This study is the largest survey ever carried out into the question of genetic diagnosis and focused on individuals at risk in families affected by CADASIL. As expected in this type of studies, the highest socio professional categories were over-represented both in already diagnosed and in at-risk individuals. However, neither the occupational activity nor the family structure differed between these two groups. Moreover, the results show that more than 9 out of 10 people, whether diagnosed or not, had first-hand experience of the disease through close contact with a patient suffering from the condition. Altogether, these findings support that a greater or lesser proximity to the disease, the socio-economic situation or even, the family structure, would not play a major role in the decision of being genetically diagnosed or not. Conversely, age might well represent a key factor in the decision. The respondents who had already undergone genetic testing were the oldest, which is consistent with the fact that they were most often already diagnosed after the onset of suggestive symptoms at a median age of over 60 years [11, 37]. As expected, on the other hand, individuals at risk were the youngest respondents and were therefore, more likely to be childless. An interesting finding is however that among respondents younger than 40 years, those who have children are more likely to have been diagnosed than those without children. Thus parenthood is apparently linked to a higher propensity to get diagnosed. Our qualitative survey nevertheless suggests that this trend is not related to the use of prenatal diagnosis or medically assisted reproduction.

Our study also shows that individuals at risk were relatively well informed about CADASIL. A vast majority of them had already searched the Internet for detailed information about this condition.More than 80% had already consulted at least one of the three websites dedicated to this topic in France, and 21% had already searched for information on all three of these sites. This is only slightly less than the proportion of patients who have already been diagnosed. They differed from subjects who had already been diagnosed in that they were significantly less likely to consult websites managed by medical or expert teams, while an equivalent proportion had consulted the family reference site available in France. However, these findings might be the consequence of our recruitment strategy: it is likely that most at-risk people accessed the questionnaire through CADASIL France website. These results also suggest that patients whose diagnosis has already been confirmed may search for more information about the disease, and/or that individuals at risk may want to keep a certain distance from the medical world.

Overall, the proportion of individuals with suggestive clinical manifestations of the disease was high-more than 70%—among those who already had undergone genetic testing. Interestingly, we observed that patients who had been diagnosed less than 3 years after they became aware of a confirmed diagnosis in their family presented more often suggestive symptoms of the disease, either mild or severe, than individuals who were diagnosed later. Their age did not differ from patients waiting longer for genetic diagnosis. In parallel, among people at risk of CADASIL who had not yet undergone diagnostic testing, both the two subjects who had planned to be tested already experienced possible disease symptoms Among at-risk individuals who had not made a decision at the time of this study, the onset of symptoms was considered by far the main reason which could lead in future to get genetic testing. These results strongly suggest that the perception of symptoms may ultimately represent a key element in the general decision to undergo a genetic diagnostic test, even in at-risk individuals who are still considered not to be ill. These results are in line with data obtained in the diagnostic context of Huntington’s disease. Subjects with few disease symptoms are three times less likely to abandon the step-by-step diagnostic procedure than individuals without any symptom of Huntington’s disease [29]. Moreover, 91% of people at risk of the condition who thought they had symptoms turned out to be carriers of the disease gene. Our results and these earlier data therefore suggest that the term ‘pre-symptomatic’ for genetic testing in some at risk individuals may ultimately be somewhat misleading, both with regard to CADASIL and Huntington’s disease. As our survey showed that individuals at risk were fairly-well informed, particularly via the Internet, it cannot be ruled out that their decision to undergo a genetic diagnosis is influenced by the appearance of symptoms, even very subtle.

In the at-risk group, half of the respondents (49%) stated that they had decided not to be tested at time of the survey, while 38% reported that they had not yet made a decision. Such results could be interpreted according to Cox et al. [7] with analyzing both the ‘meaning and experience of the decision’ to order a predictive genetic test. This approach is at odds with the “why” question, which asks why people make decisions rather than how they make them. Individual decisions to be tested or not should not be understood as the output of a rational analysis of the advantages and disadvantages. The decision-making is often gradual, and people could fluctuate between moments of opposition or ambivalence about the test, to others where the consequences are weighed up, for themselves and for others. A provisional position could gradually give way to a feeling of being ready to proceed with the test. In this context, it is therefore possible that the respondents who indicated that they had not yet made a decision were simply at the beginning of such a process. The decision not to undergo genetic testing does not seem to be akin to denial or to disease-avoidance behaviour as suggested by some authors in other comparable contexts [13]. In line with the report of Geelen et al. [17], the results of our survey do not support this hypothesis for different reasons. First, we found that, in the at-risk group, people who consulted a specialist had exactly the same position regarding the diagnosis than people who didn’t. Second, a large proportion of individuals at risk were searching for information about CADASIL. Third, over 90% of them were in close contact with someone with a confirmed diagnosis of the disease. However, we should also notice that a bias possibly related to the non-selection of individuals at risk in the real denial of the disease could not be excluded. In contrast, the concern about the disease taking over their life is by far the most significant factor holding back people at risk from being tested. Two third of individuals at risk claimed their fear that the disease might become too invasive. The burden of self-observation in the lives of those diagnosed with Huntington’s disease, even if they state that the onset of Huntington's disease does not seem to be triggered by a newfound awareness of their carrier status, has been already documented [15].

