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Assessing Genetic Risks: Implications for Health and Social Policy (1994)

Chapter: 2 Genetic Testing and Assessment

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Suggested Citation:"2 Genetic Testing and Assessment." Institute of Medicine. 1994. Assessing Genetic Risks: Implications for Health and Social Policy. Washington, DC: The National Academies Press. doi: 10.17226/2057.
×

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

Suggested Citation:"2 Genetic Testing and Assessment." Institute of Medicine. 1994. Assessing Genetic Risks: Implications for Health and Social Policy. Washington, DC: The National Academies Press. doi: 10.17226/2057.
×

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

Suggested Citation:"2 Genetic Testing and Assessment." Institute of Medicine. 1994. Assessing Genetic Risks: Implications for Health and Social Policy. Washington, DC: The National Academies Press. doi: 10.17226/2057.
×

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

Suggested Citation:"2 Genetic Testing and Assessment." Institute of Medicine. 1994. Assessing Genetic Risks: Implications for Health and Social Policy. Washington, DC: The National Academies Press. doi: 10.17226/2057.
×

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-

Suggested Citation:"2 Genetic Testing and Assessment." Institute of Medicine. 1994. Assessing Genetic Risks: Implications for Health and Social Policy. Washington, DC: The National Academies Press. doi: 10.17226/2057.
×

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

Suggested Citation:"2 Genetic Testing and Assessment." Institute of Medicine. 1994. Assessing Genetic Risks: Implications for Health and Social Policy. Washington, DC: The National Academies Press. doi: 10.17226/2057.
×

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-

Suggested Citation:"2 Genetic Testing and Assessment." Institute of Medicine. 1994. Assessing Genetic Risks: Implications for Health and Social Policy. Washington, DC: The National Academies Press. doi: 10.17226/2057.
×

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.

Suggested Citation:"2 Genetic Testing and Assessment." Institute of Medicine. 1994. Assessing Genetic Risks: Implications for Health and Social Policy. Washington, DC: The National Academies Press. doi: 10.17226/2057.
×

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-

Suggested Citation:"2 Genetic Testing and Assessment." Institute of Medicine. 1994. Assessing Genetic Risks: Implications for Health and Social Policy. Washington, DC: The National Academies Press. doi: 10.17226/2057.
×

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

Suggested Citation:"2 Genetic Testing and Assessment." Institute of Medicine. 1994. Assessing Genetic Risks: Implications for Health and Social Policy. Washington, DC: The National Academies Press. doi: 10.17226/2057.
×

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

Suggested Citation:"2 Genetic Testing and Assessment." Institute of Medicine. 1994. Assessing Genetic Risks: Implications for Health and Social Policy. Washington, DC: The National Academies Press. doi: 10.17226/2057.
×

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).

bCystic fibrosis screening for research purposes only.

Suggested Citation:"2 Genetic Testing and Assessment." Institute of Medicine. 1994. Assessing Genetic Risks: Implications for Health and Social Policy. Washington, DC: The National Academies Press. doi: 10.17226/2057.
×

counseling to aid them in making more informed reproductive choices regarding subsequent pregnancies. However, if both parents elect to be tested for carrier status, misattributed paternity can also be unwittingly exposed. 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.

Furthermore, mandatory screening has not been shown to be essential to achieve desired public health benefits (Faden et al., 1982) and screening may not be sufficient to achieve intended health benefits. Nevertheless newborn screening programs have tended to become institutionalized. Previously established newborn screening programs need to be continually evaluated to ascertain whether the goals have been realized (Holtzman, 1989). For example, a test for maple syrup urine disease, a rare, fatal, autosomal recessive condition (1 in 200,000 births), has been included in the newborn screening panel by most states for many years. The potential efficacy of such screening may not be realized since affected newborns are often seriously ill before test results are available (Kaplan et al., 1991). This may also occur in screening newborns for galactosemia (also an autosomal recessive disorder occurring in I in 60,000 births) because mental function is least impaired if a galactose-free diet is begun prenatally. Although early diagnosis and therapeutic intervention by 3 weeks of age can essentially eliminate mental retardation in galactosemia (Donnell et al., 1980), if newborn diagnosis is delayed or results of testing are delayed, the central nervous system will already have sustained damage.

Finally, future uses of stored newborn blood spots deserve careful attention. Filter paper with newborn blood spots can now be used for DNA analysis as well (Matsubara et al., 1991; McCabe, 1992). This new development has raised many new issues, including the reuse of newborn blood spots for research purposes, issues of consent for such reuse, problems raised by efforts to recontact families if other genetic conditions are found, and questions surrounding who owns and controls access to the blood spots themselves (Knoppers and LaBerge, 1990; Clayton, 1992; LaBerge and Knoppers, 1992; McCabe, 1992) (see Chapter 8 for further discussion).

CARRIER TESTING AND SCREENING

We are all potential carriers of several deleterious recessive genes that would prove lethal to our offspring if they received a double dose (McKusick, 1992). For most of these genes, the likelihood of one's mate carrying the identical mutation is very small. However, for a small number of autosomal recessive disorders, the mutant version of the gene is more common in certain ethnic and racial groups.

Suggested Citation:"2 Genetic Testing and Assessment." Institute of Medicine. 1994. Assessing Genetic Risks: Implications for Health and Social Policy. Washington, DC: The National Academies Press. doi: 10.17226/2057.
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The most common autosomal recessive disorders include CF (1 in 25 carriers in the Caucasian population), sickle cell anemia (1 in 12 carriers in the African-American population), thalassemia (variable high carrier rates in Asian, Mediterranean, and Middle Eastern populations), and Tay-Sachs disease (1 in 30 carriers in Jews of Ashkenazic descent).

Genetic drift, or variation in the frequency of genetic traits due to chance, is one of the reasons for a higher than average frequency of specific recessive diseases in a specific ethnic group. Another reason may be some unknown protective benefit of the carrier state (e.g., sickle cell trait conferring resistance to malaria), or the origin of the trait in a common ancestor (founder effect), or a combination of both mechanisms, a well-known example of which is the high frequency of Tay-Sachs disease in Ashkenazi Jewish populations. As a result of the higher population frequency of these disorders, much effort has been expended in search of the genes for these diseases. In some cases, the altered gene has been identified; in other cases, biochemical assays serve as indirect indicators of the carrier or disease state.

Carrier testing can also be conducted for X-linked recessive disorders, such as hemophilia, Duchenne muscular dystrophy, or fragile X syndrome (see Box 2-1 for discussion of fragile X syndrome). In these cases, the mother of an affected son—who has no other affected relatives—might desire carrier testing to confirm whether the disease is a heritable trait or a "fresh" or new mutation (more common in X-linked recessive disorders than in autosomal recessive disorders); the sister, aunt, or female cousin of an affected individual might also seek carrier testing.

Heterozygote detection is intended to identify carriers of one copy of the mutant gene. Persons who carry a single copy of the gene for a recessive disorder do not have that disease, nor are they symptomatic. Carrier testing involves individuals known to be at high risk of being carriers because of family history; it is almost always conducted in a specialized medical setting. 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 decision making.

When at-risk couples are both identified as carriers for autosomal recessive disorders, they have several options available to them:

  • they can take their chances, understanding there is a 75 percent likelihood with each pregnancy that the child would not be affected with the disease, or a 25 percent likelihood that each child will be affected;

  • they can avoid reproduction, consider adoption, and be fully informed about contraception or sterilization;

  • they can conceive through gamete donation, which ideally includes screening of a potential sperm or ovum donor to rule out carrier status for the same trait;

Suggested Citation:"2 Genetic Testing and Assessment." Institute of Medicine. 1994. Assessing Genetic Risks: Implications for Health and Social Policy. Washington, DC: The National Academies Press. doi: 10.17226/2057.
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BOX 2-1 Diagnostic Testing for Fragile X Syndrome

One of the most common monogenic causes of mental retardation is fragile X syndrome, so named because of an unusual constriction of the X chromosome. The syndrome affects all ethnic groups and has a disease prevalence of more than 1 in 2,000 males and a carrier prevalence of 1 in 1,000 females (Shapiro, 1991). About one-third of female carriers show mental impairment that is usually milder than the retardation seen in affected males, although learning disabilities have been noted with normal intelligence, and severe retardation has also been observed in carrier females. The disorder has posed numerous challenges to geneticists because of unusual recurrence risks in families, imprinting effects, variable expressivity, nonpenetrance, and imperfect diagnostic tests. The molecular origin of the disorder is due to mutations in the length of a trinucleotide repeat element (CGG) located within an exon of coding sequence near the beginning of the fragile X gene (FMR-1) (Fu et al., 1991; Kremer et al., 1991; Oberle et al., 1991; Verkerk et al., 1991). In the normal population the range of allele sizes varies from 6 to 54 repeats with an average of 29 repeats (Fu et al., 1991). However, in fragile X families, repeats ranging from 52 to 200 have been found not only in carrier females but also in the novel category of carrier males; these lengths represent a predisposition for the disorder. The transition to the full mutation (alleles with more than 200 repeats) occurs with high frequency when the parent transmitting the premutation chromosome is female, and the transition frequency depends on the size of the premutation (Fu et al., 1991; Yu et al., 1991; Heitz et al., 1992). Recent evidence indicates that a small number of founder chromosomes carrying the upper-normal number of repeats may explain the current mutations present in the fragile X population (Richards et al., 1992; Oudet et al., 1993).

Direct DNA analysis offers a more rapid and accurate test for the identification of normal, premutation, and fragile X (i.e., full mutation) chromosomes (Fu et al., 1991; Rousseau et al., 1991; Sutherland et al., 1991) than the previously available cytogenetic or linkage-based methods. Direct DNA analysis has also been shown to be more informative in predicting mental impairment, and testing is currently performed for confirmatory diagnosis in suspected affected males, carrier testing for at-risk females, and prenatal diagnosis for at-risk pregnancies. The DNA test may be most helpful to persons with concerns about the accuracy of cytogenetic detection methods or who have had inconclusive results in the past.

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). Proposals have also been made to screen persons in institutions.

Suggested Citation:"2 Genetic Testing and Assessment." Institute of Medicine. 1994. Assessing Genetic Risks: Implications for Health and Social Policy. Washington, DC: The National Academies Press. doi: 10.17226/2057.
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  • they can undergo prenatal diagnostic testing using amniocentesis or chorionic villus sampling (CVS) and selectively abort an affected fetus;

  • they can undergo prenatal diagnostic testing using amniocentesis or chorionic villus sampling and make preparations for the birth of an affected child; or

  • although still experimental, it may soon be possible to undergo in vitro studies in gametes (ova and polar bodies) 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. Carrier detection for each of these disorders raises unique issues (described in Chapter 1). Sickle cell and Tay-Sachs screening programs of the past have illuminated the following issues: (1) the need to recognize social and cultural differences in screening highrisk populations; (2) the need for reliable, easy, and relatively inexpensive carrier tests; (3) the importance of people understanding the benefits and risks from participating in screening; and (4) the importance of pre- and posttest education and counseling. The setting of carrier screening programs may also be a critical factor in their success because it may affect community trust and confidence in such screening programs.

