Assessing Genetic Risks Implications for Health and Social Policy (1994) / Chapter Skim
Currently Skimming:
2 Genetic Testing and Assessment
2 Genetic Testing and Assessment
Pages 59-115
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From page 59... ...
This chapter briefly describes the fundamentals of human genetics and genetic testing and their application to human health from reproduction and conception through the life span. Specifically, genetic tests are discussed in different settings and for different types of disorders: in newborn screening (e.g., phenylketonuria (PKU)
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From page 60... ...
Disorders resulting from changes in one gene alone are called monogenic (e.g., cystic fibrosis, sickle cell anemia, Duchenne muscular dystrophy)
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Examples of autosomal recessive disorders are cystic fibrosis (CF) , Tay-Sachs disease, phenylketonuria, sickle cell anemia, and thalassemia.
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Since elucidation of various genetic factors can often detect those at greatest risk, genetic testing for susceptibility might be useful in identifying groups of persons who could benefit from appropriate preventive measures. Understanding the genetic components of these disorders may lead to the development of new therapies as well.
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From page 63... ...
Here, instead of DNA remaining constant over the generations, as is usually the case, a gene segment expands in size when transmitted from parent to child. The expanded gene may cause a characteristic disease such as Huntington disease, myotonic dystrophy, spinal bulbar muscular atrophy, or fragile X mental retardation syndrome.
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From page 64... ...
Once extracted, the DNA is stable and can be stored indefinitely so that samples from individuals with genetic disorders can be collected and saved for future investigation or diagnostic tests. Two major approaches are currently used in DNA diagnosis and study of genetic disease-direct tests and indirect tests (known as linkage analysis)
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From page 65... ...
These blood spots serve as the basis for newborn screening in the United States, making newborn screening the most common type of genetic testing today (Holtzman, 1991; CORN, 1992~. These screening tools are not definitive diagnostic tests, however, and positive results must be confirmed through specific testing for the disease in question.
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From page 66... ...
Chapter 1 reviews problems that arose in the development of newborn screening, particularly for phenylketonuria and sickle cell anemia. Although these problems were well documented and addressed in the 1975 National Academy of Sciences report (NAS, 1975)
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From page 67... ...
Newborn screening programs may also lack adequate attention to education and counseling of parents who are informed that their child is affected with a genetic disorder, including cases of false positive and false negative results. Newborn screening for sickle cell anemia provides an example of the need for adequate education and counseling.
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Since states generally do not obtain informed consent for testing, the discovery of misattributed paternity is usually unexpected and unanticipated. Despite these real and complex side effects of newborn screening, which require intensive genetic counseling, few states conducting sickle cell screening in the newborn period have adequate resources for genetic counseling for the many parents whose infants will be found to be sickle cell carriers.
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From page 71... ...
Carrier screening involves individuals with no previous family history in order to determine their risk; such screening programs are usually not conducted in a specialized medical setting. Testing and screening to detect carrier status for autosomal recessive disorders are used primarily to aid in informed reproductive planning and deci .
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The practitioner counseling a family with fragile X must take these complexities into consideration when discussing which family members might wish to be tested for carrier status and deciding which diagnostic test to order. Furthermore, pilot projects are already under way in some schools (in Pennsylvania)
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From page 73... ...
or in early blastomeres to permit selective uterine implantation of embryos that are not homozygous for currently diagnosable genetic disorders. Sickle cell anemia, CF, and Tay-Sachs disease are examples of recessive disorders for which carrier testing and screening are available.
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From page 74... ...
At the same time, there is general agreement that testing to detect carrier status is appropriate in families with a history of the disorder because of the high risk of being a carrier. However, while new drugs and devices are subject to strict federal regulation requiring demonstration of safety and effectiveness, new genetic testing interventions and mass screening programs are generally not held to such standards.
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From page 75... ...
Prenatal diagnosis has focused largely on chromosomal abnormalities in pregnancies in women of advanced maternal age, couples with a family history of genetic disease, MSAFP screening for fetal neural tube defects and Down syndrome, diagnosis of hemoglobin disorders and hemophilia, and some biochemical abnormalities (WHO, 1983; NERGG, 1989; Medical Research Council, 1991; Modell, 19921. Some experts estimate that as many as 2.1 million pregnant women are now screened annually in the United States using MSAFP to determine increased risk of fetal genetic disorders (Haddow et al., 1992; J
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From page 76... ...
Basic data are needed on this and other genetics services (see discussion of basic data set on genetics services in Chapter 9) ; of all genetic testing, relatively comprehensive data exist only on newborn screening (CORN, 1992~.
