Genetic Testing

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Genetic Testing

Genetic testing examines the genetic information contained inside a person’s cells to determine if that person has or will develop a certain disease or could pass a disease to his or her offspring. The use of genetic information to predict future onset of disease in an asymptomatic (presymptomatic) person is called predictive genetic testing.

Laboratory testing techniques

A variety of laboratory techniques is used to examine genes or markers near genes. Direct analysis of an individual’s specific genes can determine if the individual suffers from diseases such as cystic fibrosis and sickle cell anemia. Indirect testing has to be done for certain diseases because the gene has not been directly identified, but are known to lie in a specific region of a chromosome.

There are many types of genetic testing:

Carrier identification includes genetic tests used by couples whose families have a history of recessive genetic disorders and are considering having children. Three common tests include those for cystic fibrosis, Tay-Sachs disease, and sickle cell anemia.
Prenatal diagnosis is genetic testing of the fetal cells from the mother’s womb. This may be done when there is a risk that they mother may be carrying a child with genes associated with diseases that could cause some physical abnormality or mental retardation. Down Syndrome is one of the most common diseases screened by this method.
Newborn screening is frequently done as a preventative health measure. Tests usually have clear benefits to the newborn because treatment is available. Phenylketonuria and congenital hypothyroidism are conditions for which testing is conducted in all 50 states.
Late-onset disorders include adult disorders such as cancer and heart disease. Genetic diseases may indicate a susceptibility or predisposition for these diseases. Diseases such as Huntington’s disease which are seen only later in life are caused by single genes.

Family information

Every aspect of humans is influenced by both genes and the environment. In the future, a strategy for influencing development may be to alter genes. At present, the environment in which genes act can sometimes be changed, and thereby moderate their impact (taking medications or avoiding specific hazards, for example). Sometimes there is no known way to change the deterministic power of a gene, though with increased knowledge of its workings there is always hope for future interventions. Whether or not the course of a disease can be altered, predictive information is increasingly available, and some people choose knowledge over uncertainty.

For generations, people have used family information to anticipate outcomes for themselves. Insurers consider parental age and cause of death for actuarial tables. Evolution in knowledge has been from information with considerable associated uncertainty to that with greater predictive capacity. Huntington disease (HD) became the prototype for predictive testing and serves to illustrate.

HD is a neurological disease with onset of symptoms usually during adulthood. It is inherited as an autosomal dominant trait; someone with an affected parent has a 50/50 chance of eventually developing the disease. The HD gene was the first human gene to be linked to an otherwise anonymous DNA (deoxyribonucleic acid) marker (a restriction fragment length polymorphism, called G8), and long before the gene itself was identified, this marker and others like it became powerful predictive tools. Families in which HD was segregating were studied to determine which variant of the marker was tracking with the mutant HD gene; once that relationship was established, the marker(s) could be used to test family members who wished to know their genetic status. This indirect approach to testing was associated with some probability of error, since the markers were only close to the gene, not within it. With discovery in 1993 of the gene responsible for HD, a direct assay was immediately possible, with or without access to samples from other family members, and results became highly predictive.

The laboratory advances made access to this information possible, but it was quickly recognized that great care would be needed in the application of such knowledge to individuals at risk. A large Canadian collaborative study of predictive testing for HD, initiated in the late 1980s, has been particularly informative for assessing the impact of such information on individuals and families and developing guidelines for the practice of predictive medicine, including the need for supportive counseling and follow-up. Lessons from experience with this relatively obscure disorder were soon applied to other late-onset diseases for which predisposing mutations were identified. Notable in this context are inherited cancers such as familial breast cancer or colon cancer, other neurological disorders such as spino-cerebellar ataxias (including Machado-Joseph Disease), and familial Alzheimer disease. Common afflictions such as heart disease, diabetes, and arthritis will eventually be amenable to similar investigations.

The Human Genome Project (HGP) recognized the need for ethical considerations to match scientific advances, and its mandate includes significant support for research into ethical, legal and social issues. This activity has set new standards for the application of knowledge, respecting public concerns about the implications of new technologies. The opportunity to know ones genetic destiny has potential risks that must be mitigated in order for the benefits to be realized. Once the predictive test for HD was available, it was soon apparent that not everyone at risk wished to be tested. The right not to know is a significant issue. The genetic nature of these diseases adds complication, because information revealed about one individual may secondarily imply information about other family members, and individual choices will impact others in the family network. Acting upon respect for individual autonomy, early guidelines have advised against the testing of children for late-onset disorders in the absence of preventive options. In countries without universal health care, insurance implications of predictive testing are huge. Will people be required to submit a clean genetic bill of health in order to secure health or life insurance?

Costs of genetic tests

The cost of genetic tests varies: chromosome studies can cost hundreds of (U.S.) dollars and certain gene studies can cost thousands of (U.S.) dollars. Insurance coverage also varies with the company and the policy.