Population carrier screening for cystic fibrosis would be unprecedented in the United States in terms of the number of individuals who could potentially be tested. CF is the most common, potentially lethal autosomal recessive genetic disorder in the United States. Current population data indicate that 1 in 2,500 newborns of European ancestry is affected by CF (about 30,000 persons), and that 1 in 25 (about 15 million Americans) is an unaffected carrier of a single copy of the gene for CF (Collins, 1992; OTA, 1992). CF causes chronic lung disease and pancreatic insufficiency, characterized by excessive production of thick mucus, primarily in the lungs, and increased risk of infection, although there is a wide range in severity of symptoms. Men with CF are usually sterile; women with CF have low fertility rates and pregnancy may exacerbate their disease. In the past, many children with CF died in early childhood. There is currently no cure available, but with improved treatments, median survival for persons born with CF in 1964 has increased to age 29 (OTA, 1992). Some individuals with CF are living into their forties and fifties. Intensive research efforts are under way to develop a variety of drug and gene therapy approaches, including gene replacement, to the treatment of CF, but the success of these efforts is still being studied at this time (ASHG, 1992).

The most common mutation causing CF is known as delta F508, a deletion of an amino acid at the 508 codon in the gene (Collins, 1992). It accounts for about 70 percent of CF mutations among those of European ancestry. Six to twelve other mutations account for an additional 15 to 20 percent of all mutations. More than 230 mutations have already been identified (ASHG, 1992), and experts sug-

Suggested Citation:"2 Genetic Testing and Assessment." Institute of Medicine. 1994. Assessing Genetic Risks: Implications for Health and Social Policy. Washington, DC: The National Academies Press. doi: 10.17226/2057.
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gest that there may be many more, some of which may be extremely rare, but some that might account for 1 to 3 percent of CF carriers (Collins, 1992).

The large number of CF mutations greatly complicates carrier detection and counseling. Even with the best tests, which can detect 85 to 95 percent of CF mutations in those of northern European Caucasian descent, the possibility of false negative tests remains (erroneously identifying persons as not being carriers when they are). The differential frequency of the various mutations in other ethnic populations—even in the Caucasian population—makes practical screening difficult. The variable expression of severity in CF is related to the particular mutation (a few mutations are associated with much milder CF than the classic type) and adds significantly to the difficulty in interpreting the results of genetic testing and in counseling individuals and families, because it is not possible to predict how severe the CF disorder will be in any given person.

In response to these complexities, the American Society of Human Genetics (ASHG) has developed a policy statement supporting testing of couples with a family history of CF, but opposing routine screening of pregnant women and other individuals in the general population for CF genes (Caskey et al., 1990). A similar policy emerged from a 1990 National Institutes of Health (NIH) consensus conference (NIH Workshop, 1990). Pilot studies were recommended to gather more data on laboratory, educational, and counseling aspects of screening; these studies were initiated and funded by the NIH National Center for Human Genome Research, the National Institute of Child Health and Human Development, and others in 1992. Opposition to routine screening of pregnant women was reviewed and reaffirmed by the ASHG in 1992, with some additional language, including recognition that "testing of highly motivated individuals in the general population may occur and should only be provided by knowledgeable health care professionals after appropriate education and counseling" (ASHG, 1992).

The central reasons for the restraint urged by the ASHG and the NIH statements regarding CF carrier screening can be found in the principle that such tests must be accurate, sensitive, and specific (Lappe et al., 1972; NAS, 1975; President's Commission, 1983). In 1989, the CF test could identify only 70 percent of carriers; thus, only 49 percent of the couples at risk would be detected. About 1 in 12 couples would have one member test positive and the other negative, with no way of knowing if the negative partner was truly negative. A consensus has been developing that routine screening should be offered only (1) when the test is 90 to 95 percent sensitive, and (2) when experience with appropriate education, counseling, setting(s), etc., for such screening has been evaluated (ASHG, 1992). 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.

Suggested Citation:"2 Genetic Testing and Assessment." Institute of Medicine. 1994. Assessing Genetic Risks: Implications for Health and Social Policy. Washington, DC: The National Academies Press. doi: 10.17226/2057.
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PRENATAL DIAGNOSIS

Prenatal diagnosis is now available for hundreds of conditions, ranging from profound mental retardation and early death (e.g., trisomies 13 and 18, Tay-Sachs), to disorders that affect daily living and shorten life span but do not cause serious mental incapacity (e.g., CF and hemophilia), and includes disorders that cause serious mental and physical deterioration but do not begin until middle age (e.g., Huntington disease). For many couples, the option of prenatal diagnosis offers the potential benefit of enabling them to have children they might not otherwise have been willing to bear because of the fear of severe birth defects or serious genetic disorders. In the vast majority of pregnancies in which it is used, the availability of information from prenatal diagnosis relieves parental anxiety (Platt and Carlson, 1992).

The most common indication for women seeking prenatal diagnosis is advanced maternal age historically at age 35 years and older. The incidence of chromosomal abnormalities increases gradually with maternal age. Prenatal diagnosis in advanced maternal age is a form of genetic testing generally provided in the United States by obstetricians as part of prenatal care during pregnancy. In a policy statement, the American College of Obstetrics and Gynecology has determined that offering prenatal diagnosis is part of the medical ''standard of care" for women age 35 and older (ACOG, 1985). Pregnant women are increasingly being offered maternal serum alpha-fetoprotein (MSAFP) screening, which is a blood test that can indicate the possible presence of a neural tube defect (NTD) (an opening in the fetal brain or spinal cord), Down syndrome, and an array of other fetal malformations. In addition, some fetal malformations of the heart, kidney, urinary tract, and stomach can be identified prenatally by using ultrasonography.

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, 1992). 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. Haddow, personal communication, 1993). Prenatal diagnosis is available for those couples identified through carrier screening as high risk. Rapid advances in genetic testing technology, especially with the advent of DNA testing (see Chapter 3), make it increasingly likely that a panel of prenatal genetic tests will soon be available, providing information on a large number of genetic disorders in the fetus—all at a relatively low cost (see Chapters 3, 4, and 8).

Chromosomal, biochemical, and increasingly, DNA-based laboratory methods are used for detecting genetic disease in the fetus (see Box 2-2). There are some important additional health risks associated with obtaining samples for anal-

Suggested Citation:"2 Genetic Testing and Assessment." Institute of Medicine. 1994. Assessing Genetic Risks: Implications for Health and Social Policy. Washington, DC: The National Academies Press. doi: 10.17226/2057.
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BOX 2-2 Current Prenatal Diagnostic Technologies

• Traditional genetic amniocentesis is performed at 14 to 16 weeks gestation. The technique was first developed in the 1950s for monitoring pregnancies at risk for Rh incompatibility. It has since become widely accepted as a safe and accurate procedure where medically indicated (NICHD, 1979; Tabor et al., 1986; Rhoads et al., 1989; Medical Research Council, 1991). Cells shed by the developing fetus are extracted from a sample of amniotic fluid that has been withdrawn from the mother's uterus by a needle. The cells are then cultured, and chromosomal, biochemical, or DNA analyses are conducted, depending on the condition for which the procedure is being performed. The procedure carries an estimated risk of fetal loss of 0.5 percent in the United States to 1.0 percent and higher elsewhere (NICHD National Registry, 1976; NICHD, 1979; WHO, 1983; Tabor et al., 1986; Canadian Collaborative Trial, 1989; Rhoads et al., 1989), but great variability can exist among operators.

There are no good estimates of the number of amniocenteses performed in the United States. There are no comprehensive reporting systems for these or other prenatal diagnostic procedures, particularly because many of these procedures are performed in individual physician's offices. The Council of Regional Networks for Genetic Services (CORN) has estimated, on a very limited sample of reporting centers, that over 1 million amniocenteses were performed in the United States in 1990 (Meaney, 1992). Since this would imply that nearly 25 percent of all pregnancies in the United States undergo amniocentesis, the committee believes that this estimate is too high. 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).

Limitations of amniocentesis are the relatively advanced gestational age at which it is performed and the waiting period associated with the culture of the amniotic cells before test results are available. These delays can result in increased patient anxiety and might limit the options available to some patients as a consequence of religious beliefs, ethical concerns, or legal restrictions concerning midtrimester abortion. Thus, patients, their genetic counselors, and physicians have sought safe methods of earlier, more rapid diagnosis.

Chorionic villus sampling (CVS) has, in part, met that need (Mennuti, 1989). CVS, first developed over 20 years ago (Steele and Breg, 1966), is now performed between 9 and 12 weeks of gestation but can be performed as early as 8 weeks of gestation (Jackson et al., 1992). Rapid reporting of results in 24 hours is also an advantage compared to the 10 to 14 days required to grow cells from traditional second trimester amniocenteses (Lancet, 1991), but cells are still cultured for karyotyping. CVS can be performed transcervically (a catheter is passed through the cervix into the uterus of the pregnant woman with the aid of ultrasound) or transabdominally (a needle is passed through the mother's abdominal wall and through the wall of the uterus) (Lancet, 1991).

Because CVS addresses some of the important limitations of amniocentesis, initial response to it was positive. A number of major international comparative trials of CVS and amniocentesis have been undertaken to determine the safety and diagnostic accuracy of these two forms of prenatal diagnosis. A 1989 study

Suggested Citation:"2 Genetic Testing and Assessment." Institute of Medicine. 1994. Assessing Genetic Risks: Implications for Health and Social Policy. Washington, DC: The National Academies Press. doi: 10.17226/2057.
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Found CVS to have a slightly higher rate of fetal loss (1 percent over background rate) (Rhoads et al., 1989). CVS is considered slightly less successful in obtaining fetal cells than amniocentesis, but comparable in accuracy (Canadian Collaborative Trial, 1989; Mennuti, 1989). Not all conditions, however, can be reliably diagnosed as early as 8 weeks of fetal development (such as some neural tube defects) (Mennuti, 1989), and follow-up anmiocentesis is still necessary in approximately 1 percent of cases (D'Alton and DeCherney, 1993).

A significant increase in fetal damage following CVS has been reported by some centers, along with scattered reports of subsequent abnormal limb development in fetuses tested using CVS techniques compared to amniocentesis (Firth et al., 1991; Hsieh et al., 1991; Medical Research Council, 1991). However, a recent report of a World Health Organization expert panel (1992) suggests that fetal limb disorders were associated with CVS done at less than 9 weeks, and may be related to the expertise of the practitioner, especially the number of procedures previously performed (Modell, 1992).

In deciding on prenatal diagnosis by CVS versus amniocentesis, the clinical disadvantages of a slightly increased risk of fetal loss or injury and potential for diagnostic error must be weighed against the benefits derived from earlier results, which can result in reduced anxiety and potentially more acceptable options for selective termination of the pregnancy. In addition, if chosen, abortion is earlier and safer.

Percutaneous umbilical blood sampling (PUBS) is another method for obtaining fetal cells for prenatal diagnosis. Fetal blood can be obtained at approximately 18 weeks gestation with a needle inserted, under ultrasound guidance, into the umbilical cord. Initially developed for the diagnosis of toxoplasmosis, the procedure allows access to the fetal circulation for evaluation of hematologic abnormalities and diagnosis of some inborn errors of metabolism. PUBS may be used in efforts to clarify ambiguous chromosomal analysis resulting from amniocentesis or CVS. Prenatal diagnosis using the PUBS technique has been reported to be associated with a 5 percent rate of fetal loss and should therefore be reserved for situations in which rapid diagnosis is essential or in which diagnostic information cannot be obtained by safer methods (D'Alton and DeChemey, 1993).

