ESHG Plenary Debate 2015: Should Clinical Geneticists have their Genome Sequenced?
Now that genome sequencing prices are dropping fast and genome/exome sequencing is increasingly offered in a diagnostic setting, the ability to counsel patients on having their genome or exome sequence is becoming increasingly important. Additionally, an increasing number of healthy individuals are having their genome sequenced, either out of curiosity or because they think that there may be a gain for their own health. With the underlying hypothesis that personal experience improves counseling skills, the statement “Should clinical geneticists have their genome sequenced?” was discussed during an interactive debate session on June 9th 2015, at the European Society for Human Genetics (ESHG) meeting in Glasgow, United Kingdom. The discussion was chaired by Joris Veltman (Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands) and Martina Cornel (VU University Medical Center, Amsterdam, The Netherlands), and the panel consisted of Carsten Bergmann (University Freiburg Medical Center, Freiburg, Germany), Kate Bushby (Newcastle University, Newcastle upon Tyne, UK), Heidi Howard (Uppsala University, Uppsala, Sweden), and Gijs Santen (Leiden University Medical Center, Leiden, The Netherlands).
The discussion started by asking the audience for their opinion on a number of related statements. Firstly, the background of the audience was assessed: the largest groups were clinical geneticists (in training) or genetic counselors (∼40%), scientists in diagnostics (∼20%), and researchers (∼30%). Regarding the attitude toward genetic testing, less than 10% had undergone any testing, ∼50% would be interested in having their genome sequenced, but 20% would definitely not want their genome sequenced. The majority of the participants felt that if geneticists’ genomes were to be sequenced, it should be offered under strict guidance. An additional 18% felt it was a waste of public money, and 12% felt it even dangerous to experiment on yourself. Finally, regarding the central statement “Should all geneticists have their genome sequenced?”, 43% disagreed, 47% either were not strongly in favor or against, and only 10% agreed.
Subsequently, a lively debate of about 1 h followed, in which both panelists and the audience gave their opinion. Strikingly, many personal experiences with genetic tests were shared by the audience. Where some reported having severely underestimated the consequences of genome sequencing, particularly toward other family members, others reported to be rather underwhelmed by the experience. Personal examples were given of both clearly false-positive findings and of findings which had potential clinical benefits.
In an attempt to structure the arguments that were outlined, I have divided the arguments between those in favor and those against.
Arguments in Favor of Geneticists Being Sequenced
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Personal understanding of the process that patients go through will improve counseling skills of clinical geneticists, and increase the understanding of research/diagnostic scientists. Indeed, some genetic professionals who had their genome sequenced reported to have underestimated the effects, especially on their family. It was argued that personal experience is more intense and therefore more valuable. Alternative methods to increase counseling skills were suggested, such as analyzing a dummy genome during training, or having an in-depth interview with a number of patients who have undergone genetic testing. Indeed, it was suggested that thinking about the statement and having the discussion itself would increase counseling skills of geneticists.
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Now that the uptake of direct to consumer genetic testing is rapidly increasing, and many non-geneticists are having their genomes sequenced, is it not important for educational and media purposes that there are some geneticists who can comment on this experience from within the field? Or should we leave this completely to non-experts, with the risk that we no longer have any influence in what the public hears about genetic testing? This could potentially lead to significant over-estimation of the utility of applying this technique to healthy individuals.
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Analyzing your own genome will stimulate people to start interpreting variants themselves. In doing so, you will have to go into literature yourself to find out what is known about a particular variant. It will be instructive to see how few variants are actually shared in open accessible databases, and on the other hand, the difficulties faced when trying to interpret literature. Indeed, many of the articles reporting pathogenic variants provide scarce evidence for this, making it difficult to reach conclusions. It is conceivable that a geneticist would go through greater lengths interpreting a variant in, for example, the BRCA1 gene when this variant is identified in their own genome, rather than a patient's. In addition, this personal experience might stimulate data sharing, for example, when the expert encounters variants which would be classified as variant of unknown significance in their genome while their phenotype facilitates classification as either phenotype associated (affecting function) or not (not affecting function).
