our genes are your destiny, right? Not necessarily, according to a report in Tuesday’s Journal of the American Medical Association. The study’s bottom line: In a general population, only a small percentage of people with gene variants linked with long QT syndrome or Brugada syndrome — two potentially life-threatening heart rhythm problems — had any evidence of the condition. In other words, having a potentially harmful genetic variant for a disorder does not always translate into having the disorder itself. To make matters worse, the three laboratories that did the testing often didn’t agree on which variants were potentially harmful.
The results of the JAMA study, done as part of the Electronic Medical Records and Genomics (eMERGE) network, raise questions about what to tell people who have their genomes analyzed. Such tests are often done to identify a specific problem, like a cancer-related gene in people with cancer in their families. But they can also identify other potentially problematic gene variants unrelated to the reason for the search. These “extra” discoveries are called incidental or secondary findings.
The American College of Medical Genetics and Genomics has recommended that doctors and researchers tell individuals about more than 50 gene variants that appear as incidental findings — including the two genes examined in the JAMA report.
Ellen Wright Clayton: Results question routine communication of incidental findings
Michael Murray: Incidental findings are a risk for a condition, not a diagnosis
Susan Wolf: Databases used to interpret gene variants are creating a “genomic health disparity”
By Ellen Wright Clayton: These results are stunning. They should call into question the wisdom of routinely telling patients about secondary findings of genetic analyses.
The concept of secondary findings isn’t new. CT and MRI scans routinely turn up unexpected discoveries. Sometimes they are important, as when they show a hidden cancer. More often, though, they don’t offer useful clinical information. As the practice of genetic analysis grows, how to handle secondary findings is becoming an increasingly important issue.
The two genes examined in the JAMA paper were thought to be poster children for returning secondary findings because they are associated with potentially dangerous arrhythmias. Knowing about the presence of the condition means you can take action to prevent a fatal cardiac arrest. But the lesson I take away from this study is that having a gene variant for Brugada or long QT syndrome doesn’t necessarily mean an individual has the disease. In fact, only one-third of the people in the study with a gene variant had any signs of an abnormal heart rhythm, and only 10 percent had been diagnosed with a prolonged QT interval.
The genetics community has expended a lot of effort to separate gene variants that we know are harmful or that are likely to cause problems from those we aren’t so sure about. The American College of Medical Genetics had identified the two genes examined in the JAMA study as having variants that are clearly pathogenic, meaning that if you found them you would be doing some good for the patient. But it looks like this often isn’t the case.
This has very large ramifications for whole genome screening in newborns or as part of the Precision Medicine Initiative. Such tests will return information about many genetic variants. Individuals will be told, “We found these variations in your genes that might be important, but we really don’t know if they are going to make you sick or what to do about them.” That will be quite confusing and could generate unnecessary fear.
It’s one thing to look for gene variants in people who already have symptoms or whose family members have a particular condition. There’s real value in that. But looking for gene variants in general populations can do more harm than good, as can routinely telling individuals about all incidental genetic findings.
Ellen Wright Clayton, MD, JD, is professor of pediatrics and law at Vanderbilt University and a member of Vanderbilt’s Center for Biomedical Ethics and Society.
By Michael Murray: The important results published in JAMA will help sharpen our focus on how best to move forward with incidental or secondary findings. But the results aren’t really surprising. The two genes the researchers evaluated have variable penetrance — meaning that some individuals with damaging changes to the gene will not have the disorder — even when targeted gene testing is carried out in patients at risk because of symptoms or family history. For example, it’s not uncommon to see one family member with a gene variant for long QT syndrome who has the condition while a brother or sister with the same gene variant doesn’t have the condition.
It’s also important to keep in mind that these researchers judged whether or not an individual had long QT or Brugada syndrome by looking at electronic health records. Although the presence of a condition in the electronic health record is expected to be quite reliable, its absence could mean that it is truly absent or that it simply wasn’t recorded. So while the health record is great source of information, it isn’t nearly as good as going back and directly evaluating the participants.
