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GENETIC TESTING

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Genetic testing has been evolving for many years. The first genetic tests were offered clinically in the late 1950s and early 1960s when disorders associated with missing or extra chromosomes (e.g., Down's syndrome, Klinefelter's syndrome) were identified. During this same period, the first biochemical tests for genetic conditions referred to as inborn errors of metabolism were being identified. There are now thousands of genetic tests available. They are used in virtually all areas of medicine, from primary care to medical specialties.

Types of Genetic Tests

There are three main categories of genetic testing. Cytogenetic tests involve the analysis of human chromosomes to identify structural or numerical changes in the chromosomes of an individual's cells. The uniqueness of each chromosome's size and staining features allow them to be individually distinguished and organized into a karyotype. These tests allow a complete analysis of the human genome, though at low resolution–capable of identifying changes that are the size of about 5 million base pairs of DNA. Biochemical genetic tests are tests that identify the presence of a genetic condition by the analysis of metabolites, including amino acids, organic acids, and sugar compounds, present in body tissues or fluids or by the analysis of enzymatic activity that reflects an underlying genetic disorder. These tests commonly identify the biochemical abnormality that results from the genetic abnormality and are therefore highly focused. Molecular genetic tests involve the analysis of DNA and RNA but also may overlap with any of the other types of testing when protein analysis is part of a molecular test or when a molecular test uses the chromosome as the target for the test (molecular cytogenetics). Molecular genetic tests are usually highly focused and identify DNA changes ranging in size from one base pair to millions of base pairs. Molecular cytogenetic methods bridge the gap between the two technologies.

Uses of Genetic Tests

There are many uses for genetic tests. They can detect genetic changes that are acquired over the lifetime of an individual–for example, those that may reflect the development of cancer and leukemia. These tests can diagnose the condition, gauge the aggressiveness of the disease, guide therapy, and suggest prognoses. However, this group of tests is targeted at changes in specific tissues or organs. Genetic tests can also be directed at the germ line that is characteristic of all cells in an individual and that could be inherited. Such tests can be used to diagnose particular conditions in an individual and can identify other members of his or her family that may be carriers of the condition, and who are at risk of having similarly affected children. Genetic tests can be performed prenatally, at birth, or later in life and can be used to diagnose an individual with late-onset genetic conditions such as Huntington's disease even before the onset of symptoms (presymptomatic testing). Genetic testing can also determine whether someone is likely to respond to a particular drug treatment. When a genetic change is not one that will invariably lead to a particular disease, the identification of a change may indicate susceptibility to a disease. The disease could manifest itself if the appropriate environmental or other nongenetic factors were present. An example of this use of genetic testing is in the determination of predisposition to breast cancer.

The most frequently used genetic tests at the beginning of the twenty-first century are those performed to diagnose newborns with treatable conditions. In the United States, over 4 million newborns are tested each year in public health-mandated screening programs to identify those most likely to have a particular treatable genetic condition. The classic example of this is testing for phenylketonuria (PKU) in newborn infants. Infants with this condition are unable to metabolize a particular amino acid, resulting in the accumulation of a product that leads to mental retardation. Treatment entails removing that amino acid from the infant's diet. Most states currently screen for three to eight genetic conditions but new tests are being introduced that can identify as many as 20 to 30 conditions.

Ethical, Legal, and Social Considerations in Genetic Testing

The power of genetic tests to assess an individual's genetic predispositions raises many concerns. At present comparatively few people outside of the newborn period are being tested for heritable traits and only certain unfavorable genetic traits can be determined, although identification of these may expose the persons affected to unfair discrimination. However, it is estimated that each person has 8 to 20 such genetic changes that could increase risks to them, or to their children. Efforts to protect individual genetic privacy will be increasingly important. As more tests are developed, it will be critical that their scientific and clinical validity be well understood so that people can make informed decisions about testing in the light of the potential benefits and risks.

New Technologies and Applications

New technologies being introduced into genetic testing are distinguished by their ability to test many samples at once for multiple genetic markers at a low cost. Tandem mass spectrometry is capable of testing for many rare biochemical genetic diseases involving amino acids, organic acids, or fatty acids in a single assay. The development of molecular microarrays and DNA and RNA chips allows for a rapid determination of the presence, absence, or expression of many DNA sequences in a single test. Arrays may replace cytogenetic testing that identifys gains or losses of genetic material, although the test results may not provide the underlying reason for that gain or loss. Arrays are also capable of determining whether or not and to what extent a particular gene is being expressed. This capability has permitted the identification of important differences between cancer cells and normal cells, which in turn has led to the development of a new generation of diagnostic tests.

The mapping of the human genome and eventual identification of all genes, combined with powerful analytical and computer technologies, will have a significant impact on the types of genetic tests that are available. Most tests are currently done to detect very rare diseases affecting a small percentage of the population. In the years to come, genetic tests will be developed for more common conditions such as breast cancer or Alzheimer's disease and will identify genetic factors that increase the risk of developing the condition that may often be amenable to change.

See also: Eugenics; Reproductive Rights; Reproductive Technologies.

BIBLIOGRAPHY

Bartlett, Kim, Simon J. Eaton, and Morteza Pourfarzam. 1998. "New Developments in Neonatal Screening." Archives of Diseases in Childhood 79:116–119.

Carpenter, Nancy J. 2001. "Molecular Cytogenetics." Seminars in Pediatric Neurology 8: 135–146.

Grody, Wayne W. 1999. "Cystic Fibrosis: Molecular Diagnosis, Population Screening and Public Policy." Archives of Pathology and Laboratory Medicine 123: 1041–1046.

Lee C., E. Lemyre, P. M. Miron, and C. C. Morton. 2001. "Multicolor Fluorescence In Situ Hybridization in Clinical Cytogenetics." Current Opinion in Pediatrics 13: 550–555.

McGlennen, Ronald C. 2001. "Miniaturization Technologies for Molecular Diagnostics." Clinical Chemistry 47: 393–402.

MICHAEL S. WATSON