What To Do When Whole Genome Sequencing Yields Unexpected Results: Is There A One-Size-Fits-All Answer?

Whole genome sequencing (WGS) is becoming increasingly common. Doctors now routinely order it for patients with puzzling diseases. The NHS (National Health Service in the UK) has declared that it will sequence 100,000 genomes over the next few years. Increase WGS…increase ethical questions The direct-to-consumer company 23andme has been experimenting with whole exome sequencing (WES), and another company, DNA DTC, is already offering its clients WES/WGS. The growing availability of WGS raises a number of ethical questions. Dilemmas to be examined by all With such powerful techniques starting to be used in mainstream diagnostics and medicine, ethical dilemmas need to be carefully examined by scientists, medics and patients alike;

• Do the sequencing companies/researchers have an obligation to scan genomes for genetic variants associated with disease?
• If researchers happen to find such variants while investigating another topic, are they obligated to reveal their findings to the DNA donor?
• What if the donor does not necessarily want to learn about these ‘incidental’ findings?
• What if the donor is a child and the variant is linked to an adult-onset disorder?

Controversial regulations In March of this year, the American College of Medical Genetics and Genomics (ACMG) stepped up to the plate by making public the first official recommendations for how to handle situations in which WES/WGS reveals unanticipated genetic risks. These recommendations proved quite controversial, though, and in May, the ACMG was forced to release a second document, which clarified the contents of the first. To many involved, it’s still not clear what the best practices in this scenario are. Why all the fuss?! 57 varieties Let’s start with the current recommendations. The ACMG stated that when WES/WGS is performed, the genome should be screened for 57 well-characterized genetic variants associated with 24 life-threatening but treatable conditions, such as retinoblastoma, breast and ovarian cancer, and very high cholesterol. If any of these variants are identified, the patient should be informed, whether they requested this information or not. Compromise autonomy? On the face of it, these recommendations may not appear particularly controversial. But critics argue that proceeding this way will (a) compromise patient autonomy and (b) contradict precedent, because in the past, ethical bodies such as the ACMG have considered it unethical to screen children for adult diseases. Does everyone want to hear bad news? Advocates for patient autonomy argue that not everyone is eager to hear bad medical news. An elderly woman may not want to learn that she carries a genetic variant associated with high rates of breast cancer, for example. Having made it this far, she is unlikely to die of this disease, which would take time to develop even if it did arise. Nevertheless, such knowledge may cause her unnecessary stress and worry. Similarly, someone battling advanced cancer may not want to learn that his or her genome has revealed high risk for another disease as well. If a patient tells their physician that they don’t want to learn about incidental findings, should their wishes be ignored? No soul-searching Dr. Robert C. Green, one of the medical geneticists who led the AMCG committee which drafted the recommendations, points out that if a dermatologist is examining a rash but sees evidence of a suspicious mole, the doctor is bound to let the patient know, no soul-searching required. In his opinion, incidental WES/WGS findings should be viewed the same way. Should there be an opt out? Critics argue that the genome screening advocated by the AMCG is not analogous to the typical incidental finding encountered in medicine. Rather than inadvertently identifying a condition like an oddly shaped mole, in this case, researchers must actively hunt for 57 genetic variants. In light of this difference, they ask whether it doesn’t make sense to include an ‘opt out’ option. A thorny quandry This thorny ethical quandary gets even more complicated when the individuals involved are children. What if parents don’t want to receive incidental findings on behalf of their children? If they do receive such findings, when should they relay them to the child? What if a child is given medical information they would not have elected to receive as an adult? A can of worms Due to unsettling questions such as these, the ACMG has previously recommended that diagnostic tests for adult-onset diseases should not be performed in children. However, from the ACMG’s perspective, incidental findings from WES/WGS were a different can of worms. Valuable information could be gleaned from sequencing, even if it was being performed for another purpose. Real life example Because the information associated with the ACMG variant list was actionable, and it could potentially affect healthcare for a child’s family members as well as the child, it didn’t make sense to the ACMG to keep it under wraps. One real-life example of how such incidental findings can benefit a child comes from a boy who underwent WGS as a participant in a research project on developmental delay, intellectual disability, and seizures. Preventing damage Prompted to look for evidence of Marfan syndrome by one of the 57 genetic variants listed by the ACMG, doctors found evidence of a weakening aorta, consistent with the disease, and were able to initiate treatment. In this case, had the incidental finding not been reported, damage to the child’s heart may have progressed much further before the syndrome was diagnosed. All okay…for just now These are recent recommendations by the ACMG and time will tell how widely they are implemented. However, at the time of writing, it appears that many sequencing companies are conforming to the ACMG recommendation to scan for 57 harmful genetic variants. At the same time, institutions seem to be giving their clients the option to ‘opt out’ despite official recommendations to the contrary. For example, GeneDx, a company that performs WES, scans the genome for the 57 variants recommended by the ACMG, but includes them in the patient report only if the incidental findings are present in the ‘proband’. Putting spin on WGS results Therefore, when the company analyzes the genomes of a child and his or her parents, trying to determine whether a novel mutation has arisen in the offspring, it reports incidental findings only for the child. GeneDX also allows patients to opt out of receiving such results. Similarly, Columbia University’s Laboratory of Personalized Genetics assesses the variants specified by the ACMG, but allows patients to opt out of receiving this information. If the current response is any indication, the ACMG recommendations have already changed practice by spurring sequencers to scan for a uniform list of variants. In the end, it seems likely that each company or institution will put its own spin on the way it handles incidental findings.