“Grasping the Grey”: Patient Understanding and Interpretation of an Intermediate Allele Predictive Test Result for Huntington Disease
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- Semaka, A., Balneaves, L.G. & Hayden, M.R. J Genet Counsel (2013) 22: 200. doi:10.1007/s10897-012-9533-7
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Since the discovery of the genetic mutation underlying Huntington disease (HD) and the development of predictive testing, the genetics of HD has generally been described as straightforward; an individual receives either mutation-positive or negative predictive test results. However, in actuality, the genetics of HD is complex and a small proportion of individuals receive an unusual predictive test result called an intermediate allele (IA). Unlike mutation-positive or negative results, IAs confer uncertain clinical implications. While individuals with an IA will usually not develop HD, there remains an unknown risk for their children and future generations to develop the disorder. The purpose of this study was to explore how individuals understood and interpreted their IA result. Interviews were conducted with 29 individuals who received an IA result and 8 medical genetics service providers. Interviews were analyzed using the constant comparative method and the coding procedures of grounded theory. Many participants had difficulty “Grasping the Grey” (i.e. understanding and interpreting their IA results) and their family experience, beliefs, expectations, and genetic counseling influenced the degree of this struggle. The theoretical model developed informs clinical practice regarding IAs, ensuring that this unique subset of patients received appropriate education, support, and counseling.
KeywordsHuntington diseasePredictive testingIntermediate allelesUncertaintyUnderstandingBeliefsExpectationsGenetic counseling
Huntington disease (HD) is considered to be one of the most devastating, inherited, neurodegenerative disorders affecting approximately 6 to 7 individuals of Northern European decent per 100,000 (Hayden 1981). It is estimated that for every person affected with HD, the disease impacts another 20 individuals, including family members, many of whom are at-risk of the disorder themselves, friends, and caregivers (Aubeeluck and Moskowitz 2008; Huntington Society of Canada 2011). The symptoms of HD include profound involuntary movements, cognitive decline, and personality and mood disturbances. Symptoms commonly begin when the individual is middle aged and progress over 15 to 20 years until death occurs (Harper 1991). There is currently no cure for HD.
The hereditary nature of HD has long been a defining feature of the disease. HD follows an autosomal dominant inheritance pattern where children of an affected parent have a 50 % chance of inheriting the genetic mutation; an expansion of a CAG trinucleotide repeat in the HD gene (The Huntington’s Disease Collaborative Research Group 1993). Individuals affected with HD have 36 or more CAG repeats, however 36–39 repeats confer reduced penetrance. Individuals with a reduced penetrance allele typically have a later age of onset and slower progression of the disease, with some individuals never developing clinical manifestations (IHA and WFN 1994; Potter et al. 2004). While an inverse relationship between the number of CAG repeats and age of onset has been documented, this correlation does not provide clinical predictions for age of onset, except for very large CAG repeats (>80 CAG) that lead to juvenile HD (Telenius et al. 1993). Normal alleles have 26 or less CAG repeats, with the most common CAG size of individuals in the general population being 17 CAG (Kremer et al. 1994). The discovery of the genetic mutation has allowed for the development of predictive genetic testing and at-risk individuals now have the opportunity to learn whether or not they have inherited the mutation that will cause the illness. However, predictive testing involves significant psychological and social challenges and, thus, only 5–25 % of individuals at-risk chose to pursue the test (Creighton et al. 2003; Laccone et al. 1999; Maat-Kievit et al. 2000).
With knowledge of the genetic mutation, the risks faced by families affected with HD were thought to be certain—you either inherited your parent’s mutation or not. However, since this discovery, we have learned that HD can occur in individuals who have unaffected parents. Approximately 8 % of patients in Australia, Canada, and Spain had no known family history of the disease (Almqvist et al. 2001; McCusker et al. 2000; Ramos-Arroyo et al. 2005). These sporadic cases of HD are considered to be new genetic mutations and the new mutation rate is estimated to be 10 % (Falush et al. 2001). New mutations are known to arise from a unique category of HD genes called intermediate alleles (Goldberg et al. 1993), also referred to as mutable alleles (Potter et al. 2004) or large normal alleles (Sequeiros et al. 2010).
Intermediate alleles (IAs) have between 27 to 35 CAG repeats, a range that falls below the number of repeats required for the disease (Semaka et al. 2006). Consequently, these individuals will usually not develop symptoms of HD. Notably, there have been a handful of case reports that suggest an intermediate number of CAG repeats caused symptoms of HD (Andrich et al. 2008; Groen et al. 2010; Herishanu et al. 2009; Kenney et al. 2007). While some of the genetic, clinical, and neuropathological findings presented in these case reports are suggestive of HD, the symptom presentation varies widely amongst the cases and not all known HD phenocopies or HD-like disorders were excluded. Therefore, at present, IAs are not considered to confer a clinical phenotype for the individual. However, the number of CAG repeats of an IA can be unstable and may increase when the gene is passed to the next generation (Semaka et al. 2006). This means that children of individuals with an IA have an increased risk of inheriting a gene with ≥36 CAG repeats and, thus, developing HD when they are adults. There is limited knowledge on the magnitude of this risk but it is believed to be low (Chong et al. 1997). Sex of the transmitting parent plays an important role in the stability of IAs and males have a higher risk of passing on an expanded IA than females (Goldberg et al. 1993).
