Genetic Testing for Huntington Disease

July 3, 2019

The profound consequences of the results guide decisions about testing. Who should be tested? And, just as important, who should not?

Dr Bishayis Professor of Anatomy and Physiology in the Department of Biology at North Park University, Chicago, IL, and Professor of Advanced Pharmacology in the School of Nursing at North Park University.

Huntington disease is an autosomal dominant neurological disorder characterized by neuron degeneration that results in progressive motor abnormality such as chorea, a decline in intellectual functions, and psychiatric conditions such as depression. Symptoms typically appear in the third to fifth decades.1 Thus, genetic determination becomes a preoccupation for many because of the consequences of knowing whether they will develop the disease later in life.

Genetic determinants

Previously, it was difficult to determine the pedigree of Huntington disease because of the late onset of symptoms and the need for a large number of individuals for the investigation. The diagnosis depended on enzymatic markers, which could exclude Huntington disease in 20% of the population.

In 1983, Gusella and colleagues1 discovered a closely related marker on chromosome 4 that could be used to localize the Huntington disease gene. The test, known as “presymptomatic testing,” relied on polymorphic DNA markers. The markers were obtained by recombinant DNA technology through restriction fragments length polymorphism (RFLP). Different-sized fragments on DNA were obtained, whether they encoded a protein or not (anonymous), and those fragments were free from repetition. Anonymous DNA fragments were found on chromosome 4. This marker showed a close linkage to Huntington disease in two separate families from the US and Venzuela; thus, the chromosome was identified despite the small sample size.

Another breakthrough occurred 10 years later. The previous technique required a sample of many family members, but in 1993 a specific mutation was discovered as a “trinucleotide repeat expansion” on the short arm of chromosome 4.2 Then a gene was targeted by cloned exons in that area. Known as IT15, the gene was composed of a trinucleotide repeat of sequence CAG: “A (CAG) repeat longer than the normal range was observed on HD chromosomes from all 75 disease families examined, comprising a variety of ethnic backgrounds and 4~16.3 haplotypes.”3

The trinucleotide repeat with at least 17 alleles in the normal population can range from 11 to 35 CAG sequence copies, but in patients with Huntington disease, the number of repeats increases to a range of 42 to 66 copies. The number shows a correlation with the age of onset: the younger the age, the larger the number of repeats. It was also found that earlier onset (before age 21) stems mainly from paternal gene transmission rather than maternal. Individuals with a larger number of normal repeats have a delayed onset of the disease; such a modifier of the gene may help in the future to counteract the mutation and possibly prevent the disease. The penetrance is full, which means that children of Huntington disease gene carriers have a 50% possibility of inheriting the gene, and those who do will eventually develop the disease.4


The Huntington disease mutation is related to an unstable gene, in a similar pattern to fragile X syndrome, spino-bulbar muscular atrophy, and myotonic dystrophy. The tandem nucleotide repeat expansion is believed to code for RNA of a protein called huntingtin, resulting in neuronal cell death. The progressive neurodegeneration in Huntington disease mainly involves the basal ganglia and cerebral cortex.


Age of onset is usually in the 30s or 40s, but it can occur in those as young as 2 to 3 years and as old as 80 years.4 The clinical picture includes motor disturbances in the form of choreiform movements, cognitive impairment, mood disorders, and behavioral changes that are chronic and progressive.

Genetic testing >>

Genetic testing

Initially, testing was done mainly by detecting the linkage. After the gene was discovered in 1993, testing could directly identify the gene itself.

The test can be done by sending blood samples to a laboratory, whether to detect the gene and confirm the diagnosis, for presymptomatic testing of carriers and high-risk candidates, or for prenatal testing. Over the years, the test has proved its effectivity and was incorporated as a National Health Service test in the UK 10 years after its establishment.2

The cost of the laboratory DNA test ranges from $200 to $300.2 In addition, there is the expense of “confirming the diagnosis,” which typically occurs in persons with a suspected diagnosis, in the absence of family history as in cases of adoption or a deceased parent, and in the event of a de novo mutation.

Candidates often choose to pay for the test out of pocket for fear of disclosure to third-party payers such as health insurance companies and for fear of exposure of their private information to their employers and potential discrimination.5 Sometimes they give false information about their identity or ask for the test anonymously.4

Consequences of the test results

The results of genetic testing for Huntington disease must be taken into consideration. The consequences of the test outcome should guide recommendations about who should be tested.

Psychological outcomes

Researchers have assessed the risk of depression in patients found to have the HD gene. In 1986, when the test involved the genetic linkage, not the direct gene, Brandt and colleagues5 conducted a study of the genetic marker of Huntington disease. Reactions to the test ranged from relief to sadness, but there was no severe depression in the short term at least.

