given based on the results of a genetic test; however, the results may prevent the person from getting additional, unnecessary testing or prevent treating the person for the wrong diagnosis. There are some ongoing gene-targeted clinical trials that a person with a genetic form of FTD may be eligible for, and as the field of FTD research advances, people with genetic FTD might be candidates for new treatment options.

Genetic Testing for Family Members of Individuals with FTD

Once a disease-causing genetic variant has been found in an individual affected by FTD, this information can be used to provide genetic counseling and testing to other individuals in the family. If a genetic cause for FTD is found, it is strongly encouraged that this information is shared with family members.

Affected family members can be tested specifically for the known variant to confirm its presence.

Unaffected adult family members who are at risk of inheriting the variant can choose to have predictive genetic counseling and consider genetic testing. Predictive genetic testing refers to testing a person without disease symptoms to determine whether they have inherited the genetic variant that causes FTD in their family. This is also sometimes called presymptomatic genetic testing, but this term is less accurate when genetic variants do not have complete penetrance. At this time, there are no preventative options available for FTD. The decision to pursue predictive genetic testing is entirely personal in nature and should be carefully considered. This testing is only available to adults (18 years of age or older), as it must be each person’s individual choice to decide whether they want to know their genetic risk status. There are many reasons a person may want to learn their genetic risk status, and many reasons why they may not want this information as well. It is very important that anyone considering predictive testing meets with a genetic counselor.

The predictive testing process provides a structured, thorough, and supportive approach to the personal decision to learn one’s genetic status. To accomplish this goal, predictive genetic testing may involve several visits with a genetic counselor. These pre-test genetic counseling sessions include detailed discussion of the testing decision. Prior to learning one’s predictive test result, it is important to explore the potential impact of the results and the risks and benefits of testing for the person being tested, their relatives, and their significant others. Before a testing decision is made, a genetic counselor can help an individual to explore the motivations or reasons for learning the test result. Genetic counselors can also help people considering predictive testing to understand what genetic test results cannot tell us, such as what exact symptoms will develop or when symptoms will begin, or in some cases, if symptoms will definitively develop at all. Some clinics may recommend the individual have a neurology exam and/or a mental health evaluation as part of the genetic testing process.

The predictive genetic testing results are reviewed during an in-person or video visit. Most centers strongly recommend bringing a support person throughout the predictive counseling process, and in particular to the results disclosure visit. The provider ordering genetic testing will discuss any special considerations for results disclosure, such as their institution’s policies for avoiding auto-release of results via a patient portal ahead of a disclosure visit.

If the individual has not inherited the genetic variant, they are not at risk for the hereditary FTD that has affected other family members. In most cases, the individual would have the same risk for neurodegenerative conditions (including FTD) as the general population. If the individual has inherited the pathogenic variant, they are at risk for developing FTD at some point in their life, and the specific risk would depend on the penetrance of the variant in the family. It is nearly impossible to predict the exact age of onset or the type of symptoms to expect, but in some cases, the specific gene or gene variant may provide some additional insight into the risk.

If a genetic cause for FTD has not been found in the family, predictive genetic counseling is still available. However, if genetic testing is desired, there are major limitations to predictive genetic testing in the absence of a known genetic cause of FTD in the family. While testing for FTD related genes can be completed, there is the chance of identifying uncertain results. Importantly, a negative result would be considered uninformative and would not rule out increased risk of FTD. This is because it is impossible to determine if the testing included the cause of FTD in the family, or there could be a yet-to-be identified gene or type of genetic variant contributing to the FTD in the family that was not evaluated on testing.

There are many factors that people consider when deciding about predictive genetic testing. A genetic counselor can help a person understand their predictive testing options, and help them explore their motivations, concerns, and potential impact of testing to facilitate decision-making.

