‘Extra’ genetic info—too much, too quickly?

Elizabeth Silverman

October 2013—In the 1997 film “Gattaca,” the movie-going public was introduced to a world in which biology was quite literally destiny. A world in which the probabilities encoded in one’s genome dictated virtually every aspect of one’s existence and where those found genetically wanting were relegated to society’s margins. Fortunately, genomics has so far yielded nothing so nefarious nor is it ever likely to, thanks in part to the vigorous debate that accompanies advances in genetic and genomic technologies. An example of this is the debate underway, and making medical news, among physicians, ethicists, and laboratory directors over the American College of Medical Genetics and Genomics’ recommendations on the reporting of incidental findings.

The dramatic decreases in the time and cost of DNA sequencing that have made it an increasingly practical clinical tool have also presented lab directors with a dilemma: What should be done with potentially clinically relevant genetic information generated in the course of diagnostic sequencing but not ordered by the physician? To the ACMG, the question was of sufficient magnitude to warrant establishing a standard, uniform policy to provide guidance. Accordingly, it convened a working group, and after 14 months of discussion, debate, analysis, and some external review, recommendations were published in March.

The ACMG recommended that laboratories performing germline exome and genome clinical sequencing also analyze and report on pathogenic mutations in 56 carefully selected additional genes involved in a variety of serious diseases (see “The ACMG list”). The criteria for selection were that the diseases be both highly penetrant and actionable. The recommendations state that these incidental, or secondary, findings should be reported to the ordering physician as a matter of routine, regardless of the age of the patient or the nature of the original diagnostic order. Further, patients would not be asked to give informed consent for each gene individually; rather, they should be counseled about the possibility of receiving these incidental findings during the diagnostic informed consent process. The ACMG intends that the list of genes that constitute incidental findings will be reviewed regularly and modified as new data become available.

The controversy and debate over the recommendations began almost immediately. The issues that sparked the debate, however, were much broader and more far-reaching than the specifics of the chosen genes. With the possible exception of the BRCA genes, the debate has not centered on which genes were chosen so much as that any genes were chosen at all.

Critics of the ACMG recommendations argue that what the ACMG considers to be the reporting of incidental findings is actually the mandating of genetic screening because the findings cannot be incidental if they are actively searched for. The ACMG believes its recommendations are no different than the reporting of incidental findings that occur as a routine part of good medical care. They compare their recommendations to the situation in which a radiologist reports a suspicious shadow on a chest x-ray ordered for a fractured rib. Robert Klitzman, MD, associate professor of clinical psychiatry at Columbia University College of Physicians and Surgeons and the Mailman School of Public Health, counters in a July 24/31 JAMA “Viewpoint” that the situation is more akin to that of a radiologist adding an abdominal x-ray to an ordered chest x-ray and reporting findings on that as well. Karl Voelkerding, MD, professor of pathology, University of Utah, and medical director for genomics and bioinformatics, ARUP Laboratories, weighs in squarely on the screening side of the issue: “There is a difference between screening and diagnostic mode—physicians order a test for a specific medical problem. The recommendations are screening.”

Critics argue that not only do the recommendations impose a burden on a laboratory to seek out and analyze variants for which there is no clinical basis or physician order, but it also must do so without the patient’s informed consent. If the whole genome must be sequenced to, for example, identify the cause of a child’s disabilities, then the 56 mutations will be analyzed, whether the clinician or patient—or the patient’s surrogate in the case of a child—wants or orders it or consents, says Lainie Friedman Ross, MD, PhD, Carolyn and Matthew Bucksbaum professor of clinical medical ethics at the University of Chicago and associate director of the MacLean Center for Medical Ethics. Dr. Ross feels strongly that what is being done is not clinical medicine but screening research—because the significance of these genes in the low-risk population has not been well explored—and that, as she told CAP TODAY and is sure to provoke sharp response, “Doing research without informed consent is conscripting people to be research subjects.”

Most of those on both sides of the debate acknowledge the impracticality of counseling and obtaining informed consent for each of the 56 genes. “It is not practical to offer a Chinese menu of options to a patient—it is neither appropriate nor feasible,” says Robert Green, MD, MPH, lead author of the ACMG recommendations and associate professor of medicine, Division of Genetics, Brigham and Women’s Hospital and Harvard Medical School, and associate director for research, Partners HealthCare Center for Personalized Genetic Medicine. ARUP’s Dr. Voelkerding agrees that “Informed consent is a challenge in such a complex area,” but adds, “Complexity should not rule the day.”

A key and perhaps defining issue that colors almost all aspects of the debate, including that of informed consent, revolves around the speed and evolution of diagnostic sequencing technology. Many laboratories now test for genes on a disease panel basis, and even those that do exome sequencing often conduct bioinformatics analyses for each disease separately. However, this is unlikely to be the situation in the near future. Dr. Green explains: “The amount of extra labor will dramatically decrease in the coming years—the recommendations weren’t developed for the next three months; they were developed for the future. Very quickly all genomic information will be revealed by the bioinformatics pipeline that is being developed. Testing will quickly become one test. The information that is uncovered could be life-saving.”

Amy McGuire, JD, PhD, a member of the ACMG working group and Leon Jaworski professor of biomedical ethics and director of the Center for Medical Ethics and Health Policy, Baylor College of Medicine, sums up the issue: “The ACMG has always been in favor of thorough informed consent. The debate turns on how you view the technical issues: whether you view it as a single test whose scope of analysis is up to the experts or whether you see it as separate tests that need informed consent for each.” Her own view: It’s a single test, and the debate is over scope of analysis, not additional testing or screening.

One of the most forceful technical arguments against the recommendations is that, although they are predicated on the selection of highly penetrant genes, the penetrance data are flawed. The data the ACMG used were obtained from high-risk populations, whereas penetrance in the general population—the population in question—is likely to be lower. How much lower, no one knows. The consequences of returning a positive finding on a gene that turns out to have lower than expected penetrance are potentially far-reaching. Patients with positive findings may be referred on for costly or invasive tests and procedures that could cause physical harm and excess anxiety and result in a lifetime of unnecessary medical surveillance. However, James R. Lupski, MD, PhD, DSc, Cullen professor and vice chair of genetics at Baylor College of Medicine, argues that not reporting these variants to the referring physician means he or she isn’t given the opportunity “to contextualize the information into a differential diagnosis enabling a management/treatment plan” and potentially denies the patient a chance at life-saving therapies.

Robert L. Nussbaum, MD, chief of the Division of Genomic Medicine, Department of Medicine and UCSF Institute for Human Genetics, says until he sees evidence to the contrary, he would expect well-vetted pathogenic mutations identified in families to be a major risk for someone who carries one, regardless of how it was found. “We know, for example, the penetrance of BRCA1/2 mutations in high-risk families with multiple affecteds is somewhat higher than in patients ascertained through population screening, but the risks are still very high.”

The ACMG acknowledges the lack of penetrance data for the general population and that it does expect these to be lower than for high-risk populations. However, it foresees that the listed genes will be reviewed and subject to modification regularly as more data on penetrance and other issues are accumulated. Its view is that the question of what laboratories should do with incidental findings exists today and needs to be addressed today, especially as the magnitude of the problem will grow as gene sequencing increasingly becomes part of medical practice. “Thousands of exomes and genomes will be sequenced clinically in the coming year,” Dr. Green points out.

Other technical issues raise objections too: for instance, that negative findings do not necessarily mean that patients are not at risk and that negative results may give patients a false sense of security. Sherri Bale, PhD, managing director of GeneDx, speaking on an Association for Molecular Pathology webinar on Sept. 17, pointed out that the recommendations do not address pathogenic structural variants and that, as an example, 28 percent of Von Hippel Lindau cases are due to a complete or partial deletion. Additionally, there are sequencing coverage issues with several of the listed genes, all of which have the potential to result in false-negatives. Then, too, results between labs may vary, particularly when different technologies are used.

That tests are not perfect is not a new idea, says Dr. Nussbaum, a member of the ACMG working group, nor is it difficult for patients to understand. “We have been having this discussion for decades around prenatal chromosome testing,” he says. “Patients understand, with counseling, that prenatal karyotyping would not ensure the birth of a child without any genetic or other birth defect.”

There is an almost universal acknowledgement that more research is needed to resolve many of these concerns, but the question of whether the ACMG recommendations were timely or premature remains a subject of intense debate.

No set of issues stemming from the ACMG recommendations arouses quite the depth of feeling as those related to patient autonomy and ethics. To the extent that the recommendations call for the automatic reporting of findings not ordered by a physician and not specifically consented to by a patient, critics see an abrogation of the enshrined principle of a patient’s right not to know. “This is a risk-benefit calculation that should not be imposed,” says Dr. Ross of the University of Chicago. Megan Allyse, PhD, postdoctoral fellow at Duke University’s Institute for Genome Science and Policy, says, “Patients should have access and information that they want and not information that other people think they should have.” Their comments represent a broad swath of ethical opinion.