“It had to be done”: Genetic testing decisions for Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC)
Holly Etchegary, PhD, Clinical Epidemiology, Eastern Health and Memorial University, St. John’s, NL, Canada Daryl Pullman, PhD, Community Health and Humanities, Memorial University, St. John’s, NL, Canada Charlene Simmonds, PhD, Health Research Unit, Community Health and Humanities, Memorial University, St. John’s, NL, Canada Terry-Lynn Young, PhD, Discipline of Genetics, Memorial University, St. John’s, NL, Canada Kathy Hodgkinson, PhD, Clinical Epidemiology and Discipline of Genetics, Memorial University, St. John’s, NL, Canada
Corresponding Author: Holly Etchegary Clinical Epidemiology, Faculty of Medicine, Memorial University Room H1407, Level 1, Health Sciences Centre 300 Prince Phillip Drive, St. John's, NL, A1B 3V6 Phone: 709-777-8893 Fax: 709-777-6995 Email: [email protected]
Conflict of interest statement: The authors declare no conflicts of interest.
Acknowledgements: We are grateful to participants for their time and interest. This research was financially supported by the Atlantic Canada Opportunities Agency (Atlantic Innovation Fund) and Genome Canada (Atlantic Medical Genetics and Genomics Initiative). This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/cge.12513
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Abstract Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is a heritable disease of the heart muscle, causing life-threatening ventricular arrhythmias, sudden cardiac death (SCD) and/or biventricular heart failure. Little research examines ARVC genetic-test decisions despite the gravity of the condition. This qualitative study used semi-structured interviews to explore the testing decisions of 21 individuals across 15 families segregating a well-studied, particularly lethal form of ARVC caused by a p.S358L TMEM43 mutation. Genetic testing decisions were rarely described as ‘decisions’ per se, but rather ‘something that had to be done.’ This perception was attributed to personality type or personal suspicion of carrying the TMEM43 mutation, but most often was described in the context of testing for other family members, usually children. Participants related a strong need to rule out risk, more for children than for themselves, but lingering doubts remained about personal and children’s risk for ARVC, even when gene test results were negative. Study findings highlight the interdependent nature of genetic-test decisions and suggest an individualistic conception of autonomy in genetic services may not meet the needs of affected families. Findings also suggest the need for follow-up support of families affected by ARVC, including for those individuals testing negative for the family mutation.
Keywords: ARVC, genetic testing, psychosocial, sudden cardiac death, SCD, TMEM43
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Introduction Genetic testing for Mendelian diseases associated with sudden cardiac death (SCD) could improve the medical management of patients (1,2). Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is a single-gene disorder of the heart muscle, marked by fibro-fatty replacement of the myocardium. It is a progressive disease, culminating in life-threatening ventricular arrhythmias which prompt SCD and/or biventricular heart failure (2-5). Research suggests that ARVC is responsible for up to 20% of SCD cases, particularly among young athletes who die suddenly (2,3). The prevalence of ARVC is estimated between 1 in 20005000, (2) although some authors suggest the real prevalence could be as high as 1 in 1000 as a result of under-recognition (6). The utility of genetic testing in the clinical evaluation of ARVC is equivocal as only about half of individuals meeting diagnostic criteria will have a disease-causing mutation identified (2,4). However, in the province of Newfoundland and Labrador (NL), Canada, the majority of ARVC cases and familial SCD due to lethal ventricular arrhythmias (7) are caused by a fully penetrant, ancestral (founder) mutation in TMEM43 (p.S358L) (8). This genetic subtype of ARVC is lethal, particularly in males, with a median age to death of 41 years compared to 71 years in females (7) and is inherited in an autosomal dominant manner, meaning that all offspring of the genetically affected parent are at 50% risk of inheriting the TMEM43 mutation. In NL, our current estimates suggest the ARVC incidence is between 1/500 and 1/1000. From a public health perspective, it is important to identify carriers of TMEM43 (S358L) who may be at high risk of SCD. Cascade genetic testing can identify blood relatives who also carry the pathogenic mutation before clinical signs or symptoms of ARVC develop. Guidelines support the importance of cascade screening in ARVC families (9,10). In this way, relatives can be routinely screened and a life-saving implantable cardioverterdefibrillator (ICD) for treatment of arrhythmias and prevention of SCD may be indicated
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(2,3,11). This can be a critical decision: at risk relatives are often young patients with few or no symptoms. They will likely have a long course with their ICD, exposing them to repeated medical procedures, shocks, ICD complications and life-long psychosocial burdens (3,12). From a genetic counseling perspective, therefore, it is important to identify and inform at risk relatives about the value of genetic testing so they can make informed decisions about cardiogenetic evaluation and treatment for themselves and their children. To our knowledge, there are no studies in the literature specifically focusing on the experience of living at risk for ARVC, and only one recent study exploring genetic-test decisions in this context (13). That study reported two approaches to decision-making: 1), an ongoing process that happened over time; or 2), a decision made so quickly that it was perceived as a "fait accompli”. Factors that affected test decisions included experiential knowledge of loss in the family, family support, gender, being symptomatic, a sense of moral duty to be tested, as well as the availability of predictive genetic testing (13). Research with individuals at risk for Hypertrophic Cardiomyopathy (HCM) and Long QT syndrome revealed that genetic testing decisions were often motivated by a ‘need to know,’ in particular a need to rule out risk for self and children (14,15). Decisions about when to test children are complex and are made in the context of children’s personalities and interests (14). Relatives of young sudden cardiac death victims in the Netherlands revealed a wide variety of reasons for undergoing cardiogenetic evaluation after the death of a loved one (16). Due to the unexpected and shocking death of a young person, relatives had a strong desire to understand the cause of their relative’s death. Others described their decision as ‘no choice’ but to be evaluated; still others expressed feelings of guilt at the possibility of having passed on a lethal mutation to children and grandchildren. A small sample of Dutch families affected with HCM suggested that fears of genetic discrimination for themselves or their children affected genetic testing decisions (17). While information on other cardiac This article is protected by copyright. All rights reserved
conditions may be relevant, it likely underestimates the true psychosocial impact of ARVC due to diagnostic challenges and continuing uncertainty and issues surrounding ICD decisions in the disorder (5). We have identified 24 families with ARVC due to TMEM43 p.S358L in the NL population, providing a unique opportunity to explore the perspectives of individuals who undergo genetic testing in order to inform the provision of health services and promote informed decision-making. Materials and methods Sampling and recruitment Semi-structured interviews were used to systematically explore the genetic testing decisions of individuals affected by ARVC and their spouses where possible. Participants were recruited from the Cardiac Genetics clinic (established in 2004) and managed by the Eastern Health Regional Health Authority in St. John’s, NL. Clinic participants receive genetic counseling, genetic and clinical testing, and follow-up clinical management. Evaluation of at risk relatives in a stepwise manner (cascade testing) is recommended after a pathogenic mutation is identified in the family (9,10). Carriers are offered lifelong cardiac screening, lifestyle advice (e.g., avoidance of extreme sports), pharmacological treatment, as well as an ICD, which significantly improves survival in this population (7,9,18). The project was approved by the local Health Research Ethics Authority (HREA reference # 12.053). Purposive sampling identified potential participants in the clinic database to represent a broad spectrum of disease experience. Study invite letters were sent to males and females in several disease categories: at risk but currently asymptomatic, carriers and non-carriers of TMEM43, with and without an ICD, declined genetic testing, and those who had had heart transplants after ICD therapy. Spouses of any of these individuals were also invited to an interview as it was thought their views would be unique and informative of the disorder’s impact on the broader family. We also invited adolescents (age 14-18) in these families to