Our survey also asked at-risk subjects about the reasons why they might change their decision not to have a diagnostic test, and on which occasion they might decide to have a genetic test. Apart from the onset of possible symptoms of the disease, as already mentioned, around one third of individuals at risk reported that they might make such a decision if they had to decide to become parents. A similar proportion would choose to be tested if they had a close relative who developed the disease. These results are in accordance with the small number of motivations found to obtain a genetic test in other conditions [24]. The importance of a parental project has been already emphasized in similar contexts [8, 18, 28, 29, 33]. In addition, the clinical manifestations observed in a close relative might contribute to making the disease an inescapable reality. Some studies put forward the desire to reduce uncertainty and anxiety and being in a better position to make decisions and plan for life as shown in the general context of genetic diagnosis of presymptomatic and symptomatic cases [22, 29, 31, 32, 36]. No investigation was previously focused only on individuals at risk who did not undergo diagnostic testing as in our study. Interestingly, the poor impact of pressure from loved ones on the decision to undergo genetic testing was similar to that reported for persons at risk of Huntington’s disease [15].

In our survey, most individuals, whether they were at risk or a mutation carrier, expressed their willingness to participate in a clinical trial. Nevertheless, 31% of mutation carriers and 27% of at-risk individuals conditioned their participation on potential side effects and duration of treatment being tested. Interestingly, in one part of our questionnaire, only 37% of individuals at risk responded that the prospect of a clinical trial would lead them to undergo genetic testing while, in another part, 73% would be willing to undergo genetic testing to participate in a clinical trial for testing a drug that could prevent disease progression. How can we explain this discrepancy? The “prospect” of a clinical trial in the first question could have referred to a less tangible situation than an actual participation in a clinical trial, as presented in the second question. This might therefore have justified a more wait-and-see stance. On the other hand, the fact that the second question offered a range of answers allowing respondents to qualify the statement and specify the clinical trials (with or without side effects, longer or shorter) may also have put them in a more realistic situation.

Overall, however, the results suggest that people at risk as mutation gene carriers are a priori relatively open to the possibility of participating in clinical trials. The question of the legitimacy of screening for a serious disease for which there is no treatment has become a hot topic of debate. In the field of Alzheimer’s disease, some authors already stressed the potential benefits of genetic screening, particularly in terms of biomarker research, improved prevention or identification of risk factors that could be reduced [1, 2]. Despite the uncertainties regarding biomarkers at preclinical stages of the disease and the potential difficulties in designing secondary prevention trials, the issue is globally approached very optimistically by reducing the ethical questions in relation to presymptomatic diagnosis at individual level to the potential collective benefits of clinical trials. However, this could also be interpreted as a highly questionable transposition of collective benefits to an individual level [10]. The legitimacy of revealing a person’s presymptomatic status, when knowledge of the long-term implications remains uncertain, is debatable. Actually, the trade-off between the individual risks (associated with this disclosure in view to participating in clinical trials) and the collective benefits expected from trials in fact, has finally become today a new ethical dilemma [16, 21]. These questions often focus more on the attitude that researchers and doctors should have, than, on the actual point of view of those primarily concerned, i.e., patients. In the context of CADASIL, our results suggest that there is a large variability in the different attitudes to this question, that many people at risk remain clearly uncertain, and that it was is to respect these different points of view and the time needed to make any decision. Other studies, in different socio-economic and cultural contexts, will clearly be needed to develop future trials at presymptomatic stage of CADASIL.

We are aware of different limitations in this study. First, as in virtually all surveys of this type, patients with a special interest in their health status were more prone to participate and women were over-represented (69% among carriers, 77.5% among those at risk) which could partly skew the interpretation of our results. Second, we cannot exclude the influence of the diagnostic protocol in place on certain responses to the questionnaires as already suggested [29]. Within the referral centre, which serves as a model for the management of the disease in France, the respect for ‘not knowing’ as much as for “wanting to know” is strongly asserted in individuals at risk. Furthermore, the systematic diagnostic procedure for subjects at risk is a long process and requires a real investment on the part of the requesters. This could reduce the number of requests and lead to more cautious decisions than in a less regulated environment. Finally, these results may apply only to countries with access to sophisticated diagnostic tools and extensive medical insurance cover. We think also that this study has multiple strengths. The survey was not set up by a medical team but was primarily prepared by a team of sociologists who was independent of the diagnostic and management process. They validated with both medical and social workers and the families concerned the different questionnaires they initially designed. This survey made it possible to obtain information from subjects who never consulted and who were not involved in research activities. Moreover, at-risk population comprised both individuals who already had consulted for CADASIL and those who had not. Such a latter subpopulation is distinct from previous approaches adopted in studies analyzing the presymptomatic diagnosis process in similar conditions. Then, our method allowed access to a wide range of people with diverse CADASIL-related experiences.

In summary, the results of this large and independent survey showed that individuals at risk among families do not actually differ from already diagnosed subjects except their younger age and frequent childlessness. They are well informed and in close contact with CADASIL patients and do not seem to be in denial about their personal risk regarding this condition. Most often, they do not undergo genetic testing for fear of being overwhelmed by concerns related to the disease and prefer to delay such a decision to the onset of the first symptoms. Finally, it is as if people at risk put off the shift from indeterminate to patient-in-waiting [34] until the disease makes its presence felt, even if discreetly. From that tipping point onwards, other uncertainties—about how the disease develops or what it is like to be an ill person—take the place of uncertainty about status [16, 21]. Reasons that could lead to a diagnostic decision other than the appearance of symptoms could then vary widely and might depend for example on the decision to become parents or on the experience of the disease in a close symptomatic relative. Finally, although the interest of subjects at risk in therapeutic development is as high as in CADASIL patients and indisputable, the influence of a possible participation in a therapeutic trial on such a decision appears ambiguous and uncertain. At first sight, such results might seem to compromise the recruitment of asymptomatic people in future clinical trials, as it would require them to engage in early diagnosis. It cannot be ruled out, however, that a more favorable scenario leading to acceptance of a proposal could take place after further reflection and in a real and very concrete situation.