A study published in 1997, after determination of the direct gene, evaluated predictors of adjustment over a 1-year period among 52 candidates who tested positive for the HD gene and 108 candidates who tested negative. The study used the Beck Hopelessness Scale (BHS) and Beck Depression Inventory (BDI) to assess adjustment. Those who had a better adjustment were married; had no children, so there was no guilt about transmitting the disease to their offspring; or were close to the age of onset.6

A review showed that carriers and non-carriers differ in their short-term but not their long-term adjustment. It also demonstrated that adjustment status before the test is the main determinant of post-test adjustment: “Carriers show either no changes from psychological adjustment before testing or only short term increases in hopelessness.”7 The authors recommend that genetic testing be preceded by and be done in the context of psychological or psychiatric counseling.

Overall, predictive testing has not resulted in suicide attempts. Revised guidelines recommend at least two or three pre-test sessions that involve a genetic counseling session, a psychological assessment, and a neurological examination, although these recommendations should be considered on a case-by-case basis.8 In general, patients cope well with test results.

Effects on the family

Some studies have reported higher rates of divorce among carriers in the first 6 months after they received the test results, compared with non-carriers.8 Some candidates denied depressive symptoms in the Minnesota Multiphasic Personality Inventory (MMPI), yet their partners confirmed the symptoms; the lie score was higher among females. There were reports of guilt among carriers who have children. Some partners reported hopelessness and less sexual satisfaction.

Pre-test marital assessment is recommended, and the reversal of roles in marital relationships must be addressed. The extended family should also be involved. Maximizing connection and autonomy throughout the phases of the disease should be stressed.

Prenatal testing

Prenatal testing is less frequently requested, primarily because many high-risk candidates have undergone the test before pregnancy and decided not to become pregnant. Presymptomatic testing during pregnancy has a profound effect on the mother who finds out that she is a carrier. If prenatal testing reveals that the fetus carries the HD gene, the couple can undergo severe distress whether they decide to terminate the pregnancy or not.

Preimplantation genetic diagnosis (PGD) is available for couples who want to avoid termination of pregnancy: “Most often PGD tests are performed on single cells biopsied at the eight-cell embryo (day 3 of development). The genetic analysis for monogenic disorders such as HD takes advantage of PCR to amplify the DNA and for detection of the repeat sizes for each chromosome.”4 The drawbacks of PGD are “allele dropout,” the high cost of the procedure, and the low success rate, yet it can still be considered.

Children of positive carriers >>

Children of positive carriers

Testing minors for Huntington disease is contraindicated. If a parent is a carrier or already has the disease, it is advisable to allow their minor children to grow up and decide for themselves whether they want to be tested. Because of the possibility of a treatment for Huntington disease in the future, there is no need to burden children with the knowledge of being a gene carrier, especially since the disease will probably not develop until they are in their late 30s or 40s.4

In general, people at risk have been familiar with the symptoms since childhood. They experience stressors that may involve their relationship with the affected parent, who may be preoccupied with her or his condition and experiencing depression or agitation as a symptom of the disease. Moreover, the choreic movements may frighten children. Family dynamics are disturbed and must be addressed in counseling, in addition to providing support and up-to-date genetic information about the disease.

Who should undergo testing for Huntington disease?

Generally, testing should be performed in the following settings4:
• Individuals at risk, who should be tested as adults not as minors
• Prenatal testing, which is best performed before high-risk candidates plan to have a child
• Preimplantation genetic diagnosis, which is an option when in vitro fertilization is used
• Confirmation of the diagnosis

Genetic, psychological, and family counseling, as well as neurological assessment must be employed. Support should be given to the patient and the carrier.


Dr Bishay reports no conflicts of interest concerning the subject matter of this article.


1. Gusella JF, Wexler NS, Conneally PM, et al. A polymorphic DNA marker genetically linked to Huntington’s disease. Nature. 1983;306:234-238.

2. Harper PS, Lim C, Craufurd D. Ten years of presymptomatic testing for Huntington’s disease: the experience of the UK Huntington’s Disease Prediction Consortium. J Med Genet. 2000;37:567-571.

3. The Huntington’s Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell. 1993;72:971-983.

4. Myers RH. Huntington’s disease genetics. NeuroRx J Am Soc Experimental NeuroTherapeutics. 2004;1:255-262.

5. Brandt J, Quaid KA, Folstein SE, et al. Presymptomatic diagnosis of delayed-onset disease with linked DNA markers. The experience in Huntington’s disease. JAMA. 1989;261:3108-3114.

6. Codori AM, Slavney PR, Young C, et al. Predictors of psychological adjustment to genetic testing for Huntington’s disease. Health Psychol. 1997;16:36-50.

7. Meiser B, Dunn S. Psychological impact of genetic testing for Huntington’s disease: an update of the literature. J Neurol Neurosurgery Psychiatry. 2000;69:574-578.

8. Tibben A. Predictive testing for Huntington’s disease. Brain Res Bull. 2007;72:165-171.