Thompson & Thompson Genetics in Medicine, 8th Edition

CHAPTER 19. Ethical and Social Issues in Genetics and Genomics

Human genetics and genomics are having a major impact in all areas of medicine and across all age-groups, and their importance will only grow as knowledge increases and the power and reach of sequencing technology improves. Yet, no single area of medical practice raises as many challenging ethical, social, and policy issues in so many areas of medicine and across so broad a spectrum of age-groups, including the fetus, neonates, children, prospective parents, and adults.

There are many categories of information that genetics and genomics deals with, ranging from ancestry and personal heritage to diagnosis of treatable or untreatable disease to explanations for familial traits to concerns about what has been or might be passed on to the next generation. Some of these were introduced in previous chapters; others are presented in this chapter. But, as we shall see, they all pose ethical, legal, social, personal, and policy challenges. And if that is true today, it will become only more commonplace in the years and decades ahead, as genome sequences (and the data-rich landscape of genomic and medical information) become available for millions—and eventually hundreds of millions—of individuals worldwide.

The ethical and social issues raised because of new information and capabilities in human genetics and genomics are especially relevant to decisions in the area of reproduction (see Chapter 17) because of the absence of a societal consensus on the religious and ethical concerns about abortion and assisted reproductive technologies. The damaging legacy of eugenics (discussed later in this chapter) hangs over discussions of reproductive genetics, now especially timely in light of the ability to evaluate the sequence of fetal genomes. Finally, privacy concerns also loom large because genetic and genomic information, in the absence of any other demographical information, may still render an individual and his or her personal sensitive health information uniquely identifiable. Yet, we share DNA variation with our family members and indeed with all of mankind, and thus privacy concerns need to be balanced against the benefits that could be derived from making personal genetic information available to other family members and to society at large.

In this chapter, we will review some of the most challenging ethical and societal issues that arise from the application of genetics and genomics to medicine. These relate to prenatal diagnosis, presymptomatic testing, the duty to inform family members of genetic conditions in the family, and the policy challenges arising from the discovery of genetic variants that confer increased risk for disease that are found incidental to diagnostic testing for another indication.

Principles of Biomedical Ethics

Four cardinal principles are frequently considered in any discussion of ethical issues in medicine:

• Respect for individual autonomy, safeguarding an individual's rights to control his or her medical care and medical information, free of coercion

• Beneficence, doing good

• avoidance of maleficence, “first of all, do no harm” (from the Latin, primum non nocere)

• Justice, ensuring that all individuals are treated equally and fairly

Complex ethical issues arise when these principles are perceived to be in conflict with one another. The role of ethicists working at the interface between society and medical genetics is to weigh and balance conflicting demands, each of which has a claim to legitimacy based on one or more of these cardinal principles.

Ethical Dilemmas Arising in Medical Genetics

In this section, we focus our discussion on some of the ethical dilemmas arising in medical genetics, dilemmas that will only become more difficult and complex as genetics and genomics research expands our knowledge (Table 19-1). The list of issues discussed here is by no means exhaustive, nor are the issues necessarily independent of one other.

TABLE 19-1

Major Ethical and Policy Issues in Medical Genetics

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Ethical Dilemmas in Genetic Testing

Prenatal Genetic Testing

Geneticists are frequently asked to help couples use prenatal diagnosis or assisted reproductive technology to avoid having offspring with a serious hereditary disorder. For some hereditary disorders, prenatal diagnosis remains controversial, particularly when the diagnosis leads to a decision to terminate the pregnancy for a disease that causes various kinds of physical or intellectual disabilities but is not fatal in infancy. Prenatal diagnosis is equally controversial for adult-onset disorders, particularly ones that may be managed or treated. A debate is ongoing in the community of persons who have a physical or intellectual disability and deaf patients and their families (to name only a few examples) about whether prenatal diagnosis and abortion for these disorders are ethically justified. The dilemma lies in attempting to balance, on the one hand, respect for the autonomy of parents' reproductive decision making about the kind of family they wish to have versus, on the other hand, an assessment of whether aborting a fetus affected with a disability compatible with life is fair to the fetus or to the broader community of persons with a disability or people with hearing impairment.