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take part. Eligible participants were identified by a team member (KH) with extensive contact and knowledge of the families. Care was taken to objectively identify potential participants who represented a broad range of experience with ARVC. Study invitation letters were sent to 73 individuals, and participants were invited to contact the research team if they were interested in completing an interview. The interviews Interviews were conducted in person by CS between August 2012 and December 2013 at a place most convenient for participants, usually their home or the researcher’s office. A minority (n=3) were conducted by telephone for those participants who had moved out of the province. Interviews lasted for 45-60 minutes and with permission, were tape-recorded and transcribed verbatim. Questions were not strictly confined to a specific order, and participants were actively encouraged to discuss any other issues they felt were important. However, a detailed question guide facilitated the tracking of all questions asked during each interview. Despite some different wording that emerged naturally during interviews, each interview encompassed the same content. Interviews covered a core set of topics such as family experiences and occurrences of heart disease and SCD, genetic testing decisions, ICD surgery decisions, as well as the perceived impact of ARVC on individual and family life. Questions were generated by one team member in line with study aims (e.g., can you tell me how you made the decision to have genetic testing for ARVC?; how would you say ARVC has impacted your life? Your family’s life?). Discussion with the team and based on the team’s clinical experience with families, as well as review by an additional genetic counselor, resulted in only minor changes. In this paper, we report specifically on genetic testing decisions. Data analysis
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Qualitative description (19) was used to explore and summarize the data pertaining to genetic testing decisions. This is a form of naturalistic inquiry that makes no a priori theoretical or philosophical assumptions about the data. Rather, it seeks to present the data in the language of participants, without aiming to present the data in more theoretical ways. The end result is a comprehensive summary of the event in question (19). Transcripts were read and re-read several times by one investigator (HE). Interview data were then isolated and organized around interview topics (e.g., family history of ARVC, genetic testing decisions, ICD surgery decisions, etc.). Only data pertaining to genetic testing for ARVC were utilized to identify and index emerging categories and themes, which were annotated on the transcripts. No qualitative software was used in the analysis. Inductive subcoding of the data relevant to these genetic testing decisions was completed using the method of constant comparison (20,21). Here, data were compared between and within transcripts to establish analytical categories and themes (19-21). This method required a constant shifting back and forth between (and within) transcripts to continuously compare the perceptions and experiences of participants. Discussion with the interviewer throughout the analysis verified emerging categories and themes until no new themes could be added and data saturation was deemed complete. Results Participants Of the 73 study invite letters sent, 12 people contacted the research team and completed an interview (five were returned as undeliverable). An additional nine participants heard of the study and contacted the research team to participate, yielding a total of 21 individuals (five male) who completed an interview and representing 15/24 ARVD5 families. Non-responders included those who had had heart transplants and those who declined genetic testing. Non-responders were also more likely to be male, while there were no significant This article is protected by copyright. All rights reserved
differences in mean age, education level, or disease severity (defined by having an ICD or not) between responders and non-responders. Only one family had been recently identified as carrying the TMEM43 mutation and did not participate in the current study. All other families had been followed clinically for many years and were known to the research team. Table 1 contains clinical and demographic information for the 21 study participants. Of the seventeen participants who had genetic testing, nine were mutation carriers (two adolescents; 14-18yrs). Of these nine participants, eight had an implantable cardioverter defibrillator (ICD), while the youngest participant did not. Prior to 2008, genetic disease status was given to participants based on haplotype analysis and confirmed when mutation testing became available subsequent to 2008 (8). All participants had a history of sudden cardiac death in their families, and this was often the initial reason for participant evaluation by the clinical team. Four spouses completed interviews; all were wives whose husbands were found to be carriers (two of these husbands completed interviews). Participant ages ranged from 16-64, with a mean age of 44 years (SD=14). Excepting the adolescents, nearly all participants were married with children. Thematic analysis Participant narratives revealed that genetic testing decisions were rarely described as ‘decisions’ per se, but rather, ‘something that had to be done.’ This perception was attributed to personality type or personal suspicion of carrying the mutation, but most often was described in the context of testing for other family members, usually children. Participants related a strong need to rule out risk, more for children than for themselves, but lingering doubts remained about personal and children’s risk for ARVC, even when gene test results were negative. The following themes summarize participants’ description of their genetic testing decisions: 1) No decision to be made; 2) Ruling out risk - genetic testing for others; 3) Lingering doubts about risk. This article is protected by copyright. All rights reserved
No decision to be made Overwhelmingly, participants revealed they did not have to think about the decision to pursue genetic testing for ARVC. The reasoning behind this description was sometimes vague. For some, it seemed linked to a personality type, usually described as ‘someone who had to know.’ For others, it was linked to a suspicion of having inherited the family history of heart disease, though not necessarily an inherited condition such as ARVC. There wasn’t a question, I don’t think a second’s hesitation to having it done…I’m the type that would want to know. –P14, unaffected female We never talked much about it because it was something we had to do. There was no choice, no decision to make. It was just something you had to do and that was it. And whatever the outcome, you had to deal with it. –P20, spouse of affected male I didn’t doubt for a minute that I had the gene, because for a year, probably when I was 21, I started having this irregular heartbeat...so when they said this heart disease was in my family, I wasn’t surprised, not in the least…so to get tested, I already knew I had it. –P3, affected female The two adolescents in the sample also revealed no decision to be made, being described instead as a choice made by their parents. One son explained: I never made no decision to get it done. Mom was like, ‘we’re going to go get your mouth swabbed.’ I said, ‘ok.’ I’m in Grade 8, I don’t even know what’s going on, what’s good for me. I had no say in that, and I’m perfectly fine with it. –P12, affected adolescent male Only one participant explicitly mentioned the nature of ARVC itself as being a part of her test decision: I’m one of the people who needed to know. I knew I had something anyway and putting a name on it wasn’t going to make any difference…when you have a disease like this, you need to know because it can be so fatal, so unpredictable, and so quick. It would lack sense in my opinion not to know. –P5, affected female Ruling out risk – genetic testing for others For the vast majority of participants, their recounting of testing decisions was clearly linked to their families, notably their children. Participants displayed a sense of genetic
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responsibility, noting their duty to be tested in order to rule out risk for other family members. Several noted they likely would not have pursued testing otherwise.
