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Recent years have seen the arrival of a new technique for genetic sequencing with an increased capacity to explore the whole exome and genome of patients: it is the Next Generation Sequencing technique (NGS). NGS brought enormous improvements in terms of investigations for research or diagnosis on inherited diseases, rapidity and lowering of the costs.

This enormous new capacity to explore the whole exome (genes that are coding for proteins) or even larger the whole genome brings also the possibility to uncover a finding that was not sought for; this is what is called incidental findings: a mutation or a variant that may indicate a potential risk of the patient to develop a specific disease.

The BIG Questions:  What to do with incidental findings? Do and how the geneticians/clinicians should or must feedback the patient with information on the findings?

This topic is becoming a hot topic among the inherited diseases research community. It was the focus of the ethical session during the 3rd annual EURenOmics project (see research project). With a session entitled:

Ethics: NGS/exome sequencing, from research to diagnosis and information to patients: Are we ready?

Different cases were presented and discussed during the session.  Daniel Renault, from FEDERG was representing the patient at the Heidelberg meeting; he presented the point of view of patients at this session.

Q: What are the cases were NGS techniques are applied with the risk of bringing Incidental findings?
There are basically two situations for which geneticians are doing a large gene investigation:
First when the first diagnosis analysis on the targeted variants (mutation) has not led to any identification of the known candidates, the gene spectrum is then highly enlarged either to the exome or to the genome with the hope to find other variants that may explain the clinical symptoms. That’s the first case in the diagnosis.
The second case is when you do research for advancing knowledge on genetic diseases with the idea of discovering other potential genetic factors that may explain partly some of the specificities of the pathology, for example for the same pathology the diverse rate of degradation of the renal function.

Q: Is the point of view of patients on incidental findings unique?  
The answer is mixed. A NO would reflect the fact that most studies on Incidental findings (IF) have not enough included the point of view of patients. So far the debate has been done within the professional community confronted to IF, and patients are “Seen but not heard” as pointed out some experts criticizing some of the initial guidelines for Ifs that some bioethical committee have produced.  The answer is YES if we want to reflect that a growing number of experts (Geneticians, clinicians, ethical experts) are considering that patient should be mostly the one to decide whether or not IF should be reported back.

Q: How can patients decide for themselves or for their child?
This question is critical, and we can see that IF related to NGS has not been enough discussed among the patient community. A decision has to be “informed”, like the informed consent that patient have to sign when they enter a survey, a registry or a trial.
There is no brochure, leaflet or booklet on the incidental findings. So patients are not enough informed, and associations and federations should create group discussions throughout our community to prepare patient for a decision.
The issue of deciding for the child is even more complex, and that why knowing other people stories will allow parents to understand better the spectrum of possible positions and the consequences for themselves and for their child.

Q: What spectrum of decisions? 
What we see, in very recent studies on patients preferences for IF is that approximately 1/3 of people wants to know everything, 1/3 do not want to know at all and 1/3 is mixed or don’t know.
Therefore there will be no single position of patients on IF except that we should be given the choice.

Q: What if the finding is very severe? 
In case of a high clinical significance, which is related to severity, certainty of diagnosis, short term health impact, there is a debate on whether the position of patient for NO feedback is still acceptable or not. The responsibility of the geneticists and clinicians are somehow engaged, and we may consider ethical that the OPT-OUT do no longer apply.  This kind of case should be discussed at an ethical committee first to avoid the bearing of the decision on only one shoulder. If the clinical significance is not high, then the choice should remain with the patient.

Q: What if the founding is very vague and uncertain?  
This case is also another case for which discussion are uneasy.  There are patients that consider they want to know everything for good reasons (See box), there are patients for which maybe the worry of knowing is too high compare to the risk. But again what is critical is the information to patient in lay language that can be assimilated by everyone.

Q: Is it important for FEDERG to invest on that issue?
Yes I believe so! Because the cost of sequencing is drastically going down and tomorrow everyone will be able to afford a whole genome sequencing from private companies.  Now what would be the quality of the genetic counselling associated to the results is a big question mark.
So it’s better to be prepared to this revolution and to share among us the stories of people that were confronted to the decision and to feedback from IF. It is good starting point for developing your own “informed position” on IF.
There is little information out there on IF because it is new. If you look for something on specific kidney pathology, on dialysis and transplant, you’ll find them in various languages. Thus there is a need to fill that gap by making a compilation of cases and suggest possible positions for IF related to Kidney genetic diseases makes sense.  FEDERG can do its part on that.


Background: LEARNING from looking back to Incidental findings.

30 years ago Ms X 2 years old, was affected by a suspected urine infection linked to a high fever illness, urine test performed to found the right antibiotics revealed haematuria, and further tests were made without any firm conclusion. But at that time parents were alerted on a possible renal disease despite the uncertainty of diagnosis (various renal diseases were candidate to explain the haematuria), the uncertainty of the onset of the renal disease, and the total absence of any treatment. A firm diagnosis of the specific renal disease came only 5 years after when a kidney biopsy was performed.

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