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Assessing Genetic Risks: Implications for Health and Social Policy 2 Genetic Testing and Assessment Genetic disease or genetic predisposition to disease is present in gametes before conception; therefore, theoretically it can be detected from that point on. If the capability exists for identifying a specific mutation, one can do so in gametes, in the zygote immediately after conception, in the early embryo, prenatally throughout pregnancy, in the newborn period, in childhood or adolescence, as part of reproductive planning in adulthood, or thereafter. A variety of technologies are used for genetic testing, including chromosomal, biochemical, or DNA-based techniques. The biological test sample may come from blood, amniotic fluid, or other tissue. In addition, DNA must sometimes be obtained from more than one family member for the test to be informative for a disorder when testing is done by a linked marker gene. The purpose of the following sections is to illustrate how genetic tests are used in practice and to identify issues raised by their use in various types of testing and in various populations. 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), sickle cell anemia), heterozygote or carrier testing (e.g., TaySachs disease), identification of signs or symptoms (e.g., myotonic dystrophy), prenatal diagnosis (e.g., neural tube defects), predictive testing for monogenic late-onset disorders (e.g., Huntington disease), and susceptibility testing for lateonset disorders of complex genetic and environmental interaction (e.g., coronary heart disease). Principles to be considered in the use of genetic tests in various populations are discussed. More detailed discussions—of genetic counseling and
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Assessing Genetic Risks: Implications for Health and Social Policy education; laboratory quality control; and social, legal, and ethical issues—can be found in later chapters of the report. Genetic disorders are discussed because they illustrate issues in genetic testing; the list of genetic disorders is not intended to be encyclopedic. BASIC HUMAN GENETICS AND GENETIC ANALYSIS Genetics explores the manner by which specific traits are passed from generation to generation and how they are expressed. Genetics can be studied at many levels. For example, study of an individual's phenotype, or observable properties, can provide information about modes of inheritance, allowing estimates for risks of recurrence. Studies of an individual's chromosomes, or cytogenetics, provide information about the person's gender and about certain diseases that are directly related to abnormal numbers or configurations of the 23 pairs of chromosomes found in humans (e.g., Down syndrome, fragile X syndrome). Genetic testing may involve studies of a physiological, immunological, or biochemical function, or may involve direct study of the genes in the individual's genome. Assessment of the molecular basis for inheritance is done by examining the specific structure and function of genetic material, or DNA. Locating a disease-causing gene on a chromosome and isolating it are an important goal of research. Elucidating the gene's structure and function may provide opportunities for diagnosis and may lead to treatment of the disorder. Molecular biology is being integrated into genetics and medicine at a rapid pace. Understanding the associations between a gene's information and the physical manifestation of its instructions is accomplished by studies of gene expression (i.e., how the organism carries out the instructions of the DNA to create products that are essential for structure and function of all cells in the body). Understanding gene expression and its regulation is the key to understanding genetic disease and hereditary variation. Hereditary variation is the result of changes—or mutations—in DNA. Changes that occur in germ cells (egg or sperm) are inherited by offspring. Changes that occur in somatic cells (body cells other than egg or sperm) are not passed to future generations but can result in disease for the individual possessing them (e.g., cancer). Changes—sometimes called mutations—can occur as a result of mistakes in coding in the coding nucleotides, rearrangements within the gene, insertion of new genetic material into the gene, or duplication or deletion of parts or all of a gene. Disorders resulting from changes in one gene alone are called monogenic (e.g., cystic fibrosis, sickle cell anemia, Duchenne muscular dystrophy). Disorders resulting from changes in several genes, usually in combination with an environmental influence, are called multifactorial. Multifactorial disorders (e.g., common types of coronary heart disease and most forms of diabetes) tend to affect far more individuals than do monogenic disorders. In human monogenic disorders, the altered gene can be located on any one of
