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Sherman Elias, M.D., John J. Sciarra Professor Emeritus & Former Chair, Department of Obstetrics & Gynecology, Feinberg School of Medicine, Northwestern University, 250 E. Superior Street, Suite 3-2306, Chicago, IL 60611, Tel.: 561- 433-5000, moc.liamg@dmsailenamrehs
In spite of the centrality of informed consent in clinical genetics and genomics, new recommendations from the American College of Medical Genetics and Genomics (ACMG) call for laboratories and clinicians to test for and report specific genetic incidental findings, even when the patient does not consent to the testing or disclosure and even when the patient is a child.
Exome and whole genome sequencing is rapidly moving into clinical application to aid diagnosis and treatment, an eagerly awaited development. However, a startling policy statement by the American College of Medical Genetics and Genomics (ACMG) may prove to be a stumbling block. (1) Rather than reconfirming the well established principles of patient autonomy and informed consent in this new domain of clinical genomics, as in medical genetics and in medical practice more broadly, the policy statement recommends an abrupt change.
Whenever clinical sequencing is undertaken to look for a “primary finding” (i.e., “a pathogenic alteration in a gene or genes that are relevant to the diagnostic indication for the sequencing was ordered”), the ACMG calls for laboratories to perform a “deliberate search for pathogenic and likely pathogenic variants” on an additional “minimal list” of 57 specified genes and report results without seeking patient consent. These “incidental findings” (also termed “secondary findings”) are “results that are not related to the indication for ordering the sequencing but that may nonetheless be of medical value or utility to the ordering physician and the patient.” However, the ACMG addresses only “the results of a deliberate search” for specific variants, not other genetic findings discovered unexpectedly, which is how the term “incidental findings” is more widely used. (2–4)
The ACMG then calls for clinicians to report the results of the deliberate search for incidental findings in the 57 genes to the patient, with no opportunity for the patient to decline unwanted information. The only choice the patient has is to decline sequencing altogether, even if medically indicated. The ACMG imposes these testing and reporting requirements even when the patient is a child who has no medical need for these results during his or her childhood. The ethical and legal problems raised are profound. We urge the ACMG to reconsider the report.
The ACMG characterizes obtaining informed consent for this deliberate search for “incidental findings” as “impractical” because “the patient whose exome or genome is sequenced would have to undergo an extensive, and possibly overwhelming, amount of genetic counseling.” Yet the report marshals no data to support this conclusion and never considers the proposals already in the literature for streamlining the consent process when large numbers of genes are evaluated. These proposals include “generic consent” allowing the patient to consider categories of genetic tests for similar conditions together (5) and a proposal to use a computer interface to support the individual’s decision-making (6). The report similarly rejects the idea that the laboratory should not analyze specific sequence data without patient consent, and instead should mask the analysis of certain genes when there was no consent to search for them or could tailor the reports, on the unsubstantiated basis that this “could place an unrealistic burden upon laboratories.”
Rejecting the need for the patient’s informed consent to look for mutations in a predetermined list of 57 genes is a profound departure from prevailing law and norms. Informed consent is a well established legal requirement designed to protect patient autonomy—not a matter susceptible to modification by experts in human genetics, no matter how learned. Circumstances in which clinicians can test without consent are rare exceptions to the rule. In a medical emergency, for example, when the life or health of an incompetent or unconscious patient is in imminent danger and no one is available to consent, society gives physicians the privilege to treat without consent. (7) However, this privilege does not apply when laboratories and clinicians perform clinical sequencing, because they are not responding to a medical emergency and are able to seek consent.
ACMG suggests that deliberately searching for incidental findings in their “minimum list” of 57 genes and reporting them without consent is like a radiologist spotting and reporting an unexpected tumor or other finding of concern on an x-ray. The analogy is misplaced. ACMG is recommending a deliberate hunt for specific “incidental findings” on a predetermined list of genes unrelated to the diagnostic reason for which the sequencing was ordered. This is very different than the unexpected finding of a tumor in or near the area of primary concern in the field imaged by an x-ray. Patients would have no reason to expect a hunt for incidental findings in the 57 disparate genes on the ACMG list, especially when the list includes genes (like BRCA1) whose analysis and reporting has long required patient consent.
The ACMG is mistaken in basing their search and disclosure recommendations on a “fiduciary duty” to prevent the harms these findings may suggest. In both ethics and law, the clinician has a core fiduciary duty to respect the patient’s right to decide what testing to undergo and what information to receive. Patients have an established right to refuse unwanted medical tests and the information they might disclose. They certainly have a right to refuse testing for incidental findings on the predetermined list of 57 genes that ACMG proposes. If the ACMG is worried about potential liability for failing to return results from their list, they should urge clinicians to document the patient’s refusal, not strip patients of the right to decide. Inflicting unwanted information on patients carries its own risk. This is especially true when the unwanted information leads to anxiety, further clinical work-up, and potentially burdensome interventions imposing further risks.