The dilemma also arises when a couple makes a request for prenatal diagnosis in a pregnancy that is at risk for what most people would not consider a disease or disability at all. Particularly troubling is prenatal diagnosis for selection of sex for reasons other than reducing the risk for sex-limited or X-linked disease. Many genetics professionals are concerned that couples are using assisted reproductive technologies, such as in vitro fertilization and blastomere biopsy, or prenatal sex determination by ultrasonography and abortion, to balance the sexes of the children in their family or to avoid having children of one or the other sex for social and economic reasons prevalent in their societies. There are already clear signs of a falling ratio of female to male infants from 0.95 to less than 0.85 in certain areas of the world where male children are more highly prized.

Other areas of ethical debate include seeking prenatal diagnosis to avoid recurrence of a disorder associated with a mild or cosmetic defect or for putative genetic enhancement, such as genetic variants affecting muscle physiology and therefore athletic prowess. Other examples are the use of prenatal diagnosis and possible pregnancy termination for what is considered by society to be a normal phenotype, such as hearing or typical stature, in a family in which both parents are deaf or have achondroplasia and consider their phenotypes to be important components of their family identity, not disabilities. Such dilemmas have so far been more theoretical than real. Although surveys of couples with deafness or achondroplasia show that the couples are concerned about having children who are not deaf or do not have achondroplasia, the vast majority would not actually use prenatal diagnosis and abortion to avoid having children who do not share their conditions.

In the future, particular alleles and genes that contribute to complex traits, such as intelligence, personality, stature, and other physical characteristics, will likely be identified. Will such nonmedical criteria be viewed as a justifiable basis for prenatal diagnosis? Some might argue that parents are already expending tremendous effort and resources on improving the environmental factors that contribute to healthy, successful children. They might therefore ask why they should not try to improve the genetic factors as well. Others consider prenatal selection for particular desirable genes a dehumanizing step that treats children simply as commodities fashioned for their parents' benefit. Once again, the ethical dilemma is in attempting to balance respect for the autonomy of parents' reproductive decision making with an assessment of whether it is just or beneficial to terminate a pregnancy when a fetus has a strictly cosmetic problem or carries what are perceived to be undesirable alleles or is even of the “wrong” sex. Does a health professional have, on the one hand, a responsibility and, on the other hand, the right to decide for a couple when a disorder is not serious enough to warrant prenatal diagnosis and abortion or assisted reproduction?

There is little consensus among geneticists as to where or even whether one can draw the line in deciding what constitutes a trait serious enough to warrant prenatal testing.

Genetic Testing for Predisposition to Disease

Another area of medical genetics and genomics in which ethical dilemmas frequently arise is genetic testing of asymptomatic individuals for diseases that may have an onset in life later than the age at which the molecular testing is to be performed. The ethical principles of respect for individual autonomy and beneficence are central to testing in this context. At one end of the spectrum is testing for late-onset, highly penetrant neurological disorders, such as Huntington disease (see Chapter 12(Case 24). For such diseases, individuals carrying a mutant allele may be asymptomatic but will almost certainly develop a devastating illness later in life for which there is currently little or no treatment. For these asymptomatic individuals, is knowledge of the test result more beneficial than harmful, or vice versa? There is no simple answer. Studies demonstrate that some individuals at risk for Huntington disease choose not to undergo testing and would rather not know their risk, whereas others choose to undergo testing. Those who choose testing and test positive have been shown to sometimes have a transient period of depression, but with few suffering severe depression, and many report positive benefits in terms of the knowledge provided to make life decisions about marriage and choice of career. Those who choose testing and are found not to carry the trinucleotide expansion allele report positive benefits of relief but can also experience negative emotional responses due to guilt for no longer being at risk for a disease that either affects or threatens to affect many of their close relatives. In any case, the decision to undergo testing is a highly personal one that must be made only after thorough review of the issues with a genetics professional.

