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ESHG, ACMG Differ Starkly in Recommendations for Reporting Secondary Findings From Genomic Tests

NEW YORK – The United States and Europe differ in many aspects, including their healthcare systems and attitudes toward privacy. Now, there appears to be another area where the two don't see eye to eye: how to report secondary findings from genomic tests.

The European Society of Human Genetics is about to publish its first recommendations for what the organization calls "opportunistic genomic screening" – in essence, the counterpart to the American College of Medical Genetics and Genomics' existing recommendations for reporting secondary findings from clinical genomic tests. Unlike the ACMG, which generally recommends the return of such findings to patients undergoing diagnostic exome or genome sequencing, ESHG does not, advocating research projects on the effects of the practice first.

During an "ASHG/ESHG Building Bridges" symposium at the American Society of Human Genetics 2020 virtual meeting on Wednesday, representatives from ESHG and ACMG explained the differences between their respective approaches and how they arrived at their decisions. The session also discussed the organizations' guidelines on variant interpretation, which revealed fewer differences between the two groups.

According to Francesca Forzano, a consultant in clinical genetics and genomics at Guy's and St. Thomas' NHS Foundation Trust in London and the chair of ESHG's public and professional policy committee, ESHG's recommendations on opportunistic genomic screening were developed in a lengthy process that involved feedback from members and a review by its board and are currently in press with the European Journal of Human Genetics.

At the root of the differences between the two guidelines lies their view of the process of seeking and reporting additional findings. While ACMG regards this process as being embedded in a clinical genomic test, Forzano said, ESHG considers it a screening test that needs to be treated differently from a diagnostic one.

ACMG published its first guidelines on how labs should report so-called "incidental findings" from clinical exome and genome sequencing tests in 2013, recommending that variants in 56 genes that could have a positive effect on a patient's health should be returned.

The following year, it updated the initial policy statement, adding an opt-out for patients who do not want to receive the information and clarifying that the guidelines apply to children as well as adults. It also renamed incidental results from genomic tests "secondary findings," since they require clinicians to actively look for changes in genes that are unrelated to the original reason for diagnostic testing. In a further revision in 2016, called ACMG SF v2.0, the college made changes to the genes reported, arriving at a list of 59 genes, and laid out a process for continued review and nominating genes for future inclusion.

According to Christa Martin, associate CSO and director of the Autism and Developmental Medicine Institute at Geisinger Health and a member of the ACMG secondary findings working group, a new publication with further revisions and clarifications on the gene review process is in the works and will come out as soon as it is reviewed by ACMG's board. In general, she said, genes on the list must be medically actionable, have available interventions, have a clear phenotype that is associated with deleterious mutations, have serious medical implications, and be associated with a highly penetrant phenotype.

The working group has been considering adding pharmacogenomic variants that are detectable by exome sequencing, she said, and has been developing a description of how genes are reviewed. It has also been thinking about expanding the gene nomination process to other medical professional societies outside of the genetics community, and has been encouraging research into the downstream impact of secondary findings.

Forzano said that when ACMG's original recommendations appeared in 2013 – shortly after ESHG released its guidance on clinical whole-genome sequencing, which recommended very targeted interpretations of the results – a lot of confusion among ESHG's member laboratories ensued. "ESHG membership felt a need for harmonization among European countries because there were inconsistencies in applications and regulations, concern about legal obligations and external quality assessment," she said.

As ESHG's committee started to formulate its own guidelines, it realized that analyzing genomic testing data more broadly "would actually amount to a form of screening," she said. "For this reason, we felt that the general framework of screening criteria should be applied."

This means, for example, that "there should be a stronger burden of proof that screening is, on balance, beneficial to those to whom it is offered," she explained. However, that was not a given for genomic tests. For example, there is "a lack of evidence that opportunistic genomic screening can alter the natural history of disease in a significant proportion of those screened," she said, and many disease-associated variants are not validated to be highly penetrant in the general population. Reporting such variants, she said, may potentially lead to iatrogenic harm and psychological stress. 