With regards to myself, I didn’t care whether or not I had the gene... My concern was for my children, just to make sure they were healthy and they weren’t going to have to deal with something further down the road. –P9, unaffected female I got tested to stop people from hounding me…if I had my time back, I don’t know if I would have gotten tested. Because we ended up getting the kids tested and really, especially [son], screwed with his plans. Whereas, if he wasn’t tested, he could have went ahead and did what he wanted, and it probably would have been easier on him. – P15, affected male For the longest time, I didn’t want to know if I had it or not, but that didn’t stop me, because of my kids you know? If I didn’t have children, I don’t know if I would of… but they had to decide whether or not they were going to have kids, so it was for them really. –P16, unaffected female Spouses of participants at risk also described a sense of ‘having to know’ their husband’s risk, even while recognizing that he may have made a different decision or they themselves might have made a different decision if they were the one at risk of ARVC. One wife explained: If it were for myself, I don’t really want to know. Let God do what he’s going to do. But when it comes to him being my spouse and having to look after the family and financial obligations and all this other stuff, I don’t want to lose him. So I’m glad he’s had the testing. –P19, spouse of affected male I kind of nagged him into going and getting tested. So he went basically for me, to shut me up. …we discussed it together, he never thought anything of it, but I said to him, ‘you should be tested, your heart sounds funny,’ and I always said that, even when we were dating…so he finally gave in and called about the testing to get me off his back. ..but I mean, it was the kind of thing where - we’ll get tested, you’ll be negative, we don’t have to worry again. That’s the way we looked at it, we’ll move on, never dreamed that it would come up positive. …it’s a learning process for both of us I guess, and it’s scary. We never dreamed he’d have it, and now he’s got it and we’re dealing with the fallout. –P18, spouse of affected male Related to the idea of genetic responsibility are participants’ views on whether other family members should also pursue testing. For some, there is a sense that testing is a positive thing and should be pursued, apparently without consideration of others’ right not to know. For example, one participant noted:
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And what really bothers me is that I have relatives and I find myself saying to them, ‘have you had your testing done?’ And they’re, ‘no I don’t want to know.’ And I think, ‘you have two teenage boys. What is your problem?’ –P16, unaffected female I think living in the dark is no way. I’m the oldest in the family, I had to find out. I was coming up on it before anyone else… so I think that when you’re the oldest child, naturally you feel, I’ve got to get this done because I got to drag everyone else along. –P8, unaffected male Lingering doubts Genetic testing did not always provide peace of mind. Participants who had tested negative revealed lingering doubts about their own risk or their children’s risk: And it still kind of scares me, but it’s like you know, there’s always that little bit of doubt in the back of your mind that you know, maybe…-P13, unaffected male It affects every part of your life because it’s always there….there’s a funny little thing in the back of your head, there’s an anxiety that you were never used to, so it does creep in everywhere. [Interviewer: even though you were told you were negative?] Yeah. –P8, unaffected male But it still doesn’t keep me from looking at my kids and wondering. I was relieved, but I didn’t feel safe. I’m still doubting. –P2, unaffected female
Discussion To our knowledge, this is one of only two studies to explore how individuals make genetic-test decisions for ARVC. It is an important focus given the emphasis placed on genetic counseling and discussions of testing and cascade screening in the management of families affected by ARVC (2,9,22-23). Understanding how test decisions are made could help evaluate such guidelines and ensure the delivery of testing services in a way that accords with families’ needs. In this paper, we sought to describe test decisions from the perspective of those who had undergone testing for ARVD5. Participant narratives revealed that for many, there was no ‘decision’ to be made. Determining whether one carried (or one’s spouse or child carried) the mutation predisposing an increased risk of sudden cardiac death was described as something that ‘had to be done,’ without sustained reflection, in line with a recent study (13). Sometimes, this was ascribed to a personality type – being someone who
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‘had’ to know, but most often, it was explained as a sense of responsibility to one’s family, particularly one’s children. Indeed, in some instances, it was implied that family members who had decided not to be tested were failing in their responsibilities to their family. There is virtually no literature on genetic test decisions for ARVC. Our findings are in line with the only other study in this area in that test decisions were clearly related to a sense of responsibility to provide information for other family members, particularly children (13). A small number of studies with individuals at risk for other cardiomyopathies provides some additional information on cardiac genetic test decisions. For example, a retrospective chart review at a cardiology clinic in the US found no factors that were related to the uptake of genetic testing for HCM or DCM, and that the uptake of testing was fairly low in at risk relatives. Variables evaluated included the proband’s age at diagnosis, years since diagnosis, number of living affected relatives, and the presence of SCD in the family (24). Manuel and Brunger (13) also report that experiential knowledge of loss and death in ARVC families influenced test uptake. Interviews with a sample of individuals from the UK who had undergone testing for HCM or Long QT syndrome revealed parents’ strong need to know their child’s mutation status, as well as great uncertainty and worry around their children’s futures (14,15).Testing was seen as a way to provide some certainty over their child’s diagnosis, although a minority were ambivalent about how much certainty testing could provide (15). Interviews with relatives of young sudden cardiac death victims in the Netherlands revealed a desire to prevent a second fatal event in their children and grandchildren and that they perceived no choice but to be evaluated (16). Genetic-test decisions across a variety of disorders have been studied most often in the theoretical framework of social cognition models (25). In these (typically) survey studies, respondents complete self-reports of attitudes or knowledge about a given genetic disorder, along with risk perception, susceptibility and severity beliefs about the disorder in question. This article is protected by copyright. All rights reserved
Survey items are combined in an expectancy-value statistical model that predicts intention to have a genetic test (or actually having the test). In these studies, however, there is normally only a weak correlation between actual test uptake and intention, and the amount of variance explained in test decisions by these socio-cognitive variables is typically low (25). Theoretically, the decision-maker in these models is constructed as autonomous and rational, thinking through the risks and benefits of the decision (usually defined as hypothetically or actually accepting a genetic test). D’Agincourt-Canning (26) notes that the current provision of genetic testing is based on a medical model that constructs the at risk person as autonomous and independent, rationally weighing the pros and cons of genetic risk-management options, including test decisions. However, a growing body of research reveals much broader social and familial contexts in which test decisions are made and genetic risk experienced. Thus, in practice, decisions about genetic testing are not always made in a completely autonomous or independent manner. Feelings of responsibility driven by duty to other family members affect (and sometimes constrain) choices to be made in the context of genetic risk (26-32). Our findings are in accordance with this latter view of genetic testing decisions. Most participants did not discuss their test decision as a ‘choice,’ nor did they describe prolonged periods of reflection or weighing the pros and cons of testing for themselves. Rather, they described the test as something they ‘had’ to do, in particular to provide information for their children, and sometimes other family members. Findings suggest that many people affected by ARVC did not construct the self as independent, rationally making choices that affected only themselves. Rather, in their genetic testing decisions, the self was constructed as interdependent (32), and the needs of important others were recognized as an integral part of the self. Thus, findings of the current research and others (13,26, 28-31) suggest that family obligations and perceptions of responsibility (to children in particular) may undermine an individualistic
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conception of autonomy in genetic-test decisions. Such a view comports well with the notion of “relational autonomy” as developed by feminist philosopher Susan Sherwin. The general idea here is that our sense of autonomy is formed broadly through individual, social and political relationships which entails that our responsibilities and obligations extend beyond simple self- interest (33). To that end, Hallowell and colleagues (31) suggested that genetic-test decisions might be viewed as a family decision, rather than an individual choice. They argued that rather than trying to eliminate family influences per se, it will be important to help individuals “acknowledge the extent to which their actions are born out of a sense of responsibility or explicitly influenced by their relatives or indeed, others factors” (p. 215). This may be important in facilitating cascade screening in a family. Counselors may need to go beyond a proband’s own health concerns to confront questions of family responsibility, that may raise ethical dilemmas about the duty of care and duty to warn (15). Indeed, members of our team (DP, KH) have argued elsewhere that with severe conditions like ARVC where an ameliorative intervention is available, a duty to warn others at risk should override a given individual’s decision not to know (34). Study findings do not imply that test decisions motivated by responsibility to other family members are necessarily involuntary or in some way not autonomous. However, we suggest that perceptions of responsibility to other family members do remind us it is important that the personal implications of genetic testing or risk-management decisions be thoroughly explored prior to testing. Left unexplored, it could be that some at risk people will be unprepared for the potential distressing effects of a positive test result (29). This might be particularly important in the context of a genetically and clinically complex illness such as ARVC.
