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Huntington's Disease Location on Chromosome 4

Huntington's Disease is one of several trinucleotide repeat disorders which are caused by the length of a repeated section of a gene exceeding a normal range. The HTT gene is located on the short arm of chromosome 4 at 4p16.3. HTT contains a sequence of three DNA bases—cytosine-adenine-guanine (CAG)—repeated multiple times (i.e. ... CAGCAGCAG ...), known as a trinucleotide repeat. CAG is the genetic code for the amino acid glutamine, so a series of them results in the production of a chain of glutamine known as a polyglutamine tract (or polyQ tract), and the repeated part of the gene, the PolyQ region. Walker FO (2007). "Huntington's disease". Lancet 369 (9557): 218–28.

Katsuno M, Banno H, Suzuki K et al. (2008). "Molecular genetics and biomarkers of polyglutamine diseases". Curr. Mol. Med. 8 (3): 221–34

Prenatal Testing

There are two types of prenatal tests being offered as a part of the presymptomatic testing program. The main form of prenatal testing that is most frequently requested is known as exclusion testing. This type of testing tells the expectant person if the fetus has inherited the short arm of chromosome 4. Chromosome 4 is known to be the locus for the Huntington's disease gene. This test is valuable in two situtations: 1. when at-risk parents do not have sufficient information on the genetics of their families to determine their own genotype and 2. when at-risk parents prefer not to know their own genotypes. If the fetus is shown to have a short arm of chromosome 4 then the parents are faced with the choice of aborting the fetus who has a 50% chance of developing the disease.

Conneally PM, JF Gusella, NS Wexler. Huntington's disease: linkage with G8 on chromosome 4 and its consequences. Prog. Clin. Biolog. Research 1985; 77:53-60.

Genetic prediction has consequences for the individual, the family, and society. The gravity of these consequences and the choices they provoke differ depending upon (1) whether the inheritance pattern is dominant or recessive, (2) age at onset of symptoms, (3) if the disease is treatable, (4) the gravity, burden, and subjective perception for the disease, and (5) the symptoms, particularly if there is loss of mental capacities. "

The Oracle of DNAä in Molecular Genetics of Neuromuscular Disease. L.P. Rowland, Editor, Oxford University Press, 1989

Genetic Testing Protocol

There are variations among countries and centers but the following represents some key elements of the basic protocol which is followed, at least in the United States and Canada: 1) There must be a minimum of three to six separate counseling sessions before diagnostic information is delivered. Each session should be several hours long. Intensive counseling regarding motivations and preparation for testing is the most essential element of the entire protocol. Post-test counseling must be part of any protocol but clients sometimes prefer to seek counseling closer to home. 2) Potential clients should be evaluated neurologically, neuropsychologically and psychiatrically. 3) Relatives at risk or symptomatic who are donating a DNA sample for a client to be tested should be evaluated neurologically as well. A diagnosis should not be accepted on the basis of hearsay evidence, even from a family member. Corroboration should be sought from the diagnosing physician and a re-evaluation should be arranged if there is any doubt. If persons at risk cannot or will not be examined, their risk should be assigned very conservatively in the linkage analysis. The disease should be confirmed in at least one relative by autopsy diagnosis or by very reliable neurological examination. 4) Clients found to have significant psychiatric disorders, particularly a history of suicide or severe depression, or those undergoing stressful life circumstances causing emotional upheaval, such as divorce or a death in the family, are not suitable testing candidates. 5) Diagnostic information must always be given in a face- to-face session, never over the telephone. Even if the outcome is genetically uninformative, clients need an opportunity to discuss what this information may mean. 6) Most programs require or strongly urge that clients be accompanied by a companion to at least one counseling session and at the disclosure session. 7) Long-term follow-up is essential, particularly for those who test positive for the gene. As the time draws near when symptoms are likely to appear, clients need to know that they have a relationship with a supportive therapeutic individual or group. 8) Some programs require that a client contact a psychotherapist prior to receiving diagnostic information. Other programs provide the therapists. These therapists can continue to see clients, particularly after a positive diagnosis. 9) All DNA determinations must be carried out independently at least twice. If contradictions appear, new DNA samples are collected. Some centers collect two independent blood samples. If blood has been donated from relatives for research purposes these samples must be re-collected unless explicit permission is given for them to be used in diagnostic testing. Even then it is best to collect new samples on crucial individuals. 10) A genetic linkage computer analysis of haplotypes generated must always be conducted. Diagnostic information must never be given on the basis of a visual analysis of the gels alone. 11) If siblings of a client need to be analyzed to determine phase or to reconstruct the haplotype of a deceased parent, the identities of these siblings should be confidential and data analyzed anonymously. This prevents those providing counseling from inadvertently receiving unwanted and inappropriate information. 12) Testing should be available only to persons aged 18 years or older who can give informed consent. One potential complication of this guideline may occur if parents have a nondisclosing prenatal test and choose to maintain a pregnancy in which the fetus is found to have a 50% risk. If the at-risk parent develops Huntington's disease, the child is de facto diagnosed. Another ethical quandary may occur when couples who wish to adopt a child at risk insist on testing as a condition of adoption. 13) All testing must be totally voluntary and the results remain totally confidential, even to other family members."

Presymptomatic Testing For Huntington's Disease: Harbinger of the New Geneticsä in Genetics, Ethics And Human Values. Human Genome Mapping, Genetic Screening And Gene Therapy. Proceedings of the XXIVth CIOMS Round Table Conference. Edited by Z. Bankowski and A.M. Capron. Tokyo and Inuyama City, Japan, 22-27 July 1990