The balance for or against testing of unaffected, at-risk individuals shifts when testing indicates a predisposition to a disease for which intervention and early treatment are available. For example, in autosomal dominant hereditary breast cancer, individuals carrying various mutations in BRCA1 or BRCA2 have a 50% to 90% chance of developing breast or ovarian cancer (see Chapter 15(Case 7). Identification of heterozygous carriers would be of benefit because individuals at risk could choose to undergo more frequent surveillance or have preventive surgery, such as mastectomy, oophorectomy, or both, recognizing that these measures can reduce but not completely eliminate the increased risk for cancer. What if surveillance and preventive measures were more definitive, as they are in familial adenomatous polyposis, for which prophylactic colectomy is a proven preventive measure (see Chapter 15) and (Case 15)? Upon testing for any predisposing gene mutation(s), individuals incur the risk for serious psychological distress, stigmatization in their social lives, and discrimination in insurance and employment (see later). How are respect for a patient's autonomy, the physician's duty not to cause harm, and the physician's desire to prevent illness to be balanced in these different situations?

Geneticists would all agree that the decision to be tested or not to be tested is not one made in a vacuum. The patient must make an informed decision using all available information concerning the risk for and severity of the disease, the effectiveness of preventive and therapeutic measures, and the potential harm that could arise from testing.

Genetic Testing of Asymptomatic Children

Additional ethical complexity arises when genetic testing involves minor children (younger than 18 years), particularly children too young to even give assent, because now the basic principles of bioethics need to be considered in the case of both the child and the parents. There are several reasons why parents may wish to have their children tested for a disease predisposition. Testing asymptomatic children for alleles that predispose to disease can be beneficial, even lifesaving, if interventions that decrease morbidity or increase longevity are available. One example is testing the asymptomatic sibling of a child with medium-chain acyl-CoA dehydrogenase deficiency (see Chapter 18) and (Case 31).

However, some have argued that even in situations where there are currently no clear medical interventions that might benefit the child, it is the parents' duty to inform and prepare their children for the future possibility of development of a serious illness. The parents may also seek this information for their own family planning or to avoid what some parents consider the corrosive effects of keeping important information about their children from them. Testing children, however, carries the same risks for serious psychological damage, stigmatization, and certain kinds of insurance discrimination as does testing adults (see later). Children's autonomy—their ability to make decisions for themselves about their own genetic constitution—must also now be balanced with the desire of parents to obtain and use such information.

A different but related issue arises in testing children for the carrier state of a disease that poses no threat to their health but places them at risk for having affected children. Once again, the debate centers on the balance between respect for children's autonomy in regard to their own procreation and the desire on the part of well-meaning parents to educate and prepare children for the difficult decisions and risks that lie ahead once they reach childbearing age.

Most bioethicists believe (and the American College of Medical Genetics and Genomics [ACMG] agrees) that, unless there is a clear benefit to the medical care of the child, genetic testing of asymptomatic children for adult-onset disease or for a carrier state should be done only when the child is sufficiently old and mature, as in late adolescence or on reaching adulthood, to decide for himself or herself whether to seek such testing.

Incidental and Secondary Findings from Whole-Exome and Whole-Genome Sequencing

Another area of controversy has arisen in patients who have given consent for whole-exome or whole-genome sequencing (WES/WGS) to find a genetic basis for their undiagnosed diseases (see Chapters 10 and 18). Laboratories searching the exomes or genomes of such patients usually develop a primary candidate gene list based on the phenotype of the patient. The laboratory considers deleterious mutations in these genes as their primary findings, that is, the results that are actively being sought as the primary target of the testing. In the process of analyzing a whole exome or genome, however, deleterious mutations may be discovered incidentally in genes known to be associated with diseases unrelated to the phenotype for which the sequencing test was originally conducted (see Chapter 16). If the mutations uncovered as incidental findings cause serious diseases that can be ameliorated or prevented, then is there benefit of drawing up a list of genes that every laboratory doing WES/WGS variants would deliberately analyze in every patient, even though they are not relevant to the primary goal of finding the genetic cause for a patient's unexplained disease? Mutations in this list of genes would be secondary findings that would be sought regardless of whether the patient wishes to know these results, because his or her providers deem the benefit of knowing is so compelling for the patient's health that it outweighs the requirement of patient autonomy, to be able to choose what kind of information he or she wants to know.