Genetic Testing for Family Planning Reasons

The topic of family planning is immensely personal. When there is genetic FTD in the family, there may be difficult feelings and questions to face regarding starting a family. Often individuals are concerned about passing the genetic risk on to their own children, the next generation of the family. There are reproductive technologies, such as preimplantation genetic testing (PGT), that have been developed to address this concern. In PGT, the process of in vitro fertilization (IVF) is used to develop embryos. These embryos then undergo genetic screening, and only embryos that did not inherit the variant are used for implantation. PGT is only one example of available reproductive options. Some individuals choose to do prenatal diagnostic testing, which is when the couple conceives a pregnancy naturally, and then tests the pregnancy using chorionic villus sampling (CVS) or amniocentesis to determine whether the fetus inherited the FTD-causing variant. If the fetus inherited the variant, the couple would have the option to have an abortion (depending on resources available at their location). There are ethical, legal, emotional, logistical/access, and financial considerations for these options that should be explored with a genetic counselor. Other family planning options include gamete (egg or sperm) donation, adoption, natural conception, or the decision not to have children. For individuals that desire more information and support regarding family planning, it is advisable to schedule a consultation with a physician or genetic counselor who specializes in providing preconception and prenatal genetic services.

Accessing Genetic Counseling and Genetic Testing

To have a clinical appointment with a genetic counselor, you can ask your neurologist or primary care physician for a referral. You can also locate a genetic counselor near you using the Association for Frontotemporal Degeneration (AFTD) interactive resource locator map: https://www.theaftd.org/find-support/ or the National Society of Genetic Counselor’s tool: https://findageneticcounselor.nsgc.org. Sometimes, you may be able to access genetic counseling and testing through a research study, such as an observational study or a program associated with a clinical trial. Research studies can be located using https://clinicaltrials.gov or by joining the FTD Disorders Registry. Finally, sometimes genetic counseling services are available as part of sponsored testing programs. Sponsored programs can be identified at https://www.theaftd.org/ftd-genetics/genetics-no-cost/.

Clinical Trials

There have been several clinical trials for interventions that target mechanisms specific to some genetic forms of FTD.

A clinical trial is a research study conducted in humans with the goal of answering specific questions about new therapies, diagnostic procedures, or new ways of using known treatments. Clinical trials are used to determine whether new drugs, diagnostics, or treatments are both safe and effective. Clinical trials have different phases in the process to develop new therapies or interventions, and these can differ in terms of the design and goals of the trial.

If a person is considering participating in clinical trials it is important that they ask questions of the study team and their medical team to determine if a specific trial is right for them. The person should ask about the time commitment and number of visits, the safety and risk information of the experimental intervention, the procedures involved in the trial and goals of the study. Some clinical trials involve the use of a placebo to prove the effectiveness of an experimental therapy, meaning a participant could be given a control intervention without a biological effect. This is often “blinded”, meaning the participant, study doctor and team do not know if the participant is getting the placebo or study drug, and “randomized”, meaning it is random chance (like flipping a coin) who receives placebo versus study agent. Many clinical trials include a period of the study where all participants receive the experimental study agent, called an open-label period. Thus, it may also be helpful to ask the study team about the chances of placebo and open-label period in a clinical trial. Each study also has specific eligibility criteria so the researchers can be confident that any changes they see are due to the study intervention, not a result of other factors. The National Institutes of Health and the US Office for Human Research Protections have useful resources for questions to ask before participating in clinical trials: https://www.clinicaltrials.gov/study-basics/learn-about-studies

One mechanism studied for gene-targeted clinical trials is genetic therapy (or gene therapy). If a variant is like a spelling mistake, gene therapy acts as the spell check and can fix the mistake or rewrite the word. There are several types of genetic therapy: cell therapy, gene editing, gene transfer, and gene silencing.

Cell therapy introduces a new gene into cells to help fight a condition. This is often done by removing an individual’s own cells and delivering the genetic material to these cells outside of the body. The modified cells are then returned to the body.
Gene editing corrects pieces of DNA by changing or deleting the information within the affected gene. Genetic material is sent to directly edit or change pieces of DNA already located within a cell to correct the protein being made by that DNA.
Gene transfer is the insertion of a functional genetic product into the body with the intent that it will work in place of the mutated gene. This is often accomplished using a carrier, called a vector. The most common gene therapy vector is viruses since viruses can recognize certain cells and carry genetic material into the cells’ genes. Gene-targeted clinical trials in FTD have tested the gene transfer method of inserting a functional genetic product into the central nervous system to get into cells in the brain (neurons). To deliver the functional genetic product directly to neurons, some trials have delivered to a space near the brain called the cisterna magna, while others have delivered directly into the brain.
Gene silencing involves delivering biological molecules called antisense oligonucleotides or silencing RNAs which either reduce or correct the expression of disease-associated genes.