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Assessing Genetic Risks: Implications for Health and Social Policy the 22 autosomal chromosomes or on a sex chromosome. Modes of inheritance of the altered gene can be autosomal dominant, autosomal recessive, or X-linked. In an autosomal dominant disorder, a single abnormal gene causes the trait to be expressed, even though the corresponding gene (all autosomal genes are paired) is normal. Thus, an individual with an autosomal dominant disorder will have one mutant gene and one normal gene (unless both parents are affected), and the person will usually be symptomatic at some level, although symptoms might vary in severity and age of onset. In autosomal dominant disorders, an affected individual generally has an affected parent. Each child of an affected individual with an autosomal dominant disorder has a 50 percent chance of inheriting the mutant gene, with the same risks for both males and females. In some cases, however, the mutation arises spontaneously (also called sporadic mutations) and is not inherited from either parent. The proportion that is due to a new mutation varies greatly for various disorders and is highest for the most severe diseases; this is because those most severely affected usually do not reproduce. In contrast, autosomal recessive disorders result in illness only if a person receives two copies of the mutant gene, one from each parent who is a carrier. Such a person is considered homozygous for the gene and is affected with the disorder. Individuals who carry only one copy of the mutated gene are called heterozygotes, or carriers, and are clinically asymptomatic. Examples of autosomal recessive disorders are cystic fibrosis (CF), Tay-Sachs disease, phenylketonuria, sickle cell anemia, and thalassemia. Autosomal recessive disorders tend to occur with varying frequencies among different racial and ethnic populations. If both parents are carriers of the same recessive trait, each pregnancy carries a 1 in 4 risk of producing an affected child (homozygous affected) and a 1 in 2 chance of producing an asymptomatic carrier, such as themselves. A 1 in 4 chance also occurs with each pregnancy that the child with be neither a carrier nor affected by the disease. Each individual has two sex chromosomes in the normal condition; males have an X and a Y chromosome, females have two X chromosomes. Theoretically, altered genes can occur on either the X or the Y chromosome, but the Y chromosome carries few genes. In X chromosomal recessive disorders (X-linked), males are disproportionately affected by these disorders because they possess only one X chromosome, which carries the mutation. Carrier females have one normal chromosome and one carrying the altered gene. Recessive diseases caused by alterations in genes on the X chromosome include Duchenne muscular dystrophy, fragile X syndrome, and hemophilia. In X-linked dominant diseases, men and women are affected equally since the abnormal gene dominates its normal partner; there can never be male to male transmission, however, because an affected father only passes a Y chromosome to his sons. A phenomenon called heterogeneity sometimes adds to the complexity of determining inheritance within and across families. For example, different genes located on different chromosomes can independently give rise to the clinically
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Assessing Genetic Risks: Implications for Health and Social Policy identical phenotype, as is the case for retinitis pigmentosa, an inherited form of blindness. Another form of heterogeneity, allelic heterogeneity, is caused by different mutations in a single gene that give rise to manifestations of a disease. In the case of CF, more than 300 mutations have been found in the same gene. To complicate matters further, a mutation that expresses itself clinically in one person may produce no detectable effect in another (reduced penetrance) or, if it does appear, it may have a wide range of symptomatology or severity (variable expressivity). Both of these phenomena may be due to other genes that ameliorate the effect of the mutated gene. Some genetic conditions do not manifest clinically until adulthood and may only become apparent in middle age or later. Predictive testing aims at predicting diseases before they are clinically expressed. Although some monogenic disorders of late onset are not particularly rare (e.g., polycystic kidney disease, hemochromatosis), they do not make up a large fraction of the disease load of the population. In contrast, common diseases of more complex etiology that include genetic factors comprise the bulk of diseases producing ill health. We are learning that many common diseases may be due to the presence of a variable number of susceptibility genes. Thus, in coronary heart disease, a yet-unknown number of genes related to fat and cholesterol metabolism, clotting susceptibility, and other effects, interacts with environmental factors such as smoking and diet, to lead to the clinical end result. The relative contribution of genes and environment varies between individuals and families. This general pattern of interaction between heredity and environment appears to apply to many common diseases such as hypertension, diabetes, and allergies. Such conditions are not commonly considered genetic diseases, but genetic factors are thought to play a significant role in their development. 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. In addition to the classical patterns of monogenic and multifactorial inheritance, several novel mechanisms of inheritance have been described in recent years. The severity and nature of the disease may depend on which parent provided the faulty gene. This phenomenon, called genomic imprinting, has recently been detected in rare disorders and is currently under intensive study. In uniparental disomy, both members of a chromosomal pair are transmitted from one parent (instead of the one chromosome that would ordinarily be transmitted from each parent); this rare event allows a recessive disorder to be expressed in a child when only one parent is a carrier for the mutant gene. In another recent development, research has focused on the diseases resulting from the DNA transmission of mitochondrial disorders. Mitochondria are energy-generating organelles (components inside the cytoplasm of every cell) and carry their own chromosomal DNA. They are thought to be descendants of an-