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It is interesting that only one participant mentioned the nature and severity of ARVC itself as a factor in her genetic test decision. From clinical experience, it is clear that affected individuals are aware of the severity of ARVC having witnessed affected parents or heard about other family members’ deaths and/or ICD experiences. In this study, however, these experiences were not explicitly referenced as factors in testing decisions. Such family history information and experiences, however, are important to explore in counseling sessions since they may underlie the perception of the genetic test as something that ‘had to be done.’ Similarly, such experiences may affect whether individuals who receive a negative test result feel reassured. Several participants in the current study noted their lingering doubt about their own and their children’s risk status. Similar findings were reported in a qualitative study with individuals at risk for HCM and Long QT syndrome in the UK (15). These findings suggest that some form of follow up support may be necessary for those who test negative in order to provide ongoing reassurance and mitigate undue anxiety and distress. Smart (15) suggests that for these individuals in particular, “any shift in care patterns (i.e., outside of specialist genetics/cardiology) needs to be handled sensitively.” Conclusions This study is one of the first explorations of the psychosocial aspects of ARVC, beginning with important insights regarding motivations for genetic testing decisions. However, some study limitations are noted. While our findings are similar to Manuel and Brunger’s recent study (13), we caution that they do not represent validation of the results in a different ARVC/D population. Rather, while the individual participants in each study were different, they were drawn from the same families (i.e., the same population of families affected by ARVC in NL). The sample size is relatively small, comprised mostly of females and individuals affected by a specific genetic subtype of ARVC (ARVD5). Additionally, nearly half of participants were part of the same large pedigree, so we cannot completely rule This article is protected by copyright. All rights reserved
out family effects. Further, the study was conducted in a comprehensive ARVC testing and management service; thus, findings may not generalize to patients seen outside such centres or to families affected by other mutations causing ARVC. We also acknowledge potential selection bias in our sample. All participants in our study had undergone testing; thus, they may display specific perceptions and experiences that cannot be generalized to all affected or at risk individuals. For example, we were unable to recruit those who declined testing and those who had progressed to heart transplants in their disease progression. We were also unable to recruit families that had only known about their risk for a short time. Rather, the families in this study had all known about ARVC for a period of years. In addition, adolescents were under-represented in this sample and findings may not generalize to younger individuals affected by ARVC. While only four spouses responded to the study invitation, we include their views as unique and important, but acknowledge they are underrepresented in the sample. Additional research that focuses solely on spouses would be informative. The cross-sectional design of this study does not allow an examination of how perceptions of responsibility might change over time. It is plausible that such perceptions will change with the unfolding of family life (e.g., with the birth of a child, a new marriage, or as the age of onset approaches). Prospective, longitudinal designs would assist in charting changing perceptions of responsibility and their effects on such domains as test decisions and clinical management. It is notable, however, that some of the moral aspects of genetic decision-making revealed in the current study correspond with studies of other risk populations, notably inherited breast and colon cancer and Huntington disease (26-32). Study findings could assist practitioners as they develop appropriate forms of guidance regarding genetic counseling, information provision, and ongoing psychosocial support for families affected by ARVC. Study findings also raise important questions for future research. If, as some participants suggested, they
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underwent genetic testing for ARVC out of perceived responsibility to family, one wonders what effect a positive test result has on their psychological well-being and quality of life. How do these people cope with unwanted genetic knowledge that may impact many facets of their lives such as career choice, insurance eligibility and social life, as well as all the clinical implications that follow? An important question for future research is whether a different kind or amount of psychological support is needed for these individuals. Longitudinal studies that measure genetic responsibility and its effect on subsequent coping and well-being would help address this important clinical question.
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14. Ormondroyd E, Oates S, Parker M, Blair E, Watkins H: Pre-symptomatic genetic testing for inherited cardiac conditions: a qualitative exploration of psychosocial and ethical implications. Eur J Hum Genet 2014: 22: 88-93. 15. Smart A: Impediments to DNA testing and cascade screening for hypertrophic cardiomyopathy and Long QT syndrome: a qualitative study of patient experiences. J Genet Couns 2010: 19:630-639. 16. van der Werf C, Onderwater A, van Langen I, Smets E: Experiences, considerations and emotions relating to cardiogenetic evaluation in relatives of young sudden cardiac death victims. Eur J Hum Genet 2014: 22: 192-196. 17. Geelen E, Horstman K, Marcelis C, Doevendans P, Van Hoyweghen I: Unravelling fears of genetic discrimination: an exploratory study of Dutch HCM families in an era of genetic non-discrimination acts. Eur J Hum Genet 2012: 20: 1018-1023. 18. Hodgkinson K, Dicks E, Connors S, Young T, Parfrey P, Pullman D: Translation of research discoveries to clinical care in Arrhythmogenic Right Ventricular Cardiomyopathy in Newfoundland and Labrador: lessons for health policy in genetic disease. Genet Med 2009: 11: 85-865. 19. Sandelowski M: Whatever happened to qualitative description? Res Nurs Health 2000: 23: 334-340. 20. Pope C, Ziebland S, Mays N. Analysing qualitative data. BMJ 2000: 320(7227):114116. 21. Glaser B, Strauss A. The Discovery of Grounded Theory. Chicago: Aldine, 1967. 22. Charron P, Arad M, Arbustini E, et al: Genetic counseling and testing in cardiomyopathies: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J 2010: 31: 27152726.
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23. Sturm A: Genetic testing in the contemporary diagnosis of cardiomyopathy. Curr Heart Fail Rep 2013: 10: 63-72. 24. Miller E, Wang Y, Ware S: Uptake of cardiac screening and genetic testing among Hypertropic and Dilated Cardiomyopathy families. J Genet Couns 2013: 22: 258-267. 25. Etchegary H: Psychological aspects of predictive genetic-test decisions: What do we know so far? Analyses Soc Issues Pub Pol 2004: 4: 13-31. 26. d’Agincourt-Canning, L: Genetic testing for hereditary breast and ovarian cancer: Responsibility and choice. Qual Health Res 2006: 16: 97-118. 27. Downing C: Negotiating responsibility: Case studies of reproductive decision-making and prenatal genetic testing in families facing Huntington disease. J Genet Couns 2005: 14: 219-234. 28. Etchegary H: Genetic testing for Huntington disease - How is the decision taken? Genet Test Mol Bio 2006: 10: 60-67. 29. Foster C, Watson M, Moyhnihan C, Ardern-Jones A, Eeles R: Genetic testing for breast and ovarian cancer predisposition: Cancer burden and responsibility. J Health Psychol 2002: 7: 469-484. 30. Hallowell N, Foster C, Eeles R, Ardern-Jones A, Murday V, Watson M: Balancing autonomy and responsibility: The ethics of generating and disclosing genetic information. J Med Ethics 2003: 29: 74-83. 31. Hallowell N, Ardern-Jones A, Eeles R, Foster C, Lucassen A, Moynihan C, Watson M: Men’s decision-making about predictive BRCA1/2 testing: The role of family. J Genet Couns 2005: 3: 207-217 32. Kenea R: The Human Genome Project: Creator of the potentially sick, potentially vulnerable and potentially stigmatized? In I. Robinson, ed. Life and death under high technology medicine. London: Manchester University Press, 2004: 49-64.
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33. Sherwin S: A relational approach to autonomy in health care. In E. Boetzkes, W. Waluchow, eds. Readings in Health Care Ethics 2nd Edition. Peterborough: Broadview Press, 2012: 14-32. 34. Pullman D, Hodgkinson K: Genetic Knowledge and Moral Responsibility: Ambiguity at the Interface of Genetic Research and Clinical Practice. Clin Genet 2006: 69: 199203.
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Sex
ID
Family ID*
Age
How did they present?
Method of diagnosis
Family history of sudden cardiac death? o 3 : SCD 39 years, o 1 : HT 55 years o 2 :SCD 29 years o 1 :SCD 32 years o 1 SCD 34 yrs. Son trans 34 yrs. o 3 :SCD 19 yrs. o 3 SCD 39 yrs o 1 SCD 19 yrs 1o SCD
F
P1
AR2
40
Clinical Screen
Genetic testing
F
P2
AR1
67
F
P3
AR1
55
F
P4
AR10
62
Clinical screen Clinical screen Clinical Screen
Genetic testing Genetic testing Genetic testing
F
P5
AR8
59
F
P6
AR2
46
Clinical Screen Pedigree
F
P7
AR8
63
M
P8
AR6
47
Clinical Screen Pedigree
F
P9
AR2
46
Pedigree
F
P10
AR12
26
F
P11
AR2
16
Clinical Screen Pedigree
Genetic testing Genetic testing Genetic testing Genetic testing Genetic testing Genetic testing Genetic testing
M
P12
AR2
19
Pedigree
Genetic testing
M
P13
AR2
44
F
P14
AR1
64
M
P15
AR2
47
Clinical Screen Clinical screen Pedigree
F
P16
AR2
60
Clinical Screen
Genetic testing Genetic testing Genetic testing Genetic testing
M
P17
AR15
37
Clinical Screen
Genetic testing
1 SCD 26yrs o 3 SCD 38 yrs o 1 SCD 30 yrs, 2o SCD 38 yrs o 1 SCD 25 yrs
F Spouse (Husband P15)
P18
AR2
47
N/A
N/A
N/A
3o SCD 39 yrs o 2 SCD 30 yrs o 1 ICD with several firings o 2 HT o 5 SCD 38 yrs o 1 ICD with several firings 2o HT 5o SCD 38 yrs 3o SCD o
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Any clinical signs of disease at presentation?