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Not all conditions, however, can be reliably diagnosed as early as 8 weeks of fetal development (such as some neural tube defects) (Mennuti, 1989)
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Many of the concerns that exist regarding the specificity or sensitivity of particular tests apply to prenatal diagnosis, as well as newborn screening and heterozygote detection (see above)
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From page 79... ...
An MSAFP test is a simple maternal blood test administered between 15 and 20 weeks of gestation as a first-step screening test to detect those pregnancies at possible increased risk for a variety of conditions; the MSAFP test does not diagnose fetal disorders. The MSAFP screening test serves as a basis for appropriately referring, for more definitive tests, women who exhibit elevated or decreased levels of the fetal protein in their blood.
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From page 80... ...
In addition with the use of folate supplements prior to or early in pregnancy the risk of NTDs may be reduced (Laurence, 1990; Scott et al., 19911; research is continuing (McPartlin et al., 19931. Several new research techniques have been developed that may hold promise for prenatal diagnosis in the future, including genetic tests on fetal cells isolated from maternal blood and genetic tests associated with preimplantation diagnosis.
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From page 81... ...
Diagnosis using fetal cells isolated from maternal blood holds the promise of noninvasive prenatal diagnosis by genetic analysis of fetal cells isolated from a sample of the mother's blood (Bianchi et al., 1991~. Techniques have been developed to isolate or concentrate genetic material from the very few fetal cells circulating in maternal blood.
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From page 82... ...
from a woman's ovaries, involving some risk to the woman. When fertilized eggs have divided into four to eight as yet undifferentiated cells, one of these cells can be removed for genetic testing.
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From page 83... ...
. Reproductive genetic testing, counseling and other genetic services can be a valuable component in the reproductive health care of women and their families.
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6. Increasing attention focused on the development and utilization of reproductive genetic testing services may further stigmatize individuals affected by a particular disorder or disability: The values that some place on health and disabilities, what people may be told about disabilities and even the use of certain language to describe the benefits of reproductive genetic testing has the potential to place a value on the worth of individuals with disabilities in society.
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From page 85... ...
One further issue deserves particular attention- prenatal diagnosis for early determination of the sex of the fetus. Historically, prenatal diagnosis for identification of fetal sex was used where pregnancies were at risk of X-linked genetic disorders such as muscular dystrophy.
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From page 86... ...
The Canadian Royal Commission on New Reproductive Technologies is preparing a statement on genetic testing for sex selection scheduled to be issued later in 1993. TESTING FOR LATE-ONSET DISORDERS Many diseases do not manifest clinically until adulthood and may become apparent only in middle age or later.
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From page 87... ...
However, since this late-onset, lethal disorder is not treatable, direct genetic testing-even without involving other family members-continues to raise many complex ethical, legal, and social issues that must be addressed through education and counseling. Alzheimer Disease Monogenic adult early-onset Alzheimer disease raises similar considerations to those raised by Huntington disease in that there is no effective treatment or cure (Marx, 19921.
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From page 88... ...
Because the test was based on the observation of DNA-linked markers and not the gene itself, it could be used only by those with genetically informative families. Prior to the existence of the test, many surveys of family interest indicated a strong desire for predictive testing but when the possibility of actually seeing the future became a reality, only a tiny fraction of those at risk chose to utilize the test.
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From page 89... ...
In autosomal recessive hemochromatosis (iron storage disease) , a significant portion, but not all of those who carry the double dose of the mutant gene (about 1 in 500 of the Caucasian population)
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From page 90... ...
Once found, more direct genetic testing should be possible. Early diagnosis of hemochromatosis, followed by treatment, is essential to prevent liver cirrhosis and early death; the life expectancy of hemochromatosis patients without cirrhosis is identical to the normal control population (Niederau et al., 1985~.
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From page 91... ...
could be tested and, if affected, treated, even though not all persons who carry the gene will develop coronary heart disease (Motulsky and Brunzell, 19921. Polycystic Kidney Disease Predictive testing for autosomal dominant polycystic kidney disease (PKD)
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From page 92... ...
Indirect DNA testing in at-risk families by tracing the coinheritance of the linked marker and the cancer gene is already possible in some instances, such as inherited breast carcinoma, and direct testing for the responsible gene can be carried out in a few instances (e.g., testing for retinoblastoma or for the pS3 gene in Li-Fraumeni syndrome see Box 2-8~. While most cancers are not caused by such Mendelian or monogenic cancer genes, the total number of affected persons with inherited cancer in the population is large.