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Assessing Genetic Risks: Implications for Health and Social Policy cient bacteria that migrated into animal cells and became essential functional parts of those primitive cells. Sperm lose their mitochondria when they penetrate the egg; thus, mitochondrial genes (and any mutations in them) are passed only from the mother. Mutations in mitochondrial genes can be detected by molecular techniques and have been positively associated with certain types of blindness (Leber optic atrophy), muscle diseases, a type of epilepsy, and dementias associated with aging. Another type of inheritance is known as allelic expansion. 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. Disease severity may be related to the size of the expanded gene. Allelic expansion accounts for a phenomenon called anticipation, in which there is earlier onset and/or increasing severity of disease as the expanding gene is transmitted from generation to generation. Molecular tests for allelic expansion are already available. Mosaicism is the existence of cells with different genetic constitution in the same organism and is of greatest clinical importance in cancer. Cancer cells usually carry genetic mutations not shared by the normal cells. The organism affected with such a mutation is a somatic mosaic, where the cancerous tissue often has a different genetic constitution from the rest of the body. Germinal mosaicism affecting gonadal cells (sperm- and egg-forming tissue) also occurs. The finding of several affected siblings with an unexpectedly nonaffected parent in diseases that are transmitted by autosomal dominant inheritance may be due to germinal mosaicism. In such cases a section of the parent's gonad carries the diseaseproducing mutation. Technologies for Detecting Genetic Disorders Technologies to detect genetic disorders have existed for some time but have expanded dramatically in their scope, accuracy, and speed over the past 20 years. The earliest forms of genetic diagnosis, still frequently practiced, were based on observation of an individual's clinical findings or constellation of anomalies, and on an assessment of the family history. Later, biochemical assays were developed to test for inborn errors of metabolism, such as phenylketonuria or sickle cell disease. These earlier techniques remain useful today. Chromosomal analysis has been in use for more than 30 years to diagnose errors in number or shape of chromosomes that can result in genetic disorders and disease. Chromosomal analysis is most often practiced in the evaluation of newborns with malformations and for prenatal diagnosis for advanced maternal age. (As a female ages, the eggs she carries are more likely to produce errors in meiosis, leading to an increased risk of bearing a child with a chromosomal anomaly.) Advances in DNA technology
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Assessing Genetic Risks: Implications for Health and Social Policy have greatly advanced our ability to directly examine the genetic basis for disease. Today, DNA-based tests encompass a variety of diagnostic techniques that allow examination of markers very near the genes (e.g., some forms of polycystic kidney disease) or direct examination of the genes themselves for the characteristic mutations (e.g., CF, sickle cell anemia). DNA can be extracted from any tissue containing nucleated cells, including the white blood cells in a blood sample. 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). In direct analysis of the gene or gene variant, family members need not be tested. Direct tests are now being conducted for cystic fibrosis, the thalassemias, and Duchenne muscular dystrophy, to name just a few. In disorders like CF, for which more than 300 mutations have been identified, screening for all mutations is not feasible. In most cases, only the more common mutations are searched for in testing. The second approach—linkage analysis—is used in cases where the gene has been localized to a region of a chromosome, but the gene has not been cloned; tracking the inheritance of linked DNA markers provides a means of predictive testing. In this situation, DNA from family members, including at least one affected family member, is essential to the determination of the genetic status of an individual. Diagnosis using linkage analysis is limited for the following reasons: (1) DNA from at least one affected family member is required (taken either from a living individual or from stored DNA from blood or other tissues), together with DNA from other unaffected family members; (2) undetected (nonallelic) genetic heterogeneity may confound the analysis unless the disease in the family is known to be due to a mutation at a specific locus; (3) maternity and paternity must be known; and (4) a phenomenon known as crossing over can occur between the marker and the gene, which can lead to erroneous diagnostic conclusions. Crossing over can be detected if multiple markers in the region of the disease locus are available. In the past, gene tracking by this method has been successfully used for Huntington disease, Duchenne muscular dystrophy, CF, and neurofibromatosis. For disorders in which the gene has been cloned but all mutations cannot be detected or are not completely known, a combination of direct testing and linkage analysis can be employed. Technology such as the polymerase chain reaction (PCR) has greatly magnified these capabilities because it allows for rapid DNA analysis using minute amounts of DNA. PCR and other advances in automation have great potential value for increasing the speed and accuracy of diagnosis in carrier screening programs, as well as lowering costs. These advances also present new challenges for quality control (see Chapter 3). Finally, even with the increased accuracy of direct tests, variable expressivity, incomplete penetrance, and heterogeneity can in-