TMEM43 p.S358L Mutation status
Disease status by genetic testing**
ICD (Year)
No
Negative
2004
No
No
Negative
2004
No
Yes
Positive
2000
Yes
Positive
2003
Yes 2002 Yes 2003
Yes
Positive
2002
No
Positive
2010
Yes
Positive
2007
No
Negative
2009
Yes 2002 Yes 2009 Yes 2002 No
No
Negative
2009
No
No
Negative
2011
No
No
Positive
2013
No
No
Positive
2013
Yes 2013
No
Negative
2005
No
No
Negative
2002
No
Yes
Positive
2012
No
Negative
2000
Yes 2008 No
Yes
Positive
2006
Yes 2007
N/A
N/A
N/A
N/A
F Spouse (Husband P17) F Spouse (husband did not do interview)
P19
AR15
38
N/A
N/A
N/A
N/A
N/A
N/A
N/A
P20
AR11
42
N/A
N/A
N/A
N/A
N/A
N/A
N/A
F Spouse (husband did not do interview)
P21
AR15
37
N/A
N/A
N/A
N/A
N/A
N/A
N/A
Table 1. Clinical and demographic characteristics of study participants Table 1 Notes: * The family numbers are listed above, the pedigrees for which can be seen in Merner 2008 (Ref 8). **Genetic Testing: Anything provided to individuals pre-2008 was by haplotype/linkage analysis. Post-2008, the analysis was by mutation. All those pre-2008 have had their linkage result confirmed by mutation testing. Clinical Screening: Family originally referred for a familial 'heart disease'. Family members invited in for clinic cardiac screening. Pedigree: Known TMEM43 family. Extended relatives at 50% pedigree risk ascertained. Genetic testing offered. Participants 11 and 12 underwent presymptomatic testing; all others were tested to confirm a suspected mutation status ICD: Implantable cardiac defibrillator HT: Heart transplant Family history of sudden cardiac death – numbers indicates which degree relative experienced sudden cardiac death (SCD) N/A not applicable
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Holly Etchegary, PhD, Clinical Epidemiology, Eastern Health and Memorial University, St. John’s, NL, Canada Daryl Pullman, PhD, Community Health and Humanities, Memorial University, St. John’s, NL, Canada Charlene Simmonds, PhD, Health Research Unit, Community Health and Humanities, Memorial University, St. John’s, NL, Canada Terry-Lynn Young, PhD, Discipline of Genetics, Memorial University, St. John’s, NL, Canada Kathy Hodgkinson, PhD, Clinical Epidemiology and Discipline of Genetics, Memorial University, St. John’s, NL, Canada
Corresponding Author: Holly Etchegary Clinical Epidemiology, Faculty of Medicine, Memorial University Room H1407, Level 1, Health Sciences Centre 300 Prince Phillip Drive, St. John's, NL, A1B 3V6 Phone: 709-777-8893 Fax: 709-777-6995 Email: [email protected]
Conflict of interest statement: The authors declare no conflicts of interest.
Acknowledgements: We are grateful to participants for their time and interest. This research was financially supported by the Atlantic Canada Opportunities Agency (Atlantic Innovation Fund) and Genome Canada (Atlantic Medical Genetics and Genomics Initiative). This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/cge.12513
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Abstract Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is a heritable disease of the heart muscle, causing life-threatening ventricular arrhythmias, sudden cardiac death (SCD) and/or biventricular heart failure. Little research examines ARVC genetic-test decisions despite the gravity of the condition. This qualitative study used semi-structured interviews to explore the testing decisions of 21 individuals across 15 families segregating a well-studied, particularly lethal form of ARVC caused by a p.S358L TMEM43 mutation. Genetic testing decisions were rarely described as ‘decisions’ per se, but rather ‘something that had to be done.’ This perception was attributed to personality type or personal suspicion of carrying the TMEM43 mutation, but most often was described in the context of testing for other family members, usually children. Participants related a strong need to rule out risk, more for children than for themselves, but lingering doubts remained about personal and children’s risk for ARVC, even when gene test results were negative. Study findings highlight the interdependent nature of genetic-test decisions and suggest an individualistic conception of autonomy in genetic services may not meet the needs of affected families. Findings also suggest the need for follow-up support of families affected by ARVC, including for those individuals testing negative for the family mutation.
Keywords: ARVC, genetic testing, psychosocial, sudden cardiac death, SCD, TMEM43
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Introduction Genetic testing for Mendelian diseases associated with sudden cardiac death (SCD) could improve the medical management of patients (1,2). Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is a single-gene disorder of the heart muscle, marked by fibro-fatty replacement of the myocardium. It is a progressive disease, culminating in life-threatening ventricular arrhythmias which prompt SCD and/or biventricular heart failure (2-5). Research suggests that ARVC is responsible for up to 20% of SCD cases, particularly among young athletes who die suddenly (2,3). The prevalence of ARVC is estimated between 1 in 20005000, (2) although some authors suggest the real prevalence could be as high as 1 in 1000 as a result of under-recognition (6). The utility of genetic testing in the clinical evaluation of ARVC is equivocal as only about half of individuals meeting diagnostic criteria will have a disease-causing mutation identified (2,4). However, in the province of Newfoundland and Labrador (NL), Canada, the majority of ARVC cases and familial SCD due to lethal ventricular arrhythmias (7) are caused by a fully penetrant, ancestral (founder) mutation in TMEM43 (p.S358L) (8). This genetic subtype of ARVC is lethal, particularly in males, with a median age to death of 41 years compared to 71 years in females (7) and is inherited in an autosomal dominant manner, meaning that all offspring of the genetically affected parent are at 50% risk of inheriting the TMEM43 mutation. In NL, our current estimates suggest the ARVC incidence is between 1/500 and 1/1000. From a public health perspective, it is important to identify carriers of TMEM43 (S358L) who may be at high risk of SCD. Cascade genetic testing can identify blood relatives who also carry the pathogenic mutation before clinical signs or symptoms of ARVC develop. Guidelines support the importance of cascade screening in ARVC families (9,10). In this way, relatives can be routinely screened and a life-saving implantable cardioverterdefibrillator (ICD) for treatment of arrhythmias and prevention of SCD may be indicated
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(2,3,11). This can be a critical decision: at risk relatives are often young patients with few or no symptoms. They will likely have a long course with their ICD, exposing them to repeated medical procedures, shocks, ICD complications and life-long psychosocial burdens (3,12). From a genetic counseling perspective, therefore, it is important to identify and inform at risk relatives about the value of genetic testing so they can make informed decisions about cardiogenetic evaluation and treatment for themselves and their children. To our knowledge, there are no studies in the literature specifically focusing on the experience of living at risk for ARVC, and only one recent study exploring genetic-test decisions in this context (13). That study reported two approaches to decision-making: 1), an ongoing process that happened over time; or 2), a decision made so quickly that it was perceived as a "fait accompli”. Factors that affected test decisions included experiential knowledge of loss in the family, family support, gender, being symptomatic, a sense of moral duty to be tested, as well as the availability of predictive genetic testing (13). Research with individuals at risk for Hypertrophic Cardiomyopathy (HCM) and Long QT syndrome revealed that genetic testing decisions were often motivated by a ‘need to know,’ in particular a need to rule out risk for self and children (14,15). Decisions about when to test children are complex and are made in the context of children’s personalities and interests (14). Relatives of young sudden cardiac death victims in the Netherlands revealed a wide variety of reasons for undergoing cardiogenetic evaluation after the death of a loved one (16). Due to the unexpected and shocking death of a young person, relatives had a strong desire to understand the cause of their relative’s death. Others described their decision as ‘no choice’ but to be evaluated; still others expressed feelings of guilt at the possibility of having passed on a lethal mutation to children and grandchildren. A small sample of Dutch families affected with HCM suggested that fears of genetic discrimination for themselves or their children affected genetic testing decisions (17). While information on other cardiac This article is protected by copyright. All rights reserved
