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ESHG Issues Recommendations on Clinical WGS


The European Society for Human Genetics has issued recommendations for laboratories performing clinical whole-genome sequencing. The guidance was published this month in the European Journal of Human Genetics.

ESHG tackles a number of issues, including when to use whole-genome sequencing clinically, informed consent, whole-genome sequencing in children, dealing with incidental findings, patient privacy, interpretation, and how to re-contact patients as new information becomes available.

Martina Cornel, chair of the Public and Professional Policy Committee of ESHG and an author of the paper, told Clinical Sequencing News that ESHG decided to take on these issues now, because while the technology "was developed very much in a research context, at the moment, it's moving into clinical settings. … Everyone wants to use it and get what is useful in the clinic as much as possible, but it's also challenging."

As such, she said it is important to start developing recommendations to guide best practices. A lot of organizations starting to use sequencing in the clinic "come from a laboratory background where the differences between screening and diagnostics [are] new or not well known," said Cornel. "The regulations for diagnostics versus screening versus research are quite different." And, it's important for the community to "reconcile those different fields because they are becoming much more blurred and intertwined."

ESHG began addressing the challenges of clinical sequencing in a joint workshop of its Public and Professional Policy Committee and Quality Committee in 2010. Following the workshop, it issued a report, and began taking feedback in order to develop the recommendations, which were approved by the ESHG board last December and published this month.

The group lists 11 different recommendations. First, it seeks to promote the establishment of formal structures by which different organizations can share their experiences with sequencing in the clinic both nationally and internationally.

ESHG recognizes that different countries or even different hospitals may approach the implementation of sequencing in a healthcare setting differently since the technology is still new, and as such, it thinks that shared experiences will be valuable for establishing the best protocols.

Ideally, once sequencing becomes standard of care, protocols should be consistent, Cornel said. But, "as long as this is new and people are exchanging ideas and trying to learn, it's not wrong to not do it the same everywhere," she said.

Collaboration will be needed not only to establish the best protocols, but also to build accurate databases of genotypic and phenotypic information, the authors wrote.

One of the most debated areas of clinical sequencing is how to deal with incidental findings. In its recommendations ESHG suggests first doing targeted sequencing or to filter results of exome or whole-genome sequencing in order to minimize such findings.

It recognizes that a balance should be struck between wanting to be comprehensive to increase the chances of making a diagnosis, but also in focusing the technology to answer a specific clinical question.

"A targeted approach could therefore hinder the diagnostic process, whereas in case of using filters after sequencing new variants could more easily be added to the interpretation by adjusting the filter," the authors wrote.

Additionally, prior to performing the sequencing, "a protocol has to be in place to give guidance on the reporting of unsolicited findings" as well as guidelines for informed consent.

The American College of Medical Genetics and Genomics also recently tackled the issue of incidental findings in clinical exome and whole-genome sequencing tests, issuing recommendations of its own (CSN 3/27/2013).

"There were a few things that were surprising and different [in ACMG's recommendations] from what ESHG has recommended," Cornel said. "One thing that's quite remarkable is that people asking for an answer on one question would automatically get an answer to other questions that they haven't been asking about," she said.

"In Europe, this seems a step too far. At least you would have to involve patients and ask them about their opinion," she said. "On the other hand, we do say in our recommendations that there could be situations where you might find something and clinicians might feel a duty to inform people."

According to ESHG guidelines, "patients' claims to a right not to know do not automatically over-ride professional responsibilities when the patient's own health or that of his or her close relatives are at stake."

However, the difference between the ESHG and ACMG recommendations is that the ACMG recommends specifically looking into a list of 57 genes, whereas ESHG recommends filtering as much as possible to minimize such incidental findings.

"Looking specifically at many things that were not the initial question of the patient is not what ESHG is considering today," Cornel added. "Wherever possible, you should first target."

Some laboratories in the US offering clinical exome and whole-genome sequencing tests are also not comfortable with ACMG's suggestion that reporting these variants be a requirement for patients to receive testing and as such are giving patients a choice to opt-out of receiving those findings (CSN 5/8/2013).

Another difference between the ESHG and ACMG recommendations on incidental findings has to do with testing in children. While ACMG says that the findings within those 57 genes should be returned to physicians of both adult and child patients, ESHG does not give a specific recommendation as to whether there should be differences in how such findings are dealt with in children versus adults. Instead, it simply says that the provider should have guidelines for dealing with such findings that "balance the autonomy and interest of the child and the parental rights and needs (not) to receive information that may be in the interest of their (future) family."

Aside from incidental findings, ESHG also addressed issues of patient privacy, recognizing that there will have to be protocols put in place that are able to make use of the massive amounts of data generated from whole-genome and exome sequencing results to create well-annotated variant databases while also still protecting patient privacy.

Because next-gen sequencing has blurred the lines between research and clinical testing, "relevant normative frameworks including consent procedures for diagnosis, research, disclosure and storage need to be reconsidered, and if necessary adapted to the challenges of the new situation," the authors wrote.

Moving forward, Cornel said ESHG will continue to evaluate its recommendations as well as consider issues of quality assurance, lab protocols, and how to educate both the public as well as healthcare professionals.