Ultrasound (or ultrasonography) was developed more than 25 years ago and has long been used alone and as an adjunct to other forms of prenatal diagnosis. Ultrasound is noninvasive and can assess gestational age and position of the fetus, evaluate fetal growth and development, guide the instruments in amniocentesis and CVS prenatal testing, identify certain structural birth defects (such as missing limbs, some cleft lip, and spina bifida), and can help identify certain highrisk pregnancies for which cesarean (surgical) delivery would be appropriate, for example, with some neural tube defects such as hydrocephalus (Nicolaides et al., 1992). Although no long-term studies have ever established clinical harms to the fetus from routine ultrasonography, concerns have been raised about its use in pregnancy. A 1984 NIH consensus development conference concluded that because long-term studies were lacking, ultrasound should be used only when medically indicated (NIH, 1984). More recently, randomized clinical trials have not demonstrated any significant reduction in perinatal mortality or other benefits from

Suggested Citation:"2 Genetic Testing and Assessment." Institute of Medicine. 1994. Assessing Genetic Risks: Implications for Health and Social Policy. Washington, DC: The National Academies Press. doi: 10.17226/2057.
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intrauterine therapy or from routine use of ultrasonography (Purkiss et al., 1988; Nicolaides et al., 1992). The low sensitivity, specificity, and predictive value of ultrasound examinations for congenital abnormalities, as well as the time and expertise needed for the procedure (Gowland, 1988; Manchester et al., 1988), have also dampened scientific enthusiasm for routine ultrasound screening for congenital abnormalities in the United States (U.S. Preventive Services Task Force, 1989; Holtzman, 1990). Although prenatal ultrasonography is not considered "standard of care" for routine obstetrical practice in the United States by the American College of Obstetrics and Gynecology, it has generally become a routine part of obstetrical practice. However, standards for ultrasound equipment and for the training and certification of personnel have not yet been developed. Some ultrasonography experts (Filly et al., 1987; Gowland, 1988; Manchester et al., 1988; Townsend et al., 1988; Goldstein et al., 1989; Lancet, 1992) report a substantial error rate (as high as 10 percent wrong diagnoses with both false positives and false negatives) among obstetricians and some centers in reading ultrasound images, and large variations in image quality associated with equipment and its maintenance.

Ultrasound is a tool commonly used by primary care providers in routine obstetrical practice where an individual practitioner will see few abnormalities. Consultation with genetics professionals and highly specialized ultrasonographers is essential when fetal abnormalities are suspected because of the inherent difficulty of interpretation and the need for experience in recognizing abnormalities. When ultrasound is performed by highly skilled operators, the sensitivity of this screening device in detecting congenital malformations can be as high as 90 percent (Manchester et al., 1988).

ysis for prenatal diagnosis. 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). The key difference is that the mother must undergo an invasive procedure that puts the fetus at risk in order to obtain this information. The risks to the fetus of a prenatal screening or diagnostic procedure need to be weighed in decisions about prenatal diagnosis, along with the risk of the birth of an affected child. There must be a much lower tolerance for false positive test results in prenatal diagnosis because of the undue anxiety that can be raised by the uncertainty (Juengst, 1988), as well as the potential for erroneously aborting an unaffected fetus.

A variety of techniques are currently in use for obtaining fetal cells for genetic analyses, including midtrimester amniocentesis, chorionic villus sampling, and the less common percutaneous umbilical blood sampling (PUBS). Ultrasonography is used for guidance of the needle in all three techniques. It is also used for fetal visualization and gestational dating, and can detect gross fetal anomalies (see Box 2-2).

Suggested Citation:"2 Genetic Testing and Assessment." Institute of Medicine. 1994. Assessing Genetic Risks: Implications for Health and Social Policy. Washington, DC: The National Academies Press. doi: 10.17226/2057.
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In use now for nearly 20 years, MSAFP screening illustrates some of the dilemmas and potential complexities of determining increased risk of genetic disorders in the fetus (Brock and Sutcliffe, 1972). It is often the first screening test used to begin the process of identifying high-risk pregnancies, and can be followed by multiple prenatal diagnostic technologies, which may include further blood testing, ultrasound, and amniocentesis. 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. High levels of AFP in the mother's blood might be associated with failure of the neural tube to close around the spinal column of the developing fetus. If the neural tube does not close completely, a variety of structural abnormalities may result, ranging from spina bifida (an open area on some part of the cover of the spinal column with varying degrees of disability) to anencephaly (the absence of the brain above the brain stem). The use of the MSAFP test for screening for increased risk of neural tube defects was approved by the U.S. Food and Drug Administration (FDA) in 1983. Although use of MSAFP for screening for increased risk of fetal Down syndrome (Cuckle and Wald, 1984; Merkatz et al, 1984; Hook, 1988) has also become widespread, this application of MSAFP testing has never been approved by the FDA (see Chapter 3). In 1985, the American College of Obstetrics and Gynecology distributed a professional liability "alert" advising obstetricians about the professional liability implications of AFP testing and advising them that "it is imperative" for them to discuss the availability of such screening with their patients and to document the discussion in the patient's chart (ACOG, 1985).

In addition, single and multiple fetal malformations, including heart, kidney, and gastric wall defects, or urinary and abdominal wall abnormalities, may be present when MSAFP is elevated (Crandall, 1992). An apparent abnormal MSAFP level may also result from misdating the pregnancy, multiple births, errors in determining or reporting race/ethnicity, diabetes mellitus, and body weight in the mother—all of which require adjustment of MSAFP levels for correct interpretation. Errors in reporting such critical information by the referring physician can result in additional laboratory errors in interpreting MSAFP results (Holtzman, 1992).

Several concerns have been raised regarding the routine use of MSAFP in prenatal care. ASHG has issued a policy statement recognizing that MSAFP testing was becoming part of routine obstetrical practice but stating that the test was not simply an office test (ASHG, 1987, p. 75). Among the concerns identified were (1) the complexity of setting cutoff levels for interpreting results due to the high rate of false positives and false negatives, doubts about the predictive value of the test results, and wide variability in the severity of the disorders for which

Suggested Citation:"2 Genetic Testing and Assessment." Institute of Medicine. 1994. Assessing Genetic Risks: Implications for Health and Social Policy. Washington, DC: The National Academies Press. doi: 10.17226/2057.
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the screening is being conducted; (2) social controversy surrounding the fact that no treatment exists for most of the conditions for which the screening is being done and that prevention of the disorders involves termination of pregnancy; (3) the critical importance of a qualified MSAFP testing laboratory (and essential criteria for quality control in such laboratories); and (4) the need for adequate education of physicians or other health professionals, as well as for facilities and personnel for follow-up of abnormally high or low MSAFP results, as well as for those whose initial results are false positive, and patient education (ASHG, 1987, 1989). 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., 1991); research is continuing (McPartlin et al., 1993).

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. These techniques are still experimental, however, and have not been thoroughly studied and evaluated for safety, reliability, and effectiveness. Despite their early stage of development, some of these techniques are already beginning to be used in clinical diagnosis (see Box 2-3).

An experimental test that is already widely used, called the "triple-marker screening test," has been reported to increase the effectiveness of MSAFP screening alone in predicting increased risk of a variety of fetal trisomies in pregnancy (Crandall, 1992; Haddow et al., 1992). The new screening test involves the analysis of the combined measurements of AFP, plus serum human chorionic gonadotropin and unesterified estriol (a component of estrogen), in maternal blood. These tests can be used between approximately 15 and 20 weeks of gestation. This triple-marker screening is reported to be more reliable than MSAFP alone in identification of pregnancies at increased risk of Down syndrome (60 percent detection versus 20 percent detection, respectively), and of some cases of trisomy 18 (a severe form of physical disability and mental retardation). Triple-marker screening is also reported to improve identification of twins, correct determination of gestational age, and improve identification of women at increased risk of late-pregnancy complications (those with unexplained high levels of MSAFP) compared with MSAFP alone. As with MSAFP alone, confirmatory amniocentesis and ultrasound are required.

Critical Issues in Prenatal Diagnosis

Many people believe that prenatal diagnosis can assure them of having a baby healthy in every respect (Wertz, 1992). However, most disorders cannot now be diagnosed prenatally, and there are few possibilities for primary prevention of most congenital abnormalities. DNA technology offers the prospect of gene therapy and genetic engineering at some time in the future, but the more immediate application of this technology is the expansion of the number of disor-

Suggested Citation:"2 Genetic Testing and Assessment." Institute of Medicine. 1994. Assessing Genetic Risks: Implications for Health and Social Policy. Washington, DC: The National Academies Press. doi: 10.17226/2057.
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BOX 2-3 New Techniques in Prenatal Diagnosis

Early amniocentesis is being used as early as 9-14 weeks of pregnancy, the time in which CVS is now used. The procedure is the same as described earlier in the chapter; just the timing of its use is different. Its safety and accuracy have not yet been adequately evaluated.

Fluorescence in situ hybridization (FISH) is a modified cytogenetic technique intended for more rapid detection of chromosomal disorders in the fetus (Klinger, 1992). Originally a research tool like many other DNA technologies, FISH is rapidly being adopted as a diagnostic tool in prenatal diagnosis as well as in cancer and infectious disease diagnosis (Caskey, 1991). FISH allows rapid cytogenetic assays based on in situ hybridization of chromosome-specific DNA probes that can be visualized by fluorescence methods (Cremer, 1988; Lichter et al., 1988; Klinger et al., 1990, 1991).

Karyotyping (analysis of chromosomes) is accurate and can often detect subtle chromosome rearrangements. However, chromosome analysis is time consuming (often taking from one to as much as two weeks); it is also labor intensive and requires highly skilled operators. The time delay is a source of anxiety for many patients, particularly for those not tested until the second trimester of pregnancy and when ultrasound has detected possible fetal abnormalities. Thus, many people have perceived a need for simple methods for the rapid detection of chromosome abnormalities (Lichter et al., 1988).

FISH can be used to count the number of copies of a specific chromosome present (aneuploidy detection), to identify unknown (marker) chromosomes present in metaphase spreads, and to identify predefined chromosome translocations (Klinger, 1992). Proficiency testing does not now exist for FISH, nor have any of the available probes been approved by the FDA (see Chapter 3). FISH analysis is now available from at least one laboratory upon physician request, and only in conjunction with a complete karyotype analysis (Klinger, 1992). This technique has also been the source of recent controversy about "a rapid (but wrong) prenatal diagnosis" (Benn et al., 1992) in which a prenatal diagnostic error resulted from a test whose accuracy is said to exceed 99 percent (see Chapter 3).

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. These techniques include fluorescence-activated cell sorting using monoclonal antibodies, polymerase chain reaction, and in situ hybridization of fetal cells. Once concentrated, selected genetic components need to be multiplied so they can be analyzed correctly. Fetal cells have been detected in maternal blood as early as 9 weeks of gestation. First trimester prenatal diagnosis of Down syndrome has now been reported in fetal cells from maternal blood (Elias et al., 1992). PCR has been used to amplify a sample for prenatal testing from a single fetal cell. One limitation of this technique is that some fetal cells may be left from previous pregnancies (Bianchi et al., 1991). The slightest contamina

Suggested Citation:"2 Genetic Testing and Assessment." Institute of Medicine. 1994. Assessing Genetic Risks: Implications for Health and Social Policy. Washington, DC: The National Academies Press. doi: 10.17226/2057.
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tion can result in incorrect diagnosis (both false positives and false negatives). This technique is still being evaluated.