Direct DNA mutation analysis examines DNA for specific gene mutations. Some genes contain more than 100,000 bases and a mutation of any one base can make the gene nonfunctional and cause disease. The more mutations possible, the less likely it is for a test to detect all of them. This test is usually done on white blood cells from a person’s blood. The test begins by using chemicals to separate DNA from the rest of the cell. Next, the two strands of DNA are separated by heating. Special enzymes (called restriction enzymes) are added to the single strands of DNA, then act like scissors, and cut the strands in specific places. The DNA fragments are then sorted by size through a process called electrophoresis. A special piece of DNA, called a probe, is added to the fragments. The probe is designed to bind to specific mutated portions of the gene. When bound to the probe, the mutated portions appear on x-ray film with a distinct banding pattern.

A technique called linkage analysis is used for indirect tests, and requires additional DNA from a family member of the affected individual for comparison.

Family linkage studies are done to study a disease when a mutated gene’s general location on a chromosome is known but its identity is not. These studies are possible when a chromosome marker has been found associated with a disease. Chromosomes contain certain regions that vary in appearance between individuals. These regions are called polymorphisms. If a polymorphism is always present in family members with the same genetic disease, and absent in family members without the disease, it is likely that the gene responsible for the disease is near that polymorphism. The gene mutation can be indirectly detected in family members by looking for the polymorphism.

To look for the polymorphism, DNA is isolated from cells in the same way it is for direct DNA mutation analysis. A probe is added that will detect the large polymorphism on the chromosome. When bound to the probe, this region will appear on x-ray film with a distinct banding pattern. The pattern of banding of a person being tested for the disease is compared to the pattern from a family member affected by the disease.

Linkage studies have disadvantages not found in direct DNA mutation analysis. These studies require multiple family members to participate in the testing. If important family members choose not to participate, the incomplete family history may make testing other members useless. The indirect method of detecting a mutated gene also causes more opportunity for error.

Genetic testing is a complex process, and the results are dependent on reliable laboratory procedures and accurate interpretation of results. The tests also vary in their sensitivity, making interpretation of the test a very complex process even for trained healthcare professionals.

Genetic counseling aims to facilitate the exchange of information regarding a person’s genetic legacy. It attempts to:

Accurately diagnose a disorder,
Assess the risk of recurrence in the concerned family members and their relatives,
Provide alternatives for decision-making, and
Provide support groups that will help family members cope with the recurrence of a disorder.

Human Genome Project

The Human Genome Project (HGP), which published its accomplishments in 2003, basically finished its goal to identify the approximate 30,000 genes in the human body. Later, in May 2006, the HGP sequenced the last chromosome, another major milestone of the project. With those genes identified and approximately 5,000 disorders caused by genetic defects, genetic counseling is important in the medical discipline of obstetrics. Genetic counselors, educated in the medical and the psychosocial aspects of genetic diseases, convey complex information to help people make life decisions. There are limitations to the power of genetic counseling, though, since many of the diseases that have been shown to have a genetic basis currently offer no cure (for example, Down syndrome or Huntington’s disease). Although a genetic counselor cannot predict the future unequivocally, he or she can discuss the occurrence of a disease in terms of probability.

A genetic counselor, with the aid of the patient or family, creates a detailed family pedigree that includes the incidence of disease in first-degree (parents, siblings, and children) and second-degree (aunts, uncles, and grandparents) relatives. Before or after this pedigree is completed, certain genetic tests are performed using DNA analysis, x ray, ultrasound, urine analysis, skin biopsy, and physical evaluation. For a pregnant woman, prenatal diagnosis can be made using amnio-centesis or chorionic villus sampling.

An important aspect of the genetic counseling session is the compilation of a family pedigree or medical history. To accurately assess the risk of inherited diseases, information on three generations, including health status and/or cause of death is usually needed. If the family history is complicated information from more distant relatives may be helpful, and medical records may be requested for any family members who have had a genetic disorder. Through an examination of the family history, a counselor may be able to discuss the probability of future occurrence of genetic disorders. In all cases, the counselor provides information in a non-directive way that leaves the decision-making up to the client.

Eventually, there will be effective therapeutic interventions for diseases such as HD and Alzheimer disease, individually tailored to the needs of those at risk. Until then, there will be controversy over the practice of predictive testing, but many will continue to choose knowledge and maintain hope for the future.

Resources

BOOKS

Carlson, Elof Axel. Mendel’s Legacy: The Origin of Classical Genetics. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press, 2004.

Hartl, Daniel, and Elizabeth Jones. Genetics: Analysis of Genes and Genomes. Sudbury, MA: Jones and Bartlett Publishers, 2005.

King, Robert C., William D. Stansfield, and Pamela K. Mulligan. A Dictionary of Genetics. New York: Oxford University Press, 2006.

Lewin, Benjamin. Essential Genes. Upper Saddle River, NJ: Pearson Education, 2006.

Lewis, Ricki. Human Genetics: Concepts and Applications. Boston, MA: McGraw-Hill, 2005.

Nussbaum, R.L., Roderick R. McInnes, Huntington F. Willard Genetics in Medicine. Philadelphia, PA: Saunders, 2001.

Rimoin, D.L. Emery and Rimoin’s Principles and Practice of Medical Genetics. London, UK; New York: Churchill Livingstone, 2002.

OTHER

National Human Genome Research Institute. “The Ethical, Legal and Social Implications (ELSI) Research Program.” (November 2006). <http://www.nhgri.nih.gov/ELSI/> (accessed November 29, 2006).

Janet A. Buchanan

The Gale Encyclopedia of Science