Another treatment option for gene-targeted clinical trials is protein replacement therapy. Protein replacement therapy is an umbrella term for medical treatments that aim to substitute or replenish specific protein deficiencies that result either from the protein being absent or non-functional due to pathogenic variants. Where gene therapy alters the genetic code to help individuals’ cells make their own proteins, protein replacement therapy directly delivers healthy protein to the body. In the case of neurodegenerative conditions, it’s important that the healthy protein is delivered to the brain.

The final treatment strategy that is currently being used for gene-targeted clinical trials in FTD is immunotherapy. Monoclonal antibodies are laboratory-produced proteins that act like the body’s natural immune system to recognize a specific target. These are proteins that are designed to target and bind to specific antigens, which are molecules on the surface of cells that can have various effects, including triggering cell destruction, blocking cell growth, flagging specific cells, and more. In the case of current FTD genetic trials, the monoclonal antibody stops the breakdown of proteins that are needed in the brain. This helps to boost the amount of protein in neurons, which may stop or slow the progression of FTD.
This is a brief overview of the recent and ongoing experimental mechanisms in clinical trials that a person with a genetic form of FTD may be eligible for, but the field of FTD research is continually growing, and new approaches may emerge beyond those discussed thus far. The FTD Disorders Registry is a great way for people to stay up to date on current research activities and opportunities: https://ftdregistry.org/.

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Q&A FAQs for FTD Genetic Testing

The following reviews some of the most frequently asked questions about genetic testing for FTD. If you have questions that are not addressed, please contact a genetic counselor or other clinician familiar with genetic testing.

Q: What is genetic counseling?

A: The goal of genetic counseling is to help people understand more about the genetic causes of FTD and how it may affect them so they may make informed decisions. Genetic counselors can explain how genetic conditions are inherited, assess an individual’s risk, provide options and guidance for genetic testing, help you weigh the benefits, risks and limitations of testing, and recommend other supports and resources. Genetic counselors can also explore a person’s experience with a condition and help them get connected to resources as they adapt to living with FTD in the family.

Q: Is there a genetic test for FTD?

A: Yes, clinical genetic testing is available to look for pathogenic variants in genes that can cause FTD such as MAPT, GRN, C9orf72, and more. Often genetic testing is completed using a multi-gene panel. Such panels can include genes related to FTD as well as overlapping conditions such as ALS and Alzheimer disease. To date, variants in more than 30 genes have been associated with FTD and/or ALS. You can ask your health care provider to refer you to a genetic counselor to receive more details about the specific genetic testing options that are most appropriate based on your symptoms and family history.

Q: How is the genetic test done?

A: There are three main ways to collect samples for genetic testing. These include a blood draw, a cheek swab (buccal), and saliva (spit) test. These samples can be used by the laboratory to isolate DNA. This DNA sample can then be analyzed for variants in the specific genes of interest. For individuals with FTD, a panel of the genes known to cause FTD is typically the first line of testing. If those results are negative, additional broader testing could be considered to look for any potential genetic variants that could cause FTD. However, for individuals that already know the specific gene variant that is present in their family, the genetic test can be targeted to just check for that known family variant.

Q: Who can get genetic testing?

A: Any individual diagnosed with FTD who is interested in genetic testing may get tested. A genetic cause is more likely in those who have a family history of FTD. The testing process for a family is most informative when a person diagnosed with a condition (FTD, or a related condition like ALS) is the first person tested. Once a genetic cause has been identified in an affected individual, other adult members of the family (18 years of age or older) may choose to be tested for the same variant even if they don’t have symptoms of FTD (predictive genetic testing). Any asymptomatic adult considering predictive genetic testing should speak with a genetic counselor prior to genetic testing.

Q: If I already have FTD, what would a genetic test tell me?