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Assessing Genetic Risks: Implications for Health and Social Policy terfere with the ability to make correct predictions regarding the extent and severity of disease. Genetic tests include the many different laboratory assays used to diagnose or predict a genetic condition or disease susceptibility. Genetic testing encompasses the use of specific assays to determine the genetic status of individuals already suspected to be at increased risk for a particular inherited condition because of family history or clinical symptoms. Genetic screening is defined as the use of various genetic tests to evaluate populations or groups of individuals independent of a family history of a disorder or symptoms. (However, although the committee has distinguished genetic testing from genetic screening, these terms are often used elsewhere interchangeably when discussing techniques for diagnosing or predicting a genetic condition or disease susceptibility.) Ideally, genetic counseling is provided in conjunction with both kinds of genetic tests. Genetic counseling refers to the communication process by which information about the nature, recurrence risk, burden, and reproductive options of a genetic condition, as well as empathic counseling and support concerning the implications of such genetic information, is provided to individuals and their family members. Genetic testing services—in the context of the delivery of medical care to individuals and families who are either self-referred or referred by other physicians—have included services offered by specialized genetics centers (provided at medical and research centers by medical geneticists and genetic counselors). Primary genetic services are also provided by pediatricians (for childhood disorders), obstetricians (for prenatal diagnosis), and family physicians, internists, and specialists (for late-onset disorders) in the course of their regular practice. Genetic screening, on the other hand, has also been offered on a population basis in communities at higher risk. Lessons learned from past experiences in newborn screening, carrier detection, prenatal diagnosis, and testing for late-onset genetic disorders are instructive in designing strategies for the future (these are discussed here and in Chapter 1). NEWBORN SCREENING Newborn screening is a preventive health measure that, once proven to be beneficial, can be made available to all neonates. Screening tests are designed to speedily and inexpensively evaluate a large number of test samples. Newborn screening tests are now performed on blood samples from just over 4 million babies born annually in the United States; these blood samples are collected on filter paper spots obtained from ''heel-sticks" of newborn infants. 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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Assessing Genetic Risks: Implications for Health and Social Policy The nature of the biochemical tests now in use requires that a trade-off be made between false positive and false negative results. False positives may have serious consequences (Tlucek et al., 1990), and the occurrence of false negatives will also be devastating to the infant and the family. Because newborn screening initially produces a high rate of false positives, parental anxiety and uncertainty can be created. Thus, accurate and timely confirmatory tests are essential to a beneficial screening program. The first population-based newborn screening program was for the purpose of presymptomatic treatment of infants with PKU. PKU is an inborn error of metabolism characterized by a deficiency in the enzyme phenylalanine hydroxylase that results in high phenylalanine levels, which if not diagnosed and corrected early in life can lead to severe, progressive mental retardation. PKU occurs in about 1 in 10,000 Caucasian births. Dietary restriction of phenylalanine, if started early in infancy and continued throughout early life, is highly effective in preventing mental retardation (Holtzman, 1991). Newborns are usually screened today for several inborn errors of metabolism and for some other disorders as well. Screening of newborns for PKU and congenital hypothyroidism—two treatable disorders—is mandatory in many states. Some states screen for as many as 11 conditions, including 42 states that screen routinely for sickle cell anemia (Table 2-1). Colorado and Wyoming added CF to their mandatory newborn screening program in 1989. Newborn screening for genetic disease is one area of genetics services that, because of its public health history and justification, has remained almost exclusively within the province of state control, although private laboratories perform newborn screening tests in eight states (CORN, 1992; also Table 3-1 in Chapter 3). 