The ACMG made an initial attempt to draw up a list of secondary findings that a laboratory should seek. The current list includes 56 genes, most of which are involved in serious hereditary cancer and cardiovascular syndromes that are (1) life threatening, (2) not readily diagnosable before the onset of symptoms, and (3) preventable or treatable. The secondary finding gene list is subject to ongoing refinement and will presumably grow over time. Furthermore, whether a given gene mutation should always be a secondary finding that must be sought is also undergoing reevaluation. The current ACMG recommendation is that patients should be provided with appropriate counseling and then given the opportunity to agree or to refuse to have such secondary findings looked for and reported.

Ethical Dilemmas in Newborn Screening

Although newborn screening programs (see Chapter 18) are generally accepted as one of the great triumphs of modern genetics in improving public health, questions about newborn screening still arise. First, should parents be asked to provide active consent or can they simply be offered the opportunity to “opt out” of the program. Second, who has access to samples and data, and how can we make sure that samples, such as DNA, are not used for purposes other than the screening tests for which they were collected and for which consent was given (or at least, not withheld)? In the United States, these questions came to a head in the area of newborn screening in the state of Texas when a group of parents of children sued the state because blood spots obtained through an “opt-out” process for newborn screening had been diverted to the Department of Defense and private companies and used for purposes other than newborn screening, without parental consent. Texas agreed to destroy their collection of more than 5 million blood spots. In doing so, the state lost samples that could have been used for legitimate purposes, such as developing new newborn screening tests and for quality control of current testing efforts.

Privacy of Genetic Information

Legal protections for genetic information are not uniform across the globe or even within different jurisdictions in the same countries. In the United States, the primary set of regulations governing the privacy of health information, including genetic information, is the Privacy Rule of the Health Insurance Portability and Accountability Act (HIPAA). The HIPAA rule sets criminal and civil penalties for disclosing such information without authorization to others, including other providers, except under a defined set of special circumstances. Genetic information, however, receives special attention because it has implications for other family members.

Privacy Issues for Family Members in a Family History

Patients are free to provide their physicians with a complete family medical history or communicate with their physicians about conditions that run in the family. The HIPAA Privacy Rule does not prevent individuals from gathering medical information about their family members or from deciding to share this information with their health care providers.

This information becomes part of the individual's medical record and is treated as “protected health information” about the individual but is not protected health information for the family members included in the medical history. In other words, only patients, and not their family members, may exercise their rights under the HIPAA Privacy Rule to their own family history information in the same fashion as any other information in their medical records, including the ability to elect to control disclosure to others.

Duty to Warn and Permission to Warn

A patient's desire to have his or her medical information kept confidential is one facet of the concept of patient autonomy, in which patients have the right to make their own decisions about how their individual medical information is used and communicated to others. Genetics, however, more than any other branch of medical practice, is concerned with both the patient and the family. A serious ethical and legal dilemma can arise in the practice of genetic medicine when a patient's insistence that his or her medical information be kept strictly private restrains the geneticist from letting other family members know about their risk for a condition, even when such information could be beneficial to their own health and the health of their children (see Box). In this situation, is the genetics practitioner obligated to respect the patient's autonomy by keeping information confidential, or is the practitioner permitted or, more forcefully, does the practitioner have a duty to inform other family members and/or their providers? Is there a duty to warn? If so, is informing the patient that he or she should share the information with relatives sufficient to discharge the practitioner's duty?

