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Genetics | Huntington's Disease | UC Davis Health

Genetic Testing and Huntington's Disease

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Predictive Testing in HD with genetic counselor, Mara Sifry-Platt

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Huntington's disease (HD) is a genetic condition of the brain. Symptoms usually begin to occur in adults between 30 and 50 years of age, although symptoms can occur in people who are younger or older as well. Even within the same family, the age of onset and symptoms may vary.

The diagnosis of HD in an individual or family member can have an immediate impact on people's perceptions of themselves, on their day-to-day lives, and on their plans for the future.  Although for some people the impact may be delayed, the challenges are no less significant. The process of adjusting to these life changes after diagnosis is different for everyone.

Each child of a parent with HD has a 50% chance of inheriting the disease.

You may recall from the Genetics Overview that human beings have 23 pairs of chromosomes in our cells and that each of our parents contributes one chromosome to each pair. The gene that causes HD is found on chromosome 4.  Each of us gets one copy of the gene from our mother and one copy from our father.

Like all genes, the HD-causing gene is made of DNA, a molecule with a twisted double helix structure. You can imagine it as a twisted ladder, as shown in the picture at the right. DNA is made from a sugar phosphate backbone (the sides of the ladder) combined with pairs of nitrogen bases that hold the two sides together (the rungs of the ladder).

These bases have names: Adenine, Thymine, Guanine, and Cytosine. The gene responsible for HD contains a sequence with several CAG repeats (Cytosine, Adenine, Guanine). We all have these CAG repeats in the gene that codes for the huntingtin protein, but people with HD have a greater number than usual of CAG repeats in one of the genes they inherited.

Although different sources vary slightly in describing the significance of CAG repeat numbers, the following explanation is based on information from the well-respected genetics website, Gene Tests:

  • Normal: 26 or fewer CAG repeats
  • Intermediate: 27-35 CAG repeats. Not at risk of developing symptoms of HD, but because of instability in the CAG repeats, a person with a CAG number in this range may be at risk of having a child with an expansion of the CAG repeats into the HD-causing range.
  • Reduced Penetrance: 36-39 CAG repeats. People who have 36-39 CAG repeats may or may not develop symptoms of HD. This size repeat is also considered unstable so that future generations could be at risk.
  • Affected: If you have 40 copies of the CAG repeats one of your HD genes, you will develop symptoms of HD over the course of a natural lifespan. If a person has 60 or more CAG repeats this would result in Juvenile onset HD.

 

Paternal Inheritance

The number of CAG repeats you have gets determined at conception and is not expected to change over time. However, the gender of the parent you inherit an HD expansion from may play a role in determining the number.

If you inherit the HD-causing gene from your father, the number of CAG repeats may increase, expanding as the gene is passed from father to child. But if you inherit the gene from your mother, the number of CAG repeats usually remains stable.

This is significant because the number of CAG repeats plays a role in the age of onset. In general, the higher the number of CAG repeats, the earlier the onset -- although exceptions occur regularly so this is only a general guideline. Other genetic and non-genetic variables also contribute to the complex issues that determine the age of onset and severity of symptoms.

Genetic Testing & Genetic Counseling

Genetic testing for Huntington's disease (HD) is a process that involves much more than just getting the results of a blood test. Many issues are at stake: financial, emotional, and social issues that involve not only the person seeking testing, but also his or her immediate family -- and often the extended family as well. Before giving a blood sample, the person seeking a test deserves an opportunity to examine these issues thoroughly with people who are experienced with genetic testing for HD.

While the actual DNA test for the HD gene expansion is a fairly straightforward laboratory process, the implications and emotional aftermath of the results are usually anything but straightforward. Since this is such a serious, degenerative brain disease and there is currently no cure for HD, the emotional burden of the results can be very challenging.

These are the reasons why genetic counseling has become an essential part of the HD testing process. Genetic counselors are non-directive and non-judgmental. Their job is to help people become better informed and to support independent decision-making around these very emotional and personal testing decisions. By discussing the issues involved with caring professionals (often together with other family members), people who are thinking about getting tested have the best opportunity to make informed decisions about whether testing is right for them at this time in their lives.