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), the committee found evidence that the basic principles that should guide newborn screening have not been followed consistently since 1975. Since the 1975 NAS report, new tests have been added to newborn screening programs without careful assessment of benefits and risks, often without the review of institutional review boards, and generally without concern for obtaining informed parental consent or even the opportunity for "informed refusal." Colorado, for example, added screening for CF to its program in 1982, despite statements by professional societies that the benefits of newborn screening for CF had not been demonstrated (Taussig et al., 1983). After Colorado adopted its newborn screening program, the National Institutes of Health and the Cystic Fibrosis Foundation funded a prospective randomized controlled study in Wisconsin to assess the benefits and risks of CF newborn screening (Fost and Farrell, 1989); after eight years of study, no clear evidence of benefit had been found in the treatment group. Nevertheless, Colorado made its CF newborn screening program manda-
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Assessing Genetic Risks: Implications for Health and Social Policy tory in 1989, based on the belief that CF screening at birth would improve health outcomes (Hammond et al., 1991). Typically, state health departments have broad discretion to introduce such tests (Cunningham, 1992), often with little oversight. Examples include testing for histidinemia and iminoglycinuria, genetic conditions that were later determined to have little clinical significance and, for which the screening itself provides little opportunity for benefit but has the potential harm of possible stigmatization. The committee is concerned that the Human Genome Project raises the prospect of the availability of multiplex testing for a number of diseases and disorders for which there is no clear beneficial treatment. The justification for requiring clear benefit to the newborn (as developed further in Chapter 8) derives from the general principle that a person should not be used as a means for the benefit of others. This principle led the committee to the conclusion that newborn screening should not be done for the purpose of identifying newborns who are heterozygous for autosomal recessive disorders, or for the purpose of helping parents determine their own carrier status. 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. Sickle cell screening, as presently conducted, identifies newborns who are carriers as well as those affected with the disease; carriers for the sickling trait will be identified about 40 times as often as an infant with sickle cell anemia in sickle cell screening programs for newborns. In contrast, in PKU, the nature of the test used for neonatal screening does not identify carrier status. There is no medical benefit to the newborn of knowing its carrier status. If a newborn is determined to be a carrier, one parent must be a carrier; if the infant is determined to be affected with sickle cell anemia, both biological parents must be obligate carriers. There are ways other than newborn screening in which couples can determine their carrier status and reproductive risks without using the newborn as a means to that end, through voluntary testing in the preconception or prenatal setting. The committee deliberated at length about the dilemma posed when a newborn is unintentionally discovered to be a carrier as in newborn tests for sickle cell anemia. On the one hand, informing parents about carrier status in the newborn (1) does not meet the principle that newborn screening be of benefit to the newborn; and (2) may result in harmful stigmatization by labeling children as carriers without any clear compensating benefits for the child. On the other hand, there is a dilemma in not communicating newborn carrier status to parents, since parents would not then have the potential advantage of learning that one of them is a carrier, so that they could consider carrier screening for themselves and genetic
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Assessing Genetic Risks: Implications for Health and Social Policy TABLE 2-1 Disorders for Which Newborns Were Screened in 1990 State Phenylketonuria Hypothyroidism Galactosemia Maple Syrup Urine Disease Homocystinuria Biotinidase Deficiency Cystic Fibrosis Adrenal Hyperplasia Tyrosinemia Toxoplasmosis Hemoglobinopathy Alabama X X X Alaska X X X X X X X X Arizona X X X X X X X Arkansas X X X California X X X X Colorado X X X X X X X X Connecticut X X X X Delaware X X X X X X X District of Columbia X X X X X X Florida X X X X Georgia X X X X X X X X Hawaii X X Idaho X X X X X X X Illinois X X X X X X Indiana X X X X X X Iowa X X X X X X Kansas X X X X Kentucky X X X X Louisiana X X X Maine X X X X X X Maryland X X X X X X X Massachusetts X X X X X X X X Michigan X X X X X X Minnesota X X X X Mississippi X X X
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Assessing Genetic Risks: Implications for Health and Social Policy Missouri X X X X Montana X X X Nebraska X X X Nevada X X X X X X X X New Hampshire X X X X X X X New Jersey X X X X New Mexico X X X X New York X X X X X X X North Carolina X X X X X North Dakota X X Ohio X X X X X Oklahoma X X X Oregon X X X X X X X Pennsylvania X X X Rhode Island X X X X X X South Carolina X X X South Dakota X X X Tennessee X X X Texas X X X X Utah X X X Xa Vermont X X X X X X Virginia X X X X X X X Washington X X X West Virginia X X X Wisconsin X X X X X Xb X Wyoming X X X X X X X X Puerto Rico X X X Virgin Islands X Total 52 52 38 22 21 14 3 8 5 2 42 a Hemoglobinopathy pilot study, June 1, 1990-March 31, 1991 (now discontinued). b Cystic fibrosis screening for research purposes only.