Learning about an incidental finding can be confusing and potentially frightening. How best to tell an individual about such findings is something that many experts are spending a lot of time thinking about.
At Geisinger, we are delivering incidental findings to participants of our MyCode Community Health Initiative. In partnership with the pharmaceutical company Regeneron, we are sequencing the genes of volunteer Geisinger patients and linking that information to their medical records. This has been done for close to 100,000 participants so far; our goal is 250,000. As part of this project, we aim to build a model for how incidental genomic results from healthy individuals might be used to improve patient care in large health care systems.
We expect to find potentially worrisome incidental gene variants in about 2 percent of the volunteers. We plan to evaluate each of these individuals. Those with the associated condition will begin treatment for it. For those without it, we will build a safety net, so if it does appear, we can deliver the appropriate care. We will also offer to reach out to their family members, evaluate them, and provide similar genetic testing.
An integral part of this project is the development of robust tools to help doctors and their patients fully understand the results of genetic analyses and have a clear idea on how to follow up on the results.
Incidental findings represent a risk for a condition, not a diagnosis of a condition. The communication of an incidental finding should be viewed as the start of a process that includes clinical evaluation and planning for long-term management.
Michael Murray, MD, is director of Clinical Genomics at Geisinger Health System in Pennsylvania.
Susan M. Wolf: The JAMA article by Sara Van Driest and colleagues offers an important challenge to the American College of Medical Genetics and Genomics (ACMG) recommendation to analyze extra genes whenever an individual’s genome is sequenced for a specific clinical purpose. The ACMG logic is that doctors should use clinical sequencing as an opportunity to screen for extra genes that confer risk. But do those genes reliably confer risk? The JAMA article cautions that predicting the presence of a disease from a genetic variant doesn’t seem to work very well. That indicates we’re really not ready for the kind of opportunistic screening that ACMG has advocated. We simply don’t know enough yet about how these genes operate in the general population.
There’s another problem with the ACMG recommendations, which were issued in 2013. They urged that these extra genes be analyzed even without an individual’s specific consent to test for each of those extra genes. This proved highly controversial, and the ACMG changed its position in 2014 to allow people to opt out of screening for the extra genes. That makes sense. When individuals undergo sequencing for a particular health problem they’re facing, they should be able to decide for themselves if they want to know about additional health problems they may face in the future. It’s up to them what psychological and health burdens to undertake. Imagine someone fighting cancer whose doctor recommends sequencing to try to identify a new target for their cancer treatment. That person might say, “Yes, sequence genes that matter for my cancer care, but I don’t want to hear about anything else. I’m fighting for my life. I don’t want to deal with unrelated risks right now.”
The new JAMA article reinforces that we need to be careful in genetic and genomic testing to avoid conveying misinformation and confusing patients. I had my own genome sequenced. A small handful of variants were reported to me as potentially harmful, but most of them made no sense, given my health history, complete lack of symptoms, and family history. I was also told about hundreds of “variants of unknown significance” that might or might not be associated with various serious diseases. The wisdom of communicating highly uncertain information to patients is debatable.
The JAMA article also mentions an enormous and looming problem in genetic analysis: The databases currently used to interpret gene variants do not adequately represent people of all ancestries. The article refers to “a relative lack of sequence data in nonwhite populations.” This is creating a genomic health disparity — a database that doesn’t work well for people of all ancestries. This is a big problem that needs to be addressed very rapidly. One of the exciting things about the Precision Medicine Initiative is its firm commitment to recruit a truly diverse cohort of 1 million people to address this. The initiative’s ambition to partner with the individuals who participate in the cohort promises to advance not only genomics and biomedicine, but also ethics and law.
Susan M. Wolf, JD, is McKnight Presidential Professor of Law, Medicine & Public Policy and chair of the Consortium on Law and Values in Health, Environment & the Life Sciences at the University of Minnesota.