The ACMG’s “minimum list” includes mutations in genes that patients have long been able to refuse testing for, including cancer risk mutations and cardiovascular risk mutations. There are all sorts of circumstances in which a patient may decline such testing and information, even if the results have the potential of opening avenues for intervention. The patient may already be battling another disease or be late in life and see more burden than benefit in seeking this added genetic information. The patient may also fear inclusion of “extra” results in their medical record, with potential vulnerability to discrimination. (8)
The whole idea behind informed consent is that patients are individuals who are entitled to the information they need to make medical decisions in keeping with their own values. It’s not just the patient’s body, it’s the patient’s life. Autonomy protects the patient’s right to make a decision different from what the clinician might choose and even to reject information and treatment that might maximize life expectancy. Just because most physicians and many patients might want this information does not mean that it can or should be forced on all.
The report also departs from long-standing consensus recommendations on testing children. The ACMG acknowledges that “The standards for predictive testing in clinical genetics recognize a distinction between providing results to adults and providing results to children and adolescents, with consistent recommendations that predictive testing for adult-onset diseases not be offered to children.” This consensus has stood since at least 1995, when the ACMG and American Society of Human Genetics published recommendations. (9) Indeed, just this year, the ACMG and American Academy of Pediatrics restated their commitment to this approach, emphasizing that “Decisions about whether to offer genetic testing and screening should be driven by the best interests of the child.” (10)
Remarkably, the report emphasizes that searching for incidental findings in the child’s 57 genes is an opportunity for “the rest of the family” to learn of variants that may be important for their own health. Yet this is exactly what past recommendations have rightly rejected. Those past recommendations have limited genetic testing and disclosure of genetic information to what is medically necessary during childhood. Delaying testing and return of genetic information not medically useful in childhood allows the child to reach adulthood and then make a choice based on his or her own values. The child’s right to genetic privacy is preserved, including what some have called the “right to an open future.”
ACMG’s list of 57 genes and the types of variants that laboratories must search for and report breaks down into three basic categories (see Table), covering a wide range of medical conditions: risks for developing cancer and noncancerous tumors, cardiovascular risks, and adverse reactions to commonly used anesthetics. The report indicates that the criteria they used to come up with their list include the following: “clinical validity and utility,” recognized or expected pathogenicity of the sequence variant, “variants with a higher likelihood of causing disease” (though ACMG notes “that there are limited data available in many cases to make that assessment”), availability of “preventive measures and/or treatment,” inclusion of mutations that “might be asymptomatic for long periods of time,” and availability of “confirmatory approaches for medical diagnosis” (though ACMG recognized “that this standard could not be met for all of the conditions listed”).
If the ACMG was trying to justify required search and disclosure of incidental findings without patient consent, the criteria should have been considerably more stringent (such as significant likelihood of substantial harm in the near future if not communicated). The broad criteria used would actually justify a much longer list of genes, including a number associated with risk of other cancers. Singling out this selection of 57 genes appears arbitrary. This arbitrariness problem is exacerbated by the fact that ACMG says, “Additional genes may be analyzed for incidental (secondary) variants, as deemed appropriate by the laboratory.” The criteria that laboratories will use remain unclear. The ACMG itself also plans to revisit its list annually. As the list expands, so will the scope of testing without consent and the number of incidental findings potentially reported to the patient.
The report tries to confine the impact of these recommendations by saying the authors chose “not [to] address preconception sequencing, prenatal sequencing, newborn sequencing or sequencing of healthy children and adults.” However, if testing for incidental findings in the minimum list of 57 genes is so important that they must be looked for whenever sequencing is performed for a primary indication, why shouldn’t they be looked for in preconception, prenatal, and newborn sequencing as well? These are logical extensions that cannot be ignored. Starting down the path of unconsented testing and reporting in clinical genomics leads to grave difficulties, and should not be done without more careful analysis.
The ACMG should reconsider this policy statement. Clinical sequencing is a medically important tool, already deployed for certain indications. Access should not be conditioned on patients’ surrender of established rights. Especially in the case of children, who will generally not even be able to exercise the option of walking away from sequencing, long-standing protections remain essential. The era of medical genomics requires a trusting partnership with patients, based on respect for their rights.
Susan Wolf’s work on this article was supported by National Institutes of Health (NIH), National Cancer Institute (NCI) and National Human Genome Research Institute (NHGRI) grant #1-R01-CA154517 (Petersen, Koenig, Wolf, Principal Investigators (PIs)) and Robert Wood Johnson Foundation (RWJF) grant #69763 (Wolf, PI). The contents of this article are solely the responsibility of the authors and do not necessarily represent the views of NIH, NCI, NHGRI, or RWJF.
Disclosures: Susan Wolf has lectured and participated in discussion on incidental findings at Mayo Clinic and at a Boston Scientific meeting. Sherman Elias, M.D., is Chair, Scientific Advisory Board, Celula, Inc., San Diego, CA.
Susan M. Wolf, University of Minnesota, Minneapolis, MN.
George J. Annas, Boston University, Boston, MA.
Sherman Elias, Northwestern University, Chicago, IL.