A: If a person has a diagnosis of FTD, a genetic test can identify whether the FTD is being caused by an underlying genetic variant. Genetic testing may help confirm the diagnosis, as finding a pathogenic variant in a gene associated with FTD would provide evidence towards the diagnosis made by the clinician. If a genetic cause is identified, the specific results (the gene and variant information) may help the person with FTD and their family better understand what to expect for the future. For example, there may be data available to inform expectations for progression and range of possible symptoms based on the variant identified. Testing may also help to identify opportunities for clinical trials and future treatments. Furthermore, genetic testing can better define the risk of FTD for other family members. There are three possible types of genetic test results: positive, negative, and uncertain.

Positive: A positive test result means the individual has an FTD-causing variant. A positive test result indicates that a genetic cause of FTD has been found. This provides the information detailed above and would further define the risk for other family members to develop FTD and allow them to pursue predictive genetic testing if interested.

Negative: A negative test result means the individual does not have a pathogenic or likely pathogenic variant in the tested gene(s). However, a negative result does not entirely rule out the possibility of a genetic cause for the following reasons:

Not all genes may have been tested. For example, some tests may look at only one specific gene, whereas others may test multiple genes.
Genetic testing methods may vary. For example, some tests only look for specific variants, whereas others look for any and all variants in the gene.
Not all genetic causes are known. Scientists are still working to find other genes that contribute to FTD.

Uncertain: An uncertain or indeterminate result means that a variant was found in a gene, but the laboratory cannot yet make a clear determination as to whether it is a disease-causing variant, a risk factor, or a benign polymorphism. Benign polymorphisms are common variations in DNA that do not cause health problems. An indeterminate result is sometimes called a variant of uncertain significance (VUS).

The interpretation of genetic test results can be confusing, and can change over time as new data becomes available. It is recommended that anyone who has genetic testing for FTD discuss the results with a genetic counselor or another medical genetics professional.

Q: What happens if I have one or more variants of uncertain significance (VUS) identified on genetic testing?

A: The interpretation of genetic test results can be complex; it is recommended that you review the results of genetic testing with a genetic counselor or another medical genetics professional. Sometimes, there are additional steps to try to clarify the meaning of a VUS. For example, if there are other living relatives with similar symptoms, testing them for the VUS may help the health care team understand whether the VUS tracks with FTD in the family. There may be research analyses that can be completed to assess the impact of the variant on the gene’s function. Genetics professionals can help to determine what follow up may be useful in understanding the variant in the present and can help reevaluate VUSs over time. Typically, commercial laboratories issue updated test reports with revised variant interpretation if enough data becomes available to reclassify a VUS as benign or pathogenic. It is common for VUSs to remain classified as uncertain for a long time, especially when there is limited data available. Health care providers typically do not recommend any medical management changes based on a VUS, nor do they recommend predictive testing of asymptomatic relatives, but each situation should be discussed with a genetics professional for individualized guidance.

Q: If I have a genetic form of FTD, what can be done about it?

A: Currently, there are research studies looking into new technologies for treating genetic conditions, but this is currently not available as a medical treatment for FTD. Identifying a causative genetic variant in a person diagnosed will not provide a cure for FTD but it increases diagnostic certainty and helps avoid any subsequent treatment for the wrong diagnosis (e.g. Alzheimer disease or psychiatric disorder).

Q: What causes a genetic variant?

A: In FTD, most identified genetic variants are passed from parent to child throughout many generations. There is likely an ancestor who was the first person to have the variant. In the genetics profession, this ancestor is referred to as the “founder.” It can be very difficult to determine why the variant ever occurred in the first place. Sometimes, there is a region of DNA that is less stable and prone to changes (i.e. variants or mutations). Our bodies can detect and correct these mistakes, but sometimes not every mistake is corrected. Genetic variants due to environmental exposures can occur but are typically restricted to the exposed person and it is unlikely the variant could be passed to the next generation. There are no reports of genetic variants causing FTD due to environmental factors. When a person has genetic FTD, they are born with the genetic variant.

Q: What are the risks that my child will also get FTD?

A: Most of the genetic forms of FTD are inherited in an autosomal dominant pattern. In this case, if an individual has a pathogenic variant in one of the known FTD associated genes, there is a 50% chance of passing on the pathogenic variant and a 50% chance of NOT passing on the pathogenic variant to his/her child. This same 50/50 risk applies to each conception. If the child inherits the pathogenic variant, he or she will most likely develop symptoms of FTD at some point in adulthood, but the age of onset, severity, and type of symptoms cannot be predicted at this time.

