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Bioethicists Urge More Research as They Consider Recommendations for Genomic Testing of Children

NEW YORK (GenomeWeb News) – A range of ethical questions are being considered as genome and exome sequencing trickles into clinical care. But children pose a unique problem for this fledgling field, and a group of bioethicists has suggested in an article published this week in the American Journal of Bioethics that more research must be done before consistent and sound guidelines will be developed.

The senior author of the study, Ellen Wright Clayton, who is director of Vanderbilt University's Center for Biomedical Ethics and Society and co-chair of the Clinical Sequencing Exploratory Research Pediatric working group of NHGRI, noted that the only two sets of recommendations proposed for addressing clinical sequencing for children – those looking in particular at whether and what kind of genetic findings should be returned to parents – are not in harmony.

Whether or not to return incidental findings from genetic tests to adult patients is a question that professional groups and other stakeholders are working on, but the central problem with children is that they cannot decide for themselves if they want to know about their genetic risk for adult-onset conditions. Many variants that are linked to diseases may not be actionable, and even those that are may not develop in individuals until much later in life.

The central questions are these: should a child be tested at all for such variants, even if a parent suspects a familial genetic risk and wants the test done? And if a child receives genome or exome sequencing for another purpose should other genetic risk findings be returned to the families?

Two organizations have tackled the issue and issued recommendations, the American College of Medical Genetics and the American Academy of Pediatrics. Early last year, ACMG and AAP both released a joint proposal recommending that predictive genetic testing for adult-onset diseases that cannot be ameliorated in childhood should generally not be performed.

About a month later ACMG released a separate report offering its guidelines on incidental findings in general. Here, and in a later clarification, ACMG said that although children should not be tested for adult-onset genetic diseases in general, that guideline would not apply if the incidental finding was a severe, actionable, pathogenic mutation.

Taken in the context of its overall recommendation on incidental findings from exome and genome sequencing, this second report recommended that labs doing the analysis should look for a set of 56 known pathogenic mutations (with the expectation that the ACMG list will change over time) that are linked to 24 genetic conditions.

Those results should be returned to the clinician who ordered the test, who would then be able to contextualize the findings for the patient's parents, ACMG advised.

The CSER Pediatrics working group found a "tension" between the two sets of recommendations, according to the paper in AJOB.

One key difference is the intended audiences, the working group found. The AAP/ACMG statement addresses clinicians and the later ACMG recommendations are aimed at the labs that are conducting the sequencing. They also differed because the AAP/ACMG document centers on the interests of the child whereas the ACMG recommendations also considered the potential benefit of parents and other family members who might find out something about themselves, genetic risks they may not have suspected before, in the child's genome.

The two documents also assessed risks and benefits differently, as the AAP/ACMG recommendation focused on averting risks to the child, while the ACMG statement placed more emphasis on the benefits to both child and family, who may be able to take steps to address any of these actionable genetic risks, according to the paper.

Because of these differences the ethical justifications underpinning the two sets of recommendations also differ "with regard to whose interest should be taken into account, how the benefits and risks should be weighed, and the decision-making roles of clinicians and parents."
More research that involves a range of stakeholders is needed, Clayton wrote.

"This research, over time, should lead to the development of ever more sophisticated, comprehensive, internally consistent, and ethically sound guidelines for genetic testing of children."

Alongside Clayton's paper, AJOB also published a cluster of response commentaries from a range of experts on clinical sequencing, bioethics, and pediatrics.

In one of these responses, a group of researchers from the Medical College of Wisconsin, one of the first institutions to use sequencing to diagnose and treat children, argued, "it is our position that absent evidence that would indicate otherwise, practice should remain consistent with broader social approaches to decision making on behalf of children. In short, absent evidence that would justify reconsideration, the default position should be parental informed consent."

The most common criticism of the ACMG recommendations, in the context of children, is that they force someone to override a child's right to not know their genetic status, the right to what the ethicists call "an open future," Tom May, associate professor at MCW's Center for Bioethics and Medical Humanities and an author on the response paper, told GenomeWeb Daily News this week.

Many adults make the decision to not know their status for Alzheimer's disease or other risk genes and variants, and there is no way of knowing how a child would decide.

"We would not force the return of these results to parents. We would allow parents choices over the types of returns they want to receive," said May.

"Genetic counseling can play a major role in making sure that the choices parents make are informed choices, so that they appreciate the potential risks that might be involved."

Making parents aware of the possible risks as well as the benefits, particularly if there are treatments available or actions they could take to mitigate their risk in the future, is important to the process, he said.

A policy that promotes this back-and-forth discussion, involving information sharing and shared decision-making, is in harmony with recommendations that the Presidential Commission for the Study of Bioethical Issues published at the end of 2013, the MCW researchers noted.

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