‘No choice for you’ according to the ACMG

Family have exome sequencing to determine son's diagnosis

Family have exome sequencing to determine son’s diagnosis

The 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 his (and his 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 an established 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 some results. It is not too far fetched to imagine that, in the hands of a health professional who doesn’t understand the limitations of the testing, that a supposed BRCA1 gene fault 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 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 somewhat.

Finally, the ACMG “Working Group encourages prospective research on incidental or secondary findings and the development of a voluntary national patient registry to longitudinally 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.

4 thoughts on “‘No choice for you’ according to the ACMG

  1. Your survey link in this article didn’t work [thanks! fixed now – AM]. I strongly believe people have right to know “incidental” findings if they wish, but this also means they have the right not to know. It should be a matter of choice for the people involved as people’s circumstances are different. Perhaps this could also be broken down into categories of what they opt to be given information about – actionable, nonactionable, fully penetrant, or risk factors etc.
    A great thought provoking article and example.

  2. Thank you for your comment. Now that I’ve fixed the link you picked up you’ll be able to go to our survey. This is where we ask specifically about the choices that people might want to make about IFs – ranging from knowing about actionable conditions through to ancestry. We’ve also got a section that asks people to rate the levels of risk that they might want to know about, e.g. if they say they’d like to know about serious life-threatening conditions, does this still hold true if the risk of this is only 1%, for example. The issue of what to do with incidental findings is so topical at the moment; the genetic counselling world is based on freedom of choice for parents and individuals, which is why the ACMG stance is such a surprise. I really appreciate you taking the time to read the blog and start the discussion!

  3. I think you touch a very sensitive issue here: whether the uncertainty of reporting a result (for which the patient was not originally tested for) could potentially do more harm than good.

    My own experience is that whether a person should be reported incidental findings or not is dependent on the psychology of the person and the family. There are some people who may feel really uncomfortable with the prospect of having to face an uncertain result, something for which not a lot is known. Some other people may feel that they would rather know as much as possible even if that adds more uncertainty.

    Thus it seems to me that ACMG’s decision to report selected mutations should be done taking into account the personal and psychological dispositions of the family: i.e. an independent assessment should be carried out before reporting results on whether the family can assimilate them. I do not think that people should be informed for a particular incidental finding unless they are ready to take and understand the result.

    Informing an incidental finding should also take into account a minimum level of understanding. I always encounter that non-geneticists, i.e., most people, have wrong ideas as to what genes can do and cannot. Even ourselves, people working on genomes, have a very poor idea of most of the effects genetic mutations do in patients. Perhaps it is a bit premature to try to make a general “recommendation” into something which is so unclear so far.

    I agree that having this kind of action catalogued as “research” would make a lot more sense as having it as “clinical service”.

  4. Pingback: 'No choice for you' according to the ACMG | OUPblog

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