Huntington’s disease is an inherited neurodegenerative disorder that’s caused by a mutation in a gene called huntingtin (HTT). This gene contains a stretch of DNA that’s composed of repeats of the building blocks C, A, and G (called CAG). In Huntington’s patients, these CAG repeats are longer than in healthy individuals.
A genetic test can determine the number of CAG repeats in the HTT gene. Every individual has two copies of each gene, one inherited from the mother and the other from the father. Huntington disease patients have an unusually high number of CAG repeats in either of the two HTT gene copies.
A normal HTT gene that is not associated with any risk of developing Huntington’s disease has 26 or fewer CAG repeats.
An HTT gene with 27 to 35 CAG repeats is called “intermediate.” In this case, the individual will not develop Huntington’s disease. However, an HTT gene with an intermediate number of CAG repeats is unstable, and the number of repeats might increase as the gene is passed on to the children. So, there is a risk that children in the next generation develop the condition.
With a number of CAG repeats between 36 and 39, it cannot be predicted with certainty whether the individual will develop Huntington’s disease. This result is called “reduced penetrance.” Some individuals develop classic Huntington’s disease symptoms, while others live a long life without any symptoms.
An HTT gene within this range is also unstable, and children might have a higher number of CAG repeats that are clearly in the HTT-positive range.
A test result with 40 or more CAG repeats is considered “full-penetrance” or HTT-positive. It is very likely the individual will develop Huntington’s disease at some point in their life. In general, the longer the CAG repeat region, the earlier the disease onset.
However, the CAG repeat expansion is not the only predictor, and other factors also determine the age at which symptoms first appear.
Different kinds of testing
There are different types of genetic tests depending on the time of testing and whether the individual is symptomatic. These are summarized below.
Prenatal testing and pre-implantation genetic diagnosis (PGD)
A woman who is affected by Huntington’s disease or has a family history of the condition might consider undergoing prenatal testing during pregnancy.
A test called chorionic villus sampling (CVS) is carried out from 11 to 12 weeks of pregnancy. A small sample of the chorion, the lining of the uterus that later develops into the placenta, is taken.
An amniocentesis is another option of prenatal testing that is performed a little later, between 15 and 19 weeks of pregnancy. A small sample of amniotic fluid is taken for the test.
PGD is an alternative to prenatal testing where embryos that are generated by in-vitro fertilization (IVF) are genetically tested before they are implanted into the uterus.
Presymptomatic or predictive testing
An individual with a family history of Huntington’s disease might decide to get tested at a young age before symptoms appear. In many countries, the person needs to be at least 18 years old before the test can be offered.
Confirmatory and diagnostic testing
A confirmatory test is supposed to confirm a clinical diagnosis that is made based on symptoms. In the case of a negative genetic test despite a positive clinical Huntington’s disease diagnosis, the diagnosis should be re-evaluated. Also, the accuracy of the diagnosis in family members should be re-assessed.
The decision to be tested for the presence of disease-causing versions of the HTT gene is very personal. A genetic counselor knows which factors should be considered and talks the individual through these individual factors.
The motivations for testing, the expectations about the test result, strategies for dealing with the result and the impact that a positive or negative test can have on the individual’s life are discussed in a genetic counseling session.
The counselor will mention that the test result will likely influence the relationship of the person with their spouse, children, other family members, and friends. The impact on finances and insurance should also be considered. A positive result might make it more difficult to purchase life, disability, or long-term care insurance.
The result of a genetic test usually has a strong emotional impact, which is difficult to predict. A positive result might result in feelings of anger, fear, and despair. It may also cause symptom watching, where occasional forgetfulness or clumsiness are interpreted as symptoms of the disease.
A negative result, on the other hand, might result in relief and joy but may also trigger feelings of guilt in an individual who escaped the disease while other family members did not.
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