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Genetic Testing - Genetic Diagnosis In Children Andadults

screening disease people mccabe

Genetic testing can also be performed postnatally (after birth) to determine which children and adults are at increased risk of developing specific diseases. By 2005 scientists could perform predictive genetic testing to identify which individuals were at risk for cystic fibrosis, Tay-Sachs disease, Huntington's disease, amyotrophic lateral sclerosis (ALS, a degenerative neurological condition commonly known as Lou Gehrig's disease), and several types of cancers, including some cases of breast, colon, and ovarian cancer.

More than 900 genetic tests were available in 2005, but public health professionals did not consider it practical to screen for conditions that are very rare, have only minor health consequences, or those for which there is still no effective treatment. The most frequently performed genetic tests were those considered most useful in terms of their potential to screen populations for FIGURE 6.4
Cutting DNA with restriction enzymes
SOURCE: "Cutting DNA with Restriction Enzymes," in U.S. DOE Genome Image Gallery U.S. Department of Energy Human Genome Program, (accessed February 16, 2005)
diseases that occur relatively frequently, have serious medical consequences (including death) if untreated, and for which effective treatment is available. There are a number of other diseases, such as alcoholism, diabetes, multiple sclerosis, and prostate cancer, for which genetic testing, when it becomes available, will have considerable health impact.

A positive test result (the presence of mutation—a defective or altered gene) from predictive genetic testing does not guarantee that the individual will develop the disease; it simply identifies the individual as genetically susceptible and at an increased risk for developing the disease. For example, a woman who tests positive for the BRCA1 gene has about an 80% chance of developing breast cancer before age sixty-five. It is also important to note that, like other types of diagnostic medical testing, genetic tests are not 100% predictive—the results rely on the quality of laboratory procedures and accuracy of interpretations. Furthermore, since tests vary in their sensitivity and specificity, there is always the possibility of false-positive and false-negative test results.

Researchers hope that positive test results will encourage people who are at higher than average risk of developing a disease to be especially vigilant about disease prevention and screening for early detection, when many diseases are most successfully treated. There is an expectation that genetic information will increasingly be used in routine population screening to determine individual susceptibility to common disorders such as heart disease, diabetes, and cancer. Such screening will identify groups at risk so that primary prevention efforts such as diet and exercise or secondary prevention efforts such as early detection can be initiated.

Diagnostic Genetic Testing

Most genetic testing is performed on people who are asymptomatic (people who are apparently healthy). The objective of these screening tests is to determine if they are carriers of a genetic disease or to identify susceptibility or risk of developing a specific disease or disorder. There is, however, some testing performed on persons with symptoms of a disease in order to clarify or establish the diagnosis and calculate the risk of developing the disease for other family members. This type of testing is known as diagnostic genetic testing or symptomatic genetic testing. It also may assist in directing treatment for symptomatic patients in whom a mutation in a single gene (or in a gene pair) accounts for a disorder. Cystic fibrosis and myotonic dystrophy are examples of disorders that may be confirmed or ruled out by diagnostic genetic testing and other methods (such as the sweat test for cystic fibrosis or a neurological evaluation for myotonic dystrophy).

One issue involved in diagnostic genetic testing is the appropriate frequency of testing in view of rapidly expanding genetic knowledge and identification of genes linked to disease. Physicians frequently see symptomatic patients for whom there is neither a FIGURE 6.5
Microarray technology
SOURCE: "Microarray Technology," in Talking Glossary of Genetic Terms, U.S. Department of Health and Human Services, National Institutes of Health, National Human Genome Research Institute, (accessed February 16, 2005)
definitive diagnosis nor a genetic test. The as-yet-unanswered question is: Should such people be recalled for genetic testing each time a new test becomes available? Although clinics and physicians who perform genetic testing counsel patients to maintain regular contact so they may learn about the availability of new tests, there is no uniform guideline or recommendation about the frequency of testing.

Population Screening

Population screening for heritable diseases is one potentially lifesaving application of molecular genetics technology. Prenatal screening has demonstrated benefits and gained widespread use; however, genetic screening has not yet become part of routine medical practice for adults. Geneticists have identified at least seven genes that might be candidates for use as population screening tests in adults in the United States. The genes include HFE, for hereditary hemochromatosis; apoE4, linked to Alzheimer's disease; CYP2D6, linked to ankylosing spondylitis (arthritis of the spine); BRCA1 and BRCA2, genes for hereditary breast and ovarian cancer; familial adenomatous polyposis, associated with precancerous growths in the colon; and factor V Leiden, the most common hereditary blood clotting disorder in the United States. As of 2005, screening for variants in these genes had not entered into routine medical practice because there was considerable controversy about the predictive value of testing for these genes and how to monitor and care for people who test positive for them.

In "Genomic Medicine: Population Screening in the Age of Genomic Medicine" (New England Journal of Medicine, vol. 348, no. 1, January 2, 2003), Muin Khoury, Linda McCabe, and Edward McCabe described the principles and practice of genetic screening in the era of genomic medicine. Historically, the decision to institute population screening involved consideration of the consequences of the specific condition to public health, the availability of an effective screening test, the availability of treatment to prevent the disease, and an analysis of the costs and benefits of screening.

