Genetic Testing and Counseling in FTD

The importance of genetics in the search for FTD treatments and a cure

As scientists pursue treatments and a cure for frontotemporal degeneration (FTD), testing to find the genetic status of persons diagnosed with FTD has become more important. While many forms of FTD are not genetic, a proportion of them have a genetic origin.

Additionally, genetic testing of biological family members of FTD-diagnosed persons may provide answers about their health. But not everyone wants to know if they have an FTD gene mutation (clinically referred to as a variant).

Please note that this glossary is available to help you understand the scientific terms used in this article. Glossary terms are shown here in bold the first time they appear.

There are different reasons people consider genetic testing for FTD. Symptoms may lead to the need for a diagnostic test to provide answers for themselves and family members about their illness, or to provide their doctors with a better understanding of their disease. The goal of diagnostic testing is to understand why a person has developed disease.

Because of a family history of a gene mutation, biological family members may seek predictive testing to see if they are at risk of developing FTD. In addition, some of these blood relatives choose to be tested before having children.

“Sometimes the decision whether to have children initiates the testing process as potential parents ask themselves if they can pass on the disease,” said Jill Goldman, M.S., MPhil, CGC, professor of genetic counseling in neurology and genetic counselor with the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain at Columbia University Medical Center in New York City.

Knowing if a person has a genetic mutation provides helpful information for their families, their physician, and for potential clinical trials. For those who do not show signs of disease, this knowledge can predict the likely possibility that they will develop the disease. However, it does not tell how old the person will be when they start showing symptoms, which specific symptoms will develop, nor the rate of disease progression.

Genetic testing is also a method to further scientific knowledge about FTD. Research is used to learn more about the contributions of genes to health and to disease. The results may not directly help participants, but they may benefit others.

“We’ve reached that point in the drug development process where there are investigational therapies in the clinic,” said Laura Mitic, Ph.D., chief scientific officer with the Bluefield Project to Cure FTD, a nonprofit research foundation focused on finding a cure for FTD caused by mutations in progranulin. “The progranulin gene was linked to FTD in 2006, so it’s been 14 years since that discovery was made. That may seem like a long time, but it is remarkably rapid given how little we knew 14 years ago.”

Recently, FTD research studies have added another reason for people to learn their genetic status — potentially qualifying volunteers for study participation. These studies focus on evaluating whether treatments are effective for people who have a certain gene mutation. In the past month, two new studies that require a positive test for the progranulin gene (GRN) mutation began recruiting volunteers:

• INFRONT-3 sponsored by Alector, Inc.
• PROCLAIM sponsored by Prevail Therapeutics

Choosing to have genetic testing “is a very personal decision and not one to be taken lightly,” said Dr. Mitic. “But at the same time, the ability to develop a cure for FTD depends on individuals participating in these trials. And these trials depend on people knowing their genetic status.”

Genes & FTD

Genes are a functional unit of heredity. They hold the information for how to make proteins that are responsible for the body’s structure, function, and regulation, as well as to pass genetic traits to offspring. The building blocks of this genetic code are nucleotides that are attached to each other in very specific sequences creating DNA (deoxyribonucleic acid), a large molecule, commonly recognized for its double helix structure. Humans have approximately 20,000 to 25,000 genes, which are spread across 46 strands of DNA called chromosomes. A human receives 22 autosomal and 1 sex chromosome from each parent. Thus, each individual has two copies of every gene.

The sequences encoded by DNA in genes are inherited, but over time variations (mutations) in the building-block sequence can occur. This “misspelling” in the DNA sequence can result in a highly negative effect, such as causing disease, or it can be carried silently with no apparent impact. Genetic testing not only reveals the presence or absence of variants, but also seeks to classify any observed variants ranging along a scale from benign, to unknown, to pathogenic (disease-causing).

Scientists have found specific gene mutations associated with FTD and related disorders. The majority of genetic FTD is caused by a mutation in one of three genes, often referred to as “the big three”:

1. C9orf72 (also known as the FTD-ALS or C9 gene)
2. MAPT — Microtubule-associated protein tau (often referred to as tau)
3. GRN — Progranulin, whose coded protein is progranulin

There are additional genes in which very rarely a mutation will cause FTD, including TARDBP, VCP, FUS, CHMP2B, SQSTM1, UBQLN1, or TBK1. As research continues, scientists find new genes.

