An informal guide to pre-symptomatic genetic testing in individuals at-risk for dominantly inherited neurodegenerative diseases
What is pre-symptomatic genetic testing:
Genetic testing is used to look at your genes (the blueprint or DNA instructions you inherit from your parents) to detect mutations or gene changes that cause disease. Presymptomatic testing is testing of individuals prior to signs or symptoms of disease. Genetic testing can help confirm or rule out the presence of a mutation, and thus help determine whether a person will develop a genetic disorder, which has previously been found in a family member with a genetic disorder.
How to decide if pre-symptomatic genetic testing is right for you:
This is a difficult, complex, and very personal decision. No one can make this decision for you and should not make this decision for you. In cases where individuals felt forced or pressured into testing, these individuals ended up having very negative psychological responses to their test results. With that in mind, it is important to take the time to determine whether genetic testing is right for you.
Are you an individual who has always “felt” that they would get it? Are you an individual who likes to plan? Are you an individual who seeks knowledge in the face of disease/fear? Individuals who have felt or expressed these views have usually gone on to get tested.
Are you an individual who tries not to think about the disease? Do you believe that much of your hope relies in not knowing about the future? Do you worry about losing that hope by getting tested? Individuals who have felt or expressed these views have usually not gone on to get tested.
If you are on the fence and feel like you change your mind regarding this decision every day, then it is probably best to wait. Most people who go on to get testing feel they “had” to get tested. For some it took years to reach this point, for others it was immediate.
Previous findings on the psychological impact of genetic testing:
Previous reports on genetic testing in individuals who chose to get testing and ended up testing positive for a mutation (i.e. they would get the disease), showed the highest levels of depression immediately to 3 months following testing. One year after testing, depression levels seemed to lower and most individuals appear to return to their previous/normal levels of anxiety by this point. For some people, results (even if confirming a mutation) can serve as a relief in eliminating uncertainty. They help provide important information for making decisions on whether to join a clinical trial, make lifestyle changes, retire early, or have a baby. For others, finding out their results can be an enormous emotional burden to carry. They find it difficult to face a disease with no treatment or cure currently available (Paulsen et al., 2013). Although these results provide evidence that individuals can return to their “normal” depression/anxiety levels one year following testing, it should be noted that no studies exist following the long-term psychological impact of genetic testing. It should also be noted that these studies only include data on individuals who pro-actively chose to get testing done. It remains unclear what would occur to the anxiety/depression levels of individuals who would normally not chose to get tested, but do.
Seeking professional help before testing:
Consider speaking with a psychologist who is specialized or has experience in treating people who have a dominantly inherited disease in their family. They may help determine whether you are emotionally ready for undertaking the testing process. If you are having trouble finding one, genetic counselors may be able to make some recommendations.
What to do before calling a genetic counselor:
Many people worry about discrimination based on their genetic test results, and rightly so. With the advent of digital patient records, informed patients should make every effort to protect their and their families’ privacy. In 2008, Congress enacted the Genetic Information Nondiscrimination Act (GINA), to protect individuals against discrimination by their health insurance provider or employer. However, GINA does not apply to long-term care, disability, or life insurance providers. Thus, it is important to consider obtaining these policies before providing your name to a genetic counselor. Some life or long-term care insurance questionnaires will ask whether you have spoken to a genetic counselor.
Consider obtaining life insurance
Consider obtaining long-term care insurance
Obtain a copy of your parent’s or family member’s positive test result (i.e. the genetic testing report they received listing the nucleotide or amino acid change; it should also have their accession number – a specific number assigned to their report by the genetic testing provider)
Begin setting up a support system. Getting tested can be an emotional rollercoaster and having 1-2 people (other than your partner) to talk to about this process can be very helpful. Individuals who have been tested recommended telling friends that you were undergoing the process, without giving away specific dates of the appointments. That way the individuals didn’t feel pressure to respond to calls or texts, but had an opportunity to process their results on their own before reaching out to others. It may also be helpful for the partner/spouse to set up a support system as well. Other individuals state it was helpful to have people know the date of their testing. Ultimately, it is a personal decision who and when to tell.
Start conversations about disclosure. It may be helpful to have discussions with your friends and family beforehand to determine whether 1) they can be your support system and 2) whether they would want to know your result. Some family members may not be ready to hear your result and it is important to have these conversations sooner than later. It may also be important to talk to family members who may also be at-risk, if you disclose your genetic status to others in the family, others may start asking about their status. These are delicate issues and although it is ultimately your decision to get tested and who to tell, it can be important to understand the relationship your at-risk family members have to genetic disclosure.
Find the right genetic counselor for you (important questions to ask or things to consider when looking for one):
Do they follow the Huntington’s Disease genetic testing protocol?