Preimplantation Diagnosis. Techniques described here require removal of ova (eggs) 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. Because there is very little DNA to work with, amplification by polymerase chain reaction makes prenatal diagnosis possible prior to implantation (Handyside et al., 1990, 1992). There is some research on testing of ova and sperm before fertilization, but these techniques are relatively early in their development and are still experimental; they have technical hazards and may have biological hazards as well. In one method, a nonfunctioning product of cell meiotic division (polar body) may be tested (Verlinsky and Kuliev, 1992), or cells destined to become placenta may be tested (Simpson and Carson, 1992).

The appeal of this earliest form of prenatal diagnosis is that it could avoid many of the difficult decisions and potential psychosocial consequences of decisions to selectively terminate a fetus affected with a genetic disorder. Couples at risk of having children affected by diagnosable genetic disorders might be spared repeated decisions in each pregnancy about possible termination of affected fetuses identified at a later stage in fetal development (Simpson and Carson, 1992). Very little is known about the technical and biological safety of these techniques.

In vitro fertilization (IVF) is the process for implantation following preimplantation diagnosis, generally six days after ovulation. It is being offered by some commercial diagnostic laboratories for as many as eight conditions, including muscular dystrophy, hemophilia, and fragile X and Down syndromes. In IVF, after hormonal stimulation, eggs (ova) are removed from the ovaries of the woman by needle aspiration under local anesthesia and placed in a culture medium. Sperm from the man is then used to fertilize these eggs. Successfully fertilized eggs begin cell division in the culture medium.

There are limitations to in vitro fertilization to which are added the limitations of preimplantation diagnosis. In the United States, only 14 percent of women deliver a live-born infant after one cycle of in vitro fertilization, and the rate of live births is no better than 1 for every 10 embryos transferred at the centers with the best records (SART, 1992). The emotional burdens of in vitro fertilization and the physical techniques for removal of eggs from the woman (i.e., by needle aspiration from the ovaries under local anesthesia) limit the appeal of this experimental method of prenatal diagnosis.

In addition to the extremely high cost of IVF (more than $15,000 per cycle), there are also substantial resource limits related to the use of these technologies, including a team highly experienced in assisted reproductive technology, experience in recovering embryonic cells in an environment free of DNA contaminants, and the ability to perform the necessary analysis with a very small amount (one cell) of DNA (Simpson and Carson, 1992). Frequently, multiple embryos will be implanted with these techniques, and the need for "fetal reduction" (an invasive procedure to reduce the number of fetuses carried to term) also diminishes the applicability of this technique.

Suggested Citation:"2 Genetic Testing and Assessment." Institute of Medicine. 1994. Assessing Genetic Risks: Implications for Health and Social Policy. Washington, DC: The National Academies Press. doi: 10.17226/2057.
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ders for which prenatal diagnosis will be possible (Holtzman, 1989, 1990; D'Alton and DeCherney, 1993).

Prenatal diagnosis has potential benefits, but it also "brings new challenges" with it (Milunsky, 1985; Mennuti, 1989). These challenges were highlighted by a recent NIH Workshop on Reproductive Genetic Testing (1991) (also see Box 2-4 for recommendations of this NIH conference).

Reproductive genetic testing, counseling and other genetic services can be a valuable component in the reproductive health care of women and their families. These services have the potential to increase knowledge about possible pregnancy outcomes that may occur if a woman decides to reproduce; provide reassurance during pregnancy; enhance maternal-infant bonding and other relationships; allow a woman an opportunity to choose whether or not to continue a pregnancy in which the expected child has a birth defect or a genetic disorder; and if continuing, facilitate prenatal or early infant therapy for their expected child when possible and prepare for bearing and rearing of a child with special needs. Conversely, these services have the potential to increase anxiety; place excessive responsibility, blame, and guilt on a woman for her pregnancy outcome; interfere with maternal infant bonding; and disrupt relationships between a woman, family members and her community.

The challenge is to provide each woman with an opportunity to have access to desired genetic services in a way that will improve her control over the circumstances of her reproductive life, her pregnancies, childbearing and parenting, within a framework that is sensitive to her needs and values and minimizes the potential for coercion. The value placed on these services by women and their families depends heavily on a mixture of psychological and ethnocultural influences, religious and moral values, and legal and economic considerations that are unique to each woman. As a consequence, women in different circumstances may weigh the merits of reproductive genetic services quite differently.

Psychological effects, including increased anxiety associated with amniocentesis and other forms of prenatal diagnosis, have been studied extensively (Blumberg and Golbus, 1975; Black and Furlong, 1984; Beeson and Golbus, 1985; Rothman, 1986, 1992, 1993; Rapp, 1988a,b, 1991; Black, 1989, 1990; Mennuti, 1989; Press and Browner, 1992, 1993). Some studies have found that women who underwent amniocentesis did not exhibit high levels of anxiety or depression in the period following amniocentesis (Rapp, 1987). Other studies, incorporating intensive interviewing techniques, found more significant impacts of the use of prenatal diagnosis, leading one commentator to coin the phrase "the tentative pregnancy" (Rothman, 1986, 1992, 1993; Tymstra, 1991) to describe the conditional relationship that some women feel is imposed between them and their developing fetus. It is difficult to measure the extent to which prenatal diagnosis increases anxiety because baseline anxiety levels differ and individual expectations vary among couples (Tymstra et al., 1991; Wexler, 1992).

Suggested Citation:"2 Genetic Testing and Assessment." Institute of Medicine. 1994. Assessing Genetic Risks: Implications for Health and Social Policy. Washington, DC: The National Academies Press. doi: 10.17226/2057.
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BOX 2-4 Recommendations of the NIH Workshop on Reproductive Genetic Testing: Impact on Women

In November 1991, the NIH conference "Reproductive Genetic Technologies: Impact on Women" made recommendations for a research and policy agenda related to reproductive genetics services. A summary of those recommendations follows (NIH Workshop on Reproductive Genetic Testing, 1991, pp. 1-8):

  1. Reproductive genetic services should not be used to pursue "eugenic" goals, but should be aimed at increasing individual control over reproductive decisions. Therefore, new strategies need to be developed to evaluate the success of such services .... Reproductive genetic services must ultimately serve personal, not public interests in improving the overall reproductive options of women .... The ideals of self-determination in family matters and respect for individual differences that lie behind the client-centered view of reproductive genetic services are jeopardized whenever the primary goal of these services becomes the prevention of the birth of individuals with a disorder or a disability. Such a goal has the potential to constrain the choices available to women and to further stigmatize those individuals affected by a particular disorder or disability. To the extent that voluntary genetic services are evaluated even indirectly in "eugenic" terms, societal pressures have the potential to threaten the important interests and desires of individual women and their families.

  2. Reproductive genetic services should be meticulously voluntary.

  3. Reproductive genetic services should be value-sensitive.

  4. Standards of care for reproductive genetic services should emphasize genetics information, education and counseling rather than testing procedures alone.

  5. Social, legal and economic constraints on reproductive genetic services should be removed.

  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. Increased sensitivity to these issues and improved communication between the biomedical and the disabilities communities is urgently needed in order for the true impact of these developing technologies to become known. Individuals with disabilities, whose lives may be significantly influenced by these technologies must be involved in the development and implementation of further research to be carried out in the future.

The primary options now available following the identification of an affected fetus are to terminate the pregnancy or to prepare for the birth of an affected child. Given the limited but real hazards of prenatal diagnostic procedures, many experts initially recommended using prenatal diagnosis only if all the options it could offer were actually going to be utilized (Littlefield, 1970). However, a broad consensus developed in the intervening years that requiring parental commitment

Suggested Citation:"2 Genetic Testing and Assessment." Institute of Medicine. 1994. Assessing Genetic Risks: Implications for Health and Social Policy. Washington, DC: The National Academies Press. doi: 10.17226/2057.
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to follow through with abortion if the fetus is identified as affected with a genetic disorder is ethically inappropriate as a criterion for selecting candidates for amniocentesis or other prenatal genetic tests (NICHD, 1979). Recent data of Wertz and Fletcher (1989a,b; Wertz et al., 1990) showed that 96 percent of the responding geneticists would perform prenatal diagnosis for a couple who requested it but who opposed abortion. There may be benefits in knowledge from prenatal diagnosis if the pregnancy is continued; for example, detection of a neural tube defect may help to evaluate the need for prelabor delivery by cesarean section.

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. In some cultures, such as India and China, however, sex identification has also been sought for planning the birth order of children of a particular sex, or for the preferential selection of children of one sex, usually males (Wertz and Fletcher, 1989b; Wertz et al., 1990; Wertz, 1992). In a recent survey in the United States, only a very small percentage (5 percent) of the public reported that they favored prenatal diagnosis for sex selection (Singer, 1991). Such practices have been called ''homemade eugenics" (Kevles, 1985, 1991).

In the surveys reported by Wertz and Fletcher, slightly less than one-third (32 percent) of responding geneticists in the United States reported that they were willing to perform prenatal diagnosis for sex selection or other non-disease-oriented traits, and another 28 percent were willing to refer patients to someone who would perform prenatal diagnosis for sex selection. In most cases their decision was governed by respect for parental autonomy; others wished to avoid paternalism and to preserve nondirectiveness. Thus, sex selection was the genetic dilemma that respondents said gave them the greatest ethical conflict, attempting to balance autonomy (the right of patients to decide) with nonmalificence (the moral obligation not to harm) (Wertz et al., 1990).

There have been several international policy statements opposing prenatal diagnosis for sex selection or for other non-disease-related traits. A policy statement from the European Council of International Organizations of Medical Sciences (CIOMS) opposes prenatal diagnosis for sex selection (Niermeijer, 1988, p. 93):

The working group considers it a misuse of new genetic technologies to use chorionic villus sampling to make a diagnosis of sex in the eighth or tenth week of pregnancy. Since sex is no disease, the use of fetal diagnosis for knowledge of fetal sex is to be discouraged, at least in European and American cultures.

The report of the Privacy Commission of Canada (1992, p. 40) also raises concern on this subject:

To what extent should genetics be employed to generate information for decisions that are repugnant to some, like abortion, as a means of sex

Suggested Citation:"2 Genetic Testing and Assessment." Institute of Medicine. 1994. Assessing Genetic Risks: Implications for Health and Social Policy. Washington, DC: The National Academies Press. doi: 10.17226/2057.
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selection? . . . The issue of genetic testing for sex selection requires further analysis ... the [Canadian] Royal Commission on New Reproductive Technologies is examining issues surrounding sex selection.

The British Medical Association (BMA, 1992) advises its physicians not to participate in sex selection in the absence of medical need. The ethics committee of the Royal College of Obstetricians has a policy statement under discussion (Choo, 1993). 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. Predictive or presymptomatic testing and screening can provide clues to which people may later develop one or more of these disorders. Often such tests will give information regarding a genetic susceptibility or predisposition, rather than providing definitive prediction. In some cases, a family history of a monogenic disorder in a close relative informs others in the family that they are at high risk for developing the disease. Appropriate testing might then resolve whether the mutant gene is present. Examples include Huntington disease and polycystic kidney disease. Sometimes a certain percentage of people with a particular disease have the genetic form. Genes have been found for familial Alzheimer disease and familial amyotrophic lateral sclerosis, two devastating, fatal, late-onset disorders. Even though the majority of those with these disorders have the nonfamilial form (e.g., Alzheimer disease), understanding the flaw in the gene that causes the familial form may lead to new treatments for all who are affected.