LEARN MORE ABOUT FTD GENES

Genes do not cause disease — genetic disorders are caused by mutations in genes that make the gene or its coded protein function improperly. When people say that they have “the progranulin gene,” they really mean they have a mutated form or variant of the GRN gene, which causes a type of FTD, explained Laynie Dratch, ScM, CGC, a certified genetic counselor with the Penn FTD Center, Perelman School of Medicine, University of Pennsylvania, in Philadelphia. All people, including those without FTD, have a version of the GRN gene. Gene mutations affect health differently, depending on where they occur and what they alter.

“We all have the genes described above such as the GRN gene,” said Dratch, “but some people have a difference in their GRN gene that makes it not work the way it is supposed to.”

A genetic predisposition (also called genetic susceptibility) is an increased possibility of developing a specific disease based on a person's genetic makeup. This increased possibility depends on several factors in addition to genetic changes. These include other genetic factors (also called modifiers) as well as lifestyle and environmental factors. Diseases caused by a combination of factors are noted as multifactorial. While a person's genetic makeup cannot be changed, some lifestyle and environmental modifications (such as smoking, diet, and exercise) may reduce disease risk in people with a genetic predisposition.

One common feature of the genetic forms of FTD is that disease does not appear until adulthood, even though an individual is born with the mutation. It is not yet possible to predict when symptoms will appear or whether there are specific external factors that encourage their appearance. These issues further complicate the presentation of FTD.

Learn more about genetics and the effects of genetic variation at MedlinePlus Genetics, an online health information resource from the National Library of Medicine (NLM), which is part of the National Institutes of Health (NIH).

The Importance of Family History

FTD is either apparently sporadic (s-FTD), meaning only one person in a family has been diagnosed, or familial (f-FTD), where one or more family members in back-to-back generations have FTD or a related neurological condition, explained Dratch. When evaluating whether a person has familial FTD, the genetic counselor or neurologist will ask questions to determine whether there are several closely related family members (such as a grandparent, parent, and adult child) from the same side of the family who have been diagnosed with FTD spectrum disorders, she noted during a presentation at the Penn FTD Center’s virtual caregivers conference in June 2020.

Up to 40% of people with FTD have some family history of FTD or related diseases. Of those, 10% to 20% have a definitive mutation in one of the FTD genes. These cases are defined as genetic FTD.

“There are some families with familial FTD for which there is no known genetic cause, which means it is very likely that there will be more genetic causes of FTD discovered in the future,” Dratch said.

Almost all known genetic causes of FTD have autosomal dominant inheritance. “Autosomal” refers to the non-sex chromosomes, which means that FTD can affect both men and women equally. “Dominant” inheritance means that only one of the two copies of a gene has to have a mutation to cause disease. The copy of the gene with the mutation is inherited from one of the parents, and most people with an autosomal dominant condition will have a family history of neurodegenerative disease.

The biggest clue to whether there is a genetic cause for FTD is family history. A person diagnosed with FTD who has a family history that includes several relatives with FTD or other neurodegenerative diseases is more likely to have a genetic cause than one with no known family history of neurodegenerative diseases.

When tracking family history, start with the person diagnosed, said Goldman. If that person tests positive for a genetic mutation, predictive testing can be done for other family members should they choose to do so. This would involve testing family members who do not have symptoms but are at risk of having the same genetic mutation.

Each person has two copies of every gene, one from mom and one from dad. A person with genetic FTD has one copy that isn’t working right. This person can pass on either the working copy or the nonworking copy. A child of a person with a dominant mutation has a 50% chance of inheriting the copy of the gene with the mutation and a 50% chance of inheriting the copy of the gene without the mutation. This is why one child can test positive and a sibling be negative.

Over the past decade, testing for mutations in genes known to cause FTD has become more readily available. It now provides a definitive means to determine whether a family member has inherited a mutation or not.

