Genetic counseling issues in predictive genetic testing for familial adult-onset neurologic diseases

Genetic Counseling Issues in Predictive Genetic Testing for Familial Adult-Onset Neurologic Diseases Catherine M. Burson and Kristina R. Markey Genetic counseling is important in any genetic testing situation in order to address the various issues related to obtaining a genetic diagnosis. Presymptomatic testing for adult-onset neurodegenerative disease, in particular, presents a complex counseling scenario. It is imperative to discuss the potential impact of test results on patients' family dynamics, insurability and employability, family planning, and future health in addition to ascertaining a complete understanding of recurrence, inheritance, and testing parameters. The Huntington disease presymptomatic testing protocol is well-defined and has been used for more than 10 years. These guidelines, which protect both patient and provider, can now be applied to other diseases as further presymptomatic testing capabilities are realized. Copyright 9 2001 by W.B. Saunders Company

ITH THE PRELIMINARY completion of the human genome sequence comes much anticipation from the medical community and consumers for advances in diagnostic abilities. The map of the human DNA sequence will allow researchers to more quickly define a gene of interest. The identification of a mutation that is associated with a disease enables investigation of the clinical manifestations among different patients resulting from that same gene change. This then guides the investigation for modifier genes and other nongenetic factors that influence disease presentation. These discoveries allow for a clearer understanding of disease etiology and pathophysiology, and as a result, new approaches to disease prevention and therapy could follow. Although these achievements will not be immediately realized, this progress is already revolutionizing medicine as we know it. The gene has already been identified for a fairly large number of Mendelian inherited diseases. Currently there are more than 50 gene tests available for neurodegenerative disorders, with more likely to be available in the future.1 However, the prediction of risk for simple Mendelian inherited diseases is not always straightforward. Although many clinicians understand basic concepts of inheritance, the phenomena of reduced penetrance and variable expression often complicate family history interpretation and genetic counseling. For the countless other disorders following more complex inheritance, susceptibility testing will prove to be even more challenging. Understandably, many nongeneticists are uncomfortable with risk assessment and find it challenging to address patient questions and concerns about the implications of genetic disease on future health and family dynamics. Along with a genetic diagnosis often comes the

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challenge of living with a chronic debilitating disease but also many other challenges, including feelings of guilt, social stigmatization, and blame. It is difficult to help families effectively adjust to a genetic diagnosis. However, as the genetic revolution continues, genetic issues will arise more commonly, and the more straightforward cases will need to be managed in the primary care setting. 2 The current advances in molecular biology have already led to a difficult era in medical genetics. Although testing is available for a growing number of conditions, the list of diseases for which effective treatment is possible remains short. Until reasonable options for prevention and treatment are available, the application of genetics technology for prenatal diagnosis and predictive testing will remain ethically controversial. Many of the ethical concerns arising in predictive genetic testing have been defined and explored with the advent of presymptomatic testing for Huntington's disease (HD). Recommended pre- and post-test guidelines have been set forth by physician organizations and lay groups to allow predictive testing to be performed in a manner that minimizes psychological harm and improves the quality of life for most tested individuals. Although preliminary studies indicate that most at-risk individuals who choose

From the Hattie B. Munroe Center for Human Genetics, University of Nebraska Medical Center, Omaha, NE; and Huntington Disease Predictive Testing Program, Department of Neurology, Universi~' of Colorado Health Science Center, Denver, CO. Address reprint requests to Catherine M. Burson, MS, 985440 Nebraska Medical Center, Omaha, NE 68198-5440. Copyright 9 2001 by W.B. Saunders C o ~ y 1071-9091/01A9803-0007535.00/0 doi:l O.l O53/spett 2001.26451

Seminars in Pediatric Neurology, Vol 8, No 3 (September), 2001: pp 177-186

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to be predictively tested for the disease gene as part of a formal testing program experience psychological benefits, 3 a smaller but significant number of tested individuals have had difficulty adjusting to the test results, a'5 The challenges that are inherent to predictive genetic testing are numerous, and experts at test sites around the world continue to urge caution regarding the delivery of predictive genetic testing services. The model designed for HD predictive testing can be modified to provide predictive testing for other genetic adult onset disorders. 6-1~This article examines how the HD predictive testing model was developed and the reasons behind the various recommendations. It outlines options for family planning for couples at risk for a child with a genetic disease. It will examine some of the social and ethical problems that inevitably arise with predictive genetic testing. The recommended guidelines for presymptomatic testing for HD are not intended as a rigid protocol to be applied in all situations. Rather, it can be adapted to fit the needs of each individual genetic testing center. Nevertheless, the lessons learned from predictive HD testing can be used in designing the guidelines for genetic testing in other diseases. DEVELOPMENT OF THE HUNTING DISEASE PREDICTIVE TESTING PROTOCOL

Those who have not been involved with predictive genetic testing may not initially appreciate the complexity of these situations. The HD model involves a multidisciplinary approach that typically involves pre- and post-test counseling. The life-changing impact of predictive testing deserves careful forethought and deliberate contemplation before the initiation of testing. The original premise of the protocol was to allow individuals to make an informed decision about these issues and to optimize the adjustment to the new risk status. As this is technically complicated and emotionally stressful information and because the process identifies hypothetical questions that deserve careful consideration, adequate time needs to be allowed for the communication process. This section highlights the thoughtful effort that occurred in developing the original HD predictive testing guidelines. With the identification of the HD locus, it was evident that a reliable method for predictive genetic testing could be developed. Preliminary studies indicated a large portion of the at-risk commu-

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nity would use such a predictive test for their own risk determination, and a smaller number would use the testing for prenatal diagnosis. 11 In 1983, as the potential for predictive testing through linkage analysis was being investigated, concern arose about the psychological and social impact of such testing. These concerns led to pilot prospective studies of predictive testing in designated test sites in the United States and Canada beginning in 1986 to assess the long-term impact of predictive genetic testing for HD by linkage analysis. It was the experience from these centers that guided the development of testing recommendations that were set forth by a committee of individuals from the International Huntington Association and the World Federation of Neurology Research Group on Huntington's Chorea. 12 The guidelines were adopted by both organizations in 1989 and were revised in 1994 after the actual disease mutation was identified. 13 These guidelines were set forth by HD Family Organizations and medical experts to protect atrisk individuals. 13 Several studies have since examined the tested individuals' post-test view of the value of such pre- and post-test recommendations, and in general, the tested individuals have believed most aspects of this program should remain available in predictive testing for H D . 14-16 Discussion among care-providers regarding the utility of the protocol continues. RECOMMENDED GUIDELINES

In general, the guidelines outlined here are intended for asymptomatic individuals with a confirmed family history of a dominantly inherited disorder, with HD acting as the model for which it was originally designed. 17 Individuals should be cognitively and psychologically able to provide informed consent. Presymptomatic testing is intended only for those individuals who have not previously received a clinical diagnosis of the disease in question. Ideally, these individuals should have a prior risk of 50%. Individuals at 25% risk can enroll, but concern arises about the potential impact of their test result on the at-risk parent and on siblings who have not chosen to be tested. The protocol is divided into several counseling sessions along with medical evaluations, with sufficient time between each to allow the patient to process the information. Patients are reminded repeatedly that they can withdraw from the protocol

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at any time. They are encouraged to bring a support person (usually a spouse, close friend, or relative not at risk) to as many of the counseling sessions as possible. The initial counseling session is used to provide the patient with information about predictive testing and the natural history of the disease, and to explore the potential benefits and potential harm of receiving a genetic diagnosis. 17'a8 For many adult onset neurodegenerative disorders, the mode of inheritance is autosomal dominant. Often individuals seeking testing are familiar with the natural history of the disease, having witnessed their parents, siblings, or other family members progressively decline. However, in some of these diseases (eg, HD), there is a significant psychiatric component to the disease expression, and family dysfunction, divorce, and suicide may interfere with complete understanding of the disease. 18 For these reasons the provider should not assume the patient has an accurate understanding of the disease pathology, even in families with a longstanding family history. In some conditions, such as Alzheimer disease, Parkinson disease, or amyotrophic lateral sclerosis, only 1% to 10% of the cases are inherited. In other conditions, such as spinocerebellar ataxia, there is considerable clinical overlap between subtypes, making diagnosis difficult without confirmatory DNA testing.1 Therefore, a first step in any genetic testing process is to confirm the diagnosis in the family and obtain medical records of affected individuals if at all possible. Because of the stresses a genetic disease poses on family dynamics, records may be difficult to obtain. Additionally, because molecular testing has only been available a relatively short time, there will often be no confirmatory DNA test results for the family. In these cases, a confirmatory test is recommended to establish whether the correct genetic test is being offered. In absence of DNA confirmation, obtaining a full family pedigree with ages of death, psychiatric histories including suicides and suicide attempts, and medical histories including any specific symptoms of the disease in question can assist in evaluating the accuracy of the diagnosis in the family. The process of eliciting the family history can also provide some insight into potential problems with family dynamics and other psychosocial issues that could influence the adjustment to the results.

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Once the complete medical, psychiatric, and family history is obtained, inheritance and recurrence risk should be reviewed in an attempt to dispel any myths about who is at-risk, is The limitations of direct DNA testing should be discussed including the concept of trinucleotide repeats and its relationship to "anticipation," the possibility of inconclusive results, and the occurrence of variable expression or reduced penetrance. Information about lifespan and predictions about disease progression will be limited because of the variability that may occur with the disease. These are difficult subjects to convey and understand, and the test's predictive value will vary depending on the disease of interest. The second purpose of the initial counseling session is to help identify support resources including social supports, religious affiliations, and intimate relationships. 18 Exploration of the financial issues, such as job security, financial resources, and insurance coverage (life, long-term disability, and health) should occur, as the individual may choose to make some changes to improve security before testing. The goal is for a more complete understanding of the possible impact of the disease and test results on financial, social, and work life, as well as potential future health care needs. 17"19A third purpose of the initial session is to discuss the personal motivations for testing. Often it is a matter of timing, such as planning a family or an impending marriage that spurs on the choice to pursue testing, ts Others pursue testing so their children can know their risk status. A smaller number test in response to the diagnosis of a family member. If a formal evaluation by a neurologist has not been completed, it should be performed after the first counseling session to assess whether the patient is symptomatic for the disease. Patients are asked if they would like to know if they are presently showing clinical signs of which they are unaware. If a patient does not wish the results of the neurologic evaluation to be disclosed, the patient can still proceed with predictive testingJ 7 Additional evaluation by a psychiatrist is necessary to assure that the patient does not have a psychiatric illness that could interfere with giving informed consent, or there is indication that the patient is at risk for adverse adjustment to the test resultsJ 8 In this psychiatric evaluation, support systems are identified, and employment, relation-

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ship status, drug use, and psychiatric history are all explored in more detail. 17 Additionally, assessments of general affect, distress, and current levels of clinical depression should be measured. 2~ Approximately 10% of individuals who have received an increased or decreased risk result have had serious psychiatric consequences. 4'5 Before collecting the blood sample for testing and several weeks after the initial counseling and medical assessments, a second counseling session is arranged to identify whether further counseling is necessary and to answer any remaining questions about predictive testing. The patient is offered the opportunity to withdraw from the protocol. From early studies, approximately 25% of patients who initially enter a program, decide not to receive results. 3'22 This number may not be as high now because the availability of predictive testing has become more publicized, and individuals are often well-informed about potential implications before they enter the program. A plan for the result session should be made, including the time, date, who will attend, and the manner in which the results are given. Counseling at this point can focus on exploring the personal feelings about each of the possible test results. 17 Results are given as soon as they are available, usually approximately 1 to 2 weeks later in a clear, direct, unambiguous, and nonjudgemental way. Even when an at-risk individual has prepared extensively, a positive result will likely be received with shock in most persons involved. Sometimes, even a negative result is received with disbelief. Therefore, ensure that adequate time is set aside for the patient and support person to begin to absorb the results before proceeding with more information. 17 A follow-up session should be scheduled for 2 weeks after results are given. This provides the opportunity to assess how patients are adjusting to their new "genetic status." Phone contact for genenegative individuals and personal contact for genepositive individuals should occur at 6 months and 1 year. Individuals who are having a more complicated adjustment process may benefit from additional counseling either through or outside the program. Through questionnaires, patients have indicated that it is important to have a 24-hour contact phone number throughout the entire protocol including post-test follow-up, although it is r a r e l y used. 16"18

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Several studies have been completed throughout the world on the number of at-risk individuals who take advantage of presymptomatic testing results when contacted by their local genetics center. The results are low, varying from 5% to 2 0 % . 23 Reasons given for proceeding with testing included the need for certainty or relief from uncertainty, making reproductive decisions, informing their children about their risk, and making decisions on practical matters such as finances, employment, and insurance. Reasons people choose not to be tested include the anticipated inability to cope with a positive test result, comfort in the uncertainty and the possibility of being disease-flee, the lack of treatment, concern of their partner and children, concern about insurance or job discrimination, and finally, the rigors of the protocol itself. 23 Some at-risk individuals who do not want to participate in a protocol because of the significant time and financial investment choose to seek alternative ways to be tested. To our knowledge, no data are available regarding these outcomes, but implications associated with testing outside a formal program need to be investigated in the near future. Anecdotally, genetic counselors have had distressing phone calls from individuals who received a positive result and have urgent questions about interpretation or implications. Presently, the standard of care for predictive testing recommends using an experienced testing site which typically has a psychologist or psychiatrist on the team. Some testing centers are able to facilitate supervision of cases with the local neurologist and psychologist to reduce the burden of travel for those living far from a test center. Failure to facilitate this standard of care could lead to charges of malpractice for the physician ordering the testing, if the patient suffers a n injury. 24 INFORMED CONSENT

Undoubtedly influenced significantly by the horrors witnessed in the eugenics era, genetics professionals maintain that genetic counseling should occur in a nondirective fashion. Genetic counseling, by definition, involves successful communication between patient and provider. It should help the individual to (1) comprehend the medical facts surrounding diagnosis, etiology, and management, (2) understand potential hereditary implications for them and other family members, (3) understand reproductive options, (4) choose a course of action

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that is appropriate in view of their risk, their goals, and their cultural values, and (5) make the best adjustment to the circumstances. 25 Thus, inherent in any testing protocol is the need for sufficient and documented informed consent regarding the proposed test. The concept of informed consent was established to protect the provider as well as the patient, and to insure that sufficient time is given to the transfer of information regarding the proposed procedure. Ineffective communication may lead to misconceptions and will reduce the power of the genetic test. Additionally, patients may underestimate or overestimate their risks of occurrence and recurrence, which might affect their decision of whether to test. Poor communication is cited as the primary cause of malpractice suits in both the United States and Canada. 26 It is critical that the patients fully understand the content of the consent form on their own terms and in their own language. This may often entail reviewing the information several times or providing several forms of the information. 26 Factors such as timing of the disclosure, language and cultural differences, and a patient's psychological state of mind are important considerations that should be recognized, and often make prepared consent forms ineffective.26 In the case of presymptomatic testing protocols, it is essential that sufficient time is set aside to explore the issues raised in this article. For many clinicians, the significant amount of time involved is the major factor precluding them from offering presymptomatic testing because the protocols are extremely involved. Medical geneticists and genetic counselors in particular, through their professional accreditation and attunement to ethical standards can play an important role in the communication process. The American Board of Medical Genetics, Inc., criteria for clinical geneticists, PhD medical geneticists, and genetic counselors, requires skills to (1) "elicit necessary information from the patient or family to reach an appropriate conclusion" and (2) "transmit pertinent information effectively, that is, in a way that is meaningful to the individual or family. ''27 In this way, individuals explore the option of testing, the protocol involved, the impact of the results on both health and social structures, and reproductive options. Once all of these areas have been explored, the patient and their family decide what course of action is appropriate in their situation.

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CONFIRMATORY SYMPTOMATIC GENETIC TESTING

The impact of receiving a confirmatory diagnosis through genetic testing can be immeasurable. For the early symptomatic patient, a diagnosis using a DNA test of greater than 99% accuracy removes protective feelings of hope and uncertainty that a working clinical diagnosis still might allow. Often, genetic testing to confirm a suspected diagnosis will elicit complicated reactions from not only patients but also their families, as the result impacts other family members' health and reproductive decision-making. Thus, the provider must take care to recognize that although a DNA test can confirm a diagnosis, a genetic diagnosis also carries great impact for most patients and should be approached with sensitivity. Genetic counseling is valuable in confirmatory testing too. It is important to stress to symptomatic individuals that although a DNA test can confirm the absence or presence of a gene mutation, it cannot give predictions about disease severity and lifespan. Technical challenges can make test interpretation difficult or results may be indeterminate. Before testing, the limitations of the individual test need to be addressed with the patient so that they better understand the results that they are given. The counselor can also assist the patient and family in adjusting to the new diagnosis and its implications. REPRODUCTIVE OPTIONS

Several studies of the at-risk HD population28"29 have found that a major factor in an individual's decision to pursue predictive testing is to assist in reproductive decision-making. In light of this, reproductive options need to be discussed as part of predictive test counseling, particularly because not all of these options require knowing the status of the at-risk parent. An at-risk individual and his or her partner who are contemplating a family might consider a number of questions, including (l) the anticipated impact of children on the couple themselves, (2) the impact on the unaffected spouse of caring for not only the affected spouse, but also the children, (3) the effect the disease progression in a parent may have on an at-risk child, and (4) how alternative options for reproduction (egg or sperm donation or adoption) affect their ideals of parenting. After contemplating these issues, some at-risk couples

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choose not to have children. For those who do decide to have children there are several options, all of which have limitations that should be addressed. For example, although adoption might seem like a reasonable option, many care providers have never considered that it may be difficult for someone at-risk for HD to adopt a child, simply because of their risk. In addition, the adoption process is time consuming and costly, whether adopting a child from the United States or from another country. For those individuals for whom a genetically related child is not as important as the experience of pregnancy and delivery, there are two options. An at-risk male could choose a sperm donor and use intrauterine insemination to achieve pregnancy; catalogues of sperm donors enable a couple to select a donor with similar physical features. An at-risk female could choose an egg donor. However, egg donors are more difficult to secure because harvesting eggs requires medical surveillance, discomfort, and risk. Egg donation also requires in vitro fertilization with reduced success rates and often prohibitive cost. Some couples have used gene-negative siblings as gamete donors so that genetic similarity can be achieved without passing on the disease gene. Some couples feel strongly that they want their own, genetically similar child, and for them, gamete donation may not be appealing. Prenatal diagnosis via chorionic villi sampling (10 to 12 weeks' gestation) or amniocentesis (routinely after 15 weeks' gestation but early amnio as early as 13 weeks) can test the pregnancy for the presence or absence of the disease gene with more than 99% accuracy. Both of these procedures have a small risk for complications leading to miscarriage. This testing is only undertaken if the parent has pursued predictive testing and is found to be gene positive or if exclusion testing is desired. If a pregnancy is found to carry the disease gene, then the family must then decide whether to continue the pregnancy. The care provider should assist the couple in carefully examining their feelings about termination of a gene-positive pregnancy before testing. In the event that a pregnancy is tested and found to be gene positive and termination is not pursued, the gene status of the child will be known. This situation brings with it all of the concerns that arise when considering the testing of minors (see be-

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low). However, pregnancy termination cannot be mandated. Because of the 50% risk with each pregnancy, patients who do terminate might be faced with multiple affected pregnancies before achieving an unaffected pregnancy. Thus, achieving a gene-negative result for some takes several years and usually has a tremendously painful emotional toll. Testing is available by chorionic villus sampling at 10 weeks, but with the advent of accurate home pregnancy tests, many couples know at 4 weeks gestation that they are pregnant. This means that they could spend 6 weeks with heightened anxiety and ambivalence before initiating testing, with test results taking an additional 1 to 3 weeks. For those choosing routine amniocentesis, this period of anxiety and ambivalence is extended, and couples would be facing termination at 17 to 18 weeks' gestation. These are painful and uncomfortable issues to consider, and although clinicians might be tempted to avoid them, one does the couple a disservice if the concerns are not pointedly explored. Prenatal exclusion testing is a method of prenatal diagnosis that can leave the at-risk parent's gene status unknown. 3~ In this instance, when the parent is at 50% risk, the pregnancy would be at 25% risk. Exclusion testing would alter the pregnancy risk to less than 1% or approximately 50%, the same as that of the affected parent. Linkage methods attempt to determine whether the fetus has inherited the disease-associated chromosome from the affected grandparent (50% risk) or the unaffected grandparent (less than 1% risk). Errors in risk assignment can occur if a double recombination event occurs, which separates the diseasecausing gene from the polymorphic marker that is being tracked. Usually samples from both members of the couple, the affected grandparent, and the unaffected grandparent are needed to interpret the risk for the prenatal sample, but the study can be done in most cases if the affected parent is deceased and no sample is available. The family studies should be coordinated before the pregnancy to be sure that the markers will be informative. Some families are not informative for any of the polymorphisms, and this method cannot be used. Again, discussion of their motivation for exclusion testing should occur. The idea of terminating a pregnancy that is only at 50% risk is unsettling for many. Pre-implantation genetic diagnosis (PGD) is the

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newest technology available to individuals at risk for passing on a genetic disease. 31 Following in vitro fertilization using the couple's gametes, the resulting embryos are tested after several cell divisions. Only embryos without the disease gene are transferred to the uterus. Prenatal diagnosis is usually then offered to confirm the gene-negative status. This option unfortunately has a low success rate for implantation and pregnancy, along with the high cost involved with in vitro fertilization. In addition, PGD remains investigational and is not widely available in the United States. This method can also be used in cases where the gene status of the parent remains unknown. 32'33 Ethical dilemmas arise as to what to do with the remaining embryos or disease gene-positive embryos. For some, discarding embryos is equivalent to pregnancy termination. Some patients note that the availability of such technology imposes pressure, and their only rational choice is to use it to ensure a child who does not carry the family disease gene. 34 Multiple options exist for family planning, although no one option is ideal. Counseling about reproductive options is most effective when done before a pregnancy occurs. Counseling should attempt to allow couples to make choices individually about each pregnancy: alternative options may be used in subsequent pregnancies. PREDICTIVE TESTING OF CHILDREN Predictive testing of children deserves a cautious approach and in most protocols is discouraged if not prohibited. A child at risk for a severe adultonset genetic disease can be a difficult burden for families. To relieve this emotional burden, parents may seek predictive testing for their at-risk child. Many parents believe that this testing option should be left to their own discretion, as they are able to make other medical decisions for their children, and they may believe that they are acting in the child's best interest. 35 However, in some cases, a discussion of parental motivations for testing the child may reveal a parent who is simply hoping for the relief that would be associated with a negative result, and they are not prepared to cope effectively with a gene-positive result. In evaluating the appropriateness of a predictive test for a child, care-providers must consider the interest of the child as well as the parents and family. Geneticists and ethicists agree that predic-

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tive genetic disease testing should be available if a clear benefit for the child can be demonstrated. If the result would help guide medical management, like in the case of a child at risk for familial adenomatous polyposis, a hereditary form of colon cancer, testing a child should be an option. The potential medical impact of testing at-risk minors includes identification of appropriate prevention, surveillance, and treatment. However, in cases of adult-onset presentation with no current therapy or treatment, there is no clear medical benefit to testing an asymptomatic child. Most geneticists believe that the risk of predictive testing of children outweigh any potential benefits. The result may disturb the relationship between the parent and the child or the child with other siblings. These responses to testing have been described in adults who pursue testing. A child typically has less mature coping skills to assist in working through these complicated emotions than does an adult. A gene-positive result could cause damage to the child's self esteem and could create anxiety for the child who begins to speculate about onset of the disease. Concerns also arise about future insurability and employability of a child who is gene positive. Most importantly, testing children removes the right for a child to decide whether to test when he is mature enough to weigh the implications for himself. Parents and care-providers should not overlook the fact that most at-risk adults have chosen not to be tested. 22 In Juvenile HD, the signs and symptoms of HD can appear at a much younger age. When a child is exhibiting symptoms that could represent onset of a childhood form of the disease, a careful review of family history and neurologic and neuropsychiatric examination should occur to clarify the differential diagnosis. Even in this instance caution should be used because children at risk for HD have been tested because of suspected signs and have been found to have a mutation that is associated with the adult-onset form of the disease. This essentially has resulted in predictive testing of the child, and the cause of the signs and symptoms has not been ultimately clarified. Waiting for a period of time to confirm the progression of the disease is appropriate before further consideration of DNA testing. 36 All of these issues deserve careful dialogue between knowledgeable care-providers and parents and usually the at-risk child. The discussion should elicit the reasons for seeking testing and an honest

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exploration of the risks and benefits of pursuing such testing. Through the counseling process, some parents seeking testing for their children will appreciate the complexities, and their conviction to test may be dissuaded. Others will remain convinced that testing the at-risk child is the right answer for their circumstance. At this time, the consensus among those experienced in this situation is that unless a clear benefit to the child can be demonstrated, predictive testing should n o t o c c u r . 37 DISCRIMINATION AND PRIVACY

There is no question that predictive genetic test results can have a profound impact on the tested individual and his or her family, but it will likely impact our social system as well. There is growing consumer concern that insurance companies and employers could use predictive or susceptibility genetic test information to discriminate against gene-positive individuals. 3s Most types of insurance use medical information to assist in riskclassification, which is used to determine eligibility, terms, and premiums. An employer may seek access to an employee's genetic test results to determine future availability or productivity, or to control the rising cost of health insurance. 39 The threat of discrimination probably differs from country to country, based on the personal protections and individual fights that are in place. 4~ From a societal standpoint, a negative impact on employability, health insurance, and disability insurance has the potential to cause the greatest h a r m . 41 Partly for these reasons, current legislation has first attempted to regulate use of genetic test information among health insurers and employers. However, insurance companies maintain that limiting the use of genetic test information in underwriting is a threat to the current insurance system. 42 Information about future health from a genetic test result will likely impact an individual's decision about the type of insurance to purchase. If the insurer does not have access to the same information, risk classification may be underestimated. Nonetheless, there is outcry from the medical genetics community that legislation protecting against the use of genetic information in the underwriting process is necessary. The basis for this argument is that genetic test information differs from other medical information in that it offers information about an individual's future health and

can also be used to predict the health of close family members. Additionally, genetic test information can be used to stigmatize and victimize an individual, as history has already shown. If consumers view discrimination to be a risk, this threat may prohibit them from pursuing genetic diagnosis, preventing any benefits they may have achieved from the genetic test. Individuals might also choose not to participate in genetic research opportunities, thereby slowing the medical understanding of dise a s e . 43