Arguments Against Geneticists Being Sequenced
Perhaps surprisingly to some, the majority of arguments raised during the discussion fell into this category. They can be divided in more practical arguments and arguments questioning the utility of sequencing geneticists’ genomes.
Practical Arguments
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It is a waste of resources to spend money on sequencing geneticists. This public money could be much better spent elsewhere in healthcare. If geneticists want to have their genome sequenced, they should pay for it themselves. However, even if geneticists would pay for their own genomes, it would potentially make patients out of otherwise healthy geneticists, which would not only take up a significant amount of time of geneticists themselves, but also of all the other doctors they would be consulting. Furthermore, the data would have to be interpreted and psychosocial counseling should be available for the geneticists who undergo sequencing. And who would analyze the data? Perhaps you would not want to analyze your own data because you do not want to risk knowing about late-onset untreatable disorders, but could you ask your dear colleagues to look at your genome data and withhold such information? And what if they find unclassified variants in colon cancer genes? “How are you doing?” coming from the person who analyzed your data will never sound the same again!
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One of the most important things clinical geneticists are taught during their training is to respect the patient's autonomy. We should not push people to make a particular decision, but should enable them to make their own. Pushing geneticists in training to sequence their genomes would be at odds with this principle: there should be no pressure on the decision.
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The law: in some countries it may be illegal to offer screening without having requested permission from the Ministry of Health. For example, in the Netherlands, it is illegal to offer total-body MRI screening. But of course, laws are subject to change.
Arguments Questioning the Relevance
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Even asking the question whether clinical geneticists should have their genome sequenced would seem odd to any medical doctor: indeed, do we ask of gastroenterologists to undergo a colonoscopy during their training? Do anesthesiologist undergo anesthesia? Do radiologists undergo total-body MRIs? Some of these procedures carry risks, which would be a reason not to undergo them. But in general, medical doctors are considered to be able to inform their patients on procedures they did not undergo themselves.
There is an exception: psychoanalysts do have to undergo a 3-year “training analysis” during their training, and so do psychiatrists at least in some countries. So perhaps the real question is whether clinical geneticists are more comparable to surgeons or psychoanalysts. Psychiatrists phrase the aim of these “training analyses” in the competences of communication (learning to manage your own role) and professionalism (adequate professional behavior and understanding your own limits). Does it help counseling a patient when you have in-depth knowledge of your own genome and the process that got you this knowledge? It is unlikely that a geneticist will use their own genome when interpreting that of a patient, but having an in-depth understanding of the process might be valuable. On the whole, however, the discussion seemed to conclude we are in that respect more like surgeons, radiologists, and other medical specialists than psychoanalysts.
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There are important differences between genome sequencing of patients and healthy individuals, such as us. In patients, we know that genome sequencing can be an efficient method to determine the genetic cause of an illness, which has implications for the patients themselves and their family. Indeed, that is the whole point! Yes, there is a risk of incidental findings, but for most patients, the risk–benefit ratio is acceptable. This is a different prospect than to ask a healthy individual to have their genome sequenced: what is the benefit that can be expected? Interestingly, several people questioned the utility of genome sequencing in healthy individuals. I think this reflects that the community realizes that at this point in time not much can be learned from the genome that would have major implications on our health, in the absence of symptoms in us or a positive family history. Indeed, interpreting an exome or genome in the context of disease is difficult enough, let alone interpreting the data in the absence of phenotypic information.
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It was also suggested that rather than sequencing ourselves, we should be sequencing both diseased individuals and older healthy individuals. One might even consider adding an option for whole-genome sequencing on the post mortem consent form. Variants identified in such populations will be much more informative than variants identified in the relatively young group of geneticists. In that sense, perhaps it would be more useful to sequence retiring geneticists rather than geneticists in training, and have geneticists in training counsel their retired peers. On the other hand, sequencing young people has a higher potential benefit: for example, knowing carrier status for recessive disease might prove beneficial for family planning.