About Genetic Testing

A genetic counselor or physician should discuss testing options and provide pretest counseling before ordering genetic screening for FTD. Individuals cannot go on their own to a lab and be tested for these diseases. FTD does not appear on the results of any direct-to-consumer testing such as 23andMe.

Tests ordered depend on genetic family history. If someone in the family is positive for a specific FTD gene mutation, only the test for that particular mutation would be done. Other times a broad panel for numerous types of dementia and neurological disease are performed.

“The major genetic testing labs all have panels that are either FTD-specific or broad dementia panels. Many have ALS genes on them as well. So it’s easy to order,” Goldman said. “If you do the dementia panels and they are negative but there is a family history, then one would probably do whole exome sequencing looking for some exotic gene that may not be an FTD or AD gene.”

“If there haven’t been other biomarkers that have narrowed it down, you are going to do a broader panel,” she said. “If for instance, someone has had a lumbar puncture which has indicated that they are unlikely to have Alzheimer’s disease [AD], one might do the narrow FTD panel.”

Goldman said there are a limited number of Clinical Laboratory Improvement Amendments (CLIA) certified laboratories in the United States that process FTD genetic tests. While one is at Columbia University where she works, labs differ in what types of tests they offer. For instance, one of the labs she uses doesn’t run the C9 test because the lab is moving to next-generation sequencing and C9 has to be done differently.

Because there are different types of tests, costs can vary from about $250 to several thousand dollars. The cost for the person being tested depends on the tests being run and whether insurance is used. Goldman has noticed that the cost of testing has come down in recent years.

Cost is very different if someone pays out of pocket versus using their insurance, she said. A testing company may charge more when billing an insurance company than when billing the consumer directly. “Insurance doesn’t always cover these types of testing for dementia because it’s not going to change medical management,” Goldman noted.

Medical test results are normally included in a person’s medical records, particularly if a doctor or other health care provider has ordered the test or has been consulted about the test results. Therefore, people considering genetic testing must understand that their results may become known to other people or organizations that have legitimate, legal access to their medical records, such as their health insurance company or employer, if their employer provides their health insurance as a benefit.

For the individual who is testing predictively, it generally is not recommended to use health insurance nor is it typically covered by insurance, Goldman said. This could minimize the possibility of genetic discrimination. Discrimination can occur when people are treated differently by their employer or insurance company because they have a gene mutation that causes or increases the risk of an inherited disorder.

While fear of discrimination is a common concern among people considering genetic testing, there are legal protections in place to prevent it. The GINA law, Genetic Information Nondiscrimination Act, protects people from discrimination for health insurance and in the workplace, but not against long-term care, disability, or life insurance.

GINA became law for all U.S. residents in 2008. The act prohibits discrimination based on genetic information in determining health insurance eligibility or rates and suitability for employment. However, GINA does not cover members of the military, and it does not apply to life insurance, disability insurance, or long-term care insurance. Some states have additional genetic nondiscrimination legislation that addresses the possibility of discrimination in those settings.

One action to take prior to having genetic testing done is to consider purchasing life insurance and long-term care, Goldman noted, because if the results are positive, traditional policies will be difficult to afford.

Neurodegenerative diseases are life-limiting. People with FTD may pass away before obtaining samples for testing. If genetic testing was not done while a person was living, it can be done using tissue collected during an autopsy, Goldman noted. However, genetic testing is separate from an autopsy, and the request must be made prior to the autopsy so that tissue is collected for testing.

The American College of Medical Genetics and Genomics has a Genetics Clinics Database for locating a U.S. genetics center.

People diagnosed with FTD or at risk for developing it may qualify to participate in an observational study sponsored by Alector, Inc. and administered by InformedDNA. The purpose of this study is to better understand the reasons why people decide to have genetic testing for FTD and to identify people who are at risk for or with FTD caused by a progranulin gene (GRN) mutation. Study participants will receive genetic testing and counseling from home as part of the study. There is no cost to participate.

About Genetic Counseling

One barrier for testing is finding either a physician or a genetic counselor who is well versed in FTD, Goldman said. Usually, certain physicians in academic medical centers and specialists in neurodegeneration will be aware of what is available, and even some of these medical professionals are not as familiar as certified genetic counselors who work in the field every day. She also noted that there are not many neurogenetic counselors.