With the discovery of IAs, the genetics of HD has become more complex. Consequently, the process of predictive testing and genetic counseling has also become more complicated. Individuals who receive an IA predictive test result (PTR) are now faced with uncertain risks for future generations of their family, in particular their children and grandchildren. While numerous studies have examined the predictive testing experience and psychosocial consequences of receiving either a mutation-positive or negative PTR, few studies have provided insight into the experience of receiving an IA PTR. One study anecdotally reported that these individuals experience guilt because, while they will not develop the disease, their children may be at risk (Maat-Kievit et al. 2001). Other common reactions included uncertainty about the risk to children and turmoil over informing family members who are unaware of a risk. While genetic counseling practices regarding IA PTRs have not been formally examined, counseling in this regard has been described as challenging, particularly in relation to communicating the uncertain clinical implications (Maat-Kievit et al. 2001; Tassicker et al. 2006). The difficulty experienced by genetic counselors is further compounded because the international predictive testing guidelines for HD do not acknowledge IAs (IHA and WFN 1994).
The purpose of this study was to explore how individuals come to understand and interpret their IA PTR and develop a theoretical model that explains this process. The overall aim of the study is to inform genetic counseling practices so that individuals who receive an IA PTR receive appropriate education, support, and counseling.
This qualitative study used grounded theory, a methodology ideal for exploring social processes and interactions (Corbin and Strauss 1990; Strauss and Corbin 1998). Grounded theory has been used to examine numerous processes in health care, such as medical decision making (Balneaves et al. 2007). Grounded theory has also been recognized as an appropriate methodology for research in the field of genetic counseling because of its ability to generate evidence-based theoretical models that can be used to inform clinical practice (Beeson 1997; Grubs and Piantanida 2010; McAllister 2001).
A sample of 29 participants who received an IA PTR and eight medical genetics service providers, including genetic counselors and medical geneticists, were recruited from four Canadian and one Australian medical genetics clinic. Ethical approval was received from the applicable university and hospital review boards. Written documentation that the participant received genetic counseling about the clinical implications of their IA PTR was required for study eligibility. Service providers eligible to participate routinely provided predictive testing for HD as part of their practice. Potential study participants were recruited through their medical genetic clinics by a mailed letter of invitation, a detailed study information sheet, and a consent form. Following the receipt of written consent, interviews were scheduled.
Data Collection Procedures
Semi-structured interviews were conducted with study participants either in their home, place of work, or over the telephone. Interviews ranged from 45 to 90 minutes in length and some participants were asked to take part in a follow-up telephone interview. The first author (A. Semaka) conducted all initial and follow-up interviews. Study participants were assigned a code number to maintain their anonymity. Interviews were audiotaped and transcribed verbatim. All recorded interviews and transcripts were checked for accuracy. Initial open-ended interview questions were designed to explore participant’s experience receiving an IA PTR, how they came to understand the clinical implications, and their perception of the significance of this result in their life and their family members’ lives. Interviews with service providers focused on their clinical practices regarding IAs during pre- and post-result genetic counseling. As the data analysis progressed, interview questions were refined to capture emerging and important concepts and develop conceptual linkages. Follow-up interviews questions were designed to ensure data saturation was achieved in all study concepts and confirm that participant’s experiences were reflected in the developed theoretical model. See Appendix I for sample questions from the participant interview guides.
Data Analysis Procedures
The qualitative software NVivo 4.0 was used to store, organize, and manage the interview data. Data analysis involved the constant comparative method in which data from each participant was continuously compared and contrasted. Throughout the analysis, written memos were used to capture decisions regarding the data and the emerging theoretical model. Coding began with a ‘line-by-line’ analysis where specific ideas or events were given a conceptual label or code. A. Semaka performed all coding and a proportion of initial and follow-up interviews were also coded by L.G. Balneaves. Any discrepancies in coding were discussed and resolved. Using constant comparison, codes were grouped together to form major categories with specific properties and dimensions. A coding framework was developed and applied to all interviews. Coding continued by exploring relationships amongst categories. The associations between categories were then modified and verified. Once these theoretical links were established, a core category was developed that encompassed the major categories into a cohesive theoretical model.
A total of 29 participants who received an IA PTR participated in this study. Both males (n = 11, 38 %) and females (n = 18, 62 %) were interviewed, with an overall mean age of 52 years (range 22–78 years). No participants displayed clinical symptoms of HD. The majority of participants were married (n = 21, 72 %) and had one or more children (n = 22, 76 %). On average, they received their IA PTR 10 years ago (range 1–16 years). Of the 29 research participants, 17 were counselled by a medical geneticists or genetic counsellor who also participated in this study.