Judges have ruled in a number of court cases in the United States on whether or not a health care practitioner is permitted or is even required to override a patient's wishes for confidentiality. The precedent-setting case was not one involving genetics. In the 1976 State Supreme Court case in California, Tarasoff v the Regents of the University of California, judges ruled that a psychiatrist who failed to warn law enforcement that his client had declared an intention to kill a young woman was liable in her death. The judges declared that this situation is no different from one in which physicians have a duty to protect the contacts of a patient with a contagious disease by warning them that the patient has the disease, even against the express wishes of the patient. In the realm of genetics, a duty to warn was mandated in a case in New Jersey, Safer v Estate of Pack (1996), in which a panel of three judges concluded that a physician had a duty to warn the daughter of a man with familial adenomatous polyposis of her risk for colon cancer. The judges wrote that “there is no essential difference between the type of genetic threat at issue here and the menace of infection, contagion, or a threat of physical harm.” They added that the duty to warn relatives is not automatically fulfilled by telling the patient that the disease is hereditary and that relatives need to be informed.

Duty to Warn

Patient Autonomy and Privacy versus Preventing Harm to Others


A woman first presents with an autosomal dominant disorder at the age of 40 years, undergoes testing, and is found to carry a particular mutation in a gene known to be involved in this disorder. She is planning to discuss the results with her teenage daughter but insists that her younger adult half-siblings (from her father's second marriage after her mother's and father's divorce) not be told that they might be at risk for this disorder and that testing is available. How does a practitioner reconcile the obligation to respect the patient's right to privacy with a desire not to cause her relatives harm by failing to inform them of their risk?

There are many questions to answer in determining whether “a serious threat to another person's health or safety” exists to justify unauthorized disclosure of risk to a relative.

Clinical Questions

• What is the penetrance of the disorder, and is it age dependent? How serious is the disorder? Can it be debilitating or life-threatening? How variable is the expressivity? Are there interventions that can reduce the risk for disease or prevent it altogether? Is this a condition that will be identified by routine medical care, once it is symptomatic, in time for institution of preventive or therapeutic measures?

• The risk to half-siblings of the patient is either 50% or negligible, depending on which parent passed the mutant allele to the patient. What does the family history reveal, if anything, about the parent in common between the patient and her half-siblings? Is the patient's mother still alive and available for testing?

Counseling Questions

• Was the patient informed at the time of testing that the results might have implications for other family members? Did she understand in advance that she might be asked to warn her relatives?

• What are the reasons for withholding the information? Are there unresolved issues, such as resentment, feelings of abandonment, or emotional estrangement, that are sources of psychological pain that could be addressed for her own benefit as well as to help the patient clarify her decision making?

• Are the other family members already aware of the possibility of this hereditary disease, and have they made an informed choice not to seek testing themselves? Would the practitioner's warning be seen as an unwarranted intrusion of psychologically damaging information, or would their risk come as a complete surprise?

Legal and Practical Questions

• Does the practitioner have the information and resources required to contact all the half-siblings without the cooperation of the patient?

• Could the practitioner have reached an understanding, or even a formal agreement, with the patient in advance of testing that she would help in informing her siblings? Would asking for such an agreement be seen as coercive and lead to the patient's depriving herself of the testing she needs for herself and her children?

• What constitutes adequate discharge of the practitioner's duty to warn? Is it sufficient to provide a form letter for the patient to show to relatives that discloses the absolute minimal amount of information needed to inform them of a potential risk?

Guidelines from international health organizations, individual national health policy groups, and professional medical organizations are not unanimous on this issue. Furthermore, in the United States, the inconsistent case law from state courts must also be considered with respect to legislative and regulatory mandates, particularly the HIPAA Privacy Rule.

Contrary to widespread belief, the HIPAA Privacy Rule permits a physician to disclose protected health information about a patient to another health care provider who is treating a family member of the physician's patient without the individual's authorization, unless the patient has explicitly chosen to impose additional restrictions on the use or disclosure of his or her protected health information. For example, an individual who has obtained a genetic test may request that the health care provider not disclose the test results. If the health care provider agrees to the restriction, the HIPAA rule prevents disclosing such information without authorization to providers treating other family members who are seeking to identify their own genetic health risks. However, the health care provider should discuss such restrictions with the patient in advance of doing the test and is not obligated to agree to the requested restriction.