The National Society of Genetic Counselors (NSGC) offers a free search tool to help people find a certified genetic counselor to meet their needs. You can choose to meet either online or in-person.

Genetic counseling is a balancing act, Goldman said. The most important aspect of it is guidance in preparation for a positive result, a negative result, and even an unknown result.

Genetic counseling occurs prior to providing a blood or saliva sample for testing. Goldman begins with a screening call to collect family history. The actual counseling session lasts about an hour. There may be follow-up meetings, calls, or emails to answer additional questions or discuss topics not covered in the initial session. If a client chooses to undergo testing, a follow-up appointment is scheduled to discuss the results.

Goldman said she never does genetic testing at the first visit she has with a person. First, she provides education about the disease, its symptoms, and genetics. The implications of family history are also covered. Most of the time she spends providing anticipatory guidance about both positive and negative test results.

“I will ask, ‘Pretend you’re sitting here and I’m giving you a result, and it’s a positive result. How are you going to respond in the short term? In the longer term? Do you think you can cope with this? Do you think it will make you more anxious or more depressed?’ ”

Goldman prefers that a support person comes with the client considering genetic testing. “If there is a partner, I like to have them bring the partner because obviously the genetic results are going to affect that person as well,” she said. “I’ll talk to both people about how they will anticipate their reaction. I will ask the partner how they think the client is going to react, so I’m getting two different opinions.”

With the coronavirus pandemic restrictions limiting face-to-face interaction, Goldman has found that having counseling sessions online has made it easier for support people to participate because they can be located anywhere and join the conversation.

“Imagine dealing with this information all by yourself. It is difficult,” she said.

These counseling conversations also cover thinking about with whom the person being tested plans to share the results. This often is not something people have considered beforehand, Goldman noted.

“Are they going to share [the results] with their families? Do their families even want to know?” she asked. “If they have siblings who have not been tested, do their siblings want to know? It’s best to find this out before rather than after.”

She recommends asking family members a hypothetical question that they are thinking about being tested and ask them if they want to be told the results?

People thinking about being tested also have to consider what kind of interaction they are going to have with a parent who is sick with the disease. Due to the nature of the disease and which type of FTD a person has, the impact usually is not what would be expected, she said. That parent can feel guilty about having passed on the mutated gene.

“If another sibling has been tested and the result is different, how would that feel? Should they sit down and talk about survivor guilt ahead of time?” Goldman said. “Not everybody does that. Family dynamics are very complex. It’s a discussion we have so that they [the client] can think about it.”

Goldman also asks about the client’s support network. “Are there friends they would share the results with so they get some support? Is there a therapist involved? Should there be a therapist involved?”

A genetic counselor also may recommend other exams prior to testing, including a psychological evaluation. This provides insight into the person’s emotional state for issues such as anxiety or depression. It is standard protocol for Goldman, but others do not always have the resources to do it, she said.

All of the above is done before the person actually provides a specimen for testing. In fact, after counseling conversations, not everyone chooses to do genetic testing for FTD. Goldman noted some reasons include:

• Testing may increase anxiety and stress for some individuals.
• Testing does not eliminate a person's risk for the disease.
• Testing may return inconclusive or uncertain results.

In some cases, people have genetic testing done but choose not to learn their results right away. If they want to know later, they can request their results without being re-tested.

Undergoing genetic testing is a personal, complicated decision, Goldman said. There are benefits and limitations. “The biggest question to answer is the motivation behind doing it.”

Learn how COVID-19 has affected genetic counseling and testing.

About Genetic Testing Results

Results from genetic tests are returned to the genetic counselor to review, interpret, and present to the client. The ordering physician also receives a copy. A session is scheduled for disclosing and discussing the results. Goldman prefers a support person is present if at all possible.

Genetic tests produce one of three results:

1. A positive result for a variant that has been shown to cause an FTD disease (known as a pathogenic variant).
2. A negative result where nothing shows up in any of the genes on the panel.
3. A result of variants of unknown significance (VUS) where there are changes in the DNA, but these changes have not been previously identified to be associated with dementia.