Demographic characteristics of study participants and medical genetics service providers
Average: 51.7, Range: 22–78
Time since predictive testing (years)
Average: 9.7, Range: 1–16
Medical genetics service providers:
Time providing predictive testing for HD (years)
Average: 10.4, Range 2–20
Overview of the “Grasping the Grey” Theoretical Model
“Where I sit with thirty-five [CAG repeat], while it’s okay for me, the grey area comes in for future generations and what’s going to happen to them. It’s not clear what the future holds for my future generations, it’s extremely grey.”
“It’s an offbeat number, it is sort of some crazy molecule that is not really well understood. It’s grey, there’s a lot of unknowns.”
“Regardless of whether it’s an intermediate allele from the general population or from a new mutation [family], all patients seem to struggle with this result and what the risks are to their kids and grandkids. In my experience most [patients] have a tremendously difficult time understanding intermediate alleles and the impact it will have [on their lives].”
“I struggle with what is [this result] going to do to my children and even their potential children and also, there’s a lot of unknowns about this [result] so I definitely think a lot of us struggle with that too.”
Number of study participants in each category of the “Grasping the Grey” Model
Out of the blue
Growing up with HD
Beliefs about HD
Black & White
Pre-test genetic counselling
Predictive testing expectations
Yes or No
Free & Clear
Sitting on the fence
Could be worse
Participants’ family experience with HD significantly influenced their understanding and interpretation of an IA PTR. The two different familial contexts in which an IA can be identified, a new mutation family or a family with a long-standing history of the disease, created two different familial experiences — “out of the blue” and “growing up with HD” (Fig. 2). Participants’ family experience was shaped by their exposure to HD, including their age when they were first exposed to HD, the number of affected persons in their family and the relationship to the participant (i.e. affected sibling, parent, extended family members), and their social and geographical proximity to affected family members. Although several participants in both types of family experience spoke of providing care for family members affected with HD during the interviews, they did not overtly link this responsibility to their understanding and interpretation of an IA PTR.
A total of 14 research participants experienced HD “out of the blue”, of which 10 had an elderly parent and four had a sibling unexpectedly diagnosed with HD (Table 2). No participants who experienced HD unexpectedly had a family member previously identified with an IA. The remaining 15 participants had a “growing up with HD” family experience (Table 2). For three of these participants, a family member, either a sibling or parent, was previously identified as having an IA in the context of a long-standing family history.
Out of the Blue
“We were just dazzled because we’d never heard of HD before. I mean I’d heard of [HD], but I’d never heard of it in my family.”
“When my mother came [to Canada], I noticed it right away, that there’s something wrong with her mouth, with her facial muscles and expressions. I was thinking at that moment, because she has dentures, that the dentures were not properly done and they were bothering her so she was doing that movement.”
“When my father began to exhibit symptoms, it took forever, maybe five or six years, before he was [diagnosed] and I think because of his age, he was in his seventies, people were not thinking Huntington’s.”
“[My sister’s] first diagnosis was actually that she had Tourette’s [syndrome] and then she got progressively worse with the falling so we proceeded taking her to another doctor and yet another doctor until finally we went [back] to the family doctor and he arranged for the Huntington’s blood work to be done.”
“I was shocked and I suppose in a way I didn’t believe it at first, even though we had the positive diagnosis, I just started to question [the diagnosis], like we don’t have a family history of HD, so it can’t be? How could [my mother] have this when we haven’t seen it in any other family members?”
“We went back to the family tree, based on church records, to about like 1600 and there was never any Huntington’s. Of course they wouldn’t recognize it [as HD] then but there was nothing unusual.”
Growing Up with Huntington disease
“I’ve seen my grandfather go through it when I was just in elementary school and I thought it was the most devastating thing, and now I’ve seen my aunt and two of my uncles die from it too.”
“I was about thirty when I became aware of quote ‘Huntington disease’, but I was a young teenager when I first started to see the impact of it [on] my family.”
“I can remember as a child driving with my uncle and sort of being afraid because he was driving and he was shaking and turning and sort of carrying on. I remember sitting in the car and not feeling safe driving with him.”
“My mom was in a bed and even though the sides came up on it, they’d find her on the floor in the morning, her movements were that violent. I mean that’s scary, really scary.”
“It’s frightening, very frightening. It’s like almost every year we’re hearing that somebody else in the family has [HD].”
“When we found out we were pregnant, we figured that it would be a good opportunity to try to find my father because I had no contact with him for over twenty-eight years. We were able track him down and that’s when he told us about the Huntington’s family history and I was like, okay, Huntington’s, never heard of it.”