Moreover, the actionability of the information depends on the context in which it is delivered, she added, and the availability of resources for follow-up screening and counseling should be explored beforehand.

"For these reasons, ESHG currently continues to recommend a generally cautious approach," she said. "We did not feel that we should currently recommend opportunistic genomic screening as part of our professional standard. Having said that, we feel that it will be important to collect adequate data to address these limitations properly." For example, she explained, genomic screening could be conducted as part of pilot studies embedded in a research framework to explore questions like the penetrance of variants in the general population or the effects of secondary findings on follow-up testing.

In addition, Forzano said, ESHG decided not to create a specific gene list. Instead, it plans to discuss with stakeholders which genetic disorders, genes, and variants to include in specific pilot projects, in accordance with the resources available for such studies.

Martin said that penetrance is also a hot topic for ACMG, and one goal of the working group is to get a more unbiased view of penetrance estimates. "Most of the data we work with [has been created] from a phenotype-first perspective, where testing has been done to look for the causative phenotype," she said. "Having good data on penetrance is really important. As more data comes out from population screening, we're learning a lot about the penetrance of different diseases on the variant level."

Her committee spends a lot of time deciding which variants are considered to have high enough penetrance to be included, she added. "So far, we've stayed away from disorders referred to as low penetrance, [and] more data around that will continue to help us make more informed decisions about the minimum secondary findings the ACMG is using."

She also acknowledged that there is a lot of debate around the potential use of the ACMG gene list in general population screening, outside of clinical diagnostic exome or genome testing. "While we know that about 2.4 percent of patients are estimated to have one of these [secondary] findings when they undergo clinical testing, ACMG is still encouraging further ascertainment of these genotype-phenotype correlations, and research, really trying to establish the efficacy of interventions in asymptomatic patients before saying this list should be used for any type of genomic screening," she said. To that end, ACMG has generated a working group for genomic screening in asymptomatic patients and another one for population screening.

One more difference between the two guidelines is that ACMG does support reporting secondary findings for minors, since both children and their parents can benefit from the results, whereas ESHG only supports this in a restricted manner. "We felt that there will be no objections in considering screening for well-known pharmacogenomic variants or variants that may lead to early-onset actionable conditions, but we felt that it would not be appropriate to test minors for variants leading to later-onset actionable conditions," Forzana explained. However, ESHG does make exceptions, for example for minors who are "not expected to become competent adults," she added.

Another area where the ESHG recommendations diverge from their American counterpart is in the role of the patient. ESHG proposes an opt-in model of consent for receiving secondary results, rather than following ACMG's opt-out model. "One of the reasons why we thought the opt-in was a better decision is that the patient has to make an active choice, has to engage in the process, and kind of takes an effort to be responsible for the decision," Forzano explained. Having to opt out, on the other hand, might make a patient "feel a bit induced to accept what will be the routine without thinking too much, or maybe feeling a bit judged if you might not want to have this information."

Martin said that when the ACMG recommendations initially came out, the lack of an opt-out "was one of the hottest points of contention and feedback that ACMG received." She said that members wanted patients to have more autonomy in deciding, even though this is not common practice in other areas of medicine. "If you have a lung scan done for a diagnostic reason, if somebody sees cancer [on that scan], they will tell you that," she said.

Forzano argued that the comparison of a genome scan with a lung scan is somewhat misleading because seeing cancer on a lung X-ray is a truly incidental finding, whereas actively looking for variants in a genome is more akin to opportunistic screening. "This is probably one of the sources of the conflict and the confusion," she said.

Martin said that when ACMG first issued its recommendations in 2013, restricting secondary findings to highly actionable variants that are likely to cause disease, it did so "knowing that you had this information that could be transformative to somebody's life and preventing disease or detecting it earlier. … How can we not give that information back to a patient?" From her personal experience, she said, "the majority of patients I see who get these [results] back find the information to be valuable – it changes their medical care, it changes their family's medical care, because these are genetic disorders. I believe in giving these types of results back."