conditions may be relevant, it likely underestimates the true psychosocial impact of ARVC due to diagnostic challenges and continuing uncertainty and issues surrounding ICD decisions in the disorder (5). We have identified 24 families with ARVC due to TMEM43 p.S358L in the NL population, providing a unique opportunity to explore the perspectives of individuals who undergo genetic testing in order to inform the provision of health services and promote informed decision-making. Materials and methods Sampling and recruitment Semi-structured interviews were used to systematically explore the genetic testing decisions of individuals affected by ARVC and their spouses where possible. Participants were recruited from the Cardiac Genetics clinic (established in 2004) and managed by the Eastern Health Regional Health Authority in St. John’s, NL. Clinic participants receive genetic counseling, genetic and clinical testing, and follow-up clinical management. Evaluation of at risk relatives in a stepwise manner (cascade testing) is recommended after a pathogenic mutation is identified in the family (9,10). Carriers are offered lifelong cardiac screening, lifestyle advice (e.g., avoidance of extreme sports), pharmacological treatment, as well as an ICD, which significantly improves survival in this population (7,9,18). The project was approved by the local Health Research Ethics Authority (HREA reference # 12.053). Purposive sampling identified potential participants in the clinic database to represent a broad spectrum of disease experience. Study invite letters were sent to males and females in several disease categories: at risk but currently asymptomatic, carriers and non-carriers of TMEM43, with and without an ICD, declined genetic testing, and those who had had heart transplants after ICD therapy. Spouses of any of these individuals were also invited to an interview as it was thought their views would be unique and informative of the disorder’s impact on the broader family. We also invited adolescents (age 14-18) in these families to
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take part. Eligible participants were identified by a team member (KH) with extensive contact and knowledge of the families. Care was taken to objectively identify potential participants who represented a broad range of experience with ARVC. Study invitation letters were sent to 73 individuals, and participants were invited to contact the research team if they were interested in completing an interview. The interviews Interviews were conducted in person by CS between August 2012 and December 2013 at a place most convenient for participants, usually their home or the researcher’s office. A minority (n=3) were conducted by telephone for those participants who had moved out of the province. Interviews lasted for 45-60 minutes and with permission, were tape-recorded and transcribed verbatim. Questions were not strictly confined to a specific order, and participants were actively encouraged to discuss any other issues they felt were important. However, a detailed question guide facilitated the tracking of all questions asked during each interview. Despite some different wording that emerged naturally during interviews, each interview encompassed the same content. Interviews covered a core set of topics such as family experiences and occurrences of heart disease and SCD, genetic testing decisions, ICD surgery decisions, as well as the perceived impact of ARVC on individual and family life. Questions were generated by one team member in line with study aims (e.g., can you tell me how you made the decision to have genetic testing for ARVC?; how would you say ARVC has impacted your life? Your family’s life?). Discussion with the team and based on the team’s clinical experience with families, as well as review by an additional genetic counselor, resulted in only minor changes. In this paper, we report specifically on genetic testing decisions. Data analysis
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Qualitative description (19) was used to explore and summarize the data pertaining to genetic testing decisions. This is a form of naturalistic inquiry that makes no a priori theoretical or philosophical assumptions about the data. Rather, it seeks to present the data in the language of participants, without aiming to present the data in more theoretical ways. The end result is a comprehensive summary of the event in question (19). Transcripts were read and re-read several times by one investigator (HE). Interview data were then isolated and organized around interview topics (e.g., family history of ARVC, genetic testing decisions, ICD surgery decisions, etc.). Only data pertaining to genetic testing for ARVC were utilized to identify and index emerging categories and themes, which were annotated on the transcripts. No qualitative software was used in the analysis. Inductive subcoding of the data relevant to these genetic testing decisions was completed using the method of constant comparison (20,21). Here, data were compared between and within transcripts to establish analytical categories and themes (19-21). This method required a constant shifting back and forth between (and within) transcripts to continuously compare the perceptions and experiences of participants. Discussion with the interviewer throughout the analysis verified emerging categories and themes until no new themes could be added and data saturation was deemed complete. Results Participants Of the 73 study invite letters sent, 12 people contacted the research team and completed an interview (five were returned as undeliverable). An additional nine participants heard of the study and contacted the research team to participate, yielding a total of 21 individuals (five male) who completed an interview and representing 15/24 ARVD5 families. Non-responders included those who had had heart transplants and those who declined genetic testing. Non-responders were also more likely to be male, while there were no significant This article is protected by copyright. All rights reserved
differences in mean age, education level, or disease severity (defined by having an ICD or not) between responders and non-responders. Only one family had been recently identified as carrying the TMEM43 mutation and did not participate in the current study. All other families had been followed clinically for many years and were known to the research team. Table 1 contains clinical and demographic information for the 21 study participants. Of the seventeen participants who had genetic testing, nine were mutation carriers (two adolescents; 14-18yrs). Of these nine participants, eight had an implantable cardioverter defibrillator (ICD), while the youngest participant did not. Prior to 2008, genetic disease status was given to participants based on haplotype analysis and confirmed when mutation testing became available subsequent to 2008 (8). All participants had a history of sudden cardiac death in their families, and this was often the initial reason for participant evaluation by the clinical team. Four spouses completed interviews; all were wives whose husbands were found to be carriers (two of these husbands completed interviews). Participant ages ranged from 16-64, with a mean age of 44 years (SD=14). Excepting the adolescents, nearly all participants were married with children. Thematic analysis Participant narratives revealed that genetic testing decisions were rarely described as ‘decisions’ per se, but rather, ‘something that had to be done.’ This perception was attributed to personality type or personal suspicion of carrying the mutation, but most often was described in the context of testing for other family members, usually children. Participants related a strong need to rule out risk, more for children than for themselves, but lingering doubts remained about personal and children’s risk for ARVC, even when gene test results were negative. The following themes summarize participants’ description of their genetic testing decisions: 1) No decision to be made; 2) Ruling out risk - genetic testing for others; 3) Lingering doubts about risk. This article is protected by copyright. All rights reserved
No decision to be made Overwhelmingly, participants revealed they did not have to think about the decision to pursue genetic testing for ARVC. The reasoning behind this description was sometimes vague. For some, it seemed linked to a personality type, usually described as ‘someone who had to know.’ For others, it was linked to a suspicion of having inherited the family history of heart disease, though not necessarily an inherited condition such as ARVC. There wasn’t a question, I don’t think a second’s hesitation to having it done…I’m the type that would want to know. –P14, unaffected female We never talked much about it because it was something we had to do. There was no choice, no decision to make. It was just something you had to do and that was it. And whatever the outcome, you had to deal with it. –P20, spouse of affected male I didn’t doubt for a minute that I had the gene, because for a year, probably when I was 21, I started having this irregular heartbeat...so when they said this heart disease was in my family, I wasn’t surprised, not in the least…so to get tested, I already knew I had it. –P3, affected female The two adolescents in the sample also revealed no decision to be made, being described instead as a choice made by their parents. One son explained: I never made no decision to get it done. Mom was like, ‘we’re going to go get your mouth swabbed.’ I said, ‘ok.’ I’m in Grade 8, I don’t even know what’s going on, what’s good for me. I had no say in that, and I’m perfectly fine with it. –P12, affected adolescent male Only one participant explicitly mentioned the nature of ARVC itself as being a part of her test decision: I’m one of the people who needed to know. I knew I had something anyway and putting a name on it wasn’t going to make any difference…when you have a disease like this, you need to know because it can be so fatal, so unpredictable, and so quick. It would lack sense in my opinion not to know. –P5, affected female Ruling out risk – genetic testing for others For the vast majority of participants, their recounting of testing decisions was clearly linked to their families, notably their children. Participants displayed a sense of genetic
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responsibility, noting their duty to be tested in order to rule out risk for other family members. Several noted they likely would not have pursued testing otherwise.