More frequently a disorder is multifactorial—or complex—in its causation, including both multiple genetic factors and environmental effects. Many common diseases of adulthood fall in this category, including coronary artery disease, some cancers, diabetes, high blood pressure, rheumatoid arthritis, and some psychiatric diseases (King et al., 1992). Different sets of genes can operate in different families (genetic heterogeneity), and environmental factors may interact with only one set of genes and not with another. There may also be interaction between the various genes involved, so that the effects of multiple gene action cannot be predicted by separate analyses of each of the single genes. In such cases, definitive prediction will rarely, if ever, be possible, and it will be impossible to group individuals into two distinct categories—those at no (or very low) risk and those at high risk (Risch, 1992).

On the other hand, the availability of presymptomatic and predispositional testing can provide an opportunity for physicians and patients to work toward prevention of disease. Since environmental factors are often essential for the

Suggested Citation:"2 Genetic Testing and Assessment." Institute of Medicine. 1994. Assessing Genetic Risks: Implications for Health and Social Policy. Washington, DC: The National Academies Press. doi: 10.17226/2057.
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manifestation of complex diseases, the detection of those at high risk will identify some individuals who are more likely to benefit more from certain interventions (e.g., dietary measures in coronary heart disease). The newly acquired ability to identify some persons at high risk for certain cancers now permits more frequent monitoring for the earliest manifestations of cancer (e.g., bowel cancer). Further research and the unfolding of the Human Genome Project are very likely to reveal the underlying genes mediating predisposition to numerous common diseases, and genetic susceptibility testing will be increasingly possible. The current state of knowledge of some disorders illustrates some of the complexities of genetic testing for disorders of late onset.

Monogenic Disorders of Late Onset

Huntington Disease

The problems posed by monogenic diseases of late onset vary considerably. Huntington disease has received the most study, since indirect DNA testing has been available for nearly a decade (Gusella et al., 1983; Conneally et al., 1984; Martin and Gusella, 1986) (see Box 2-5). Indirect DNA diagnosis requires testing of an affected family member and other relatives in order to diagnose the disease in a person at risk. The identification of the genetic defect for Huntington disease as a trinucleotide expansion (Huntington's Disease Collaborative Research Group, 1993) now permits direct DNA testing and eliminates the many difficulties and the measure of uncertainty that accompanies indirect DNA testing using linkage analysis. 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, 1992). Approximately 5 percent of all cases of Alzheimer disease are transmitted as an autosomal dominant trait, and several different genes have been implicated in various families (St. George-Hyslop et al., 1990; Goate et al., 1991; Schellenberg et al., 1992), requiring a different test probe for indirect DNA testing for each of these genes. When these genes and the corresponding mutations responsible for Alzheimer disease are identified, a direct DNA test may become feasible. When a better test is developed, however, difficult decisions will still have to be made about whether, if ever, to offer testing. These dilemmas will affect many more people should predictive testing become available for the more common Alzheimer disease that starts late in life (70 to 80 years of age).

Suggested Citation:"2 Genetic Testing and Assessment." Institute of Medicine. 1994. Assessing Genetic Risks: Implications for Health and Social Policy. Washington, DC: The National Academies Press. doi: 10.17226/2057.
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BOX 2-5 Presymptomatic Testing for Huntington Disease

Huntington disease (HD) is an autosomal dominant neurodegenerative disorder of late adult onset with a prevalence of 1 in 10,000. In the United States, 30,000 persons are symptomatic and another 150,000 individuals are at risk. HD causes involuntary movements of all parts of the body, including chorea and dystonia, cognitive impairment including failures of organizational capacities and memory, and psychiatric disturbances, particularly severe suicidal depression, apathy, or obsessive-compulsive disorders. Symptoms usually manifest between the ages of 30 and 50 but can appear as early as age 2 or as late as 80 years of age (Farrer and Conneally, 1985). Once symptoms take hold, there is a 10-20 year unremitting and inexorable progression toward death. Children progress more rapidly and are more severely affected in motor function and behavior. There is no effective treatment or cure.

HD was the first autosomal disorder to be localized to a chromosome using novel recombinant DNA techniques. In 1983, it was discovered to be in the telemeric region of the short arm of chromosome 4 (Gusella et al., 1983).

The existence of DNA markers tightly linked to the gene made presymptomatic and prenatal testing possible in 1986. The test was offered in only a limited number of settings, primarily universities specializing in HD or neurogenetics, in the United States, Canada, and Europe. 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. Even many people who contacted testing centers decided not to pursue the test after learning more about it and considering the possible consequences of learning whether one is free of, or destined to die from, this disease.

There have been fewer than 300 individuals tested in the United States, and it is too early and the numbers are still too small to know the long-term effects of presymptomatic testing. Not surprisingly, a wide range of reactions has been observed. Some of the people have found the information useful to help shape their lives, even if they were found to be gene carriers; others have been severely traumatized to learn that they have escaped the disease since they have built an identity around the certainty that Huntington disease was in their future. Some have had babies secure in the knowledge that the illness would never strike them; others were so devastated by their experience of the testing process and by the news that their own risk had increased to almost 100 percent that they proceeded to have children and not test the pregnancy. Some families found that all the siblings were diagnosed; others none, and still other families had to cope with a mix of positive and negative outcomes. Some have been hospitalized for depression on learning that Huntington disease was to be their fate; others felt more tranquil after resolving the uncertainty. Some people coped with the news of a diagnosis by deciding that the test was wrong or that they represented a recombination event or that God or science would find an answer in time for them.

The linkage test to date has been given in sophisticated centers familiar with Huntington disease. The test was initially made available under the aegis of pilot

Suggested Citation:"2 Genetic Testing and Assessment." Institute of Medicine. 1994. Assessing Genetic Risks: Implications for Health and Social Policy. Washington, DC: The National Academies Press. doi: 10.17226/2057.
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research projects to assess the best way to deliver it. A uniform protocol has been adopted in all centers giving the test. It requires three to six sessions of pretest counseling and education, and as many or more hours of posttest counseling and follow-up. Extensive neurological, neuropsychological, and psychiatric evaluations are performed to determine if the person is already symptomatic and to learn more about a person to help him or her cope better with either possible outcome. People are requested to select a therapist—prior to getting diagnostic information—who can be available as necessary. They are also asked to bring a companion with them to the counseling sessions and particularly to the outcome session.

On March 26, 1993, after 10 arduous years of searching for the Huntington disease gene, it was finally isolated by the Huntington's Disease Collaborative Group. Although the protein it makes is still unknown, the mutation was found to be a small expanded repeat of CAG, coding for glutamine. Children with HD have the highest numbers of repeat, but below a certain number, the correlation between numbers of repeat and age of onset is too loose to be diagnostically useful.

The discovery of the gene permits a direct presymptomatic diagnostic test for HD. Anyone in the population can be screened. The PCR-based test is significantly less expensive than the previous test. It is also more subject to laboratory error. The diagnostic information one learns from this new test, however, is the same as the old: HD is still a fatal, progressive, neurodegenerative disease. Technological ease at the bench should not diminish the intensive education and counseling both prior to and following testing. The technological imperative should not sweep people into being tested without very careful consideration of its consequences. HD is also a disorder for which people are frequently denied insurance, have difficulties obtaining employment, are turned down for adoptions, and which can be otherwise socially stigmatizing.

The World Federation of Neurology Research Group on Huntington's Disease and the International Huntington's Disease Association, representing family organizations throughout the world, joined together to develop guidelines for presymptomatic testing for HD. These guidelines have been recently revised to take into account the discovery of the gene and availability of direct testing for HD.*

_________

*  

Revised guidelines for testing for Huntington disease are available from the Hereditary Disease Foundation, 1427 Seventh Street, Suite 2, Santa Monica, CA 90401; 301458-4183

Hemochromatosis

Unlike Huntington and Alzheimer disease, hemochromatosis is a treatable condition (see Box 2-6). 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), will develop symptoms and be at risk of death from liver cirrhosis, heart muscle failure, diabetes, and liver cancer (Bothwell et al., 1989). The excess iron can be removed by frequent bloodletting, and the disease is then completely curable, with a normal life span, provided that treatment starts before clinical manifestation (Niederau et al., 1985). Al-

Suggested Citation:"2 Genetic Testing and Assessment." Institute of Medicine. 1994. Assessing Genetic Risks: Implications for Health and Social Policy. Washington, DC: The National Academies Press. doi: 10.17226/2057.
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BOX 2-6 Hemochromatosis

Hemochromatosis is a common autosomal recessive disorder characterized by excessive iron deposits in the liver, heart, pancreas, and other organs, caused by increased iron absorption over many years. Functional organ impairment characteristically begins in middle age and, once developed, is usually fatal (see Bothwell et al., 1989 for extensive references). Symptoms may be nonspecific, such as lethargy and weakness, or atypical arthritis. Cardiomyopathy, cirrhosis and liver cancer, skin pigmentation, and diabetes are late manifestations of hemochromatosis.

Men are 10 times more frequently affected clinically than women, presumably because periodic blood loss during menstruation removes excess iron. The condition can easily and successfully be treated by periodic bloodletting to rid the body of excess iron. While the abnormal gene has been mapped to the short arm of chromosome 6 in close vicinity to the HLA-A locus, the basic defect causing increased iron absorption has not yet been discovered. About 1 in 300 to 1 in 800 Caucasians carries the double dose of the mutant gene and, therefore, may potentially become clinically affected. The actual frequency of clinically significant overload is not well defined. Between 8 and 12 percent of the population are singledose carriers of the gene or heterozygotes. The heterozygous status for hemochromatosis is clinically benign and does not cause significantly increased iron storage.

Laboratory tests for the condition currently rely on assessment of the phenotypical consequences of abnormal iron metabolism (serum iron, the extent of serum iron binding by transferrin, and serum ferritin levels) since no DNA test exists. A combination of these tests is required for diagnosis of iron overload due to hereditary hemochromatosis. There are many false positive and false negative tests, depending on the cutoff for laboratory values that are selected as abnormal. A definitive diagnosis currently requires liver biopsy to demonstrate the characteristic deposits of iron in hepatic parenchymal cells.

The detection of hemochromatosis among family members (but not in the population) can be aided by a linkage study using the closely linked HLA locus. Such linkage analysis requires a blood sample from an affected homozygous relative. Siblings will have a 25 percent chance of being homozygotes and will share both HLA haplotypes of the affected sibling. Various DNA markers linked to the hemochromatosis locus are also beginning to be used for family linkage studies. However, whether DNA testing has advantages over HLA testing is not clear.

Diagnosis of the heterozygous state currently requires family studies with linked genetic markers such as HLA types. Various tests of iron status are often slightly abnormal in heterozygotes, sometimes making it difficult to distinguish between carrier heterozygotes and affected homozygotes. The current complexity of testing highlights the importance of the search for the basic defect in hemochromatosis. 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). A potentially fatal disease, therefore, can be transformed into one with a normal life expectancy. Once liver cirrhosis has developed, iron depletion does not reduce the frequency of liver cancer often seen in hemochromatosis. These facts emphasize the importance of early detection among family members once a patient has been diagnosed, and the possible use of population screening in the future if a practical test system has been determined to be effective in pilot studies.

