No choice for you

Guest Co-Author: Dr Anna Middleton is an Ethics Researcher and Registered Genetic Counsellor, based at the Wellcome Trust Sanger Institute, UK.

StethCollage1The American College of Medical Genetics (ACMG) has recently published recommendations for reporting incidental findings (IFs) in clinical exome and genome sequencing. These advocate actively searching for a set of specific IFs unrelated to the condition under study. For example, a two year old child may have her (and her parents’) exome sequenced to explore a diagnosis for intellectual disability and at the same time will be tested for a series of cancer and cardiac genetic variants. The ACMG feel it is unethical not to look for a series of incidental conditions while the genome is being interrogated, conditions that the patient or their family may be able to take steps to prevent. This flies in the face of multiple International guidelines that advise against testing children for adult onset conditions. The ACMG justify this as “a fiduciary duty to prevent harm by warning patients and their families”. They conclude that “this principle supersedes concerns about autonomy”, i.e. the duty of the clinician to perform opportunistic screening outweighs the patients right not to know about other genetic conditions and their right to be able to make autonomous decisions about testing.

There is strength in the above argument if opportunistic genetic screening did indeed reveal a definite predisposition to a treatable and preventable condition where steps could be taken to protect the individual or their family. But this isn’t the case with some of the conditions the ACMG insist on testing for. There are many apparently ‘disease causing’ variants that appear in healthy people with no evidence of disease, and in the absence of a strong family history it will be difficult to interpret these results. It is not too far fetched to imagine that, in the hands of a health professional who doesn’t understand the limitations of testing, that a supposed BRCA1 variant will be identified in a women who is then advised to have preventative surgery to remove her ovaries and breasts. And yet in the absence of symptoms or a family history, it is impossible to tell whether the BRCA1 gene fault is fully penetrant and whether there are any modifying genes at play.

The ACMG acknowledge “there are insufficient data on clinical utility to fully support these recommendations… and… insufficient evidence about benefits, risks and costs of disclosing incidental findings to make evidence-based recommendations”. Yet, they clearly felt the need to draw a line in the sand and create a starting point. This is a bold and fearless move. The result is that a set of conditions, genes and variants are listed, many of which will reveal uncertain pathogenicity in the absence of a family history. Moreover, in many cases, there is no screening programme available. (What should be offered to a child with a P53 mutation? There is no universal agreement on whether screening for rhabdomyosarcoma is appropriate.) The intent was to identify “disorders where preventative measures and/or treatments were available” but the reality falls short.

Finally, the ACMG “Working Group encourages prospective longitudinal research on incidental or secondary findings and the development of a voluntary national patient registry to follow individuals and their families who receive incidental or secondary findings as part of clinical sequencing and document the benefits, harms and costs that may result.” In effect, what they are saying is that we don’t really know what the impact of this technology will be, and only time will tell whether our risk predictions are correct. Given such uncertainty and also the fact that many of the families and individuals who will be accessing this technology are incredibly vulnerable (by virtue of their desperate need for a diagnosis for example, for a developmental disorder), it strikes us that this all should actually be part of a research project and not offered as a clinical service. Under the guise of ‘research’ this makes much more sense. What do you think? If you want to contribute to other discussions about ethics and genomics, see our survey.

Consider the ACMG guidelines with the following fictitious case study in mind….

Case study

Bobby is a severely disabled 6 year old. He has learning disability, hyperactivity and is incontinent. Numerous paediatricians have seen the family over many years, but existing tests haven’t led to a diagnosis. Bobby’s parents are anxious to have a name for his condition. Without an actual diagnosis it is more challenging to access the educational and respite care he needs.

At their latest paediatric review, Bobby’s parents are given the first glimmers of hope – there is a new test, an exome sequence, that will explore the subtle changes in Bobby’s genes to (hopefully) reveal previously undetected genetic causes for his condition. However, there is a catch – the testing comes in a package where other conditions are also explored at the same time.  The parents aren’t interested in anything else and they are confused when the paediatrician tells them Bobby will be tested for a whole set of adult-onset cancers as well as cardiac conditions. The paediatrician explains that these latter conditions are likely to be totally unrelated (‘incidental’) to Bobby’s condition, may not be relevant until Bobby grows up and also it may not be possible to tell with any certainty what the actual risks are of developing them. The parents are surprised – isn’t this a paediatric clinic? Why is a paediatrician talking to them about adult conditions completely outside her area of expertise?