With regards to myself, I didn’t care whether or not I had the gene... My concern was for my children, just to make sure they were healthy and they weren’t going to have to deal with something further down the road. –P9, unaffected female I got tested to stop people from hounding me…if I had my time back, I don’t know if I would have gotten tested. Because we ended up getting the kids tested and really, especially [son], screwed with his plans. Whereas, if he wasn’t tested, he could have went ahead and did what he wanted, and it probably would have been easier on him. – P15, affected male For the longest time, I didn’t want to know if I had it or not, but that didn’t stop me, because of my kids you know? If I didn’t have children, I don’t know if I would of… but they had to decide whether or not they were going to have kids, so it was for them really. –P16, unaffected female Spouses of participants at risk also described a sense of ‘having to know’ their husband’s risk, even while recognizing that he may have made a different decision or they themselves might have made a different decision if they were the one at risk of ARVC. One wife explained: If it were for myself, I don’t really want to know. Let God do what he’s going to do. But when it comes to him being my spouse and having to look after the family and financial obligations and all this other stuff, I don’t want to lose him. So I’m glad he’s had the testing. –P19, spouse of affected male I kind of nagged him into going and getting tested. So he went basically for me, to shut me up. …we discussed it together, he never thought anything of it, but I said to him, ‘you should be tested, your heart sounds funny,’ and I always said that, even when we were dating…so he finally gave in and called about the testing to get me off his back. ..but I mean, it was the kind of thing where - we’ll get tested, you’ll be negative, we don’t have to worry again. That’s the way we looked at it, we’ll move on, never dreamed that it would come up positive. …it’s a learning process for both of us I guess, and it’s scary. We never dreamed he’d have it, and now he’s got it and we’re dealing with the fallout. –P18, spouse of affected male Related to the idea of genetic responsibility are participants’ views on whether other family members should also pursue testing. For some, there is a sense that testing is a positive thing and should be pursued, apparently without consideration of others’ right not to know. For example, one participant noted:
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And what really bothers me is that I have relatives and I find myself saying to them, ‘have you had your testing done?’ And they’re, ‘no I don’t want to know.’ And I think, ‘you have two teenage boys. What is your problem?’ –P16, unaffected female I think living in the dark is no way. I’m the oldest in the family, I had to find out. I was coming up on it before anyone else… so I think that when you’re the oldest child, naturally you feel, I’ve got to get this done because I got to drag everyone else along. –P8, unaffected male Lingering doubts Genetic testing did not always provide peace of mind. Participants who had tested negative revealed lingering doubts about their own risk or their children’s risk: And it still kind of scares me, but it’s like you know, there’s always that little bit of doubt in the back of your mind that you know, maybe…-P13, unaffected male It affects every part of your life because it’s always there….there’s a funny little thing in the back of your head, there’s an anxiety that you were never used to, so it does creep in everywhere. [Interviewer: even though you were told you were negative?] Yeah. –P8, unaffected male But it still doesn’t keep me from looking at my kids and wondering. I was relieved, but I didn’t feel safe. I’m still doubting. –P2, unaffected female
Discussion To our knowledge, this is one of only two studies to explore how individuals make genetic-test decisions for ARVC. It is an important focus given the emphasis placed on genetic counseling and discussions of testing and cascade screening in the management of families affected by ARVC (2,9,22-23). Understanding how test decisions are made could help evaluate such guidelines and ensure the delivery of testing services in a way that accords with families’ needs. In this paper, we sought to describe test decisions from the perspective of those who had undergone testing for ARVD5. Participant narratives revealed that for many, there was no ‘decision’ to be made. Determining whether one carried (or one’s spouse or child carried) the mutation predisposing an increased risk of sudden cardiac death was described as something that ‘had to be done,’ without sustained reflection, in line with a recent study (13). Sometimes, this was ascribed to a personality type – being someone who
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‘had’ to know, but most often, it was explained as a sense of responsibility to one’s family, particularly one’s children. Indeed, in some instances, it was implied that family members who had decided not to be tested were failing in their responsibilities to their family. There is virtually no literature on genetic test decisions for ARVC. Our findings are in line with the only other study in this area in that test decisions were clearly related to a sense of responsibility to provide information for other family members, particularly children (13). A small number of studies with individuals at risk for other cardiomyopathies provides some additional information on cardiac genetic test decisions. For example, a retrospective chart review at a cardiology clinic in the US found no factors that were related to the uptake of genetic testing for HCM or DCM, and that the uptake of testing was fairly low in at risk relatives. Variables evaluated included the proband’s age at diagnosis, years since diagnosis, number of living affected relatives, and the presence of SCD in the family (24). Manuel and Brunger (13) also report that experiential knowledge of loss and death in ARVC families influenced test uptake. Interviews with a sample of individuals from the UK who had undergone testing for HCM or Long QT syndrome revealed parents’ strong need to know their child’s mutation status, as well as great uncertainty and worry around their children’s futures (14,15).Testing was seen as a way to provide some certainty over their child’s diagnosis, although a minority were ambivalent about how much certainty testing could provide (15). Interviews with relatives of young sudden cardiac death victims in the Netherlands revealed a desire to prevent a second fatal event in their children and grandchildren and that they perceived no choice but to be evaluated (16). Genetic-test decisions across a variety of disorders have been studied most often in the theoretical framework of social cognition models (25). In these (typically) survey studies, respondents complete self-reports of attitudes or knowledge about a given genetic disorder, along with risk perception, susceptibility and severity beliefs about the disorder in question. This article is protected by copyright. All rights reserved
Survey items are combined in an expectancy-value statistical model that predicts intention to have a genetic test (or actually having the test). In these studies, however, there is normally only a weak correlation between actual test uptake and intention, and the amount of variance explained in test decisions by these socio-cognitive variables is typically low (25). Theoretically, the decision-maker in these models is constructed as autonomous and rational, thinking through the risks and benefits of the decision (usually defined as hypothetically or actually accepting a genetic test). D’Agincourt-Canning (26) notes that the current provision of genetic testing is based on a medical model that constructs the at risk person as autonomous and independent, rationally weighing the pros and cons of genetic risk-management options, including test decisions. However, a growing body of research reveals much broader social and familial contexts in which test decisions are made and genetic risk experienced. Thus, in practice, decisions about genetic testing are not always made in a completely autonomous or independent manner. Feelings of responsibility driven by duty to other family members affect (and sometimes constrain) choices to be made in the context of genetic risk (26-32). Our findings are in accordance with this latter view of genetic testing decisions. Most participants did not discuss their test decision as a ‘choice,’ nor did they describe prolonged periods of reflection or weighing the pros and cons of testing for themselves. Rather, they described the test as something they ‘had’ to do, in particular to provide information for their children, and sometimes other family members. Findings suggest that many people affected by ARVC did not construct the self as independent, rationally making choices that affected only themselves. Rather, in their genetic testing decisions, the self was constructed as interdependent (32), and the needs of important others were recognized as an integral part of the self. Thus, findings of the current research and others (13,26, 28-31) suggest that family obligations and perceptions of responsibility (to children in particular) may undermine an individualistic
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conception of autonomy in genetic-test decisions. Such a view comports well with the notion of “relational autonomy” as developed by feminist philosopher Susan Sherwin. The general idea here is that our sense of autonomy is formed broadly through individual, social and political relationships which entails that our responsibilities and obligations extend beyond simple self- interest (33). To that end, Hallowell and colleagues (31) suggested that genetic-test decisions might be viewed as a family decision, rather than an individual choice. They argued that rather than trying to eliminate family influences per se, it will be important to help individuals “acknowledge the extent to which their actions are born out of a sense of responsibility or explicitly influenced by their relatives or indeed, others factors” (p. 215). This may be important in facilitating cascade screening in a family. Counselors may need to go beyond a proband’s own health concerns to confront questions of family responsibility, that may raise ethical dilemmas about the duty of care and duty to warn (15). Indeed, members of our team (DP, KH) have argued elsewhere that with severe conditions like ARVC where an ameliorative intervention is available, a duty to warn others at risk should override a given individual’s decision not to know (34). Study findings do not imply that test decisions motivated by responsibility to other family members are necessarily involuntary or in some way not autonomous. However, we suggest that perceptions of responsibility to other family members do remind us it is important that the personal implications of genetic testing or risk-management decisions be thoroughly explored prior to testing. Left unexplored, it could be that some at risk people will be unprepared for the potential distressing effects of a positive test result (29). This might be particularly important in the context of a genetically and clinically complex illness such as ARVC.