If an individual with FTD does not have a pathogenic variant in a known FTD gene and does not have a family history suggestive of a hereditary cause, the risk to children is much lower and is likely close to the general population risk, which is low. If an individual with FTD does not have a genetic cause identified, but does have a family history suggestive of a hereditary cause, it is important for that family to consider getting involved with an FTD genetic research study to try to determine whether a genetic cause or risk factor can be identified. This information would be crucial for providing accurate information to individuals possibly at-risk. As with any condition, there may be both environmental and/or genetic risk factors that could increase susceptibility. At this time, there are no known risk factors that could indicate susceptibility to FTD, but ongoing research is working to better understand risk factors for FTD.

Q: What is the difference between clinical and research genetic testing?

A: The purpose of clinical genetic testing in a medical setting is to provide health information for the person with FTD and their family. The test is performed in an accredited laboratory. A report of the results is generated and will be part of the official medical record. There is a charge for clinical testing, which may or may not be covered by insurance. Clinical genetic testing does not help scientists discover a cure or new treatments for FTD and currently the results do not affect medical management (because there are no approved treatments). However, results may lead to new research opportunities (e.g. gene-targeted clinical trials) and have other benefits for the diagnosed person and their family members.

The purpose of research genetic testing is to discover and better understand the genetic causes of FTD and how these impact clinical presentation and brain pathology. In research, personal identifiers remain confidential and results do not become part of the participant’s official medical record. There is no fee when participating in a research study, and whether results are returned to participants depends on the study protocol and the type of genetic testing being completed. Many individuals choose to participate in research genetic testing to help advance FTD science for the benefit of future generations. Research genetic testing may lead to a better understanding of the causes of FTD and the development of better treatments or a cure in the future. Research testing may also identify or test for new disease-associated genes before they are available as a clinical test.

Q: If I have a family history of FTD, should I be tested even if I do not have symptoms?

A: Testing a person who is currently not showing symptoms, but who is at risk for inheriting a known family variant is called predictive (or presymptomatic) testing. For predictive testing, it is most informative if a causal variant is first identified in the family so that the clinician knows the appropriate test to order and can properly interpret the results. If a genetic cause of FTD or a related condition is not yet known in the family, genetic testing can still be considered, but the interpretation of the results is complex (e.g. a negative result would not entirely rule out risk, and uncertain variants may be detected). Individuals in the same family may have differing opinions on whether to pursue predictive testing. The pursuit of predictive testing is a very personal decision that may be confusing and emotionally difficult. Therefore, genetic counseling and mental health assessment are usually required to help the individual throughout the testing process.

Q: If I am asymptomatic but found to have a pathogenic variant, will I definitely get FTD?

A: The implications of genetic test results vary and should be discussed with a genetic counselor in the context of personal and family medical history. Some genetic variants will not always cause symptoms. This is called incomplete penetrance; not everyone with the variant will develop FTD. Penetrance can differ based on the relevant gene, as well as the specific variant within a gene. Sometimes, there are other genetic or environmental factors that modify risk of symptom development. Additionally, some genetic variants can cause a wide variety of symptoms (“variable expressivity”). For example, a person found to have a pathogenic repeat expansion in C9orf72 can develop FTD, or ALS, or symptoms of both conditions, or none at all. In this case, we cannot predict if, when, or what exact symptoms will develop based on the genetic test result.

Q: Is there protection from genetic discrimination?

A: The Genetic Information Nondiscrimination Act (GINA) was signed into federal law in 2008. GINA provides legal protections against genetic discrimination in health insurance coverage and matters related to employment. Two exceptions to this coverage are for those employed by the military (although subsequent protections were passed for military personnel) and those employed by small companies with less than 15 employees. GINA does not provide protections for life insurance, long-term care insurance, or disability insurance. Individuals who are considering predictive genetic testing to determine their risk for FTD are encouraged to learn more about protections GINA does and does not provide (A guide to GINA is provided in “Helpful Links and Resources”.) There are also some additional protections provided by state laws; individuals should check the legal protections available in their home state. Finally, there is always a possibility for future changes to legislation that cannot be predicted.