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Assessing Genetic Risks: Implications for Health and Social Policy If and when such techniques as fluorescence in situ hybridization (FISH), triple-marker screening, or fetal cells isolated from maternal blood are validated for genetic testing, the committee recommends that (1) their use in prenatal diagnosis should be reviewed with the same careful considerations as those that were applied to current prenatal diagnostic techniques; and (2) professional groups work together to develop standards for the use of these technologies. Nevertheless, even when simpler, safer methods of testing are available, prenatal diagnosis will continue to raise significant social and ethical issues for individuals and for society, and these issues and consequences need to be weighed carefully in prenatal education and counseling. The committee recommends that prenatal diagnosis not be used for minor conditions or characteristics. In particular, the committee felt strongly that the use of fetal diagnosis for determination of fetal sex or use of abortion for the purpose of preferential selection of the sex of the fetus is a misuse of genetic services that is inappropriate and should be discouraged by health professionals. However, the committee recognizes the desire to use prenatal diagnostic technology for identifying the sex of the fetus at high risk for an X-linked disorder where direct testing is not available. The committee is concerned that entrepreneurial pressures may expand the offering of prenatal diagnosis for preferential selection of one sex over the other, and that this practice may become a greater problem in the future. The committee believes this issue warrants careful scrutiny over the next three to five years as the availability of genetic testing becomes more widespread, and especially as simpler, safer technologies for prenatal diagnosis are developed. Testing for Late-Onset Disorders The committee recommends caution in the use and interpretation of a predispositional or predictive test, especially for multifactorial diseases. The dangers of stigmatization and discrimination are areas of concern, as is the potential for harm due to inappropriate preventive or therapeutic measures. Quality assurance in both testing and test interpretation is crucial in predictive testing with special attention to conditions for which effective interventions exist. The committee recommends that—in the current state of knowledge—reproductive interventions, including prenatal diagnosis and termination of the fetus, not be conducted for increased genetic susceptibility to multifactorial disorders. Testing in later life for these conditions may be appropriate. The benefits of the various presymptomatic interventions should be weighed against the potential anxiety, stigmatization, and other possible harms to individuals who are informed that they are at increased risk of developing future disease. 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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Assessing Genetic Risks: Implications for Health and Social Policy widespread application of such tests is undertaken, the committee recommends that their predictive value be thoroughly validated in prospective studies of sufficient size and statistical power. If no effective preventive or therapeutic measures exist, the dilemma of whether to test for a cancer predisposition is somewhat similar to the problems raised by predictive testing for monogenic and other conditions that are only possibly treatable. Some individuals would want to have the test while others would not, and extensive counseling is required to aid in decision making. If partially effective prevention (such as frequent monitoring) or treatment is available, extensive counseling will be required to consider the benefits and harms that may be associated with testing and possible treatment interventions. If effective prevention or treatment is available, genetic testing should be offered. The decision about the point at which treatment or prevention is so efficacious that testing becomes routine will vary for different cancers and will require extensive deliberation. The appropriate time for initiation of testing will often vary. The committee believes that presymptomatic screening in children for adult cancers would rarely be appropriate unless effective preventive or therapeutic measures exist and require early implementation for effectiveness. In addition, the optimal time to start screening in adults may vary for different cancers. In the future, prenatal screening may become possible, and the possibility for prenatal diagnosis of many late-onset conditions raises troubling issues when the condition is potentially curable. The committee