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Debating the Ethics of Returning Incidental Findings

NEW YORK (GenomeWeb News) – A pair of articles published online today in Science debate the pros and cons of returning incidental findings from clinical sequencing tests.

The articles are in response to recommendations recently issued by the American College of Medical Genetics and Genomics that condone returning to the ordering physician incidental findings under certain conditions, regardless of patient preference for receiving those results. ACMG recommended returning the incidental findings if they relate to a set of medically actionable, pathogenic variants on 57 genes corresponding to 24 disorders.

In an article supporting the ACMG guidelines, researchers from Baylor College of Medicine; Harvard Medical School; the University of California, San Francisco; the National Human Genome Research Institute; the University of Alberta; and Brigham and Women's Hospital argue that laboratories "have an obligation to report clinically beneficial incidental findings."

Countering that argument, researchers from the University of Minnesota, Boston University, and Northwestern University make the case that "returning genetic incidental findings without patient consent is misguided."

ACMG initially released its recommendations at its annual meeting in March, and since then issued a clarification of those recommendations that sought to further explain its rationale behind the guidelines. As reported by Clinical Sequencing News, several laboratories have adopted the recommendations but only in part, including an opt-out option for patients.

Making the case in support of the ACMG guidelines, the researchers wrote that the recommendations "represent an initial attempt to set a professional standard for best laboratory practices that will responsibly minimize variation in laboratory analysis and reporting of clinically beneficial incidental findings."

Currently, there are no standards guiding the reporting and analysis of incidental findings from clinical sequencing. So clinicians may receive different results depending on which laboratory performs the sequencing. Additionally, the recommendations restrict the list of incidental findings to variants that are "unequivocally pathogenic," that have a very high probability of leading to disease, and where "evidence strongly supports the benefits of early intervention."

Regarding patient autonomy, the researchers argued that even though ACMG recommends that consenting to the return of variants on the minimum list be a requirement of obtaining clinical sequencing, patients still have autonomy in that they can choose not to be sequenced. The argument that this is "borderline coercive" is inherently flawed because it "assumes that analysis of clinically beneficial incidental findings is a discrete test requiring separate consent, whereas in reality it is integral to the primary interrogation," the authors wrote.

Additionally, the authors said, applying these guidelines to children as well as adults makes sense because the alternative "withholds information that is potentially life-saving for the child, one of the parents, and potentially other family members — information that they would otherwise have no reason to suspect." This recommendation does not go against ACMG's general recommendation about genetic testing in children, which says that children should not be tested for adult-onset conditions. Instead, the current recommendations "address a very different context," in which both the child and the family's interests should be considered.

On the other side, the researchers argue that the ACMG recommendations constitute an "abrupt change" in medical genetics.

The authors primarily take issue with the idea of informed consent and argue that "patients have an established right to refuse unwanted medical tests and the information they might disclose, even if that information would offer potential medical benefit."

Additionally, ACMG's list of genes "includes mutations in genes that patients have long been able to refuse testing for, including cancer risk mutations (such as BRCA1) and cardiovascular risk mutations," they wrote. The authors go on to cite many reasons why a patient would not want such results. For instance, the patient may have late-stage cancer and may see "more burden than benefit," or the patient "may fear that 'extra' results in their medical record will invite risk of discrimination."

The researchers also disagree with ACMG that the recommendations should be applied to children and adults in the same way.

ACMG argues that returning the variants in children could provide valuable information to the child's other family members. However, the researchers argue that "this is exactly what past recommendations have rightly rejected, in limiting genetic testing and disclosure of genetic information to what is medically necessary during childhood."

They disagree with the ACMG that a clinical sequencing test for a specific condition constitutes an exception to the accepted practice of not testing children for adult-onset conditions.

The authors also take issue with the list itself, saying that the genes chosen appear "arbitrary." The criteria for inclusion onto the list should have been more stringent, they wrote, restricted to variants that would lead to "significant likelihood of substantial harm in the near future if not communicated," for instance.

The authors argued that ACMG should reconsider its statement. "The era of medical genomics requires a trusting partnership with patients, based on respect for their rights," they wrote.

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