Although the genetics practitioner is most knowledgeable about the clinical aspects of the disease, the relevance of the family history, and the family risk assessment, the many legal and ethical controversies surrounding HIPAA and the duty to warn suggest that consultation with legal and bioethics experts is advisable should a conflict arise over the release of a patient's medical information.

Use of Genetic Information by Employers and Insurers

The fourth major ethical principle is justice—the requirement that everyone be able to benefit equally from progress in medical genetics. Justice is a major concern in the area of the use of genetic information in employment and health insurance. Whether healthy individuals could be denied employment or health insurance because they carry a genetic predisposition to disease was not a settled issue in the United States until passage of the landmark Genetic Information Nondiscrimination Act (GINA) of 2008. Under this act, private employers with 15 or more employees are prohibited from deliberately seeking or using genetic information, including family history, to make an employment decision because genetic information was not considered to be relevant to an individual's current ability to work. Similarly, GINA prohibits most group health insurers from denying insurance or adjusting group premiums based on the genetic information of members of the group.

Outside of the United States, however, equivalent GINA laws are not in place. For some countries with national health systems and with private health insurance that is not risk-rated, genetic discrimination in health insurance may not be an issue. However, for most other countries (and in the area of employment in all other countries), there is widespread agreement that genetic discrimination should not be permitted, but legislation banning the practice remains to be enacted.

Significantly, GINA does not apply in the area of life, disability, and long-term care insurance. Insurers that sell such products insist that they must have access to all pertinent genetic information about an individual that the individual himself or herself has when making a decision to purchase one of these policies. Life insurance companies calculate their premiums on the basis of actuarial tables of age-specific survival averaged over the population; premiums will not cover losses if individuals with private knowledge that they are at higher risk for disease conceal this information and buy extra life or long-term disability insurance, a practice referred to as adverse selection. If adverse selection were widespread, the premiums for the entire population would have to increase so that in essence, the entire population would be subsidizing the increased coverage for a minority. Adverse selection is likely to be a real phenomenon in some circumstances; in one study of asymptomatic individuals tested for the APOE ε4 allele, those who chose to know that they tested positive were found to be nearly six times more likely to purchase extra long-term care insurance than those who did not choose to know their APOE genotype. Knowledge that one carried an APOE ε4 allele did not, however, affect life, health, or disability insurance purchases.

At present, there is little evidence that life insurance companies have actually engaged in discriminatory underwriting practices on the basis of genetic testing. Nevertheless, the fear of such discrimination, and the negative impact that discrimination would have on people obtaining clinical testing for their own health benefit as well as on their willingness to participate in genetic research, has led to proposals to ban the use of genetic information in life insurance. In the United Kingdom, for example, life insurance companies have voluntarily agreed to an extended moratorium on the use of genetic information in most life underwriting, except when large policies are involved or in the case of Huntington disease, for which disclosure of a positive test result by the patient is required.

There must be, however, a clear distinction between what are already phenotypic manifestations of a disease, such as hypertension, hypercholesterolemia, and diabetes mellitus, and what are predisposing alleles, such as BRCA1 mutations (see Chapter 15) and APOE ε4 alleles (see Chapters 8 and 18), that may never result in overt disease in the individual who carries such an allele.

Eugenic and Dysgenic Effects of Medical Genetics

The Problem of Eugenics

The term eugenics, introduced by Darwin's cousin Francis Galton in 1883, refers to the improvement of a population by selection of only its “best” specimens for breeding. Plant and animal breeders have followed this practice since ancient times. In the late 19th century, Galton and others began to promote the idea of using selective breeding to improve the human species, thereby initiating the so-called eugenics movement, which was widely advocated for the next half-century. The so-called ideal qualities that the eugenics movement sought to promote through the encouragement of certain kinds of human breeding were more often than not defined by social, ethnic, and economic prejudices and fed by antiimmigrant and racist sentiments in society. What we now would consider a lack of education was described then as familial “feeble-mindedness”; what we now would call rural poverty was considered by eugenicists to be hereditary “shiftlessness.” The scientific difficulties in determining whether traits or characteristics are heritable and to what extent heredity contributes to a trait were badly overestimated because most human traits, even those with some genetic component, are complex in their inheritance pattern and are influenced strongly by environmental factors. Thus, by the middle of the last century, many scientists began to appreciate the theoretical and ethical difficulties associated with eugenics programs.