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From page 93... ...
Linkage studies in affected families are already providing some women with predictive tests. Current technology is available in some large families to identify family members at risk for breast cancer by testing DNA markers co-segregating with the cancer gene.
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. Testing for Multifactorial Genetic Disorders Coronary Heart Disease Coronary heart disease is a common cause of morbidity and death.
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A surrogate for genetic testing reflecting the action of both genetics and environment is already being used. The finding of elevated cholesterol levels (Motulsky and Brunzell, 1992)
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than hypertension among Caucasians, suggesting genetic heterogeneity in the mechanism of hypertension in these populations. Much more work will be needed before genetic tests can be useful as practical tools for predicting high blood pressure and directing therapy.
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Since this form of diabetes is very common (affecting 3 percent of the population) and the disease is associated with a wide range of related health effects, the development of accurate predictive testing and effective prevention and therapy would be
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From page 98... ...
Genetic factors affecting cellular HLA immunity have been implicated in many different infections. Associations of HLA alleles have been claimed for immunologic responses to a variety of vaccines (e.g., tetanus, influenza, hepatitis A and B)
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From page 99... ...
when treatment and follow-up are available for affected newborns. The committee recommends that states with newborn screening programs for treatable disorders also have programs to ensure that necessary treatment and follow-up services are provided to affected children identified through newborn screening.
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The committee recommends that couples in high-risk populations who are considering reproduction seek carrier screening for themselves. When newborn screening might lead to the identification of carrier status in an infant, parents should be informed in advance about this possibility and about the benefits and limitations of genetic information and genetic counseling, including that the information has no bearing on the health of their child.
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From page 101... ...
Newborn screening programs should include provision for counseling of all parents who are informed that the child is affected with a genetic disorder, including those for whom the diagnosis in the child proves to be false in later testing. Since some existing programs may not have been subject to careful evaluation, the committee recommends that ongoing programs be reviewed periodically, preferably by a body independent of the program or laboratory performing the testing, such as a broadly representative state commission or advisory council (see Chapter 9~.
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From page 102... ...
The committee is unaware of any additional autosomal recessive disorders that have a sufficiently high frequency in the general population to be recommended for heterozygote screening for reproductive purposes at this time. Carrier screening has been suggested in females to detect carriers of fragile X, the most common form of serious mental retardation.
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From page 103... ...
Prenatal diagnostic services for detection of genetic disease for which there is a family history, as well as genetic counseling, should be reimbursed by insurers as medically indicated or "necessary" (see Chapter 71. Within these categories of increased risk for genetic disorders, the ability to pay should not restrict appropriate access to prenatal diagnosis, with the recognition that this recommendation has implications for the delivery of genetics services and the cost of such medical care.
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From page 104... ...
Furthermore, the committee recommends that third-party insurers and payers should reimburse for appropriate prenatal diagnostic services (see Chapter 7) for those at increased risk of serious genetic disorders, or screening to determine increased risk, including genetic counseling as an essential service, and that third-party payers should be neutral on the reproductive outcome of the prenatal diagnosis and subsequent reproductive decision making; third-party payers should not be informed of the results of prenatal screening and diagnosis.
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From page 105... ...
The principles for predictive testing of inherited cancer susceptibility are identical to those suggested for other late-onset genetic disorders: before any
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From page 106... ...
To prepare for the issues associated with genetic testing for psychiatric diseases in the future, all psychiatrists will need more training in genetics and genetic counseling; such training should include the ethical, legal, and social issues in genetic testing. The committee recommends that population screening for late-onset monogenic diseases be considered only for treatable or preventable conditions of relatively high frequency.
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From page 107... ...
1992. Statement of the American Society of Human Genetics on cystic fibrosis carrier screening.
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From page 108... ...
. Issues in state newborn screening programs.
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From page 109... ...
American Journal of Human Genetics 37:350-357. Fearon, E., and Vogelstein, B
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American Journal of Human Genetics 43:160164.
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From page 111... ...
. Newborn screening: American Academy of Pediatrics policy statements and issues related to DNA and RNA microextraction from newborn screening blood spots.
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National Institutes of Health (NIH) Workshop on Reproductive Genetic Testing.
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American Journal of Human Genetics 52:298-304. Parfrey, P., et al.
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From page 114... ...
U.S. newborn screening system guidelines: Statement of the Council of Regional Networks for Genetic Services.
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From page 115... ...
American Journal of Human Genetics 46: 1200- 1213. Wexler, N
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