Beliefs about the Genetics of Huntington disease
Participants’ beliefs about the genetics of HD played an important role in the “Grasping the Grey” model. Individuals’ beliefs about HD were largely developed within the context of their family experience. As a consequence of either experiencing the disease “out of the blue” or “growing up with HD”, participants mainly developed two different belief systems about the genetics of HD and how the disease is inherited—“blank slate” or “black & white” beliefs (Fig. 2). Of the 29 research participants, 12 individuals had “blank slate” beliefs and 17 established “blank and white” beliefs (Table 2).
“I think that people who do have it in their family, they know [HD], they know how it works, but for us everything was brand new, we’re like a blank slate, we just know nothing about it.”
“As soon as I knew [my sibling] had HD, I got an awful lot of information and just tried to find out as much as I could about it because I didn’t know a thing.”
Individuals who had a “blank slate” belief system appeared to experience less difficulty understanding the clinical implications of their IA PTR. These participants were in the process of establishing their beliefs, given their “out of the blue” family experience and expressed limited conflict with previous beliefs about HD when discussing their IA result. For these individuals, the meaning of IAs appeared to be more easily incorporated into their developing belief system about the disease.
Black & White
“It’s black or white, we each have that 50 % chance of getting it, and it never skips a generation, sometimes a disease will skip [a generation] but HD never skips a generation.”
“The way [HD] kind of works is if your father has it then, you have that 50 % chance but if he doesn’t have it, then you’re in the clear.”
“If you don’t develop Huntington’s, your kids won’t develop Huntington’s, normally that’s true but not with this [result].”
“With this result, it’s like we’re the exception to the rule.”
Pre-test Genetic Counseling
All participants in this study received post-result genetic counseling about the clinical implications of an IA PTR. However, the pre-test genetic counseling participants received differed and this played an important role in the “Grasping the Grey” model. Medical genetics service providers indicated that they addressed IAs in every pre-test counseling session when discussing the CAG repeat continuum. However, the amount of information, time, and emphasis placed on the possibility of an IA PTR varied based on the individuals’ family history. The genetic counseling participants’ received not only influenced their beliefs but also shaped their predictive testing expectations. Two types of pre-test genetic counseling were identified—“ABC” and “50–50” (Fig. 2). Of the 29 research participants, eight individuals received “ABC” genetic counseling and 21 were provided “50–50” counseling (Table 2).
“A family history where I might give intermediate alleles more face-time or discussion time is if somebody comes in and they have a sibling who’s affected and their parents have no signs or symptoms.”
“[My genetic counselor] said there were basically three result options, A, B or C.”
Individuals who received “ABC” pre-test genetic counseling described being able to easily accept and understand the meaning of their IA PTR. The additional education on, and preparation for, this result possibility likely assisted them in understanding their “grey” result and the development of a belief system that incorporated IAs.
“I’ll have looked at the family history and if clearly the parent has a CAG repeat in the affected range I will use the language that it’s ‘50–50’. I may mention a small possibility for an intermediate allele but that’s a complicated thing so I try not to spend a lot of time on it.”
“My [genetic] counselor told me that I had a fifty percent change of having the [genetic] mutation and that it carried on to my children and they [would] have a fifty percent chance. I didn’t know about this funny in-between result until later [when I got my result]”
“50–50” counseling was the predominant pre-test genetic counseling and was provided to all participants who had an affected parent, including individuals who had a “growing up with HD” family experience (n = 12) and a number of individuals who experienced HD in their family “out of the blue”, when an elderly parent was unexpectedly diagnosed (n = 10). For participants who grew up with HD and developed “black & white” beliefs, this type of pre-test genetic counseling reinforced their beliefs, which conflicted with the clinical implications of an IA, and likely intensified their struggle to understand and grasp the meaning of their result. For the participants who first experienced HD unexpectedly in an elderly parent and held “blank slate” beliefs, this pre-test genetic counseling supported the formation of a “black & white” belief system. In contrast to individuals who held well-established “black & white” beliefs, these individuals appeared to struggle to a lesser degree in understanding their “grey” result.
Predictive Testing Expectations
Participants’ expectations about predictive testing played an integral role in the “Grasping the Grey” model. Individuals’ beliefs about the genetics of HD and the pre-test genetic counseling they received interacted to create expectations of what PTRs were possible and the degree to which these results would relieve their uncertainty about their genetic status and its consequences for their children. Participants had either “option C” or “yes or no” predictive testing expectations (Fig. 2). Of the 29 research participants, six individuals had “option C” expectations and 23 had “yes or no” expectations (Table 2).
“I knew the three [result] possibilities were that I wouldn’t have the mutation, [that] there was this intermediate area of numbers, and then of course, there was [a chance] I would get [HD].”
“I knew before [receiving my result] that there was a third option.”
“Option C” predictive testing expectations appeared to minimize the difficulty participants experienced when grasping the meaning of their IA PTR. With the expectation that a “grey” result was possible, participants did not experience intense shock at receiving this result and described conversations with their medical genetic service providers in which they were able to hear, comprehend, and interpret the information being provided about their IA result.