Eugenics is commonly thought to have been largely discredited when it was resurrected and used in Nazi Germany as a justification for mass murder. However, it should be pointed out that in North America and Europe, involuntary sterilization of institutionalized individuals deemed to be mentally incompetent or disabled was carried out under laws passed in the early part of the 20th century in support of eugenics and was continued for many years after the Nazi regime was destroyed.

Genetic Counseling and Eugenics

Genetic counseling, with the aim of helping patients and their families manage the pain and suffering caused by genetic disease, should not be confounded with the eugenic goal of reducing the incidence of genetic disease or the frequency of alleles considered deleterious in the population. Helping patients and families come to free and informed decisions, particularly concerning reproduction, without coercion, forms the basis for the concept of nondirective counseling (see Chapter 16). Nondirectiveness asserts that individual autonomy is paramount and must not to be subordinated to reducing the burden of genetic disease on society or to a theoretical goal of “improving the gene pool,” a totalitarian concept that echoes the Nazi doctrine of racial hygiene. Some, however, have argued that true nondirective counseling is a myth, often acclaimed but not easy to accomplish, because of the personal attitudes and values the counselor brings to the counseling session.

Nonetheless, despite the difficulties in attaining the ideal of nondirective counseling, the ethical principles of respect for autonomy, beneficence, avoidance of maleficence, and justice remain at the heart of all genetic counseling practice, particularly in the realm of individual reproductive decision making.

The Problem of Dysgenics

The opposite of eugenics is dysgenics, a deterioration in the health and well-being of a population by practices that allow the accumulation of deleterious alleles. In this regard, the long-term impact of activities in medical genetics that can affect gene frequencies and the incidence of genetic disease may be difficult to predict.

In the case of some single-gene defects, medical treatment can have a dysgenic effect by reducing selection against a particular genotype, thereby allowing the frequency of harmful genes and consequently of disease to increase. The effect of relaxed selection is likely to be more striking for autosomal dominant and X-linked disorders than for autosomal recessive disorders, in which the majority of mutant alleles are in silent heterozygous carriers.

For example, if successful treatment of Duchenne muscular dystrophy were to be achieved, the incidence of the disease would rise sharply because the DMD genes of the affected males would then be transmitted to all their daughters. The effect of this transmission would be to greatly increase the frequency of carriers in the population. In contrast, if all persons affected with cystic fibrosis could survive and reproduce at a normal rate, the incidence of the disease would rise from 1 in 2000 to only approximately 1 in 1550 over 200 years. Common genetic disorders with complex inheritance, discussed in Chapter 8, could theoretically also become more common if selection were removed, although it is likely that as with autosomal recessive diseases, most of the many susceptibility alleles are distributed among unaffected individuals. Consequently, reproduction by affected persons would have little effect on susceptibility allele frequencies.

As prenatal diagnosis (see Chapter 17) becomes widespread, increasing numbers of pregnancies in which the fetus has inherited a genetic defect may be terminated. The effect on the overall incidence of disease is quite variable. In a disorder such as Huntington disease, prenatal diagnosis and pregnancy termination would have a large effect on the incidence of the responsible gene. For most other severe X-linked or autosomal dominant disorders, some reduction might occur, but the disease will continue to recur owing to new mutations. In the case of autosomal recessive conditions, the effect on the frequency of the mutant allele, and consequently of the disease, of aborting all homozygous affected pregnancies would be small because most of these alleles are carried silently by heterozygotes.

One theoretical concern is the extent to which pregnancy termination for genetic reasons is followed by reproductive compensation—that is, by the birth of additional, unaffected children, many of whom are carriers of the deleterious gene. Some families with X-linked disorders have chosen to terminate pregnancies in which the fetus was male, but of course, daughters in such families, although unaffected, may be carriers. Thus reproductive compensation has the potential long-term consequence of increasing the frequency of the genetic disorder that led to the loss of an affected child.