Suggested Citation:"2 Genetic Testing and Assessment." Institute of Medicine. 1994. Assessing Genetic Risks: Implications for Health and Social Policy. Washington, DC: The National Academies Press. doi: 10.17226/2057.
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though not all persons who are homozygous for the mutant gene for hemochromatosis will develop clinical disease, frequent bloodletting might be the preferred course of action because the risk of treatment is less than the risk of developing the disease. The availability of therapy favors efforts aimed toward testing firstdegree relatives of affected individuals. Many physicians and medical geneticists would recommend informing siblings that they are at high risk (25 percent) of developing a potentially fatal but treatable disease (see Chapter 8 for discussion of issues in informing relatives).

Familial Hypercholesterolemia

Familial hypercholesterolemia (Goldstein and Brown, 1989; Motulsky, 1989) associated with coronary artery disease illustrates issues in predictive testing for a disease for which preventive treatment is available. Familial hypercholesterolemia (frequency of about 1 in 500) results from a monogenic defect that causes elevated LDL (low-density lipoprotein) cholesterol levels that lead to heart attacks in 50 percent of male heterozygotes by the age of 50 years and in 50 percent of female heterozygotes by the age of 65 years. There are almost 200 different mutations at the locus causing familial hypercholesterolemia (Hobbs et al., 1990). Diagnosis by biochemical techniques can be difficult since cholesterol and LDL cholesterol levels may not be definitive. Physical findings can be absent. Differentiation from the more common types of hypercholesterolemias that are associated with complex gene action interacting with environmental factors is often difficult (see below). Because of the large number of mutations, a clinically useful DNA test for this entity is not yet available. Effective treatments that reduce cholesterol levels exist and decrease the probability of heart attacks. In the event that an accurate predictive test is developed, high-risk individuals (by virtue of high cholesterol levels or family history) could be tested and, if affected, treated, even though not all persons who carry the gene will develop coronary heart disease (Motulsky and Brunzell, 1992).

Polycystic Kidney Disease

Predictive testing for autosomal dominant polycystic kidney disease (PKD) raises additional issues (Grantham and Gabow, 1988; Gabow, 1992). This condition has a frequency of 1 in 500 to 1 in 1,000. The most common gene is mapped to chromosome 16p but has not yet been cloned; the site of the other gene is not known. At least 50 percent of those carrying the more common of the two genes that can cause this condition will develop renal failure by the age of 70 (Parfrey et al., 1990). Many individuals will develop renal failure in middle age, and 8 to 10 percent of end-stage renal disease is caused by this disorder. There is no definitive treatment that has been shown to defer the onset of renal failure, although

Suggested Citation:"2 Genetic Testing and Assessment." Institute of Medicine. 1994. Assessing Genetic Risks: Implications for Health and Social Policy. Washington, DC: The National Academies Press. doi: 10.17226/2057.
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treatment of hypertension and urinary infections may help to do so (Ravine et al., 1991). In the absence of dialysis or kidney transplant, renal failure leads to death.

The positive advantages of knowing whether one carries the gene and the potential advantages of symptomatic treatment must be weighed against problems with discrimination in occupation, insurance, and other areas of life (Sujansky et al., 1990). Full discussion of such issues should be carried out before testing is initiated for the presence of polycystic kidneys. Phenotypic testing by ultrasound and indirect testing through family linkage studies are currently available (Ravine et al., 1992). When both ultrasound and DNA diagnosis are offered to well informed at-risk patients, most chose ultrasound testing alone. The DNA test can indicate if one is a carrier and will develop the disease in the future while the ultrasound reveals one is affected at that time. People seem more interested in determining current status than future probabilities (Gabow, 1992).

Inherited Susceptibility to Cancers

It has been speculated for some time that genetic factors influence susceptibility to cancer; in fact, rare but highly heritable familial forms of specific cancers have been identified as constituting approximately 5 percent of all cancers (see Box 2-7) (Schimke, 1992). Specific genes that are inherited have already been localized in breast cancer (Hall et al., 1990) and identified in colon cancer (Nishisha, 1991). 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 p53 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. Screening for inherited susceptibility to cancers raises many issues, including appropriate therapy, access, intense anxiety, and discrimination.

Another set of diseases for which predictive testing is now being investigated is cancers of complex origin. In addition to the cancer genes that have a large effect in predisposed individuals, other genes affecting DNA repair and the metabolism of carcinogenic substances may have a significant effect in determining who will be at greatest risk of developing cancer (Caporaso et al., 1990; McLemore et al., 1990; Nazar-Stewart et al., 1993). Population screening is not yet feasible for common cancer predispositions.

Much attention is currently being given to a very rare syndrome, Li-Fraumeni syndrome, in which mutations of a common tumor suppressor gene (p53) are transmitted by autosomal dominant inheritance and may cause tumors in multiple organs, including breast cancers and sarcomas, sometimes beginning in childhood (Malkin et al., 1990; Hollstein et al., 1991). Recent guidelines on predictive test-

Suggested Citation:"2 Genetic Testing and Assessment." Institute of Medicine. 1994. Assessing Genetic Risks: Implications for Health and Social Policy. Washington, DC: The National Academies Press. doi: 10.17226/2057.
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BOX 2-7 Determining Susceptibility to Breast Cancer of Early Onset

For some years it has been inferred that a heritable gene that predisposes women to breast cancer is responsible for about 5 percent of cases-specifically the rare inherited form that strikes women in their thirties and forties. Approximately one woman in 200 inherits the defective gene, and those who do face an 80 to 90 percent risk of developing the disease. The same altered gene seems also to predispose to ovarian cancer. Identification of this gene could lead to new methods for detection far earlier than is currently possible, with the advantage of earlier and more aggressive treatment. 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. For early detection of the gene to be beneficial, individuals carrying the inherited cancer gene may need, in the future, to undergo further periodic screening using biomarker approaches in the target organ. At the present time, women at risk can be closely monitored with physical examinations and mammograms for signs of malignancy. Presented with the options, however, many will choose bilateral preventive prophylactic mastectomy and often also removal of their ovaries after completion of childbearing as a preventive measure.

The development of this predictive test has raised numerous questions regarding wide-scale screening and testing (Marshall, 1993). It is currently impossible to identify women at high risk of inherited breast cancer by general population screening. Identification of the normal and mutant sequence(s) of the critical susceptibility gene(s) would be necessary for this purpose. For now, testing is limited to large families at risk. With anticipated discovery of the gene(s) in the near future, however, it is conceivable that efforts would be made to screen the general population. The psychosocial consequences of receiving such loaded information have not yet been fully evaluated, nor has the effect of such information on insurability. Pilot studies will be needed to determine to whom the test should be offered, including where and when. Current research protocols provide intensive counseling by genetic counselors and physician geneticists. This process is very costly and may not be feasible economically or in terms of available trained personnel if largescale genetic screening interventions in breast cancer or other forms of cancer are developed.

ing for p53 (see Box 2-8) were developed in NIH consensus conferences (Li et al., 1992, p. 1160):

An overall benefit of predictive p53 testing cannot be assumed and should be evaluated along with harmful effects in research protocols. Potential psychological, economic, and social benefits to those who test negative should be weighed against the increased distress to those who test positive.

Suggested Citation:"2 Genetic Testing and Assessment." Institute of Medicine. 1994. Assessing Genetic Risks: Implications for Health and Social Policy. Washington, DC: The National Academies Press. doi: 10.17226/2057.
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BOX 2-8 Predictive p53 Testing Among Cancer-Prone Individuals

Recent NIH consensus conferences have made the following recommendations for predictive p53 testing for germline mutations in clinically healthy individuals from cancer-prone families (Li et al., 1992). With recent reports of germline mutations in families with Li-Fraumeni syndrome (multiple cancers in families, often occurring early in life), there is the possibility of genetic testing of healthy persons from high-risk families. This possibility of such testing also raises issues about the appropriate use and protection of genetic information, including issues of autonomy, privacy, confidentiality, and equity, and may raise complex family issues as well, including the testing of minors.

  • The p53 carriers should be counseled to seek early medical attention for signs and symptoms of cancer, and their changes in patterns of utilization of health services should be evaluated.

  • Evaluation should be made of psychosocial effects, both beneficial and harmful, that result from predictive testing. Effect of support services to ameliorate harmful consequences should be monitored.

  • The p53 carriers should be counseled and urged to pursue a healthier lifestyle and diet, with avoidance of cigarette smoking, excess alcohol use, and exposures to other carcinogens; compliance should be evaluated.

  • Pilot chemoprevention research studies should be considered in p53 mutationcarriers, such as a tamoxifen trial to prevent breast cancer.

  • Physicians of test subjects need to be educated about the extraordinary risk of cancer in p53 carriers, the need for confidentiality, and the importance of attention to complaints that might be attributed to cancer.

  • Because reduction in cancer morbidity and mortality will require many years to evaluate, test subjects should have long-term follow-up.

  • Evaluation of benefits and harm will be hampered by the limited numbers of eligible study subjects. Large effects, whether beneficial or harmful, might be detectable with as few as 10-15 subjects. However, smaller effects are likely to require study of 100 or more subjects. Therefore, test centers should be encouraged to use protocols with some similar elements so that these results can be pooled to increase statistical power.

  • Registries should be established to collect data on Li-Fraumeni families and collate findings from p53 testing programs worldwide.

  • A national advisory group should be established to address additional issues, such as professional and public education, that are generic to predictive testing for mutations in cancer-susceptibility genes.

Testing for Multifactorial Genetic Disorders

Coronary Heart Disease

Coronary heart disease is a common cause of morbidity and death. Various genes are often predisposing factors and are better understood than the genetic

Suggested Citation:"2 Genetic Testing and Assessment." Institute of Medicine. 1994. Assessing Genetic Risks: Implications for Health and Social Policy. Washington, DC: The National Academies Press. doi: 10.17226/2057.
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etiology of many other complex disorders. In most cases, no single gene can be identified; a variety of genes (mostly affecting lipid-related proteins) as well as environmental factors such as high-fat and cholesterol diets have been defined (Motulsky and Brunzell, 1992). Other more poorly understood factors are also involved, such as those affecting blood coagulation and vessel wall response. Genetic susceptibility testing for coronary heart disease requires the assessment of a variety of predisposing genes. Only occasionally will a single gene such as that causing familial hypercholesterolemia (Goldstein and Brown, 1989) be the major factor. Most affected persons will carry a combination of the underlying predisposing genes, but the specific set of genes accounting for susceptibility is likely to vary from family to family.

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) constitutes a probabilistic measure of risk for coronary heart disease. However, cholesterol levels alone remain an imperfect predictor of coronary heart disease since many patients with ''normal" cholesterol levels develop coronary heart disease. Furthermore, many individuals with high cholesterol levels will not be clinically affected. Other predictors of coronary heart disease are already known, such as low levels of high-density lipoprotein (HDL) and high lipoprotein (a) (Lp(a)) levels. Ongoing work is likely to elucidate the role of various genes and their interaction in the pathogenesis of coronary heart disease. Based on this knowledge, it is likely that a small battery of tests reflecting the major susceptibility genes and their biochemical correlates (which also reflect environmental interaction) will be developed to predict the probability of coronary heart disease better than current tests. High-risk individuals in the population could, therefore, be identified who could take preventive actions by dietary and possibly pharmaceutical interventions.