Diagnostic testing is very similar to the process most of us are used to when visiting a doctor. We have a symptom that's bothering us and want to know what's causing it. Whether or not we have a family history of Huntington's disease, we may nevertheless show up at the doctor's office with symptoms typically associated with HD. 

If our symptoms and/or our family medical history causes the doctor to suspect HD, a diagnostic blood test will be ordered to determine whether we have HD or to rule it out. The result will be the number of CAG repeats in the HD genes.

If the number of CAG repeats is in the normal range, HD can definitely be ruled out. If the number is in the intermediate range, we are not likely at risk for ourselves, but there is a chance that our children could be affected. And if the number is high, then we are sure to develop symptoms of HD at some point during our lives.

Pre-symptomatic testing for Huntington's disease, also known as predictive testing, is a bit more complicated than diagnostic testing. Pre-symptomatic testing happens when people who know they may be at risk for HD but who do NOT have symptoms seek testing to learn whether they will get HD in their lifetimes.

Many people who are at risk for HD do not seek pre-symptomatic testing, preferring not to know their future. However, for those who choose to be tested, research has shown that learning their test results after going through a pre-symptomatic testing protocol enables them to cope with the information better than not going through the protocol.

The pre-symptomatic testing protocol isn’t in place to make it difficult for people to get the information they want, but rather to provide support and to encourage thought and discussion about important issues in order to help people feel ready to learn this very significant information.

Some of the issues to be explored include:

  • What is your life experience with HD?
  • Are you testing for yourself and not feeling pressured by others to do so?
  • How would the results change your life? Would you do things differently? (For example issues around education, marriage, having children, setting life priorities, etc etc)
  • How does your family feel about you getting tested?
  • How do you feel you would react if the results are positive? Negative?
  • Are their any other major life stressors going on at the same time you are seeking this information? (For example, death of loved one, divorce, pregnancy, or other major life changes.)
  • Why are you interested in getting this information now?

There are many, many reasons people choose to test or not to test. Just a few reasons people choose to test can include: alleviating anxiety about needing to know, planning for the future (marriage, children, and education), creating a support system, and living life to the fullest.

Some reasons people choose not to test include: there’s no cure, not emotionally prepared for results or testing process, not wanting to know the future, conflict with loved ones about testing, and concern about discrimination. Of course this is just a partial list. Everyone approaches testing with a personal set of issues which can be explored as part of the genetic counseling process.

The pre-symptomatic testing protocol involves meeting with a genetic counselor, neurologist, and also somebody who can provide emotional counseling and support (therapist, social worker, etc) before testing is performed. This process may require three to four visits, and the results are given in person.

This process also allows time for people to think through the issues thoroughly. Some people change their minds after starting the process, choosing to delay the test or not to do it at all. We remind people seeking this testing that once you learn the results, you can never not know your status again. There are studies suggesting a higher rate of depression in people who know their positive gene status -- but there are also many amazing people who have used the knowledge that they will develop HD in very positive and inspirational ways.

Insurance Issues

Insurance Discrimination is a major concern for many people considering pre-symptomatic testing for HD. There are several laws that protect against insurance discrimination.

First, all medical information is protected by HIPAA (Health Insurance Portability and Accountability Act of 1996). In general, HIPAA doesn’t allow group health insurance issuers to create any rule of eligibility for a person or his/her dependents that discriminates against that person based on any health factor. The term “health factor” includes genetic information.

Secondly, a law has been passed called GINA (Genetic Information Non-discrimination Act) which provides some security against employment and medical insurance discrimination. GINA does not yet cover life, disability, or long term care insurances which are often of some concern to people in families with HD. GINA protects against discrimination based on positive gene status in healthy individuals who are gene positive but do not have HD. Once a person actually has signs or symptoms of the disease the protection disappears. GINA doesn’t apply to the military and Indian reservations. See the NIH Fact Sheet on GINA for more detailed information about GINA.

Lastly, there are also California laws that provide some protection for those who are gene positive but do not yet have the diagnosis of HD.

Other resources if you choose to read more about these issues: