Ethical Dilemmas in Genetic Testing: Examples from the Cuban Program for Predictive Diagnosis of Hereditary Ataxias
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- Mariño, T.C., Armiñán, R.R., Cedeño, H.J. et al. J Genet Counsel (2011) 20: 241. doi:10.1007/s10897-010-9347-4
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Predictive testing protocols are intended to help patients affected with hereditary conditions understand their condition and make informed reproductive choices. However, predictive protocols may expose clinicians and patients to ethical dilemmas that interfere with genetic counseling and the decision making process. This paper describes ethical dilemmas in a series of five cases involving predictive testing for hereditary ataxias in Cuba. The examples herein present evidence of the deeply controversial situations faced by both individuals at risk and professionals in charge of these predictive studies, suggesting a need for expanded guidelines to address such complexities.
KeywordsEthical dilemmasPredictive testing programSpinocerebellar ataxia type 2Hereditary ataxiasCuba
The Republic of Cuba covers an island of 110,860 km2 with a population of 11,308,764 and is comprised of 14 provinces and 169 municipalities. The health system is public and completely financed by the government. Genetic services on the island are population based, and for that reason special centers have been created in response to regional health problems. For example the Center for the Research and Rehabilitation of Hereditary Ataxias (CIRAH) was established in the Holguín province, where spinocerebellar ataxias (SCA2) has a prevalence of 40,18/100,000 inhabitants (Velázquez et al. 2009). This center is part of a National Network of Medical Genetics.
The Network serves the entire country and is responsible for the diagnosis, prognosis, treatment and prevention of genetic disorders and birth defects (Lantigua et al. 2007). It is also responsible for the accuracy and maintenance of national statistical information and includes more than 100 clinical geneticists throughout the country and two or more health professionals with the degree of master in genetic counseling per municipality. The 1 year genetic counseling training program began in 1996 at the National Center of Medical Genetics at La Havana. Most of the genetic counselors were initially specialized in Integral General Medicine and other medical specialties such as Gynecology, Obstetrics, Pediatrics, Psychiatry, Neurology and Ophthalmology, although nurses, special educators and biologists are also trained as genetic counselors (Lantigua et al. 2007).
In our center in the Holguín province, we have ascertained 753 individuals belonging to 200 unrelated families affected with a form of hereditary ataxia, with Spinocerebellar ataxia type 2 (SCA2) the most common, accounting for approximately 7,000 asymptomatic individuals at risk. Mainly characterized by ataxic gait, cerebellar dysarthria, dysmethria, dysdiadochokinesia and an autosomal dominant inheritance pattern, SCA2 is generally considered a late onset disease. In some cases, however, it begins in childhood. This wide spectrum of age at onset is explained by anticipation (Velázquez et al. 2009). Friedreich ataxia, in contrast, is an autosomal recessive condition that usually begins before the age of 25 and is the most frequent hereditary ataxia worldwide (Pandolfo 2009). Both conditions, SCA2 and Friedreich ataxia, produce a significant disability mainly affecting the capability to walk, to talk, and motor coordination.
Protocols for genetic counseling, presymptomatic testing and prenatal diagnosis of hereditary ataxias were established in Holguín in 2001 (Paneque et al. 2007a). First, a multidisciplinary team of the CIRAH assessed the acceptance of presymptomatic testing and prenatal diagnosis by descendants at risk of SCA2 in this region of Cuba (Paneque et al. 2001). The national program for the predictive diagnosis of hereditary ataxias was developed taking into account international guidelines for predictive testing in Huntington disease, Machado-Joseph disease and other hereditary ataxias (European Community Huntington Disease Collaborative Study Group 1993; Sequeiros 1996).
To date more than 900 individuals have participated in this program over a period of 8 years and a great number of requests are still received, suggesting its general acceptance in the at-risk population as well as a favorable impact in the affected families (Paneque et al. 2007b; Paneque et al. 2009). Nevertheless, for an individual, predictive testing may be experienced as a challenging life event. Both the counselee and the counselor are faced with many ethical dilemmas related to complex psychosocial issues that individuals at genetic risk must face during their life (Bondor et al. 2008; Durr and Viville 2007; Parker and Lucassen 2002; Rolim et al. 2006).
In the present paper we describe some of the ethical dilemmas that arose in a series of cases involving predictive testing for hereditary ataxias in Cuba. We explore the genetic counseling process and the decisions made by the individuals during presymptomatic testing and prenatal diagnosis.
A descriptive study was designed to assess ethical dilemmas in the context of the Cuban Program for the Predictive Diagnosis of Hereditary Ataxias. The protocol for the predictive testing program implemented at CIRAH has been published elsewhere (Paneque et al. 2007b). All participants were informed about the predictive testing procedures and protocol, as well as the possibility of using information from clinical records in clinical research, and they gave their separate written consent for both. The study was approved by the Institutional Ethics Committee.
In brief, the predictive protocol included at least two genetic counseling sessions, psychological assessment prior to genetic testing and psychological follow-up assessment at 1 week, 4 weeks, 6 months and 1 year after disclosure of the genetic testing results. Five clinical scenarios were selected from among case histories. Selection criteria for the series of cases presented were based upon different situations interpreted as ethical dilemmas in each case, with implications for the genetic counseling provided and the decisions made by the individuals.
Results and Discussion
Case 1: Presymptomatic Testing for SCA2 in Monozygotic Twins
Initially the patient was accompanied by her husband for genetic counseling, where it was explained that it was not possible to give her a presymptomatic diagnosis without implications for her co-twin. After a lengthly discussion informative written material was provided and they agreed to share this information with the co-twin, who also became interested in presymptomatic testing. One week later, all three returned to the clinic. Haplotype analysis documented that the sisters were monozygotic. Molecular diagnosis of SCA2 gene showed two normal alleles of 22 repeats each for both sisters, meaning they were not carriers of the expanded gene; therefore the risk of SCA2 for them and for the fetuses was near 0%, making it unnecessary to perform the prenatal diagnosis.
In the event that the twins were carriers, the recurrence risk for the fetuses would have been high (50%) and prenatal diagnosis would have been offered to our patient as she had expressed her intention to terminate the pregnancy in the case the twin fetuses were carriers. Taking into account that the fetuses could have been discordant for the SCA2 gene, a selective abortion of the gene positive fetus (fetal reduction) could have been an option for the couple. However, it is not an available technique in Cuba. The couple would have had two options, either aborting both fetuses or continuing to term having one of them diagnosed as an SCA2 presymptomatic carrier.
Prenatal diagnosis is aimed at preventing the burden of genetic conditions (Boyle and Savulescu 2003). The Cuban prenatal program for SCA2 only proceeds with molecular testing when the couple indicate that they will request an abortion if the fetus is a carrier. Otherwise, diagnosing a fetus as a carrier means performing a presymptomatic diagnosis without consent (of the fetus) and undercuts the individual’s (fetus’) future right to decide whether to know or not know his/her gene status. Couples are vastly informed about this before they declare their intention to terminate or maintain an affected pregnancy.
The fact that monozygotic twins share almost 100% of their genetic information in and of itself presents a dilemma. In cases where one of the co-twins refuses to participate in a predictive program monozygosity could be considered as an exclusion criterion, due to the necessity of protecting all individuals as far as possible and respecting an individual’s right to not know. A co-twin’s decision to decline predictive testing would therefore preclude the other’s request. These are especially difficult issues when reproductive decisions and prenatal diagnosis are involved.
More complexity is added if we consider that 5% of twins have incorrect clinically assigned zygosity (Ohm and Derom 2006). Aditionally, counseling twins presents several challenges not only regarding the implications of a test result but also regarding their participation per-se. Certain cases will require a confirmation of zygosity. In terms of psychological support, cases may have unique requirements including possibly the need to counsel families faced with a “double event” wherein both twins are concomitantly identified as gene positive.
The Ethics Committee of the CIRAH was convened to discuss the pertinence of offering prenatal diagnosis in twin cases where the fetuses have unknown zygosity. The committee agreed that under CIRAH guidelines, the woman, if a carrier, would have qualified for prenatal diagnosis because her descendents were at 50% risk. The special circumstances in this case were noted, and the need for more intensive counseling and thorough discussion of the decision-making process were underscored. In our view, the guidelines as written were incomplete and did not adequately cover the ethical complications occasioned by twin pregnancies.
Case 2: Carrier Diagnosis Three Generations in Advance to the Onset of the Disease
Following that explanation, her grandmother (II.2 in Fig. 2) requested to participate in the program. She was diagnosed as a carrier and immediately thereafter her father and aunt (III.1 and III.2 respectively in Fig. 2) also applied for the presymptomatic testing and were both diagnosed as presymptomatic carriers. Now with 50% risk, IV.1 was admitted to the program: her test showed she was also a carrier. The effect of a cascade diagnosis in three generations challenged the family dynamics, the structure and functioning of the family as well as the psychological well-being of each individual diagnosed. Thus, health professionals must be aware of the cumulative impact of presymptomatic testing in such a family.
Late onset of disease in this family explains the unusual number of asymptomatic individuals. Molecular testing increased the young woman’ risk from 12.5% a priori to 100% a posteriori, but did not change the reality that her experience with the disease is several generations removed.
It has been shown that personal experience with the disease, which is related to the duration of contact with the disease and kinship, seems to influence the psychosocial impact of pre-symptomatic testing, as expressed by the levels of anxiety and depression, before and after testing (Paneque et al. 2009). The sudden knowledge of the genetic status by four members of this family, as well as the lesser kinship with the affected parent must be taken into consideration by counselors, and psychological follow-up and appropriate support should be offered for all family members to ensure the best adjustment possible.
In our experience most of the individuals diagnosed as gene carriers report that they had expected to receive a positive test result, being therefore prepared to receive such news. These individuals usually remain calm during the communication session, although sometimes they show the emotional impact by expressing their unhappiness, sadness and/or crying. In this particular case, individuals III.1 and III.2 had a strong emotional reaction immediately after the communication of the test result, they hugged each other laughing and saying they felt happiness for being carriers; they also expressed their intention to celebrate with a party. It is one of many examples where both fraternal siblings request their simultaneous inclusion in the presymptomatic test. Their euphoria may have been sustained by the fact that they shared the same result; it is nevertheless a very uncommon reaction in our patients.
One week after the communication of the results individuals III.1 and III.2 seemed better adjusted and their levels of anxiety and depression had diminished in comparison to the pre-test evaluations, according to Spielberger and Beck scales, commonly used in presymptomatic testing Cuban protocols (Paneque et al. 2007a). This family will be re-evaluated after a 6 month period; family cohesion and functioning are aspects to be assessed, as well as communication of genetic information among family members.
Family issues should be taken into consideration during presymptomatic testing consults and follow-up. Family functioning affects the psychological well-being of participants in predictive testing from the very beginning (Paneque et al. 2009). In our view, family issues matter throughout the whole process of diagnosis, but mainly in the post-test period, while coping strategies are activated and validation and social support are needed. As it has been reported previously, some separations, changes of roles and lack of communication may be experienced by these families (Tibben 2007).
In this family it was possible to determine the carrier status in IV.1 three generations in advance of the onset of the disease. Fortunately this information may now be used to the benefit of all family members, and options such as genetic counseling, clinical and psychological follow-up, and prenatal diagnosis might be offered.
Furthermore, according to the Cuban Guidelines for SCA2 predictive studies it is not possible to perform a molecular test in a presymptomatic individual if the progenitor at risk does not want to know his/her genetic status. Again, the guiding principle is that the right not to know precludes the right to know. This rule may seem unsatisfactory, particularly if family members have irreconcilable differences in their desire for testing. However, bioethical principles such as autonomy, beneficience and non-maleficience justify this limitation on the right to test. The right to privacy and confidentiality of medical information is ethically essential (Harper et al. 2000).