Hypertension

Familial aggregation, twin, and adoption studies have shown that genetic factors play a role in high blood pressure (Burke and Motulsky, 1992a). Multiple genes interacting with environmental factors are likely to be involved, since monogenic inheritance is not observed. Hypertension does not exist in individuals in primitive populations but may develop when such individuals are translocated to a Western environment with more salt intake and stress. Salt sensitivity (i.e., raised blood pressure associated with salt intake) may be under genetic control. Several candidate genes for predisposition to hypertension are under study (Burke and Motulsky, 1992b); these include genes controlling sodium ion transport and other metabolic processes affecting the renin-angiotensin system.

Hypertension is a risk factor for strokes, kidney failure, heart failure, and certain eye diseases. Genetic tests that predict the development of hypertension would be useful once preventive measures to avoid high blood pressure are clear-

Suggested Citation:"2 Genetic Testing and Assessment." Institute of Medicine. 1994. Assessing Genetic Risks: Implications for Health and Social Policy. Washington, DC: The National Academies Press. doi: 10.17226/2057.
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ly defined. Since the genetic causes of hypertension are likely to differ among individuals, definition of the genetic-biochemical defect(s) in a given person may lead to more rational therapy directed to the underlying cause. Thus, salt restriction might be advisable for salt-sensitive persons but not for all individuals, and a specific class of drug to lower blood pressure could be selected when drug therapy becomes indicated. Medications that lower blood pressure are currently used empirically, without defining the specific cause of high blood pressure. There is now some evidence that hypertension among African-Americans is less likely to respond to certain classes of drugs (beta-blockers) 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.

Cancers of Complex Origin

Unlike those cancers with inherited susceptibility, discussed earlier, most cancers have complex etiology; they are caused by alteration of the genetic material (DNA) in somatic cells of various organs (such as breast and colon) that occur after birth. Most cancers, therefore, may be classified as somatic genetic disease. Unlike classic heritable diseases where every body cell carries the altered DNA, the characteristic molecular and cellular alterations in cancer affect only the descendants of the original cancer cell in a given organ, which grow in an unregulated fashion and may spread to other organs.

Detection of the somatic mutations of cancer is becoming increasingly possible by genetic techniques, and many of these techniques are already coming into clinical use. In hematologic cancers, different specific alterations characteristic of a given disorder were initially observed in the chromosomes of the involved tissue (IOM, 1992). The genes affected by these cytogenetic anomalies are being identified and can sometimes be utilized for molecular diagnosis. Occasionally, detection of a specific chromosomal or molecular abnormality is helpful in predicting the clinical severity of the cancer and in a few cases may aid in selecting the most appropriate treatment (IOM, 1992). In colon cancer and probably in many other cancers, a sequential series of different mutations of the involved somatic tissue is required for the ultimate development of the malignant tumor (Fearon and Vogelstein, 1990). Once characteristic genetic alterations have been recognized, increased monitoring may make possible early diagnosis of a tumor in the affected organ and provide the appropriate treatment.

Better still, a tumor may be recognized in its premalignant stages, allowing prevention of its growth by life-style changes, chemoprevention, or a variety of other interventions. Mutations of common tumor suppressor genes such as the p53 gene are often involved (Frebourg and Friend, 1992). Screening of the general population for common somatic cancers for which everyone is at risk may become feasible using such tumor biomarkers by examining DNA from cells in

Suggested Citation:"2 Genetic Testing and Assessment." Institute of Medicine. 1994. Assessing Genetic Risks: Implications for Health and Social Policy. Washington, DC: The National Academies Press. doi: 10.17226/2057.
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stool, blood, sputum, and urine, and in breast, cervical, and prostatic fluids. This kind of screening for tumors promises to be a major application of genetic screening tests in the future. It cannot yet be done, and the exact applications in practice require more research. Once available, extensive pilot studies will be required to assess the value of such investigations, their potential impact on reducing cancer mortality, and their cost-effectiveness. Generally, this type of screening is similar to current screening by mammography for breast cancer or search for occult blood in stool for colon cancer. Specifically, the search detects an abnormality already present. It should be contrasted to screening for cancers where an inherited mutation transmitted from one or both parents makes individuals more susceptible and therefore warrants additional screening (discussed earlier), although they may not yet have developed a neoplasm.

Diabetes

Two principal varieties of diabetes exist: early-onset or insulin-dependent diabetes, and late-onset or non-insulin-dependent diabetes (Rotter et al., 1992). Both types have unrelated genetic determinants. Insulin-dependent diabetes usually starts early in life and is associated with severe insulin deficiency. Genes of the HLA complex on chromosome 6 have been implicated as etiologic factors in this form of diabetes associated with autoimmune destruction of the pancreas; other genes are likely to be involved but have not been clearly elucidated. However, even in family testing, 75 percent of siblings identified to be at risk by HLA testing never develop clinical diabetes. Although preventive therapy of high-risk persons by immunosuppressive drugs is being considered, the drugs currently available are too toxic for general use. Predictive tests may become practical in the future when better methods of testing and less toxic therapies are available to prevent diabetes. Population testing cannot be recommended at this time, and even family testing has limited use because of low prediction rates and the absence of preventive treatment.

Non-insulin-dependent diabetes tends to manifest in middle age and is usually milder clinically. This form of diabetes has much stronger genetic determinants, based on identical twin studies in which concordance is almost 100 percent. Unfortunately, the specific genes causing the disease are unknown. Since transmission patterns do not fit monogenic inheritance, different interacting genes are likely to be at work; it is likely that different genes are operative in different families, and genes affecting the biochemical action of glucose and insulin are being investigated (Leahy and Boyd, 1993; Mueckler, 1993). No definitive measures are currently known that will prevent clinical non-insulin-dependent diabetes. Definition of the involved genes may lead to such preventive measures. 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

Suggested Citation:"2 Genetic Testing and Assessment." Institute of Medicine. 1994. Assessing Genetic Risks: Implications for Health and Social Policy. Washington, DC: The National Academies Press. doi: 10.17226/2057.
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a major health advance. Although a number of genes are under active study, predictive testing is not feasible at this time.

Rheumatoid Arthritis

Rheumatoid arthritis is a common, often disabling disease that in severe cases can shorten life expectancy markedly (King et al., 1992; Winchester, 1992). Certain genes in the HLA system help to determine susceptibility, and other HLA alleles help to determine the severity of the illness. However, other poorly defined genetic and environmental factors are also involved in the etiology of rheumatoid arthritis.

Infectious Diseases

Genetic host factors affecting susceptibility and resistance to many different microbial infections, including viruses, have been recognized for many years in experimental animals (Childs et al., 1992). Genetic variation also occurs in the offending microorganism. The effect of genetic variation in both host and microorganism on mortality has become well recognized, although mechanisms governing susceptibility and resistance are often specific for a given infection and may not be related to immunity. Twin and adoption studies show some evidence of genetic influences in infectious disease mortality. 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) and for infectious diseases (tuberculosis, leprosy, measles, AIDS, and malaria).

The clearest evidence for specific gene involvement in the host—unrelated to immune factors—comes from malaria. Lack of expression of the Duffy gene in red blood cells is a common genetic trait in Africans and their descendants in the United States. Lack of expression of this gene provides complete resistance to vivax malaria and is an example of how an altered gene prevents entry of a microorganism into cells. Genes for hemoglobin S, alpha- and beta-thalassemia, and glucose-6-phosphate-dehydrogenase (G6PD) deficiency are all involved in conferring relative resistance to falciparum malaria in respective gene carriers.

It has already been shown that HLA alleles are involved in influencing the course of HIV (human immunodeficiency virus) infection. The interplay of genetically influenced immunologic responses together with more specific genetic variation affecting inborn resistance could affect the natural history of HIV infections. The search for genetic variation among appropriate populations (e.g., persons with short versus long latency periods, individuals resistant to HIV infection despite exposure, and identical and fraternal twins) may ultimately uncover the specific mechanisms, and such findings might be useful in devising novel approaches to prevention and therapy in the future.

Suggested Citation:"2 Genetic Testing and Assessment." Institute of Medicine. 1994. Assessing Genetic Risks: Implications for Health and Social Policy. Washington, DC: The National Academies Press. doi: 10.17226/2057.
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Psychiatric Diseases

Nowhere is the need for caution more apparent than in predictive testing for psychiatric diseases. The most common psychiatric diseases are schizophrenia and manic depressive disorders. Based on extensive family, twin, and adoption studies, there is agreement that genetic factors play an important role in the causation of these diseases (Goldin et al., 1992; Hanson and Gottesman, 1992). However, the nature and number of the underlying genes are entirely unknown. Mendelian inheritance is rarely observed, and the mechanisms of transmission are generally obscure. There was much excitement when genetic linkage studies using anonymous DNA markers appeared to map specific genes in schizophrenia (Sherrington et al., 1988) and manic depressive disorders (Egeland et al., 1989), but repeated tests to replicate this work have, to date, yielded negative results (Kelsoe et al., 1989; Baron et al., 1993). Some other neuropsychiatric disorders in which genetic factors have been implicated include panic disorders (Crowe, 1992), Tourette syndrome, and certain types of alcoholism (Propping, 1992). However, no specific genes have been mapped or otherwise identified in any of these disorders.

It is likely that multiple genes, often interacting with yet poorly understood environmental factors, will be operative in many psychiatric disorders. As with other complex conditions, predictive testing in psychiatric diseases is unlikely to be as accurate as prediction in monogenic diseases. Prediction will always be more probabilistic, and there will be uncertainty regarding whether the disorder will ever manifest and, if so, at what age. The implications of predictive testing for mental disorders raise even more problems than those for other complex medical diseases, because of the heightened potential for stigmatization and discrimination.

CONCLUSIONS AND RECOMMENDATIONS

Newborn Screening

The benefits of screening have been demonstrated in diseases such as PKU and congenital hypothyroidism, because of the overall benefit of early diagnosis of diseases for which effective treatment is available. Screening may offer no benefit if no treatment exists or services are not available. The committee recommends that newborn screening only take place (1) for conditions for which there are indications of clear benefit to the newborn, (2) when a system is in place for confirmatory diagnosis, and (3) 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.

Suggested Citation:"2 Genetic Testing and Assessment." Institute of Medicine. 1994. Assessing Genetic Risks: Implications for Health and Social Policy. Washington, DC: The National Academies Press. doi: 10.17226/2057.
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The committee recommends that newborns not be screened for disorders that have no beneficial treatment available, and that newborns not be screened using multiplex testing for many disorders unless those disorders are treatable (see also Chapter 8). To determine clear benefit, well-designed, peer-reviewed studies will be required to demonstrate the safety and effectiveness of the proposed screening program. Proposals for new population-based newborn screening programs should be subject to the same standards as other experimental interventions on nonconsenting subjects. Although DNA typing will provide new tools for newborn screening, in general, the committee recommends that these tools be employed only when genetic heterogeneity is small; when the ability to detect disease-causing mutations is high; when a high percentage of such mutations for a given disease is known; when costs are reasonable; and when the benefits to newborns of early detection are clear.