Yes or No
“They threw me with the third option, rather than the yes or no. I thought that you either had it or didn’t.”
“When the news came out, it wasn’t as clear cut as I thought it would be.”
“My expectation of [medical] tests in general, is that testing is an like an on-off switch, you don’t generally experience a grey area; you have strep throat or you don’t; you are pregnant or you’re not; and if you’re going for [HD] genetic testing, you’re looking at a definitive answer.”
“You’re in shock [because] it’s not the answer you’re expecting. You’re going in expecting ‘a or b’ and then someone gives you a ‘c’ choice, which is not at all what you were expecting.”
“I was just stunned to find out that there was actually a possibility that our child could develop it. I never considered that a possibility unless I was [mutation-] positive so I was just blown away that there was actually a risk that my child could develop it.”
“I think when you hear that [IA] result, they tell you what it means and you’re listening but you’re not really hearing so when you go home, you think, ‘What did they say?’ I was listening but not really absorbing what they were saying to me.”
The reaction of “shutting down”, combined with “yes or no” predictive testing expectations, possibly became barriers to participants’ ability to process and understand the novel information being provided about their IA PTR and likely contributed to their struggle to understand and interpret their “grey” result.
Understanding of an Intermediate Allele Predictive Test Result
Participants’ understanding of their IA PTR consisted of their knowledge of its clinical implications and surrounding scientific facts, such as the occurrence of new genetic mutations, general population IAs, CAG repeat instability, and the impact of gender on the risk of CAG repeat expansion. Individuals’ understanding, particularly regarding the clinical implications of an IA, varied along a continuum of poor (n = 6), uncertain (n = 8), and good (n = 15) understanding.
Participants with poor understanding believed that since they would not develop HD, their children were no longer at-risk to develop the disease. In other words, these participants’ understanding reflected the clinical implications of a mutation-negative result. Importantly, these individuals were certain in their understanding and did not perceive themselves as having misunderstood the clinical implications of their PTR.
“I don’t understand what [my result] means. Does it mean I have Huntington’s because I’m a thirty-four? I really honestly don’t know at this point; I’m a little confused.”
“I don’t have Huntington’s, I understand that much. [But] the kids, can they or can’t they; will they or won’t they? Does it mean they’re safe or not? I don’t know.”
“My result means there is a small chance my kids could still develop HD, but I could be mistaken, I’m not really sure, I don’t really know.”
Another group of participants had good understanding about the clinical implications of their result for themselves and their children. These individuals understood that while they would not develop HD, their children or future generations of their family remained at-risk of the disease. These individuals were also aware of the inherent uncertainty due to the limited scientific knowledge that currently exists about IAs.
“I think the concept of [CAG repeat] instability is something that people really have to get a hold of, just because you’re not going to get [HD], instability exists and therefore your children can still develop it. Your [CAG repeat] number can jump and expand if you’re in the grey area.”
“If people really thought about it then they would be conscious of the fact that [the intermediate allele] could come from the other side [of the family] but you kind of disregard the side [of the family] where [HD] isn’t exhibited. I mean I didn’t give any consideration to that [possibility] so I was really surprised.”
Understanding the scientific facts surrounding IAs played an important role in the “Grasping the Grey” model as it appeared to assist many participants in feeling more certain about their understanding of the unusual clinical implications of an IA PTR.
Interpretation of an Intermediate Allele Predictive Test Result
The interpretation of a “grey” PTR refers to participants’ perception of the significance the result will have in their life and the lives of their children. Participants’ interpretations were highly influenced by their understanding of the clinical implication and scientific facts of IAs. Individuals’ interpretations occurred within the context of their family experience, beliefs, genetic counseling, and expectations and evolved over time, shifting in response to new experiences and knowledge. Four different interpretations of an IA PTR were described by participants: six individuals interpreted their result as “free & clear”, eight individuals were “sitting on the fence”, 10 individuals interpreted their result as something that “could be worse”, and five individuals viewed their result as a “threatened future” (Fig. 2, Table 2).
Free & Clear
“I’m free and clear and my children are even better because it’s 50–50.”
“As far as my kids go, because I don’t have it, they can’t have it, so it’s no use them getting tested, for us, it’s just bygones.”
“The amazing thing was that [the geneticist] said my [unaffected] mother had the gene too. How they figured that out, I don’t know, because she was long since dead, but that wasn’t really a big thing, it was just like, it’s on your father’s side and oh by the way, your mother had a strain of it too.”
Sitting on the Fence
“When I got an intermediate, [the geneticist and genetic counselor] were like, oh, we don’t really know much about this [result]. So that left me kind of sitting on the fence thinking, you’re telling me I’m not positive, you’re telling me I’m not negative, instead you’re telling me I fall in the middle but you don’t really understand what that means. Well, guess what? Neither do I!”