Cultural Components
There were also some general remarks made which were of interest, but do not fall in any of the categories above. First of all, it was suggested that there is a clear cultural component to this discussion. Apparently, in some areas of the US, many people are undergoing genome sequencing or other genetic tests already, and it was suggested that were this statement debated in the American College of Medical Genetics (ACMG) the response would have been much more favorable. Also, arguments were made that we should protect the public from freely accessible genome sequencing until quality standards are in place and we are better available to interpret variants. Then again, we should not underestimate the public's ability to deal with uncertainties.
Final Perspectives
Following this lively exchange of arguments, several additional questions were asked of the audience. Interestingly, although only a minority had previously indicated to support the statement, ∼85% of attendants felt that if their genome were sequenced, they would want to know their carrier status of the 56 (mostly oncogenetic and cardiogenetic) genes selected by the ACMG for which effective interventions are available. Also, a similar proportion of attendants would want access to the raw data. Rather provocatively, it was asked whether clinical geneticists thought it possible to explain the results of whole-genome sequencing in under half an hour. Unsurprisingly, 80% thought this was not feasible.
Finally, the central statement was voted on again: “Should all geneticists have their genome sequenced?” This time, more people chose the more extreme answers. Where the number of people agreeing with the statement had increased from ∼10% to ∼12%, the number of people disagreeing increased from ∼43% to ∼53%, reflecting the preponderance of negative arguments given in the debate.
In conclusion, the majority of the audience believed that there might be some benefit in sequencing geneticists’ genomes, although it was argued these benefits could potentially be obtained using alternative approaches. There are many arguments against, both practical in nature and related to the utility of performing this exercise. The general consensus was that it would be important for some geneticists to have their genome sequenced, as it would enable them to influence the public opinion from within the genetic community, but that there should be no pressure on the genetic community as a whole to have their genomes sequenced. Regarding the statement itself, it was felt that in retrospect it might have been better to rephrase the statement to “Is it useful for geneticists to have their genome sequenced,” as the current phrasing may be interpreted to imply mandatory genome sequencing for geneticists, which clearly was never the intention.
Personally I had been considering whether to have my genome sequenced in view of the rapidly dropping sequencing prices prior to the debate. I decided against it, mainly because I did not expect to experience any health-related benefits. In contrast, I considered the risks of identifying variants that would unnecessarily worry me about myself or my children as too high. I have no objection against genetic testing per se: I did have my CFTR gene tested before having children because I felt this could yield useful results. The problem I anticipated is known by anyone involved in exome/genome analysis: any person has a lot of variants that can be easily classified as pathogenic, and therefore genome analysis is exceedingly difficult in the absence of a clearly defined phenotype. Even for known pathogenic variants, that most geneticists would want to know about, the risk in absence of a family history has not been established, let alone cost-effectiveness of screening the whole population carrying this variant. It is likely that the families we counsel in daily practice represent the tip of the iceberg, carrying several additional genetic risk factors alongside the highly penetrant mutations we routinely identify.
The debate at ESHG did provide an argument I had not previously considered: would it help me in counseling patients? I can see that it might, but I am not wholly convinced. For one, as discussed above, I am not asking my patients to have their genome sequenced just for the fun of it; it has a purpose. Likewise, I do not think I would advise my family and friends to have their genomes sequenced. Perhaps it should be investigated whether undergoing genome sequencing improves counseling: counseling skills before and after having one's genome was sequenced could be measured, and a group could be included who would interview a number of patients who had genetic testing instead of having their genomes sequenced. If it were shown that counseling skills would be improved, I would revisit this question. However, whether I would volunteer for this study is something I have not decided upon.
The video of the debate is freely accessible at the following URL: http://clent.cntv.at/eshg2015/PL3
Acknowledgments
I would like to thank the organizers of the debate (Joris Veltman and Martina Cornel) as well as the co-panelists (Carsten Bergmann, Kate Bushby, and Heidi Howard) for their input during the debate and on this manuscript; Johan den Dunnen for comments on an earlier version of this manuscript; an anonymous reviewer for valuable suggestions; and the audience present at the debate for making the discussion lively.
