Reporting incidental genetic findings could be a goldmine

So, now that the cost of whole genome sequencing (WGS) is falling to nearly affordable levels, you're thinking of having your genome sequenced.  Or maybe you could just do your whole exome (WES), which if you don't know it already is the sequence for all the protein-coding regions--a very small part--of the genome.  Perhaps you've already been genotyped and you know your ear wax type and your purported generic risk of diabetes, but you think that if it's possible to know more about your genes and genetic risk factors, you really want to know.  Maybe you wonder if you're at risk of a specific disease that may run in your family, or maybe you're just curious.

Or, perhaps you've got a rare life-altering disease, you're the only member of your family with this disease as far as you know, and you'd like to know why you have it, if possible.  Maybe you'd like to know whether you're at risk of passing it on to any children you may have.  Or, WES or WGS might simply be diagnostic.

Or, you believe that the more whole genome sequences in public databases the better, and you'd like to contribute yours.  You understand that many genetic risk factors aren't yet well-defined or understood, but you'd like to contribute to the learning process.

Reasons for sequencing vary greatly, from personal choice to clinical indication, but at least these questions apply to everyone: How much do you want to know?  And should you be able to make that decision for yourself?

A piece published in Science on May 31 reports that you may not be able to answer these questions for yourself in the future:

The American College of Medical Genetics and Genomics (ACMG) recently issued a statement recommending that all laboratories conducting clinical sequencing seek and report pathogenic and expected pathogenic mutations for a short list of carefully chosen genes and conditions. The recommendations establish a baseline for reporting clinically relevant incidental findings and articulate ethical principles relevant to their disclosure.

That is, the ACMG is recommending that anyone undergoing WGS for clinical purposes -- for diagnosis or evaluation of a tumor for treatment purposes, e.g. -- be informed if they have one of the disease-related mutations on the list of the College's choosing, mutations that are not related to the purpose of the initial testing--that is, not related to the disease that initiated the sequencing. These would be incidental findings.  They add that they "recognize that there are insufficient data on clinical utility to fully support these recommendations" but that the list will be revised as data improve.

The diseases currently on the list were chosen, according to the Science piece, based on "the potential for medical intervention to mitigate disease, the strength of association between specific gene abnormalities and the condition, and penetrance of those genes." They are generally pediatric, rare diseases and incidental findings with respect to these diseases will, the ACMG estimates, affect perhaps 1% of people for whom clinical sequencing is done.  But how useful is this, even for those 1%?

Healthy people probably don't mind learning of incidental findings, and might even welcome them, though they are already often asked if they are interested in knowing their genotype for a small set of diseases -- Alzheimer's is one -- because that information is more sensitive than, say, eye color.

But, someone already living with a challenging disease or disorder may not want to know whether they have a higher than average risk of diabetes or breast cancer or dementia, particularly if onset is decades in the future.  That is, they've got a 'right not to know.'  They might feel they've already got enough to worry about.  Indeed, even the ACMG recognizes that risk assessment is iffy at best, even for many monogenic diseases.

The most straightforward of these diseases are generally familial, often congenital or with early onset, and families are likely to already be aware of their risk, or can be or have been genotyped for causal variants or carrier status.  So, it's arguable that there's little clinical advantage to reporting apparent risk of these kinds of disorders because it will be redundant.  Or more importantly, uninformative. Indeed, for many such disorders it's not clear what the population frequency of 'causal' variants is, and thus how likely the variant is to actually be causal.

And, as we've discussed many times here on MT, it's impossible to predict environmental exposures into the future.  Risk is always determined retroactively, given past exposures, because that's all we've got.  If a disease or disorder is due to a gene x environment interaction, as many are, including BRCA1 and 2 to some degree, then knowing that we carry a potentially causal variant is not enough information to predict disease.  Indeed, that information does not exist.

Further, all of us, whether we're healthy or already affected by a genetic variant, are carrying a not insubstantial number of genetic variants, including copy-number variants, deletions or insertions, and single nucleotide polymorphisms that may or may not be associated with disease.  Often not.

Currently, people undergoing clinical WGS or WES are given extensive genetic counseling, and asked whether or not they prefer to be informed of findings unrelated to their condition.  The ACMG says this is not going to be practicable in the near future, when sequencing is more common and the laboratory doing the sequencing is not involved in reporting findings to the patient.  Incidental findings will simply be reported as a matter of course.

We recognize that this may be seen to violate existing ethical norms regarding the patient’s autonomy and “right not to know” genetic risk information. However, in selecting a minimal list that is weighted toward conditions where prevalence may be high and intervention may be possible, we felt that clinicians and laboratory personnel have a fiduciary duty to prevent harm by warning patients and their families about certain incidental findings and that this principle supersedes concerns about autonomy, just as it does in the reporting of incidental findings elsewhere in medical practice.

But reporting incidental findings to a patient without genetic counseling is, we propose, harmful. Further, 'harm' can include telling someone who's already dealing with a challenging disorder or disease that he or she carries a genetic variant that may or may not cause disease sometime in the future. There are very rarely absolute risks associated with genetic variants.

The Science piece argues that to treat genetic information any differently from other kinds of medical information is wrong.  A piece in Genetics in Medicine, published online May 30, argues that the situation is akin to when a patient has a chest x-ray to diagnose pneumonia and the radiologist sees a tumor in the lung -- of course the patient is told.  It would be wrong otherwise.  But a visible mass is different from a probabalistic risk.

It's true that there are many kinds of laboratory results that are not definitive, but they are evaluated within a clinical context.  Risk of heart disease is rarely based on blood lipid levels alone.  It seems premature to conclude, rather patronizingly at that, that patients must be told incidental genetic findings that may or may not be meaningful.

Or.....not?  A remedy for reporting bias against negative results?
On the other hand, perhaps there is a very valuable piece of information that the medical establishment may, in this context, not want to know even themselves!   As we noted above, many of the 'incidental' findings have to do with severe, usually early onset traits.  Incidental findings of that sort in people who already know they don't have such a disease (since, for example, they're grown-ups without the pediatric problem), actually are valuable negative evidence for the genotype's causative role!

We and many others have criticized the many incentives that lead to over-claiming of results in the genomics arena, such as the publication bias against negative results.  But here we may have a gold mine of tempering evidence, to undermine the kinds of confident predictions often offered.  Every case of a supposedly causal mutation (or a devastating mutation in a causally associated gene) that turns up as an incidental finding should be used to adjust, and often to reduce the risk associated with a putative gene or allelic variant.  Here, without mounting a specific study and then only reporting positive findings, we can accumulate negative findings in a classically unbiased way--by studying people without the target trait (similar to studying a disorder, like stroke, by age-sex matched hospital patients who are there for unrelated diseases).

Could incidental findings be a gold mine of discovery for variants that do not yield as high a risk as has been thought (or hyped)?