“[The genetic counselor] referred to the results as black, grey, and white. I think for my sisters and myself, I mean we still say it now, ‘Thank God we’re in the grey area’ yet we don’t really know what being in the grey area means.”
Could Be Worse
“I felt lousy in a way, knowing that [my children] could possibly get it but then the way I understood it, it was a lot less chance that they would [get it], whereas in Huntington’s you’re 50–50 that you’d get it or not get it.”
“[My children] could get multiple sclerosis or autism. I would rather have what we’ve got than that. There are dozens of diseases and situations out there that are worse.”
“It’s just something that is kind of like a grey cloud that looms, that maybe I could have still have passed [HD] on [to my children].”
“I do a lot of thinking [about] how lucky I am that although I kind of have the gene, it’s not enough that I will actually get the disease, nor can I pass it to my children because I’m a woman.”
“As much as I’d like to say we don’t think about [my result], I don’t think a day goes by that [my wife and I] wouldn’t think about it. We’re always thinking, is [our son] going to be affected? Are [our] grandkids going to be affected? We’re just praying everyday that Huntington’s is out of our family.”
“Any possibility that I had inflicted this on my daughter was just enormous, it really wouldn’t matter what the percentage was. The legacy you want to give your child is values, education, ability, everything in the world; the one legacy you don’t want to give your child is a genetic disease that will kill them.”
“We were hoping to expand our family, we wanted to have more than one child but if Huntington’s was a potential factor, we knew immediately that that’s something we were going to stop and obviously finding out these results, we’ve opted not to extend our family and that’s very difficult.”
“The whole idea is to snip [HD] in the bud and if I’m going to have kids, I mean it’s different now that there’s prenatal testing but it’s not business as usual if you get an intermediate.”
Over a century ago, Dr. George Huntington described HD and its hereditary nature as: “An heirloom from generations away back in the dim past” (Huntington 1872). With our evolving knowledge on the genetics of HD, we know that the genetic thread of HD is not always inherited from an affected individual in the previous generation. The discovery of IAs has challenged beliefs about HD inheritance established almost 150 years ago and extends the risk of HD to the general population and families who have no history of the disorder.
This is the first study to explore how individuals come to understand and interpret an IA PTR. The “Grasping the Grey” theoretical model indicates that many individuals struggled to understand the clinical implications of an IA and had difficulty interpreting its significance for themselves and their family. Individuals’ understanding and interpretation was influenced by their family experience, beliefs, pre-test genetic counseling, and predictive testing expectations. Many individuals either misunderstood, or were uncertain about, the clinical implications of their result. For individuals who had good understanding of their IA PTR, many struggled with the uncertain risk of CAG repeat expansion causing a new mutation due to limited scientific knowledge.
Most striking in the “Grasping the Grey” theoretical model was the profound impact an individual’s family experience had on their understanding and interpretation of an IA PTR. Many studies have reported the powerful influence of family history on other aspects of the HD experience, including predictive testing decision making (Cox 2003; Hamilton and Bowers 2007) and risk perception (Cox and McKellin 2001). Given the hereditary nature of HD, there is the general perception that families affected with HD have a long-standing history of the disease. However, there is growing awareness that for some families, HD can be a new diagnosis, something never heard of in the family before. Similar to the work of Etchegary (Etchegary 2006) and Forrest Keenan (Forrest Keenan et al. 2007; Forrest Keenan 2009), individuals in this study described two different family experiences: “growing up with HD” or experiencing HD “out of the blue”. Individuals who grew up with HD had greater difficulty understanding an IA PTR compared to those who experienced HD unexpectedly. Individuals with a long-standing family history have well-established “black and white” beliefs about the genetics of HD that conflict with IAs. These beliefs, together with pre-test genetic counseling, which focuses on the “50:50” inheritance pattern created “yes or no” expectations about predictive testing that were not met when they received an IA PTR. It is likely that the discordance between individuals’ beliefs and expectations and the novel information on IAs acted as a barrier to their understanding.
How individuals come to understand and interpret uncertain genetic test results has received the most attention in the context of BRCA 1 or 2 genetic testing for hereditary breast and ovarian cancer. Known BRCA 1/2 mutations account for only 20–25 % of familial breast and ovarian cancer cases (van Dijk et al. 2006). The majority of women receive inconclusive results, meaning that while a genetic alteration was identified, it is unclear whether or not it is a cancer-causing mutation or a benign change in DNA sequence. In some cases, testing family members can help clarify an uninformative result but in many cases uncertainty about the risk of cancer remains due to the limitations of current genetic technology and knowledge. Similar to the present study, Maheu (Maheu and Thorne 2008) found that many women were shocked to receive an inconclusive BRCA 1/2 result and had difficulty interpreting its meaning for themselves and their family based on personal beliefs and family experience. Hallowell (Hallowell et al. 2002) found that some women misinterpreted their inconclusive result to mean that they either had a genetic mutation that significantly increased their cancer risk or that they did not have a mutation and, thus, their cancer risk was drastically decreased. Comparable results were found in our study where a proportion of individuals either interpreted their IA PTR to mean they were still at-risk of the disease or that they and their family were free from the disease.