Q: If I did not inherit the genetic variant that caused FTD in my family, could FTD still appear in my own children?

A: If an individual has been tested for a pathogenic variant that is known to cause FTD in their family, and they do not have it, they are not at risk themselves for genetic FTD. Additionally, if they did not inherit the variant, they cannot pass it to their own children.

Sometimes people refer to the idea of a condition “skipping a generation;” this is a common genetic myth. A truly genetic condition cannot skip generations, as the only way to get the condition is the direct inheritance of a disease-causing variant from parent to child.

There are several reasons a genetic condition may appear to skip a generation in a family, even though the genetic variant itself does not skip a generation. For example, an individual with the genetic variant may die from an unrelated cause, like cancer or heart disease, in early adulthood before ever developing symptoms. Also, some variants do not always cause symptoms because of incomplete penetrance. In both of these scenarios, the person with the genetic variant can still pass it on to the next generation, even though they never became symptomatic themselves.

Q: Everyone has always said that I look and act just like my parent, who has been diagnosed with FTD. Does this mean I’m more likely to also get FTD?

A: Having a resemblance to or characteristic of a relative with FTD does not increase the risk of also developing FTD. It can be very easy to assume that if we strongly resemble one of our parents, we are destined to share the same fate. From a purely biological standpoint, humans are a 50/50 combination of both parents’ genes, even if a person cannot see that combination by looking in a mirror. The vast majority of FTD is inherited in an autosomal dominant pattern, meaning a parent with the FTD-causing variant has a 50% chance of passing the variant to each child and a 50% chance of not passing it. A person’s biological sex has no influence on transmission; a parent’s sex does not affect the likelihood of passing on the variant, and a child’s sex does not affect the likelihood of inheriting it.

Glossary of FTD and Genetic Terminology

Allele – Another word for gene. Sometimes used when referring to different versions of a gene.

Amino acids – Small chemical units that link together to form a protein.

Autosomal dominant – A type of inheritance in which only one copy of a gene pair needs to have a pathogenic variant to cause the condition.

Behavioral variant FTD (bvFTD) – The clinical term for an individual with behavioral and personality changes as the primary symptoms of FTD.

C9orf72 – A gene of unknown function with a specific type of variant, called a hexanucleotide repeat expansion (a large, repeated section of genetic material) on chromosome 9. This is currently understood to be the most common genetic cause of hereditary FTD and/or ALS in people of European ancestry.

CHMP2B – A very rare cause of genetic FTD, this gene makes the charged multivesicular body protein 2b.

Chromosome – A unit of tightly wound and packaged DNA. Each chromosome has thousands of genes.

Co-pathology – The coexistence of two or more distinct pathological protein aggregates in the same brain.

Corticobasal syndrome (CBS) – An FTD-related diagnosis that typically first presents with motor symptoms, similar to Parkinson disease. The term corticobasal degeneration (CBD) is also used but usually is reserved for the final autopsy diagnosis of this condition.

DNA – Deoxyribonucleic acid. DNA is a long, double-stranded structure of genetic material.

Frontotemporal degeneration (FTD) or Frontotemporal dementia (FTD) or Frontotemporal lobar degeneration (FTLD) – These terms are used interchangeably to refer to a spectrum of disorders that cause progressive changes in personality, behavior, communication, and/or movement.

FUS – The FUS gene makes the fused in sarcoma protein, which is believed to help support normal DNA functions. Pathogenic variants in this gene are a rare cause of genetic FTD. Pathogenic variants in this gene can also cause ALS, and tend to cause a younger onset, more rapidly progressive form of ALS.

Gene – A unit of DNA that carries the instructions to make a specific protein.

Genetic testing – The process of using laboratory techniques to analyze genetic material (DNA).

GRN – see Progranulin.

Loss of function – A mechanism causing a genetic condition. This is caused by a variant in a gene that results in a protein product with reduced or completely absent activity. This can be caused by different types of genetic variants within the DNA code. For example, a nonsense variant is a change in the DNA code that creates a stop signal, leading to a smaller protein that usually loses its function or has reduced function. Sometimes missense variants (a change in the DNA code that changes the amino acid it codes for) can also lead to loss of function.

