AFTD recommends that you speak with a genetic counselor prior to pursuing genetic testing, so you can plan how to best receive and consider your results. In most cases a follow-up visit (in person, phone, or video) will be required for the results disclosure. During the post-test genetic counseling visit, the genetic counselor will review the results.
Several possible results can come from genetic testing:
A positive test result means that the laboratory found a genetic variant that is associated with FTD.
A negative result means that the laboratory did not find a variant associated with FTD in the genes tested. The significance of a negative result can mean different things based on your situation – read additional guidance below.
Variant of Uncertain Significance (VUS)
A genetic change is called a variant of uncertain significance when there is not enough evidence about the impact of that change on the gene and whether it is benign (does not impact the risk of FTD) or is associated with disease. Some variants of uncertain significance may be reclassified over time as more information is gathered. People who have a variant of uncertain significance should check in with their genetic counselor occasionally to determine whether any additional information is available on their variant.
The classification of variants as negative, positive, or a variant of uncertain significance relies on an understanding of background genetic variation – the awareness of normal, non–disease-causing variants in a specific population.
Current understanding of FTD genetic variants draws predominantly from people of European, and primarily Caucasian, backgrounds. As a result, people of color – including but not limited to African, African American, Asian American/Pacific Islander, and Hispanic individuals – are more likely to receive VUS results. Additional work to diversify genetic research and increase the availability of clinical genetic testing in diverse populations is needed to reduce this disparity.
A positive result means that the lab found a genetic variant in a gene associated with FTD that is believed to cause or significantly contribute to the risk of FTD.
People with a positive result will be told which gene they have a variant in, and any relevant information that may be known about that gene. For example, you may learn particular symptoms that may be more common in people with variants in that gene, average age of onset, or the likelihood of developing symptoms (also known as penetrance). The penetrance of specific variants may differ.
In addition, the genetic counselor will provide information about any research studies or medical recommendations relevant to people with variants in that specific gene.
People with a positive result should understand the potential ramifications for other family members. The genes currently associated with FTD are inherited in an autosomal fashion. That means that each child of someone who has an FTD genetic variant has a 50% chance of inheriting it. The genetic counselor can provide tools and support for communicating genetic results to other family members.
While some people with genetic variants associated with FTD do not have a family history of FTD or related diseases, siblings and other relatives may benefit from having this information shared with them, as they would alsobe expected to have an increased risk to carry the variant identified.
A negative result means that the laboratory did not find a variant in the genes tested. A negative result has different implications depending on whether you are showing FTD symptoms.
For people with symptoms of FTD it is important to understand four key points about negative results:
1) The majority of people with FTD but without a family history of disease do not have an identifiable genetic variant.
2) Not everyone with a family history has an identifiable genetic variant.
3) The lab only reports on the genes that were included in the test order. If the test order did not include all genes associated with FTD, additional testing may be indicated.
4) Genetic testing today is limited to the genes related to FTD that have been discovered.
Over time scientists will likely identify additional genes that play a role in the risk to develop FTD. People who test negative should check with their healthcare provider or a genetic counselor over time to determine if additional testing is appropriate based on changes in our understanding of the genetics of FTD.
For a person without symptoms of FTD, a negative result can have different meanings depending on whether or not there is a known genetic variant in the family.
Om there is a known genetic variant in the family, a negative result is a true negative. A true negative means that the variant associated with FTD in the family is known and the lab looked for it, but did not find it, meaning that the person tested did not inherit it. While this individual’s risk of FTD is not zero, they are expected to have a risk comparable to the general population of developing FTD.
Children of a person with a true negative result do not need genetic testing for FTD, and are not at risk to inherit the familial variant. But it is important to note that outside of the parent/child relationship, one family member’s result does not impact the results of others. For example, imagine a family where the father has a GRN variant and one child tests negative. That person’s siblings are each still at 50% risk to inherit the GRN variant. Results for siblings are independent of each other; a result (positive or negative) in one sibling does not increase or decrease the chance that another sibling will test positive.
For a person without symptoms who does NOT have a known genetic variant in their family, a negative genetic test result is considered an uninformative negative. Whenever possible, a symptomatic person should be the first person tested in a family. Other family members may still pursue testing, but negative results will be difficult to interpret. What if the FTD in their family is caused by a gene that scientists have yet to identify? As science advances, more genes will be identified and retesting may be indicated.
A special note about C9orf72 testing: Within the C9orf72 gene, there is a string of letters, GGGGCC. Most people have this string of letters repeat a few times in each copy of their C9orf72 gene (everyone has two copies of this gene – one from each parent). A genetic test is considered negative by most labs if there are fewer than 30 copies of this string of letters. It is important to realize that although labs typically include the number of GGGGCC repeats found in each copy of the C9orf72 gene, the presence of a small number of GGGGCC repeats is normal.
Variant of Uncertain Significance
Testing that reveals a variant of uncertain significance (VUS) occurs when there is not enough evidence about the impact of that change on the gene and its role in disease risk. In some cases, laboratories offer free testing to family members of a person with a variant of uncertain significance if they believe testing other people in the family can help clarify the impact of the variant identified.
People who have a variant of uncertain significance should check in with their genetic counselor occasionally, to determine whether any additional information is available on their variant over time. Retesting may be indicated in the future, as more genes associated with FTD are identified.
The classification of a variant as negative, positive, or as a VUS relies on an understanding of background genetic variation, the awareness of normal, non-disease-causing variants in a specific population.
As a significant challenge to inclusion that our field needs to address, the understanding of FTD genetic variants today draws predominantly from people of European, and primarily Caucasian, backgrounds. As a result, people of color – including but not limited to African, African American, Asian American/Pacific Islander, and Hispanic individuals – are more likely to receive VUS results at this time. Additional work to diversify genetic research and increase the availability of clinical genetic testing in diverse populations is needed to reduce this disparity.
What is the risk to our children if I’ve learned that I or my partner has an FTD-causing genetic variant?
All known genetic forms of FTD are inherited in an autosomal dominant fashion. That means that each child of a person with an FTD-causing genetic variant has a 50% chance of inheriting the genetic variant associated with FTD.
For individuals who are concerned about the risk to their future children, there are several reproductive options:
- Prenatal testing – the fetus can be tested for the genetic variant in the family as early as 10 weeks using chorionic villus sampling.
- Preimplantation genetic diagnosis (PGD) – this involves the couple going through the in vitro fertilization (IVF) process (in which the woman’s eggs are extracted and fertilized by her partner’s sperm) with genetic testing for the known genetic variant in the family performed on the embryos. Only those embryos without the genetic variant are implanted in the uterus. For parents who do not want to know their own status, PGD may be offered without requiring that the parent learn whether they themselves carry the gene variant.
- Sperm donation – if the male partner is the one who carries a genetic variant for FTD, the couple may choose to conceive using a sperm donor.
- Egg donation – if the female partner is the one who carries a genetic variant for FTD, the couple may choose to conceive using an egg donor.
- Adoption – for those concerned about the chance of passing on a familial condition, adoption is another reproductive option to consider.
Reproductive planning is a personal decision. However, genetic counselors have specialized training and can help couples explore options to help find the reproductive option that is right for them.
Many of the options described above require planning pre-conception. If you are thinking about starting a family and have concerns about the risk to future children, we strongly encourage consultation with a genetisk rådgivare.