Do they have electronic patient records? Would they be willing to keep you off those records and/or only keep you in their paper files?
Would they be willing to allow you to test under a pseudonym?
Do they open your results/envelope only once in your presence?
What to expect while going through the genetic testing process:
No. of sessions: 2
Avg. length of a session: 30 min – 1.5 hr
Cost: $100 - $2,000 (dependent on company and type of genetic testing)
Type of tissue collection: blood, saliva, cheek swab
Avg. wait time before receiving result: 1 – 3 months
In session 1, the genetic counselor will discuss the inheritance of the gene of interest/ disease heritability. They should help answer any questions you may have regarding genetics, including: 1) what is an autosomal dominant disease, 2) how are genes passed on in my family, 3) what are my chances of getting the disease, 4) what are the chances of my family and offspring getting the disease, etc. They will ask for a family tree and who has been affected by the disease, and whether these individuals have been tested. This is also when you will provide a report of any family member’s genetic testing results, if you have one.
They will also help walk you thru potential scenarios and your responses to a negative and positive test result. For both sessions, you will be asked to bring in a support person. They often require or recommend that this person not also be at-risk for the gene getting tested (i.e. a sibling would not be recommended). If you intend on bringing a spouse or partner, the counselor should help prepare them for the result as well. Some spouses have not had as much time to deal with the social and psychological consequences of hearing a loved ones’ result, so it may be helpful to speak with a loved one about this earlier.
In the last part of session 1, the genetic counselor will ask if you are ready to provide tissue for testing. If you agree to proceed, you’ll need to work out how the payments will be made. Make sure that if you are working under a pseudonym that you either bring cash or a cashier’s check to the appointment. After that blood, saliva, or cheek swabs will be taken and then placed in an envelope to send to the test facility. This is a good time to work out any more logistics with your counselor (i.e. how long you’ll have to wait until your result is ready, how long they recommend you wait, whether you prefer them to wait to open your result/envelope until you are there, how you prefer to be contacted, etc.).
In session 2, the genetic counselor will ask you are ready to hear your result. In most cases, the counselor has not read the result so you shouldn’t “read” into any of their behavior prior to them opening the envelope. The counselor will open the envelope and confirm the presence or absence of the mutation in your DNA sequence. There have been many cases where individuals decide to wait to hear their results, so there is no pressure to do it any sooner than when you are ready. Either way, the individual should seek a mental health professional or psychologist to help digest the results on a more long-term timeline than the genetic counselor can provide.
Reported consequences of genetic testing:
Transient increased anxiety and/or depression (extreme and catastrophic events have been reported, but are rare)
Improved understanding and knowledge for assisting future decisions
Heightened awareness of genetic status, disease stigmatization, and possible discrimination
Socioeconomic issues related to the need for long-term follow up of individuals with positive result
What if I don’t have a positive control (i.e. I don’t have any DNA from any family member that had the disease/disease-causing mutation):
There are different types of genetic testing procedures that companies will employ to determine whether there is a mutation in your DNA: Sanger sequencing and Next Generation Sequencing (NGS). Both methods are commonly used to sequence or “read” DNA fragments for clinical research. Sanger sequencing is the most common sequencing method and most cost-effective option when sequencing a single gene (e.g. in the case of dominantly-inherited Alzheimer’s disease where there is one single nucleotide mutation). NGS, on the other hand, can sequence the entire genome and has a lot higher sensitivity in detecting variants (changes) in the genetic code. If a patient has a positive control (i.e. they have DNA from a family member who has a mutation), then Sanger sequencing is sufficient to detect and confirm the absence or presence of a mutation. If a patient no longer has a positive control, it is recommended that the patient pursue Sanger sequencing, but also confirm their genetic findings with NGS (this is due to the very small chance of allele drop-off to occur, which is explained below).
Limitations of genetic testing:
Allele drop-off: At time of testing, a company will request a sample from a family member that tested positive for the gene of interest. This is due to what is called allele drop-out. This occurs when the company’s primer (which attaches to the DNA allowing the DNA to be read and sequenced) cannot attach to the individual’s DNA. If the primer cannot attach then the only DNA copy that will be read, will be the “normal” copy because the “disease” copy has “dropped off.” While allele drop out is a rare event, it can happen. The only way to confirm there wasn't allele drop out in a negative patient is to test a previously identified positive family member. If the company confirms the mutation or variant in the positive control family member, then they know that their primer design/testing procedure works successfully for that family and can confirm that the patient being tested is a true negative. If a company does not receive a sample from a positive family member, they will list this limitation on the report they provide to a family member with a negative test result. You can speak more about this phenomenon with your genetic counselor.