recommends that, if predictive tests for mental disorders become a reality, results must be handled with stringent attention to confidentiality to protect an already vulnerable population. If no effective treatment is available, testing may not be appropriate since more harm than good could result from improper use of test results. On the other hand, future research might result in psychological or drug treatments that could prevent the onset of these diseases. Carefully designed pilot studies should be conducted to determine the effectiveness of such interventions and to measure the desirability and psychosocial impact of such testing. Interpretation and communication of predictive test results in psychiatry will be particularly difficult. 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. Under such guidelines, population screening should only be offered after appropriate, reliable, sensitive, and specific tests become available. The committee also recommends extensive pretest counseling, to ensure voluntariness and informed consent, as well as counseling after testing, and medical management where appropriate for those identified with potentially deleterious genes. Providers who conduct such testing should be well schooled in
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Assessing Genetic Risks: Implications for Health and Social Policy the principles of genetics and genetic counseling, including the ethical, legal, and social issues in genetic testing (see Chapters 4, 6, and 8). The availability of presymptomatic testing for Mendelian disorders and the possibility of predispositional testing for complex disorders, such as cancers and heart disease, raise unique issues not evident in genetic testing of newborns or for reproductive planning, particularly pertaining to confidentiality—both inside and outside the family—and create new challenges for the physician-patient relationship. The availability of presymptomatic and predispositional testing provides an opportunity for physicians and patients to work toward prevention of disease. Thus, the goal of nondirective counseling (as discussed in Chapter 4), so crucial in genetic services pertaining to reproductive planning, may not always be appropriate when primary prevention or effective treatments are available. In such instances, it is considered appropriate for practitioners to give guidance to patients regarding the relevant interventions after fully explaining what is known about the potential benefits and harms of testing and of following such advice. In considering the use of presymptomatic tests, the committee recommends that the patient be the ultimate decision maker. One concern about genetic tests for common, high-profile, complex disorders is that the potential number of such tests is likely to make them widely available; for-profit testing facilities may not be equipped to deal with the complexities of testing, interpretation, communication of results, and genetic counseling. The committee recommends strict guidelines for efficacy and standards for use to prevent premature introduction of this technology in disorders of late onset; this would be an appropriate role for the recommended national advisory body and its Working Group on Genetic Testing (see Chapter 9). REFERENCES American College of Obstetricians and Gynecologists (ACOG). 1985. Professional Liability Implication of AFP Testing (Liability Alert). Washington, D.C., May. American Society of Human Genetics (ASHG), 1987. Statement on maternal serum alpha-fetoprotein screening programs and quality control for laboratories performing maternal serum and amniotic fluid alpha-fetoprotein assays. American Journal of Human Genetics 40:75-82. American Society of Human Genetics (ASHG). 1989. Update [on MSAFP Screening]. American Journal of Human Genetics 45:332-334. American Society of Human Genetics (ASHG). 1992. Statement of the American Society of Human Genetics on cystic fibrosis carrier screening. American Journal of Human Genetics S1:1443-1444. Baron, M., et al. 1993. Diminished support for linkage between manic depressive illness and X-chromosome markers in three Israeli pedigrees. Nature Genetics 3:49-55. Beeson, D., and Golbus, M. 1985. Decision making: Whether or not to have prenatal diagnosis and abortion for X-linked conditions. American Journal of Medical Genetics 20:107-114. Benn, P., et al. 1992. A rapid (but wrong) prenatal diagnosis; A reply from Integrated Genetics. New England Journal of Medicine 326(24): 1638-1640. Bianchi, D., et al. 1991. Fetal cells in maternal blood: Prospects for non-invasive prenatal diagnosis. Presented at the International Congress of Human Genetics, Washington, D.C., October.
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Representative terms from entire chapter: