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

Those with concerns about the ethics of what has been recommended believe their argument is strengthened by the fact that compulsory reporting of incidental findings applies not only to the patient undergoing clinical sequencing but also to any individual, such as parents or siblings, whose DNA is being sequenced for use as a control. None of these individuals would have a choice about whether to receive incidental findings despite their not being the patient. Moreover, the all-or-nothing nature of the recommendations means patients who do not wish to have information on the 56 genes would not be candidates for clinical DNA sequencing. They would have to forego diagnostic testing or find a way to obtain the testing by another modality, if available.

The recommendations also affect the autonomy of the ordering physician who may now be forced to counsel patients on a matter wholly unrelated to that which brought them to his or her office or to refer them for additional counseling or further testing or both. Critics of the recommendations cite the shortage and expense of genetic counselors as a purely practical impediment to carrying out the ACMG recommendations. Although the ACMG estimates that positive findings would affect one percent of patients and therefore not impose an undue burden, especially in light of the potential benefits, Dr. Bale noted that anecdotally lab directors are seeing rates of positive findings that exceed five percent. Wayne Grody, MD, PhD, professor of pathology and laboratory medicine, pediatrics, and human genetics at UCLA School of Medicine, asks, “Can you force the lab director to do something they are not comfortable with? The recommendations may be asking a little too much of lab directors.” He offers patients an opt-out in his laboratory, as do some other labs. Says Columbia’s Dr. Klitzman, “It is unclear whether physicians, labs, and hospitals are ready for this type of testing.”

Laboratories find disease-causing variants in the course of exome and genome analysis, even when not explicitly looking for those variants, and being asked to withhold findings puts labs in a difficult spot, says Heidi Rehm, PhD, director of the Partners Healthcare Laboratory for Molecular Medicine, Cambridge, Mass., and a member of the ACMG working group. “We find that families are asking for these results and are even surprised we would consider not returning them.”

Also controversial is the reporting of adult onset diseases to the parents of pediatric patients. Here there is concern that the information is not immediately actionable and that patient autonomy would be infringed when the patient is too young to offer informed consent. There is also the fear that this information may affect how parents view their child. However, as pediatric oncologist Steve Joffe, MD, MPH, Emanuel and Robert Hart associate professor and director of the Penn fellowship in advanced biomedical ethics, Department of Medical Ethics and Health Policy, University of Pennsylvania Perelman School of Medicine, points out: “There is scant data to address that question. We don’t know what impact it will have, and there are no data to support any conclusions.” The traditional guidelines of waiting until a child is an adult to offer him or her testing for the predisposition to an adult onset condition are overly restrictive, in his view, and should be revisited when there are actionable gene variants, independent of age of onset. He cites the net medical benefit of alerting a child’s family to a risk they might otherwise not have known about and the secondary benefit to other family members. His primary concern with the ACMG’s recommendations is technical in nature: the difficulty of determining what constitutes a pathogenic variant.

Another issue is the degree to which parents want or are capable of receiving information about an additional, potential illness while in the midst of dealing with the condition that brought their child to the sequencing lab in the first place. Dr. Voelkerding asks, “Do parents really want information on the genes on the list when they are worried about a specific problem their child has? One has to respect patient and family autonomy and guard against paternalism in medicine.” Also difficult, Dr. Grody says, is when parents have to be informed that the diagnostic sequencing did not provide an answer but that the sequencing did uncover an unrelated problem. Will parents want to know or even be able to process such extraneous information?

The problem of coping with the extra information applies to adults as well. Says Dr. Klitzman: “The one-size-fits-all policy is not always the best. Someone undergoing sequencing for metastatic breast cancer may not want to know about these other things that may be wrong with them.”

All of these cogent and well-reasoned arguments must be balanced against ethical arguments related to having the ability to discover and deliver potentially life-saving information and not using it. The arguments are strengthened if one believes that genome and exome sequencing are likely to become one comprehensive test with one bioinformatics readout in the not too distant future.

Although the ACMG recommendations do not address financial and reimbursement issues, these will certainly have an impact on the medical community’s ability to carry them out. Physicians worry about the financial burden of genetic counseling, which is not always covered by insurance, and of followup testing and the resulting treatment or surveillance. The costs could make following the recommendations prohibitive. “We don’t have unlimited health care dollars,” Dr. Voelkerding says. “There should be continued discussion and research to better understand how to best apply this expensive technology in terms of clinical practice and to determine its true cost benefit.”

For the lab director as well, the recommendations could have significant financial consequences. The recommendations specify what genes to report on but not which variants. Dr. Bale estimates that it takes one-half hour to three hours to search databases, download purchased papers, read and review the papers, and interpret the data. Her lab confirms positive findings with Sanger sequencing, which takes several days. There is no billing code that covers the reporting of secondary findings and no obvious way to get paid for the extra work. She worries about whether labs will incur increased legal liability for reporting or not reporting the recommended findings. This is especially true since BRCA testing is on the list and still the subject of litigation.

Added to the issues for which there is consensus—the need for more data, the likelihood of penetrance being lower in the general population, and the impracticality of informed consent for all 56 genes—there is general agreement that implementing the recommendations is going to highlight the need for more education of physicians and patients. Historically, genetics has been subject to medical exceptionalism and physicians referred cases involving genetics to geneticists and genetic counselors. This reflected an era when most available genetic information was associated with narrow but difficult areas largely restricted to reproductive matters and rare diseases often seen in pediatrics. Physicians and patients were unlikely to have encountered many other health issues related to genetics, and physicians relied on the specialized training of genetic counselors to help patients understand and absorb the information.

However, as genetic information moves into mainstream clinical practice, most notably in oncology, it raises the questions, what is so unique about the genome and does it merit continued exceptionalism? Physicians, after all, have a wealth of experience in contextualizing diagnostic information and helping patients understand complex medical conditions. Patients rely on the expertise of their physicians in the selection of diagnostic tests without any special counseling. Tests to diagnose one medical problem sometimes result in finding others.

It is therefore likely that the exceptionalism that requires the use of specialized geneticists and genetic counselors in every case, for all situations, will gradually decline over time. This is particularly true as more data are accumulated and genetic information becomes more actionable and perhaps less of an enigma to patients. Physicians will, however, need to be brought up to speed and patients made more comfortable with the positive impact that genetic information can have on their health. The educational aspects of the field may be no easy task considering that most physicians attended medical school before the initial $3 billion genome was sequenced in 2003. The question of how this extra education is going to be achieved and in what time frame also forms part of the current debate to the extent that the ACMG recommendations are a step toward the clinical mainstreaming of genetic and genomic information.

The ACMG recommendations have caused discomfort in other ways. There is a feeling that they are too rigid and that results should be reported on a case-by-case basis in consultation with the ordering physician. No one is opposed to patients receiving the information, the argument goes, but the way the recommendations are written allows little wiggle room for individual patient situations; this may place an undue burden on the ordering physician who has to make the ultimate decision about which findings, if any, to share with the patient. Some feel this is a bridge too far too fast. “In conventional medicine the need for tests drives the use of the test,” Dr. Klitzman says. “With genetics this is not the case—the technology is driving the use.” While the rapid decline in the cost of sequencing and the flow of new products and easier–to-use instrumentation make sequencing increasingly practical as a clinical tool, some question whether the advances in technology have outstripped the medical community’s ability to understand and integrate the results into the medical mainstream.

There is wide agreement that the debate over the recommendations is a positive development and that genetic information and technology bring with it many difficult questions that are not easily answered. Nevertheless, there is also a feeling that there was not enough debate before the recommendations were released. “I am glad that there is a healthy and vigorous debate,” Dr. Voelkerding says, “but it’s unfortunate that it’s post hoc with respect to the recommendations being released.” He says they were insufficiently vetted by all relevant stakeholders and therefore were premature, “as evidenced by the current debate.” Others feel that the recommendations are premature because more research needs to be done. But in the ACMG’s view, calling for more research does not address the current problem of providing guidance, however preliminary, to laboratory directors who uncover abnormal findings. Says Dr. Green: “Incidental findings cannot be hidden away or the responsibility shifted to the patient. The data are not perfect—everyone agrees, but it is not an ethical question. It is an ethical and medical imperative to report the results.”

“Do no harm” is getting harder to define in the age of molecular medicine. Individuals on all sides of the current argument strongly believe they have the patient’s best interests at heart and that harm might be done by either following or not following the recommendations. Are the recommendations forward-thinking and visionary or do they represent the views of a more academic style of medicine that overlooks important clinical practicalities? There is no easy answer but the debate itself is part of an important process. Whether the recommendations represent a step forward into the genomic future or backward into the paternalistic past, it remains unarguable that it is the singular goal of all medicine—molecular or otherwise—to assess, analyze, and act on clinical findings to ensure that biology is not inexorably destiny. And we can all rest easy that those who make their voices heard, today and in the future, guarantee that “Gattaca” will forever remain just an entertaining piece of science fiction.

Elizabeth Silverman, of New York, NY, is a writer who covers genomics.

The ACMG List

Hereditary breast and ovarian cancer BRCA1&2
Li-Fraumeni syndrome TP53
Peutz-Jeghers syndrome STK11
Lynch syndrome MLH1, MSH2, MSH6, PMS2
Familial adenomatous polyposis APC
MYH-associated polyposis; adenomas, multiple colorectal, FAP type 2; colorectal adenomatous polyposis, autosomal recessive, with pilomatricomas MUTYH
Von Hippel Lindau syndrome VHL
Multiple endocrine neoplasia type 1 MEN1
Multiple endocrine neoplasia type 2 RET
Familial medullary thyroid cancer RET
PTEN hamartoma tumor syndrome PTEN
Retinoblastoma RB1
Hereditary paraganglioma-pheochromocytoma syndrome SDHD, SDHAF2, SDHC, SDHB
Tuberous sclerosis complex TSC1, TSC2
WT1-related Wilms tumor WT1
Neurofibromatosis type 2 NF2
Ehlers-Danlos syndrome, vascular type COL3A1
Marfan syndrome, Loeys-Dietz syndromes, and familial thoracic aortic aneurysms and dissections FBN1, TGFBR1, TGFBR2, SMAD3, ACTA2, MYLK, MYH11
Hypertrophic cardiomyopathy, dilated cardiomyopathy MYBPC3, MYH7, TNNT2, TNNI3,
TPM1, MYL3, ACTC1, PRKAG2, GLA, MYL2, LMNA
Catecholaminergic polymorphic ventricular tachycardia RYR2
Arrhythmogenic right ventricular cardiomyopathy PKP2, DSP, TMEM43, DSG2
Romano-Ward long QT syndrome types 1, 2 and 3, Brugada syndrome KCNQ1, KCNH2, SCN5A
Familial hypercholesterolemia LDLR, APOB, PCSK9
Malignant hyperthermia susceptibility RYR1, CACNA1S