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. If the parents wish information on the infant's carrier status for consideration in their reproductive decision making in the future, this information should be communicated to them; the decisions of the parents about whether or not they wish to receive such information should be respected. Ideally, this information should only be conveyed within the context of genetic counseling.

For a variety of reasons, including problems associated with carrier detection in newborn screening, the committee recommends that informed consent be an integral part of newborn screening. Disclosure should include (1) benefits and risks of the tests and treatments; (2) the possibility of uncovering misattributed paternity; and (3) the policy of not volunteering results that offer no benefit for the infant. States should, at the least, anticipate the problems discussed above and have in place protocols, including genetic counseling, for dealing with such potential crises as the inadvertent discovering of misattributed paternity. Genetic testing should not be used in ways that disrupt families. The committee recognizes the complexities of identifying information about misattributed paternity, but on balance, the committee recommends that such information be revealed to the mother but not be volunteered to the mother's partner. There may be rare special circumstances that warrant such disclosure, but these situations present difficult counseling challenges (see Chapters 4 and 8).

The committee believes that mandatory offering of established tests (e.g., PKU, congenital hypothyroidism) that lead to the diagnosis of treatable conditions is appropriate. If there is no other way to ensure that affected newborns will be identified and have access to effective treatment (e.g., in PKU, congenital hypothyroidism), then mandatory newborn screening is accept-

Suggested Citation:"2 Genetic Testing and Assessment." Institute of Medicine. 1994. Assessing Genetic Risks: Implications for Health and Social Policy. Washington, DC: The National Academies Press. doi: 10.17226/2057.
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able. In the rare instance where parents would be considered negligent for refusing an indicated test, established legal procedures should be used to obtain necessary parental authorization.

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). The evaluation should include technical issues such as the sensitivity and specificity of the tests, quality control procedures, and evidence that early detection actually improves outcome. Furthermore, once tests are instituted, newborn screening laboratories should have strict standards for quality control and proficiency testing (see Chapter 3 for further discussion). Detailed statutory requirements for specific tests may be unduly inflexible; the committee recommends that the states would be better served by an advisory mechanism that is authorized to add, eliminate, or modify existing programs, and to provide guidance for standards.

The committee recommends that stored newborn blood spots should be made available for additional research only if identifiers have been removed; as with other research involving human subjects, such research proposals should be reviewed by an appropriate institutional review board. If identifiable information is to be disclosed beyond the immediate purpose of an approved service program, informed consent of the infant's parent or guardian should be obtained prior to use of the specimen (see Chapter 8 for further discussion).

Carrier Testing and Screening

Determination of carrier status involves decisions concerning significant reproductive issues (i.e., abortion, medically assisted conception, adoption, sterilization, etc.). There was consensus among committee members that pregnancy is not the preferred time for carrier screening because reproductive options are limited. Because of the significant anxiety that may be raised by learning of carrier status for the first time during pregnancy, testing to determine carrier status before pregnancy is optimal. Carrier testing and screening must be voluntary and must be preceded by education and counseling. High standards of explicit informed consent must be met, with attention to ensuring that a couple is told, in easily understood terms, the medical and social choices available to them should one or both of them be determined to be carriers. Some members of the committee realized that much of carrier screening would be pushed back into pregnancy because of inertia, lack of education, and the difficult logistics of

Suggested Citation:"2 Genetic Testing and Assessment." Institute of Medicine. 1994. Assessing Genetic Risks: Implications for Health and Social Policy. Washington, DC: The National Academies Press. doi: 10.17226/2057.
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widespread testing of young adults prior to childbearing. In general, however, the committee had reservations about carrier screening programs in the high school setting in the context of the health and educational systems of the United States, or carrier testing of persons younger than age 18; the committee was dubious that sufficient education, counseling, and follow-up would be provided in such settings. Research is needed to develop innovative methods for carrier detection in young adults at a time before pregnancy, and to evaluate these methods through pilot studies.

The committee believes that, until benefits and risks have been demonstrated, genetic screening programs are a form of human experimentation. Therefore, such programs should be preceded by pilot studies demonstrating their safety and effectiveness. Standard safeguards such as institutional review, requirements for demonstrated safety and effectiveness, voluntariness, and informed consent should be applied in initiating a new carrier detection program. In addition, the nature of the disorder for which testing is to be carried out must be of sufficient severity, impact, frequency, and distribution to warrant population based screening. Since it seems likely that screening will be done increasingly as part of routine medical care, the same principles should apply regardless of the setting of testing or screening.

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. The availability of a DNA test for this condition is likely to lead to more extensive testing before or during pregnancy for reproductive decisions since no treatment is available, but pilot studies are needed before such programs are implemented for fragile X (see Box 2-1). Hemochromatosis is a high-frequency, common autosomal recessive disease, but its onset is usually later in life and reproductive decisions are rarely, if ever, raised; heterozygote detection, therefore, is not indicated, and testing for the homozygote state, which occurs in about 1 in 500 Caucasians, is best deferred until adulthood (see Box 2-6).

Finally, the committee recommends that multiplexed tests should be grouped into categories of tests and disorders that raise similar issues and implications, both for informed consent and for genetic education and counseling. If found to be a carrier in such multiplex testing, individuals should be informed of their carrier status to allow testing and counseling to be offered to the partner (who usually will be found not to be a carrier). However, if both partners are carriers, they should be referred for genetic counseling to help them understand available reproductive options, including the possibility of abortion of an affected fetus. Once multiplex testing of this kind becomes possible, pilot studies of its appropriate use need to be carried out.

Suggested Citation:"2 Genetic Testing and Assessment." Institute of Medicine. 1994. Assessing Genetic Risks: Implications for Health and Social Policy. Washington, DC: The National Academies Press. doi: 10.17226/2057.
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Prenatal Diagnosis

Prenatal diagnosis can provide the context in which to choose whether or not to continue a pregnancy in which the expected child has a birth defect or a genetic disorder. It can allay anxiety and, in some cases, may allow high-risk couples to undertake a pregnancy they previously would have avoided. If, following identification of a fetus at high risk for a genetic disorder through prenatal diagnosis, a decision is made to continue the pregnancy, such information can, in some cases, facilitate prenatal or early infant therapy, as well as prepare for the delivery of an infant who may need special care at birth or delivery by cesarean section. These services also have the potential to (1) increase anxiety; (2) place excessive responsibility, blame, and guilt on a woman for her pregnancy outcome; (3) interfere with maternal-infant bonding; and (4) disrupt relationships among a woman, her family members, and her community.

Autonomous decision making should be the goal in prenatal diagnosis and the committee recommends that health professionals, society, and the state be neutral on the outcome of individual reproductive choices. Reproductive genetic services should be aimed at increasing individual control over reproductive options and should not be used to pursue eugenic goals. The committee recommends that offering prenatal diagnosis in circumstances associated with increased risk of carrying a fetus with a diagnosable genetic disorder, including for advanced maternal age, be considered an appropriate standard of care. The committee recommends that a family history of a diagnosable genetic disorder warrants comprehensive genetic counseling, including offering of prenatal diagnosis, regardless of maternal age, as does determination of carrier status in one or both parents of a disorder for which prenatal diagnosis is available. 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 7). 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.

However, the recommendation that prenatal diagnosis be offered should not be taken to mean that prenatal diagnosis should be undertaken without the woman's prior consent based on adequate information, even if it becomes possible in the future to perform prenatal diagnosis with simple, less invasive techniques such as the use of fetal cells isolated from maternal blood (see Box 2-3). In addition, the committee believes that prenatal diagnosis and selective abortion for carrier status for an autosomal or X-linked recessive disorder are not generally appropriate.

The benefits of maternal serum alphafetoprotein (MSAFP) screening are its low physical risk (using only a blood sample from the pregnant woman) and its

Suggested Citation:"2 Genetic Testing and Assessment." Institute of Medicine. 1994. Assessing Genetic Risks: Implications for Health and Social Policy. Washington, DC: The National Academies Press. doi: 10.17226/2057.
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ability to identify, at an early gestational age, fetuses at increased risk of neural tube defects or Down syndrome for further follow-up prenatal diagnosis, including a second MSAFP test, ultrasound, and amniocentesis. However, a serious drawback in the use of this screening test in a broad population is the anxiety it creates for women and their families. Generally, the women being tested had no reason to be concerned about genetic disorders in their fetus based on family history or other indications of high risk; when test results are negative, parental anxiety created by the screening can often be relieved. On the other hand, the committee heard testimony about the significance of the anxiety raised by MSAFP screening, as well as evidence that the initial screening nature of the test may not be well understood by pregnant women to whom it is offered (Faden et al., 1985; Hoyt, 1992; Press and Browner, 1992a,b). Given the nature of MSAFP screening, with its high rate of initial positives and the variety of conditions that aberrant levels might indicate, the committee recommends intensive follow-up, both to confirm predictive value and to ensure counseling for women with abnormal screening results.

Thus, the committee recommends that anyone considering prenatal diagnosis be informed about the risks and benefits of the testing procedure, and the possible outcomes, as well as alternative options to testing and other reproductive options that might be available. Principles of disclosure for informed consent, whether for routine or experimental prenatal screening or diagnosis, should include (1) fair and balanced explanation of the procedures and their safety; (2) a description of the risks and benefits; (3) consideration of all possible outcomes, including the possibility that one option might be termination of the pregnancy; (4) knowledge of the potential need for and availability of psychosocial counseling; (5) documentation of consent; and (6) full information concerning the spectrum of severity of the genetic disorders for which prenatal diagnosis is being offered (e.g., CF, Down syndrome, fragile X). Furthermore, invasive prenatal diagnosis is justified only if the pursuant diagnostic procedures are accurate, sensitive, and specific for the disorder(s) for which prenatal diagnosis is being offered. All candidates being offered prenatal screening and diagnosis should be informed about all of the risks and benefits described above to ensure that participation is voluntary.

The committee recommends that standards of care for prenatal screening and diagnosis should include education and counseling before and after the test. Thus, prenatal diagnosis should always be provided in conjunction with genetic counseling, either directly or by referral. 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.

Suggested Citation:"2 Genetic Testing and Assessment." Institute of Medicine. 1994. Assessing Genetic Risks: Implications for Health and Social Policy. Washington, DC: The National Academies Press. doi: 10.17226/2057.
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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

Suggested Citation:"2 Genetic Testing and Assessment." Institute of Medicine. 1994. Assessing Genetic Risks: Implications for Health and Social Policy. Washington, DC: The National Academies Press. doi: 10.17226/2057.
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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

Suggested Citation:"2 Genetic Testing and Assessment." Institute of Medicine. 1994. Assessing Genetic Risks: Implications for Health and Social Policy. Washington, DC: The National Academies Press. doi: 10.17226/2057.
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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).

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Raising hopes for disease treatment and prevention, but also the specter of discrimination and "designer genes," genetic testing is potentially one of the most socially explosive developments of our time. This book presents a current assessment of this rapidly evolving field, offering principles for actions and research and recommendations on key issues in genetic testing and screening.

Advantages of early genetic knowledge are balanced with issues associated with such knowledge: availability of treatment, privacy and discrimination, personal decision-making, public health objectives, cost, and more. Among the important issues covered:

  • Quality control in genetic testing.
  • Appropriate roles for public agencies, private health practitioners, and laboratories.
  • Value-neutral education and counseling for persons considering testing.
  • Use of test results in insurance, employment, and other settings.
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