Implications for Practice
The amount of information that should be provided about IAs during genetic counseling for HD predictive testing has been debated (Maat-Kievit et al. 2001; van den Boer-van den Berg and Maat-Kievit 2001) and concerns over inconsistencies in the information being provided between different testing centers have been raised (Tassicker et al. 2006). Interview data from both participants and medical genetics service providers suggested that there were no discrepancies in the information provided about IAs between the five predictive testing clinics. However, inconsistencies in the type of pre-test genetic counseling provided were observed across participants and appeared to be influenced by family history. Only those individuals who had a sibling diagnosed with a new mutation received comprehensive pre-test information about IAs. This likely reflects an assumption within the medical genetics community that IAs are most often identified in families in which a new mutation has occurred. However, it is important to note that in this study, IAs were most often inherited from an unaffected parent on the non-affected side of an HD family. A recent study from Portugal found 6 % of individuals in the general population had an IA for HD (Sequeiros et al. 2010). It is these ‘general population’ IAs that are often coincidentally ascertained, in the context of genetic testing, on the non-affected side of an HD family. While further studies on the frequency of IAs in different general populations are needed, this study suggests that approximately 1 in 20 individuals undergoing predictive testing may receive an IA from the non-HD side of their family. As such, comprehensive information on IAs should be provided to all individuals, irrespective of their family history, during pre-test genetic counseling. Moreover, future predictive testing guidelines should aim to standardize pre- and post-test genetic counseling practices regarding IAs to ensure all individuals receive sufficient information and support.
This study highlighted the persuasive power of health beliefs and subsequent predictive testing expectations on the ability of participants to appreciate that IAs were a potential outcome of predictive testing. Despite all medical genetics service providers indicating that IAs were addressed in every pre-test counseling session when discussing the CAG repeat continuum, few participants specifically recalled this discussion. These findings suggest that equal emphasis is needed on all four possible PTRs (normal, intermediate, reduced, and full penetrance) and counseling needs to prepare individuals for results that do not conform to their expectations. Careful preparation of individuals in the pre-test counseling phase to all test outcomes, while time consuming, may help reduce feelings of shock and subsequent misunderstandings. Moreover, in order for individuals to make a fully informed decision about predictive testing, they must be aware of all result options. In addition to stressing the possibility of unforeseen results, pre-test counseling should address the clinical implications of all PTRs and highlight the uncertainties in scientific knowledge. This is of particular importance given that many individuals’ motivation for pursuing testing is to relieve uncertainty about the future. Individuals may also benefit from a discussion that explores their feelings about receiving a “grey” result that does not provide the certainty they may desire.
Given that the genetic and clinical implications of IAs are complex and uncertain, individuals who receive an IA PTR likely have different education and support needs compared to persons who receive a mutation-positive or negative PTR. Hallowell (Hallowell et al. 2002) suggested that since the women in her study all received information on the clinical implication of an inconclusive BRCA 1/2 result, their misunderstanding likely did not arise due to lack of information but instead the information may have been too complex for them to understand. It is possible that participants in the current study also struggled to understand the genetic complexity and uncertainty of IAs, particularly since the genetics of HD is largely perceived to be straightforward. Individuals’ understanding of IAs may be improved with additional post-test genetic counseling to review the complex clinical implications and discuss the limitations of scientific knowledge. In particular, individuals with a long-standing family history may benefit from additional counseling as their engrained “black and white” beliefs and “yes or no” expectations may impede their ability to understand an IA PTR. Additional post-test counseling would also provide an opportunity for genetic service providers to assess the level of understanding individuals have gained about IAs, identify misunderstandings, and provide additional information and support. This is particularly important for those individuals with poor understanding who assumed that their family was “free and clear” and thus, were not motivated to pursue additional counseling. The provision of written material describing the genetic and clinical aspects of an IAs would likely also benefit individuals’ understanding, especially given that the information and resources available on IAs within the HD community are often vague and can conflict with current scientific knowledge. As such, genetic counseling is likely one of the only sources of accurate knowledge on IAs. Individuals who receive an IA PTR should also be encouraged to remain in contact with their medical genetics clinic and inquire about new knowledge and research on IAs.