Escapees: Most studies have shown that a person’s age of onset for developing disease is very close to the age in which their previous family members have gotten the disease. For example, if the father developed Alzheimer’s at 45 years of age then the son who tested positive would likely develop the disease between 44-46 years of age. However, there have been instances where individuals test positive for a mutation, but are 10-20 years after the age of onset and have still not developed the disease. Current studies are underway to determine how this is occurs in these individuals. The existence of these individuals, however, means that if an individual tests positive for a disease-causing mutation they do not have a 100% chance of developing disease, but rather a 99.5% chance.
We have also included excerpts from scientific literature found in Huntington’s disease (HD) patients, which face similar decisions and situations to those of familial/dominantly inherited Alzheimer’s disease. There is much more literature on this patient population, which is relevant to other inherited neurodegenerative diseases.
Excerpts from Paulsen et al. 2013:
Effects of testing on quality of life in HD patients:
Papers span from 1992 to the present, represent 15 cities across nine countries, range in sample sizes from four to over 2,000, include repeat assessments for up to seven time points, and measure health outcomes from one week to 25 years since predictive genetic testing. In general, no direct catastrophic reactions were reported, there were few differences between the groups who received a negative versus a positive test result, and most differences reported dissipated with time. Briefly, one study reported greater adverse events (such as depressed mood) in mutation carriers (Almqvist et al., 2003), one reported greater hopelessness in mutation carriers (Timman et al., 2004) and two reported a more avoidant coping style in mutation carriers (Decruyenaere et al., 2003) that disappeared by three years in one study (Tibben et al., 1997). Twelve studies reported improvements from baseline assessments in groups receiving a positive gene test as well as those receiving a negative gene test. Improvements were cited in mental health symptoms (Timman et al., 2004; Wiggins et al., 1996), psychological distress (Almqvist et al., 2003), depression and anxiety (Decruyenaere et al., 2003), well-being (Wiggins et al., 1992), coping methods (Licklederer et al., 2008; Timman et al., 2004), attitudes of perceived positive outcomes secondary to having genetic testing (Codori and Brandt, 1994; Taylor and Myers, 1997), decision-making (Tibben et al., 1993a), and relief from uncertainty (Dufrasne et al., 2011). Nine studies reported that health outcomes were equivalent in both groups, irrespective of gene test result. In Australia, 70% of respondents on a survey (n=60) reported that they strongly agreed that it was important to find out their genetic status, with strong agreement that knowing can provide a greater sense of personal control (58%) and help plan one's future (68%), including the decision to procreate (47%). Sixty-eight percent reported feeling ‘great benefit’ from knowing their test results. Reported benefits included planning for the future, making decisions, active participation in the HD community and advocating for themselves or families at risk for HD. Many individuals found personal meaning and a sense of community from knowledge of genetic information and from the ability to participate in research. Concerns were noted from participants about family members coping with the results (48%), insurance (30%), employment (20%), and being treated differently (27%). Interestingly, no participants were strongly concerned that the test is not useful as there is no cure for HD (Goh et al., 2013).
Effects of testing on quality of life in HD patients:
The genetic counseling paradigm initially developed for HD has been successfully adapted for use with these family members (Steinbart et al., 2001). Health-related outcome studies of predictive testing for AD are few. One study followed nine persons from three different families at risk for early onset familial AD, FTD or fatal familial insomnia and used the HD genetic testing protocol (Molinuevo et al., 2005). Anxiety increased in some gene carriers, but no significant negative psychological reactions were observed and all participants positively valued the program. Another study reported on 21 persons at risk for familial early onset AD or FTD who requested predictive testing (Steinbart et al., 2001). Seven of the persons were symptomatic and of the remaining 14 asymptomatic persons, 13 reported that predictive testing was beneficial. There were no significant adverse events and no reported discrimination although two persons reported anxiety and one reported depression. Another study followed 18 members of an extended family with identified early onset AD (Lannfelt et al., 1995) who chose to undergo predictive testing. Rather than report on group data, the authors describe three particular cases, two who tested negative and one who tested positive. Although the gene mutation carrier experienced depression, anxiety and suicidal ideation after receiving results, at one year after testing the individual was back to work and coping well. The authors felt that weekly counseling and appropriate education facilitated positive outcomes following predictive testing for AD. Although genetic counseling always recommends a structured counseling schedule, no guidelines specify that sessions need to occur weekly.
Paulsen JS, Nance M, Kim JI, Carlozzi NE, Panegyres PK, Erwin C, Goh A, McCusker E, Williams JK. (2013). A review of quality of life after predictive testing for and earlier identification of neurodegenerative diseases. Progress in neurobiology, 110, 2–28. doi:10.1016/j.pneurobio.2013.08.003.
Can be found here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3833259/