In our experience, a multidisciplinary and a case by case approach has been useful. A genetic counselor and other health professionals involved (psychologist and social worker) recommend a family discussion of the decision in a consultation setting. With sufficient information, counseling and psychological support, as counselees understand the familial implications of their condition, an increased uptake of presymptomatic testing has been noted. Confidentiality and psychological follow-up need to be guaranteed (Coustasse et al. 2009; Gargiulo et al. 2009).
Additionally, the Ethics Committee of CIRAH has discussed expanding inclusion criteria to include individuals with 25% risk when these individuals are also interested in prenatal diagnosis and belong to a family where the mutation is unstable and anticipation may lead to affected children or young adults. When the first individual in the former situation requested the presymptomatic testing, a letter of confidentiality was signed by the individual at risk, his wife, and the members of the predictive testing program, in an attempt to preserve as much as possible the right of his own father to not know the results of such testing. The negative test result did not significantly modify the a priori risk.
Had the test been positive, the option of prenatal diagnosis would have been available for the couple without sharing the results of the test with the rest of the family. Undoubtedly, there will always exist the chance that the letter of confidentiality could be ignored and that unexpected information could reach other members of the family, bringing about unpredictable consequences; that is why the letter of confidentiality will be considered only in very few cases where the benefit is understood as greater than the probable risk if the information were disclosed. Nevertheless, genetic counseling attempts to educate members of the family about the potential risks, and by signing the letter, they become responsible for keeping the information confidential. The multidisciplinary follow-up of the family should allow the members of the program to identify any potential conflict rising in the family and to make relevant interventions accordingly. This case and its possible outcomes, demonstrate how challenging it can be to adequately protect the rights of all parties, particularly in light of complexities such as anticipation and variable age of onset.
Case 3: Prenatal Testing and the Right not to Know
The husband was interested in knowing the results of prenatal diagnosis in the fetus’ molecular studies but rejected knowing his own status. As the inheritance pattern of SCA2 is well known, when positive, the fetal molecular study implies a carrier diagnosis in the father. During the genetic counseling session the implications of a positive prenatal diagnosis which implies a carrier diagnosis in the at-risk father were explained in detail. The couple left the office aware that the option of prenatal diagnosis was limited by gestational age and they did not return, presumably declining prenatal diagnosis.
Once again, genetic testing may reveal information about the gene status of other family members. Sometimes an individual’s rights to autonomy and privacy may be blurred by the obligation to generate and pass on genetic information to their children (Edge 2008). Some research suggests that having a specific reason to take the test, helps individuals cope better throughout the program (Hallowell et al. 2003). In this case through genetic counseling the couple understood that it was not possible to accept their request for prenatal diagnosis and at the same time respect the father’s right to privacy and confidentiality.
Reproductive technologies such as In Vitro Fertilization with Pre-Implantation Molecular Diagnosis might be a good option for cases such as this, but they are not currently available in Cuba.
Case 4: False Paternity Disclosure Through Molecular Diagnosis of SCA2
Because the family history suggested the possibility of a dominant mode of inheritance; they both were tested for SCA2 with a positive result. The diagnosis was confirmed, genetic counseling was provided, and the inheritance pattern was explained. Subsequently other members of the family requested presymptomatic testing. The hypothesis that II.3 carried a new mutation due to intergenerational instability of a large normal allele and a susceptible haplotype in one of her parents was ruled out through haplotype analysis. The same studies revealed false paternity.
For all other family members not eligible for presymptomatic testing, there was no reason to share the non-paternity information, which could be reasonably anticipated to have emotional consequences. There are potential problems inherent in the intervention of genetic medicine into family relationships (Turney 2005). Disclosure will clearly change the family’s basic premises of membership and identity and the information may affect different parties in unpredictable ways (Li 2008).
Cuban Guidelines for the predictive program of SCA2 (Paneque et al. 2007b) state that false paternity should not be disclosed when it is identified as a collateral result of molecular tests for the disease. Genetic counseling, nevertheless, must be available to all the members of the family, especially those at risk (e.g., siblings and descendants of the first clinically affected individual), and presymptomatic testing must be available for them.