Genetics in Medicine

The 20th century will be remembered as the era that began with the rediscovery of Mendel's laws of inheritance and their application to human biology and medicine, continued with the discovery of the role of DNA in heredity, and culminated in the completion of the Human Genome Project. At the beginning of the 21st century, the human species has, for the first time:

• A complete representative sequence of its own DNA

• A comprehensive, albeit likely incomplete, inventory of its genes

• A vigorous ongoing effort to identify and characterize mutations and polymorphic variants in DNA sequence and copy number

• A rapidly expanding knowledge base in which various diseases and disease predispositions will be attributable to such variation

• Powerful new sequencing technologies that allow sequencing of an exome or genome at a tiny fraction of the cost of the first human genome sequence

With such knowledge comes powerful capabilities as well as great responsibilities. Ultimately, genetics in medicine is not about knowledge for its own sake, but for the sake of sustaining wellness, improving health, relieving suffering, and enhancing human dignity. The challenge confronting us all, both future health professionals and members of society at large, is to make sure that the advances in human genetics and genomics knowledge and technology are used responsibly, fairly, and humanely.

General References

Beauchamp TL, Childress JF. Principles of biomedical ethics. ed 5. Oxford University Press: New York; 2001.

Kevles D. In the name of eugenics: genetics and the uses of human heredity. Harvard University Press: Cambridge, Mass; 1995.

References for Specific Topics

Biesecker LG. Incidental variants are critical for genomics. Am J Hum Genet. 2013;92:648–651.

Elger B, Michaud K, Mangin P. When information can save lives: the duty to warn relatives about sudden cardiac death and environmental risks. Hastings Center Report. 2010;40:39–45.

HIPAA regulations on family history. http://www.hhs.gov/ocr/privacy/hipaa/faq/family_medical_history_information/index.html.

MacEwen JE, Boyer JT, Sun KY. Evolving approaches to the ethical management of genomic data. Trends Genet. 2013;29:375–382.

McGuire AL, Joffe S, Koenig BA, et al. Point-counterpoint. Ethics and genomic incidental findings. Science. 2013;340:1047–1048.

Offit K, Thom P. Ethicolegal aspects of cancer genetics. Cancer Treat Res. 2010;155:1–14.

Visscher PM, Gibson G. What if we had whole-genome sequence data for millions of individuals? Genome Med. 2013;5:80.

Yurkiewicz IR, Korf BR, Lehmann LS. Prenatal whole-genome sequencing—is the quest to know a fetus's future ethical? N Engl J Med. 2014;370:195–197.

Problems

1. A couple with two children is referred for genetic counseling because their younger son, a 12-year-old boy, has a movement disorder for which testing for juvenile Huntington disease (Case 24) is being considered. What are the ethical considerations for the family in testing?

2. A research project screened more than 40,000 consecutive, unselected births for the number of X chromosomes and the presence of a Y chromosome and correlated the sex chromosome karyotype with the sex assigned by visual inspection in the newborn nursery. The purpose of the project was to observe infants with sex chromosome abnormalities (see Chapter 6) prospectively for developmental difficulties. What are the ethical considerations in carrying out this project?

3. In the case described in the Box in the section on duty to warn, consider what might be your course of action if you were the genetic counselor and the disease in question were the following: hereditary breast and ovarian cancer due to BRCA1 mutations (see Chapter 15(Case 7); malignant hyperthermia due to RYR1 (ryanodine receptor) mutations (see Chapter 18); early-onset, familial Alzheimer disease due to a PSEN1 (presenilin 1) mutation (see Chapter 12(Case 4); neurofibromatosis due to NF1 mutations (see Chapter 7(Case 34); or type 2 diabetes mellitus (Case 35).

4. Draw up a list of a dozen genes and disorders that you believe should be analyzed as secondary findings during a whole-exome or whole-genome sequence for undiagnosed diseases. Explain how and why you chose each of these dozen genes and conditions.