The National Center for Human Genome Research developed the Ethical, Legal, and Social Issues (ELSI) branch to examine these and other issues and to propose legislation designed to protect individuals from genetic discrimination. 43 It is presumed that individuals may have some protection from employment discrimination under the Americans with Disabilities Act. The Health Insurance Portability and Accountability Act (HIPPA), a 1996 federal law, offers some protection from insurance discrimination for those who have group health insurance. Most states have passed legislation for protection of genetic test information. These laws vary from state to state. It is crucial for providers who discuss genetic testing to be familiar with their individual state laws and to keep abreast of new developments in this area. Recent studies have attempted to examine the actual occurrence of discrimination in the United States, as reported by physicians and genetic counselors, and found the actual occurrence seems to be rare. 44'45 However, these studies did not evaluate whether a discrepancy in premiums occurs. If such discrimination were to occur for an individual, it could be devastating. The manner in which insurers and consumers use genetic test results in their decisions about insurance will inevitably shape the business of insurance. Presently, it is not possible to know what shifts will occur and ultimately, how a genetic test will influence an individual's future insurability or employability. Because of these uncertainties, acknowledging the potential risk for discrimination is appropriate to include in discussion with a patient considering predictive genetic testing as part of the informed consent. 46 To avoid the possibility of discrimination, some at-risk individuals choose to pay out-of-pocket so the insurance claim does not bring their risk status to the insurer's attention. However, this situation does

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impact the accessibility of predictive genetic testing, as only those individuals who can afford the costly pre- and post-test counseling can participate. Because of concerns of privacy in the workplace and risk of insurance discrimination, 22 some individuals request "anonymous testing." Multiple problems with anonymous testing have been identified. 47 If the test result is negative, an individual may ultimately want to disclose the result to the insurer or employer to reduce risk for discrimination. Anonymous testing also poses challenges to the patient-provider relationship, as pre-test and post-test counseling necessitates discussion of family history and psychosocial information. For individuals who experience psychologic difficulty with the testing process, anonymous testing may become a barrier to obtaining necessary care. Furthermore, it remains unclear what benefit there may be in anonymous testing, and no consensus has been reached about whether this approach should be facilitated by care-providers. There are concems about the legality of using a pseudonym on an informed consent form, and professionals who facilitate anonymous testing may be assisting at-risk individuals in deceiving third-party payors. Approaches to anonymous testing have been outlined, 47 although little data are available about its impact. Until further data are available, a position statement regarding anonymous genetic testing would be useful. 48 CONCLUSION

Predictive genetic testing for an adult-onset neurodegenerative disease is simple in execution from

a laboratory standpoint once a family's disease gene is identified. However, from experience it is clear that predictive genetic testing should not be pursued lightly, as the possible ramifications on individual and family life can be complicated. Establishing set testing guidelines, and adhering to them stringently will help avoid some of the potential pitfalls and hazards that may occur when using new technology for diagnosis. Assisting patients to become fully informed and providing the opportunity to make educated and nondirected decisions regarding determining their genetic status will enable providers to ensure that patients adjust to their new genetic status in a positive way. Although clinicians may prefer to refer patients to established testing centers rather than facilitate presymptomatic testing themselves, it is still invaluable for them to be familiar with the testing protocols. Patient education that begins in the primary care setting provides a more effective transition for the patient's testing process. For those providers who choose to facilitate predictive testing protocols themselves, lessons learned from predictive testing for HD should be applied in creating guidelines for other adult-onset diseases as predictive tests becomes available. A thoughtful approach should be encouraged with predictive testing for any chronic debilitating condition for which there is no cure or treatment. The issues outlined in this article should be considered when establishing a protocol to thoroughly and adequately address the issues potentially raised in the complicated scenario of predictive testing for inherited disease.

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