Khoury, McCabe, and McCabe observed that each state, as well as the District of Columbia, designated the diseases and methods for screening its newborns, and the only universally conducted screening was for PKU and hypothyroidism. The criteria for adding a screening test are similarly uneven and Khoury, McCabe, and McCabe noted that there was "a lack of research to demonstrate the effectiveness of screening and treatment for a disorder, either before or after the disease is added to the newborn-screening program." They explained that, while new technology such as tandem mass spectrometry, which detects more than twenty disorders, may be used to screen newborns to identify potentially treatable inborn errors of metabolism such as medium chain acyl-coenzyme A (CoA) dehydrogenase deficiency, the test also identifies conditions for which there are no treatments. Furthermore, they cautioned that tests such as tandem mass spectrometry may detect variations of unknown clinical significance, generating unnecessary worry in parents and medical professionals.

Genetic Susceptibility

Susceptibility testing, also known as predictive testing, determines the likelihood that a healthy person with a family history of a disorder will develop the disease. Testing positive for a specific genetic mutation indicates an increased susceptibility to the disorder but does not establish a diagnosis. For example, a woman may choose to undergo testing to find out whether she has genetic mutations that would indicate likelihood of developing hereditary cancer of the breast or ovary (BRCA1 and BRCA2, respectively). If she tests positive for the genetic mutation, she may then decide to undergo some form of preventive treatment. Preventive measures may include increased surveillance such as more frequent mammography, chemoprevention—prescription drug therapy intended to reduce risk—or surgical prophylaxis, such as mastectomy and/or oophorectomy (surgical removal of the breasts and ovaries, respectively).

Khoury, McCabe, and McCabe observed that there are questions about the risks and benefits of identifying and treating asymptomatic people who have been identified through population screening as at high risk for hereditary disorders. They used population testing for mutations in HFE, the gene for hereditary hemochromatosis (HHC), as an example of the complicated range of issues involved in recommending population screening. HHC is an autosomal recessive disorder of iron metabolism that results in iron overload. Without early diagnosis and treatment, HHC is fatal; however, with prompt diagnosis and treatment, affected people can have normal life spans. About one in ten people are carriers, and HHC affects about one in 300 people.

Khoury, McCabe, and McCabe reported that a panel of experts from the Centers for Disease Control and Prevention and the National Human Genome Research Institute determined that population genetic testing for mutations in HFE was not recommended because of uncertainty about the natural history of the disease, age-related disease penetrance, effective care for asymptomatic people identified as carrying mutations, and the psychosocial impact of genetic testing. Concurring with this recommendation, Khoury, McCabe, and McCabe noted that despite the relatively high prevalence of the mutations, studies indicated that the disease penetrance for HFE mutations is low—a large study found that just one of the 152 subjects who were homozygous for the C282Y mutation (i.e., those that had the highest risk of HHC) had symptoms of hereditary hemochromatosis.

Testing Children for Adult-Onset Disorders

In 2000 the American Academy of Pediatrics Committee on Genetics recommended genetic testing for people under age eighteen only when testing would offer immediate medical benefits or when there is a benefit to another family member and there is no anticipated harm to the person being tested. The committee considered genetic counseling before and after testing as essential components of the process.

The American Academy of Pediatrics Committee on Bioethics and Newborn Screening Task Force recommended the inclusion of tests in the newborn-screening battery based on scientific evidence. The academy advocated informed consent for newborn screening. (To date, the majority of states do not require informed consent.) The Committee on Bioethics did not endorse carrier screening in people under eighteen years of age, except in the case of a pregnant teenager. It also recommended against predictive testing for adult-onset disorders in people under eighteen.

The American College of Medical Genetics, the American Society of Human Genetics (ASHG), and the World Health Organization (WHO) have also weighed in about genetic testing of asymptomatic children, asserting that decision making should emphasize the child's well-being. One issue involves the value of testing of asymptomatic children for genetic mutations associated with adult-onset conditions such as Huntington's disease. Since no treatment can be begun until the onset of the disease, and presently there is no treatment to alter the course of the disease, it may be ill advised to test for it. Another concern is testing for carrier status of autosomal-recessive or X-linked conditions such as cystic fibrosis or Duchenne muscular dystrophy. Experts caution that children might confuse carrier-status with actually having the condition, which in turn might provoke needless anxiety.

There are, however, circumstances in which genetic testing of children may be appropriate and useful. Examples are children with symptoms of suspected hereditary disorders or those at risk for cancers in which inheritance plays a primary role. In "Genetic Testing and Screening" (American Journal of Nursing, vol. 102, no. 7, July 2002), Dale Halsey Lea and Janet Williams cited children with a family history of familial adenomatous polyposis (FAP) and those diagnosed with certain childhood cancers, such as multiple endocrine neoplasia, as appropriate candidates for genetic testing. They observed that testing can help to determine planning, surveillance, and treatment for those who are found to have the FAP genetic mutation. Genetic testing for certain childhood cancers may serve to predict risk and improve detection of second malignancies. Lea and Williams concurred that the child must agree to and understand the function of genetic testing and they reiterated that to administer genetic testing to a child requires the consent of both the parents and the child.

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