The study findings highlight the degree of misunderstanding that exists within the HD community about IAs. While much of this uncertainty may be a result of the complexity of the information and its discrepancy from commonly held beliefs about HD, cognitive dissonance may also contribute to individuals’ struggle to understand their “grey” PTR. Cognitive dissonance results in psychological discomfort when an individual perceives inconsistencies between their prior understanding and beliefs and new knowledge (Festinger 1964; Grover 2003). Individuals who had more difficulty assimilating the novel information on IAs into their entrenched belief system may have subconsciously dismissed the meaning of their result in order to maintain their beliefs and relieve psychological stress. For example, in the breast cancer literature, van Dijk and colleagues (van Dijk et al. 2005) suggested that women who appeared to misinterpret the meaning of their inconclusive BRCA 1/2 result may have been psychologically motivated to interpret their results incorrectly to cope with the associated clinical uncertainty. It is possible that individuals in this study, particularly those who grew up with the fear of HD, are using their misunderstanding or uncertainty as a coping strategy for dealing with the distressing and uncertain possibility of HD continuing in their family. More research is needed to explore the role of cognitive dissonance in how individuals come to understand and interpret uncertain genetic test results. Additionally, genetic counseling has to carefully balance an individual’s need to protect themselves from psychological distress while ensuring they have the appropriate information to allow informed decision making.
The impact of an IA PTR on the psychological functioning of individuals is largely unknown. However, this study suggests that these individuals experience a range of negative emotions including confusion, fear, guilt, anxiety and uncertainty. van Dijk (van Dijk et al. 2008) demonstrated that while women who received an inconclusive BRCA 1/2 test result do not report any adverse psychological consequences, their functioning was significantly worse than that of women who received a true negative result. Furthermore, women who reported feeling uncertain experienced higher levels of distress. These authors also showed that women who perceived themselves as having a high risk for a BRCA 1/2 mutation based on a strong family history, had the greatest difficulty coming to terms with an inconclusive result (van Dijk et al. 2006). Collectively, these findings suggest that some individuals who receive an IA PTR may experience increased psychological distress, particularly those participants who had a long-standing family history or were uncertain about the meaning of their “grey” result. Longitudinal research on the psychological impact of an IA is needed to identify potential psychological risk factors for adverse events after receiving an IA PTR. An important caveat to future research on the psychological impact of an IA PTR is the possibility that the distress experienced is a result of poor understanding about the clinical implications of an IA (Bish et al. 2002).
Studies that examine how IA PTRs are being communicated within families are also needed. While examining the familial communication process was not a specific aim of this study, the findings suggest that this process presents yet another challenge for individuals. Some participants discussed feeling unsupported by family members who discounted the clinical significance of their IA PTR. Studies that explore the experience of disclosing an IA PTR result may point to areas in which individuals can be supported in this communication process. Family counseling may be one way to support individuals in sharing IA PTRs. Educating family members about IAs provides an important opportunity to promote awareness of this unique result and shift the predominant beliefs in the community to include IAs.
This study is not without some limitations. Firstly, participants in this study were a self-selected group with great diversity with regards to when they received their IA PTR. Therefore, it is possible that the “Grasping the Grey” theoretical model does not reflect the collective experience of individuals and recall biases may have influenced the findings. However, there was a good distribution amongst the different categories of the model, which suggests a range of experiences and perspectives were captured. Another limitation is that for participants who misunderstood their result, we were ethically unable to explore why they did not understand their result without informing them of their incorrect understanding. This weakness highlights the ethical challenge inherent to this research and raises questions about researchers’ clinical responsibility to research participants who misunderstand the clinical implications of genetic test results. Lastly, this cross-sectional study examined understanding and interpretation at a single moment in time. Longitudinal studies are required to explore in more detail how understanding and interpretation of a “grey” result may shift over time.
IA PTRs have changed the landscape of predictive testing for HD. While there is a multitude of psychological and social challenges that make this process difficult for individuals and their families, IAs have introduced additional complexity. The unexpected element of uncertainty in predictive testing is not only challenging for the tested individual, but also medical genetics service providers who struggle to interpret and communicate this clinical uncertainty. While uncertainty is not uncommon in the field of medical genetics, the experience of receiving “grey” genetic test result will become increasingly more common as our scientific knowledge and technology advance. Moreover, as research gets closer to discovering a treatment for HD, more people will likely pursue predictive testing, and consequently there will be a growing number of persons who will receive an IA PTR. Therefore, it is essential that we increase our scientific knowledge on IAs, specifically whether they impart any disease manifestations for the individual and the risk of CAG repeat expansion into the affected range causing a new mutation. The “Grasping the Grey” model adds to our limited knowledge on the experience of receiving uncertain genetic test results. While more research is needed to examine how individuals come to understanding and interpret ambiguous genetic information in other genetic diseases, the developed theoretical model may assist in ensuring this unique subset of individuals receive appropriate support, education, and genetic counseling.
We would like to thank the study participants and medical genetics service providers who shared their time and experiences with us. Funding for this study has been provided by the Canadian Institutes of Health Research. Alicia Semaka is funded by a Senior Trainee Award from the Michael Smith Foundation for Health Research and a Doctoral Award from the Canadian Institutes of Health Research. Lynda Balneaves holds a New Investigator Award from the Canadian Institutes of Health Research. Michael Hayden is a Killam University Professor and holds a Canada Research Chair in Human Genetics and Molecular Medicine.