The paediatrician explains that this is just the same as having a full blood count done or an X-ray – there is always the chance of picking up something unexpected. But, the lab will be specifically searching for a set of additional conditions, there doesn’t seem to be much that is ‘incidental’ about this. ‘Call it opportunistic screening’ says the paediatrician’; however, what shocks Bobby’s parents is the fact there is no choice. In order to access the exome sequencing technology they have to receive information on a set list of conditions, there is no opt-out only an opt-in. So, they have to proceed.

Some months later they receive a telephone call from their paediatrician, the exome did not reveal an obvious genetic diagnosis for Bobby’s disabilities however, after several weeks of additional exploratory work by the laboratory staff, they reported a change in a gene called ‘P53’ that is ‘likely’ to given him an increased risk of cancer. The lab had spent a long time looking through the medical literature and although the gene change looked as if it should be significant in that cancer was possible, the fact that no-one in the family had already had cancer (and the family was large with many people living well into old age), it was difficult to know what this actually meant for Bobby and his parents and whether cancer screening would be necessary or not. Bobby’s parents are stunned, they proceeded with testing that they had no choice about and now have to deal with uncertain results together with an uncertain plan of action. Should they be worrying about this result or not? Does it have implications for other members of the family? The paediatrician isn’t sure.


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6 Responses to “No choice for you”

  • Most of these ethical issues could easily be eliminated if the sequencing was done prenatally.

  • Prenatal is worse! It is extremely difficult for an anxious couple to cope with hearing about hypothetical, potential risks in a detached and analytical manner. In the prenatal setting you need as much certainty as possible.
    I think this decision, to notify of incidental findings, comes from medico legal fears from the labs. We have similar issues with CGH arrays, reporting 200kb duplications containing no genes! We are obliged to tell the family as the result then sits in their medical record and could be accessed later. It often takes an hour to explain these, in a public service where patients wait 12 months for an appointment. It is a massive waste of resources.

  • Important to note that many parents will simply do this on their own, even if it is not perfect. Direct to Consumer kits will allow parents and individuals to test themselves. Many more people have signed up for kits than are in geneticists’ offices. I think researchers will have to take this into account. The control WILL be in the patients’ hands and there is no way to stop that.

  • Vincent Plagnol

    I find the focus on these difficult situations a bit misleading. There are certainly plenty of individuals out there for whom the confidence in an incidental finding is strong (familial hypercholesterolemia caused by loss-of-function in the LDL receptor, HCM causing variants with confident reports in the literature…). To me, what the ACMG is saying, is that in situations where there is something that can be done, it is a duty to inform the patient.

    Indeed, if a doctor knew that I am positive for familial hypercholesterolemia, and tells me after my first cardiovascular event that he was not in a position to let me know about this, I would find this behaviour inacceptable (and most people will agree with me I think). Not letting the patient know seems vastly more problematic than the possible fear and confusion created by the knowledge of variants with unclear effects.

    There will always be difficult situations, and one will have to make subjective calls. But these difficulties should not change the rather obvious fact that, in the relatively rare cases where genetic knowledge can avoid a major health issue, common sense suggests that we must act. We should deal with the complexity and define appropriate guidelines, rather than using these difficulties as an excuse for not doing the obvious right thing.

  • “I think this decision, to notify of incidental findings, comes from medico legal fears from the labs.” – comment above from Genedoc.

    Wow! This is totally not the case! In fact, the labs are in an uproar about these recommendations. We are at medico-legal risk by reporting this rather odd set of “known pathogenic” and “expected pathogenic” (terms not defined by the ACMG) due to they are so open to interpretation, lack of available information to assess variants (BRCA1/2 being the most egregious), subjective decisions about what are KP or EP. And we have to report them regardless of whether the patient/family wants them. And we fly in the face of other guidelines that recommend against reporting adult-onset disorders in minors. The costs associated with this new guidance is totally not re-imbursable. I could go on and on….

  • I am not sure why there are so many blog postings in such a short time on this topic on this site (particularly from the same author), as various comments from many of us are sprinkled throughout the other postings. But, in response to Sherri Bale above, I will reiterate that we live in a capitalist world, and most people will NOT do the right thing if it costs them money, unless they HAVE to. These guidelines are one SMALL step toward doing the right thing.

    To explain why I say this, I would like to get to a world of millions of whole genomes shared and analyzed for numerous additive, epistatic interactions and gene X environment interactions, so that we can only then begin to make any reliable predictions for any one human being, particularly taking their ancestry into account. We need to sequence and collate the raw data from thousands and then millions of exomes and genomes, so that we can actually begin to really understand the expressivity patterns of any mutation in the human genome in any one person. I also talked about this in the comments section over at the Nature blog regarding the recent ACMG guidelines as well:

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