Labs differ about what they return, said Goldman, and some labs return more VUSes than others. Receiving a VUS is lousy, she noted, and sometimes there are several.

“Sometimes you can discount the VUS. For instance, if it’s in an unrelated gene, it is most likely a red herring,” or distraction, she said. “If it’s in a gene that is inherited in an autosomal recessive fashion so that you would need two variants to have the disease but you only have one, you know that it’s not related.”

Goldman warns people about this, and it is included in the consent forms, so they know what results are possible. “They have to know that if that happens, the lab may reclassify it in a year or two as more information comes into these databases.”

If a VUS comes back as the only change in the results, other people in the family cannot be tested because there is nothing to test for. “We can’t test for something when we don’t know what it means,” she said.

While reactions vary greatly, most people who receive a negative test result are very happy about it, she said.

“You really don’t know what your reaction is going to be. With Huntington’s disease and autosomal dominant Alzheimer’s disease, I’ve had situations where a negative result has come back and because they were so invested in the identity of having the disease, belonging to that part of their family, that they never really considered what it would be like to be disease-free,” Goldman said.

With a disease like FTD, some people have survivor guilt, she said. Others experience a feeling of having wasted time.

“It also depends on the motivation for testing: Why did they come in for testing,” Goldman said. “I would say that probably two-thirds of my clients come in for reproductive options. If they don’t have to do IVF [in vitro fertilization], it’s a very good thing.”

Genes and Research

“We’re now at the point where a number of the promising ideas that academics and drug developers had about how to potentially make an impact on FTD caused by mutations in progranulin can be tested,” said Dr. Mitic.

Many new clinical trials require that individuals know their genetic status. This is especially critical for gene therapy, which introduces genetic material that may stay in a person's body permanently.

“In the case of gene therapy, which is a specialized case, there’s no alternative; you have to know your genetic status,” Dr. Mitic said. But even in trials not using gene therapy, it is likely one will need to know their status to enroll because the therapies work on the pathways affected by the genetic mutation. So a person who does not have the genetic mutation will likely not respond to such specific therapy.

“A common thought about having people learn their mutation status is ‘why bother,’ especially in those younger when they can’t do anything about it,” said Mitic. “That concern is changing now that drug companies are starting to test sophisticated, targeted investigational therapies in mutation carriers.”

Dr. Mitic noted that being a mutation carrier does not guarantee entrance into a clinical trial. There may be additional criteria, such as being at a specific age or stage of the disease, not having other conditions, or living near a participating trial site, that may impact a person’s ability to participate in a trial. It is important for individuals who are considering learning their genetic status in order to participate in a trial to make sure they speak with their doctor and understand the enrollment process.

“We are at the beginning of a paradigm shift that maybe something actually can be done,” she said. “Genetic testing is a very personal decision, but for some people, perhaps they might decide it’s time to think about finding out their mutation status in case they would like to participate in a trial.”

Performing genetic testing and collecting exome sequencing increases the knowledge about FTD. Genetic patterns and their association with diseases continue to be at the forefront of medical research. New discoveries raise new questions and lead to new clinical trials.

Researchers hope that people who have an FTD gene mutation may one day be able to delay or even prevent the emergence of the disease. Genetic testing is a vehicle to reach this goal.

“Anyone who chooses to participate in research, whether it be observational research or investigational trials, we owe a huge debt of gratitude to them. This is a gift to the community,” said Dr. Mitic. “There are many very dedicated individuals working hard to learn as much as we can and to develop therapies so we can find cures for FTD.”

“As a basic scientist, I am conditioned to be cautious” she added, “but we’ve never been in a better position to have hope that some of these new therapeutic approaches may be highly effective.”

Learn more about FTD genetics and the risk within families and individuals during an Association for Frontotemporal Degeneration (AFTD) webinar at 4:00 p.m. EDT (1:00 p.m. PDT) on Thursday, October 29, 2020. The presenter will be Jamie C. Fong, M.S., LCGC, certified genetic counselor and assistant professor with Baylor College of Medicine, Department of Molecular and Human Genetics, in Houston, Texas. This will be the first of three AFTD webinars on the Genetics of FTD. Watch for registration in mid-October.