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It is interesting that only one participant mentioned the nature and severity of ARVC itself as a factor in her genetic test decision. From clinical experience, it is clear that affected individuals are aware of the severity of ARVC having witnessed affected parents or heard about other family members’ deaths and/or ICD experiences. In this study, however, these experiences were not explicitly referenced as factors in testing decisions. Such family history information and experiences, however, are important to explore in counseling sessions since they may underlie the perception of the genetic test as something that ‘had to be done.’ Similarly, such experiences may affect whether individuals who receive a negative test result feel reassured. Several participants in the current study noted their lingering doubt about their own and their children’s risk status. Similar findings were reported in a qualitative study with individuals at risk for HCM and Long QT syndrome in the UK (15). These findings suggest that some form of follow up support may be necessary for those who test negative in order to provide ongoing reassurance and mitigate undue anxiety and distress. Smart (15) suggests that for these individuals in particular, “any shift in care patterns (i.e., outside of specialist genetics/cardiology) needs to be handled sensitively.” Conclusions This study is one of the first explorations of the psychosocial aspects of ARVC, beginning with important insights regarding motivations for genetic testing decisions. However, some study limitations are noted. While our findings are similar to Manuel and Brunger’s recent study (13), we caution that they do not represent validation of the results in a different ARVC/D population. Rather, while the individual participants in each study were different, they were drawn from the same families (i.e., the same population of families affected by ARVC in NL). The sample size is relatively small, comprised mostly of females and individuals affected by a specific genetic subtype of ARVC (ARVD5). Additionally, nearly half of participants were part of the same large pedigree, so we cannot completely rule This article is protected by copyright. All rights reserved
out family effects. Further, the study was conducted in a comprehensive ARVC testing and management service; thus, findings may not generalize to patients seen outside such centres or to families affected by other mutations causing ARVC. We also acknowledge potential selection bias in our sample. All participants in our study had undergone testing; thus, they may display specific perceptions and experiences that cannot be generalized to all affected or at risk individuals. For example, we were unable to recruit those who declined testing and those who had progressed to heart transplants in their disease progression. We were also unable to recruit families that had only known about their risk for a short time. Rather, the families in this study had all known about ARVC for a period of years. In addition, adolescents were under-represented in this sample and findings may not generalize to younger individuals affected by ARVC. While only four spouses responded to the study invitation, we include their views as unique and important, but acknowledge they are underrepresented in the sample. Additional research that focuses solely on spouses would be informative. The cross-sectional design of this study does not allow an examination of how perceptions of responsibility might change over time. It is plausible that such perceptions will change with the unfolding of family life (e.g., with the birth of a child, a new marriage, or as the age of onset approaches). Prospective, longitudinal designs would assist in charting changing perceptions of responsibility and their effects on such domains as test decisions and clinical management. It is notable, however, that some of the moral aspects of genetic decision-making revealed in the current study correspond with studies of other risk populations, notably inherited breast and colon cancer and Huntington disease (26-32). Study findings could assist practitioners as they develop appropriate forms of guidance regarding genetic counseling, information provision, and ongoing psychosocial support for families affected by ARVC. Study findings also raise important questions for future research. If, as some participants suggested, they
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underwent genetic testing for ARVC out of perceived responsibility to family, one wonders what effect a positive test result has on their psychological well-being and quality of life. How do these people cope with unwanted genetic knowledge that may impact many facets of their lives such as career choice, insurance eligibility and social life, as well as all the clinical implications that follow? An important question for future research is whether a different kind or amount of psychological support is needed for these individuals. Longitudinal studies that measure genetic responsibility and its effect on subsequent coping and well-being would help address this important clinical question.
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Sex
ID
Family ID*
Age
How did they present?
Method of diagnosis
Family history of sudden cardiac death? o 3 : SCD 39 years, o 1 : HT 55 years o 2 :SCD 29 years o 1 :SCD 32 years o 1 SCD 34 yrs. Son trans 34 yrs. o 3 :SCD 19 yrs. o 3 SCD 39 yrs o 1 SCD 19 yrs 1o SCD
F
P1
AR2
40
Clinical Screen
Genetic testing
F
P2
AR1
67
F
P3
AR1
55
F
P4
AR10
62
Clinical screen Clinical screen Clinical Screen
Genetic testing Genetic testing Genetic testing
F
P5
AR8
59
F
P6
AR2
46
Clinical Screen Pedigree
F
P7
AR8
63
M
P8
AR6
47
Clinical Screen Pedigree
F
P9
AR2
46
Pedigree
F
P10
AR12
26
F
P11
AR2
16
Clinical Screen Pedigree
Genetic testing Genetic testing Genetic testing Genetic testing Genetic testing Genetic testing Genetic testing
M
P12
AR2
19
Pedigree
Genetic testing
M
P13
AR2
44
F
P14
AR1
64
M
P15
AR2
47
Clinical Screen Clinical screen Pedigree
F
P16
AR2
60
Clinical Screen
Genetic testing Genetic testing Genetic testing Genetic testing
M
P17
AR15
37
Clinical Screen
Genetic testing
1 SCD 26yrs o 3 SCD 38 yrs o 1 SCD 30 yrs, 2o SCD 38 yrs o 1 SCD 25 yrs
F Spouse (Husband P15)
P18
AR2
47
N/A
N/A
N/A
3o SCD 39 yrs o 2 SCD 30 yrs o 1 ICD with several firings o 2 HT o 5 SCD 38 yrs o 1 ICD with several firings 2o HT 5o SCD 38 yrs 3o SCD o
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Any clinical signs of disease at presentation?
TMEM43 p.S358L Mutation status
Disease status by genetic testing**
ICD (Year)
No
Negative
2004
No
No
Negative
2004
No
Yes
Positive
2000
Yes
Positive
2003
Yes 2002 Yes 2003
Yes
Positive
2002
No
Positive
2010
Yes
Positive
2007
No
Negative
2009
Yes 2002 Yes 2009 Yes 2002 No
No
Negative
2009
No
No
Negative
2011
No
No
Positive
2013
No
No
Positive
2013
Yes 2013
No
Negative
2005
No
No
Negative
2002
No
Yes
Positive
2012
No
Negative
2000
Yes 2008 No
Yes
Positive
2006
Yes 2007
N/A
N/A
N/A
N/A
F Spouse (Husband P17) F Spouse (husband did not do interview)
P19
AR15
38
N/A
N/A
N/A
N/A
N/A
N/A
N/A
P20
AR11
42
N/A
N/A
N/A
N/A
N/A
N/A
N/A
F Spouse (husband did not do interview)
P21
AR15
37
N/A
N/A
N/A
N/A
N/A
N/A
N/A
Table 1. Clinical and demographic characteristics of study participants Table 1 Notes: * The family numbers are listed above, the pedigrees for which can be seen in Merner 2008 (Ref 8). **Genetic Testing: Anything provided to individuals pre-2008 was by haplotype/linkage analysis. Post-2008, the analysis was by mutation. All those pre-2008 have had their linkage result confirmed by mutation testing. Clinical Screening: Family originally referred for a familial 'heart disease'. Family members invited in for clinic cardiac screening. Pedigree: Known TMEM43 family. Extended relatives at 50% pedigree risk ascertained. Genetic testing offered. Participants 11 and 12 underwent presymptomatic testing; all others were tested to confirm a suspected mutation status ICD: Implantable cardiac defibrillator HT: Heart transplant Family history of sudden cardiac death – numbers indicates which degree relative experienced sudden cardiac death (SCD) N/A not applicable
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