Genetics of Huntington disease

Debra Collins, M.S., CGC

Genetic Counselor
Division of Endocrinology, Metabolism and Genetics
University of Kansas Medical Center

Huntington disease (HD) is a genetic disorder of the central nervous system with symptoms usually appearing in adults within the third or fourth decade of life, although symptoms can occur in individuals younger or older than this. Within the same family, the symptoms vary both in their rate of progression and in the age of onset. Symptoms may include involuntary movements and loss of motor control. In addition, personality changes may occur, with loss of memory and decreased mental capacity. Symptoms in individuals, as well as confirmation of diagnosis in other family members, are used to determine the diagnosis. Huntington disease is inherited as an autosomal dominant condition.

 The human body contains 100 trillion cells. A nucleus is inside each human cell (except red blood cells). Each nucleus contains 46 chromosome arranged in 23 pairs. One chromosome of every pair is from each parent. The chromosome are filled from each tightly coiled strands of DNA. Genes are segments of DNA that contain instructions to make proteins and other building blocks of life.

Each of us has 46 chromosomes which come in pairs, one member of the pair comes from each parent. Therefore, 23 chromosomes are from the mother, and 23 chromosomes are from the father. There are two types of chromosomes: 1) autosomal chromosomes, which are the first 22 pairs, and 2) sex chromosomes, which are the 23rd pair (the 23rd pair in females consists of two X-chromosomes, and the 23rd pair in males consists of an X-chromosome and a Y-chromosome). Since Huntington disease is autosomal dominant, this means the gene involved is on an autosomal chromosome (not one of the sex chromosomes) and recently has been localized on the fourth autosomal chromosome pair (the #4 chromosome). In affected individuals, one gene of this gene pair (the HD gene) is not functioning correctly and expresses itself more strongly, or 'dominates', the other working gene. Since it is not on one of the sex chromosomes, it can affect both males and females. Males and females have the same chance of having affected children.

An affected parent passes either the HD gene, or the other working gene, to their off spring. There is a 50% (1 in 2) chance at each pregnancy that a child of an affected parent will receive the gene for Huntington disease. The age of onset, degree and type of clinical symptoms, as well as rate of progression varies with HD.

 During a clinic visit with a neurologist or geneticist, it may or may not be possible to clinically determine whether an individual has the HD gene. With increased age, and without symptoms, the likelihood of having the gene without evidence of disease decreases, and the risk becomes less than 50%. Therefore, the risk for passing the gene to children decreases. However, if symptoms begin, and a diagnosis is made, each child of an affected parent has a 50% chance of having the Huntington disease gene. Information about the genetics of HD should be shared with children prior to their family planning so that they can receive the most current information.

 The gene for Huntington disease on the fourth chromosome has been characterized in recent years. The chromosome is composed of genes, and each gene is composed of a string of molecules called nucleotides. The nucleotides are adenine (A), cytosine (C), guanine (G), and thymine (T). The gene is made up of a series of three nucleotides which form the structure of DNA in the gene. Each gene has its own unique sequence of base pairs. In Huntington disease, the DNA sequence, CAG (cytosine-adenine-guanine), is part of this sequence. This sequence may be duplicated many times in individuals, up to 26 times in the general population. The duplication of this segment is called a "trinucleotide repeat" in which these three nucleotides (CAG pattern) are repeated over and over again.  Individuals with Huntington disease may have from 40 to over 100 repeated CAG segments.  Specific laboratory and clinic evaluations are needed to interpret other repeat levels, which may be referred to as indeterminate, intermediate, non-penetrant, or reduced penetrance, with meiotic instability.  It is not known how this repeated sequence causes Huntington disease, but research to develop therapies to treat Huntington disease is ongoing.

 Genetic Testing

A variety of genetic testing options may be discussed with the genetics personnel, or personnel familiar with genetic testing, during a clinic visit, depending upon information specific to your family and your individual situation. These options might include direct detection of the HD gene on an affected individual and subsequent testing of relatives. The genetic testing of an individual's DNA can be obtained from a blood sample. Tissue samples that have been stored or donated for research from extended family members may also be useful in genetic testing. Most genetic testing and analysis should be done before a family member begins a pregnancy. The decision by an individual to undergo genetic testing is an intensely personal decision and can be made only by that person. Friends and family, no matter how fervent their wishes for the person to be tested, can not make that decision for that competent adult.

At this time the HDSA, in conjunction with researchers and clinicians involved in caring for people and families with Huntington disease, does not support the testing of minors who are at risk for the development of Huntington disease.

This page was last updated on February 15, 1999.
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