When genetic counselors discover nonpaternity, the most widely used practice is to withhold this information from the assumed father (Brown 2008). The concept of a new mutation could be used as a rational explanation for the sudden and unexpected onset of the disease in the family, although misinformation may undermine trust of medical practitioners if the true circumstances come to light in the future. If genetics professionals withhold information about paternity, people may fear that other genetic information will be withheld (Brown 2008). While the rationale is not to disrupt families with the confirmation of a genetic disorder, the diagnosis may have unnecessary consequences for other family members, for example, erroneous information may influence their future reproductive choices.
There are legitimate questions about who “owns” this information: the affected woman? Her mother? Her putative father? Each of these individuals has a stake in knowing the truth, but disclosure to any or all of these individuals may harm the family as a unit, raising profound questions about the responsibility of the health care provider. The debate on whether to disclose nonpaternity extends beyond the clinical setting, as it is a social as well as a medical dilemma that is difficult to resolve (Li 2008).
Different approaches have been suggested but the solution is not simple (Caenazzo et al. 2008; Draper 2007). Some experts argue that people should receive the information for which they were tested (Wertz and Fletcher 2004). Certainly, this option could avoid revealing potentially harmful information and might prevent complex family dilemmas. Another approach is to adopt a policy of discussing the possibility of misattributed paternity during pre-test counseling, and to make it a standard part of informed consent (Wertz and Fletcher 2004); but even when patients are informed of the risk prior to testing, counselors are still left with the question of what they should do with any unexpected paternity information the test reveals (Lucast 2007).
Additionally, we think that some individuals perceive individuals’ right and family obligations differently. Therefore this is an important issue to be discussed in a multidisciplinary context, raising awareness of possible biases and cultural values that may affect counseling processes and outcomes. What are the genetic counselors’s moral responsibilites in cases of non-paternity in the context of a predictive testing program? Certainly, this is a topic that deserves more discussion among providers.
Case 5: Carrier Status Diagnosis in the Partner of a Freidreich’s Ataxia Obligate Carrier
For the Cuban population, the carrier frequency for the Friedreich ataxia gene has been estimated to be 1 in 745 individuals (Cruz et al. 2010b) suggesting an a priori probability of 1/2,980 for her to have an affected child. The couple’s molecular test, meant to rule out carrier status, would determine whether it was necessary to consider prenatal diagnosis as a reproductive option. The genetic counselor explained this information to the woman who decided to inform her husband, and he agreed to take the molecular test. It was determined that he was not a carrier and therefore their child was at a 50% risk to inherit the maternal expanded allele, but the risk of developing the disease is near 0%.
Carrier diagnosis must be available for at risk relatives, as well as spouses/partners of known carriers and affected individuals, allowing accurate assessment of risk and family planning counseling (Lynch and Farmer 2002). The significance of carrier status is personal, and in this case the perceived impact was affected by the woman’s fear of stigma and the potential implications of communicating this information to her husband. Holding her genetic status confidential would have impeded appropriate genetic counseling. Had she not informed her husband, and without knowledge of his carrier status, the request for prenatal diagnosis would have been rejected according to the Cuban Guidelines requiring an identified mutation in both parental genes in autosomal recessive conditions. This is another standard that is subject to discussion, particularly in those cases of unknown or unaccepted paternity, where the paternal sample would not be available.
Ethical guidelines and existing protocols anticipate many dilemmas that may arise during predictive testing. But, as demonstrated in the present cases involving presymptomatic testing for hereditary ataxias, every patient and family is unique, making predictive genetics far more complex for the individuals at risk and the professionals involved. Expanded guidelines are needed, specifically for late onset neurodegenerative disorders, where genetic testing has shown great advances and, increasingly, molecular diagnosis is becoming available. Ethical challenges demand a multidisciplinary approach, where genetic counselors, psychologists, social workers, medical doctors, bioethicists, and other health professionals consider the psychological, socio-familial and medical issues surrounding predictive testing in an integrated manner.
The authors are deeply indebted to patients affected by SCA2 and Friedreich ataxia that participated in the current research, and to the Cuban Health Care Ministry. We are thankful to José Luis Guisao Martínez for his language corrections and to Dr. Patrick MacLeod for his critical review of the article.