Between 3 and 6 million Americans have some form of heart arrhythmia: an alteration in the pattern of heartbeats that raises risk of stroke, heart failure and cardiac arrest. Doctors are interested in identifying patients with arrhythmias early because its easier to treat and can prevent catastrophic complications like a heart attack.
Two genes have been associated with specific types of arrhythmias. So a group of doctors and geneticists wondered if people who have risky versions of these genes would help them find people who have these dangerous heart patterns. Unfortunately, they didn’t. According to their results only 17 percent of patients who had these gene variants had an arrhythmia according to the patient’s medical records. Compare that to 13 percent of people without these gene variants.The vast majority of patients with the risky genes don’t get sick.
So what should or doctors do when our genomes turn up with risky gene variations? Should they tell us about variants even though they can’t tell which of us will go on to develop a condition and which of us will be just fine? Bioethicists, geneticists and physicians have been debating the topic every since genetic analysis has become part of mainstream medical care.
Not every patient will have their genes sequenced. But a patient with cancer or a disease linked to a known genetic mutation likely will in order to match the best chemotherapy drugs or confirm a diagnosis. Alongside those results patients can also get the results of a few dozen other gene variants. They are called ‘incidental findings.’ The American College of Medical Genetics and Genomics (ACMG) recommends about 50 of them because they’re known to be significantly associated with developing a disease. The breast cancer related BRCA 1 and 2 genes are among them. The two arrhythmia genes, SCN5A and KCNH2, in this study are also recommended to be reported back to patients.
The ACMG recommendations say that patients should be told about these gene variants so that they understand they might be at higher risk of developing these diseases and can get extra screening or take on lifestyle changes aimed at prevention. This seems innocuous enough. But it could lead people to wrongfully think they will definitely develop disease. Or it could cause them to ask their doctors for extra tests and treatments.
The heart of the problem is that geneticists don’t really understand what causes someone with disease risk genes to develop the disease. That’s called penetrance. A gene variants’ penetrance is the likelihood that it manifests. It’s dependent on many factors that aren’t well understood and likely more that we haven’t even identified yet. Penetrance is low, even in well-established cases like the variants in this studies. It’s difficult to say if knowing you have a risky variant is worthwhile to a patient who can’t know if they will go on to develop disease.
The way genes have been studied up to this point is part of the problem. Before gene sequencing got cheap, scientists took people who were sick — who had already developed the phenotype of a gene — and then started looking at their genetics. This is how gene variants that predicted risk of a particular condition were found. But the goal of using genetics in medicine is the opposite. Precision medicine advocates want to take people’s genotypes and identify them before they get sick. It’s the other side of the problem, Larry Husten at CardioBrief described it well:
We overestimate penetrance because, for most of the last several decades, human genetics has been about a phenotype-first approach. We find people with unusual or extreme phenotype and ask what genotype leads this condition. However, such results do not imply that every time you see the given genotype, the phenotype will follow. To get true estimates of penetrance, you need a genotype-first approach, i.e., find everyone with a given genotype and ask what are the phenotypic consequences. Thankfully, due to cheap genome sequencing now, we are in the midst of a revolution in medical genetics where we are moving from phenotype-first to genotype-first studies.
The hope is that with new precision medicine initiatives can flip the paradigm. Programs like the NIH’s million genome project and the eMerge network where researchers analyze genomic data alongside a huge bank of patient’s electronic medial records. Until now, we’ve largely searched for disease-causing mutations in people who were already sick. Medical geneticists don’t have a very good picture of what those same variants are like in the general population.
The arrhythmia study brings up another issue inherent in medical genetics so far: racial and ethnic discrepancies. The authors pointed out that one variant of the SCN5A gene is much, much more common in people of Asian descent. They wrote (paywall) that it was unlikely these were disease-causing mutations in that population. Basically, they called the tool worthless for Asian people. Its possible there are many more examples like this, but because of ethnicity-related inequality in sequencing, it might be a while before geneticists are able to find them. Susan M Wolf, a bioethicist at the University of Minnesota, wrote:
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.
Wolf did note that part of the U.S. Precision Medicine Initiative is to sequence genomes across the full diversity of the country’s population.
The main reason that professional organizations and studies like this suggest that incidental findings not be communicated is because it could cause harm. But incidental findings aren’t unique to genetics. They’re also found every time a patient gets a CT scan or MRI. If something funny shows up on an imaging test, a doctor and patient decide to go further with testing or to watch and wait. It’s only different in genetics because instead of an odd looking spot on a scan the anomalous result is a probability. That’s difficult for a patient to wrap his or her head around. It’s difficult for a physician, too.
Some who argue against returning incidental findings claim patient’s peace of mind should be protected. “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,” said Ellen Wright Clayton.
But modern medicine is experienced with lots of these associations. Obesity, blood pressure, nutrition, sleep duration and cardiovascular disease are all intimately related in ways that are unique in each individual. Physicians don’t shy away from counseling their patients about these inter-related measures even though they don’t have all the answers.
Other proponents of censoring incidental findings point to the chance a patient who finds out about a risky allele will request procedures they don’t need. In the case of arrhythmia, the study authors suggested some patients would even request surgery to insert pacemakers to regulate their heartbeats, the most aggressive form of treatment for the condition. But unnecessary care isn’t special to medical genetics. It happens all the time. As Atul Gwande, himself a doctor, writes at the New Yorker, at least a third of Medicare patients received some unnecessary care in the last year. The procedures in the study had nothing to do with genetics. There are many reasons doctors order tests that aren’t needed including patient preference and fear of malpractice suit, so called ‘defensive medicine.’
The costs and complexities of applying genetics to healthcare are significant. And although we’ve been talking about genomes for 15 years, the field of medical genetics is really still in its infancy. But if precision medicine is going to prove itself out, one way or another, physicians and patients can’t ignore it. Doctors should be honest about what they know and don’t know. If nothing else, incidental findings can help identify which patients need extra monitoring.
Meredith Knight is a contributor to the human genetics section for Genetic Literacy Project and a freelance science and health writer in Austin, Texas. Follow her @meremereknight.