Microtubule-Associated Protein Tau (MAPT) – The official name of the gene that makes the tau protein.

Motor neuron disease – Also known as amyotrophic lateral sclerosis (ALS) or Lou Gehrig’s disease. A progressive loss of the neurons that control muscle movement. Up to approximately 15% of people with FTD may also develop symptoms of ALS, and the two disorders are now considered to be part of a disease spectrum given neuropathological and genetic overlap.

Mutation – Older term for a pathogenic variant (see below) which is being abandoned by the biomedical scientific community due to pejorative connotations.

Nucleotide – An individual chemical unit; nucleotides are the letters that make up the spelling of DNA. In DNA, the nucleotides are A, T, G, and C.

Parkinsonism – A term used to describe motor symptoms that are similar to those seen in Parkinsons’s disease, such as tremors, stiffness, and walking/balance difficulties.

Pathogenic variant - A difference in DNA that affects a gene’s ability to make a protein. May result in a health condition.

Penetrance – The likelihood that a genetic variant will cause symptoms of a condition to develop.

Pick’s disease – An old diagnostic term for FTD, named for the physician that first described the condition. It is also used as a pathological diagnosis for some types of FTD.

Polymorphism – A benign variation in the DNA code. In contrast to disease-causing variants, polymorphisms do not directly cause health problems.

Preimplantation genetic testing (PGT) – In vitro fertilization (IVF) with PGT is an alternative reproductive method. This can be performed to better understand the genetics of an embryo before it is transferred to the uterus. If there is a known genetic cause of FTD in the family, IVF with PGT may be available as a reproductive option to avoid passing down genetic risk for FTD. There are other reproductive options that may be available (see Genetic Testing for Family Planning Reasons).

Primary progressive aphasia (PPA) – The clinical term for an individual with FTD with language difficulties as the primary symptom. There are several different types of PPA, including semantic, non-fluent/agrammatic, and logopenic.

Progranulin – The progranulin gene (GRN) makes the progranulin protein, which functions in cell growth and repair. Pathogenic variants in GRN cause hereditary FTD.

Progressive supranuclear palsy (PSP) – A diagnosis related to both FTD and Parkinson disease that causes both cognitive and movement difficulties, including a characteristic difficulty with eye movements.

Protein – A molecule that serves a specific function in the body. Proteins are made up of individual units called amino acids.

RNA - ribonucleic acid is a molecule that uses a gene’s DNA instructions to help cells make proteins and plays other roles in regulating which proteins get made and when.

Sequencing – A genetic testing method in which the letters of the genetic code are read nucleotide by nucleotide and then compared to the reference (typical) sequence in humans to look for differences or misspellings.

SQSTM1 - The sequestosome 1 gene makes the protein called ubiquitin-binding protein p62. Pathogenic variants in this gene are a rare cause of FTD. Some variants in this gene have been associated with Paget disease of bone and ALS.

TARDBP – The tar DNA-binding protein, also known as TDP-43, is made by the TARDBP gene. Pathogenic variants in this gene can cause genetic FTD and/or ALS.

Tau – This protein is found in just under half of persons with FTD at autopsy. While not all FTD with tau protein is genetic, there are some people who have FTD that was caused by a pathogenic variant in the gene that makes the tau protein (MAPT).

TBK1 – The tank-binding kinase 1 gene makes a protein called a serine/threonine kinase signaling molecule. Pathogenic variants in TBK1 have been associated with both FTD and ALS.

TDP-43 – This protein is found at autopsy in about half of persons with FTD and almost all people with ALS. The function of TDP-43 in the brain and its relation to neurodegeneration is not fully understood.

TMEM106B – The transmembrane protein 106B is made by the TMEM106B gene. This protein is involved in lysosome regulation. Different versions of this protein may serve as risk or protective factors for FTD, also known as modifiers. Thus far, this modifier effect has been most pronounced in people with pathogenic variants in GRN.

Variant of uncertain significance (VUS) – a difference in DNA that has an unknown clinical impact.

VCP – The valosin-containing protein is made by the VCP gene. Pathogenic variants in this gene cause several different conditions, including FTD, inclusion body myopathy with Paget disease of the bone and FTD (IBMPFD), and vacuolar tauopathy.