Synopsis: Genetic testing has become a widespread reality in the past five years, but doctors are struggling with what many genetic findings really mean. Should patients should be told about the presence of genes that might be either dangerous… or perfectly harmless? Experts discuss.

Host: Reed Pence. Guests: Dr. Dan Roden, Professor of Medicine, Pharmacology and Biomedical Informatics and Assistant Vice Chancellor, Personalized Medicine, Vanderbilt University Medical Center; Dr. Gerald Feldman, Professor of Molecular Genetics in Medicine, Pediatrics and Pathology, Wayne State University and President, American College of Medical Genetics and Genomics; Dr. Ellen Wright Clayton, member, Center for Biomedical Ethics and Society and Professor of Pediatrics and Law, Vanderbilt University

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16-12 incidental genetic findings

Reed Pence: If our biology is our biography, then our genes are the roadmap directing our lives. So scientists have spent decades of time and billions of dollars figuring out what each of our genes does, in hopes we can predict and even influence some of the outcome. But what we’ve learned is so new that even scientists don’t know what to do with all that knowledge yet.

Roden: It’s not so much more research is required, but we’re in a very, very rapidly changing world. So, we’re just trying to figure out how best to manage this new information flow.

Pence: That’s Dr. Dan Roden, Professor of Medicine, Pharmacology and Biomedical Informatics and Assistant Vice Chancellor for personalized medicine at the Vanderbilt University Medical Center.

Roden: The problem is there are millions and millions of sequence variants and we just don’t have enough information on what to tell people about the consequences of most of those variants yet. It sounds like we’ve painted ourselves into a scientific corner I would argue that we have had this technology available to us literally for five years, the ability to sequence large numbers of patients. And it’s not a surprise, therefore, that we’re still trying to understand how good the quality of the sequence is, how good the quality of the interpretation is, how we’re going to put these large data sets together so that we understand better at a population level how common things are and what kinds of human conditions are associated with particular variants.

Pence: Although direct to consumer genetic testing is available, most of the time a test is ordered by a doctor for a good reason rather than idle curiosity. Dr. Gerald Feldman is Professor of Molecular Genetics in Medicine, Pediatrics and Pathology at Wayne State University and President of the American College of Medical Genetics and Genomics.

Feldman: There should be an indication for ordering such a test in the first place and so the clinical indication is usually for a whole x-zone test or looking at many genes at the same time has to do with the presence of some kind of physical findings, birth defects, developmental delay, some other clinical reason for ordering the test and so yes, definitely there should be an indication for ordering a test in the first place.

Roden: The need for having genetic testing is really determined by your current health problems, so if there is a very strong family history of heart attacks at an early age, those people need to be tested to see if they carry risk factors for heart attack at an early age. One of those that we’re getting very interested in is very high cholesterol, which turns out to be genetic. If you understood that it’s genetic in one person, you would then council that person but then say, ‘I want to see your brother, I want to see your kids, I want to see your nephews and nieces in my clinic’ because I want to be able to do the genetic testing or the other testing, the LDL, the cholesterol testing, to see whether they’re also at risk’ so if you have somebody who has a problem, the genetic testing is really very, very useful not only to understand the nature of their problem, but to figure out who in the family should be tested.

Pence: However, genetic tests are not the panacea some people with a family history would like.

Roden: People want genetics to be black and white. They want a test that says, ‘you’re at no risk for cancer’ or ‘you’re at high risk for cancer,’ and the genetics don’t do that. The genetics say, ‘well, you used to be at moderate risk for cancer and now your risk is a little bit higher’ or ‘now your risk is a little lower.’ Genetics provides shades of grey, it doesn’t provide black and white.

Pence: A good example, and some of the consequences of this kind of uncertainty, can be seen in Roden’s study in the journal of the American Medical Association. His team looked at genes controlling heart rhythms.

Roden: The two genes that we looked at are genes where it’s clear that rare-variants, rare genetic variants, can cause very serious arrhythmias. The kind of arrhythmias that can make young people die suddenly on the basketball court or during sleep, so people have become very interested in genetic variation in those genes are markers of arrhythmia susceptibility across the board.

Pence: Roden’s team sequenced the DNA of a number of people known to have these genes– the kind who might have a family history. They also looked at a random population and found those genes in a surprisingly large proportion of people. It means that apparently having a gene thought to be a trigger for heart problems often causes no problems at all.

Roden: When we do that, we actually find that something between 5-10% of people walking around, apparently healthy, have changes in their DNA in those two genes that would change the protein sequence. We call those non-synonymous variants and we think that many of those are likely to actually change the function of the heart in the electrical system of the heart. So that’s 5-10%, that’s a big number.

Dr. Ellen Wright Clayton: I think the reason were sort of surprised at this is because people thought that the idea of looking for arrhythmia genes or variants was going to be a really good idea. Because if you have one that actually is pathogenic or causes you to be sick, what happens if you have an arrhythmia is that you often just die. So it seemed like well, this would be a good thing to look for so you could think about, you know, whether you needed to start using defibrillators or whatever or a pacemaker. So this is what we think of in the field as sort of low-hanging fruit, the ideal thing to be looking for.

Pence: That’s Dr. Ellen Wright Clayton, a member of the Center for Biomedical Ethics and Society, and Professor of Pediatrics and Law at Vanderbilt University.

Clayton: To find out in this study that only 10% of the people who have a variant that was thought to be disease causing actually really had current evidence that they were actually affected was really pretty remarkable.

Pence: But what should doctors do when a genetic test looking for something else turns up a gene whose importance is completely unclear? What if a test meant to look for the so-called breast cancer gene also locates another gene that may or may not be potentially fatal? Feldman says those are called incidental findings.

Feldman: Reporting secondary findings or incidental findings in medicine is really not a new thing. There is always the possibility of finding additional information beyond the reason for why that test was ordered and it’s no different than in other medical specialties, for example if a patient comes in with a complaint of pneumonia and their physician orders a test X-ray and the radiologist sees some other suspicious finding that might suggest some other diagnosis that radiologist is certainly going to report that.

Pence: The American College of Medical Genetics and Genomics recommends that no matter what a genetic test is looking for, the lab should also report back positive findings on more than 50 other variants, incidental findings that would include the two heart arrhythmia genes.

Feldman: The genes that the American College of Medical Genetics and Genomics chose were ones in which early intervention would be likely to reduce morbidity or even mortality if a patient was identified with a known pathogenic change within those. Those genes are also chosen because there are additional testing that can be done on the patient, so the disorders were carefully chosen, they included things such as breast and ovarian cancer, certain types of colon cancer, other kinds of cancers as well, other types of genetic conditions that have significant risk factors for heart problems for example, or other types of medical problems.

Pence: However, the labs doing the tests make the decision on what to report and what not to report. Roden asked what the labs would tell patients in the case of the two heart arrhythmia genes.

Roden: We turned to genetic testing companies and labs that specialize in genetic testing in a research environment and asked them, ‘if you had a patient who had this particular genetic variant, what would you say in your report to the physician? Would you say that this is a variant that is not relevant to the patient’s health? Would you say that this is a variant that has been reported many times before as something that confers serious risk for arrhythmias or would you say you don’t know?’

Pence: Roden says there were 122 rare gene variants. Of those, there were 48 that at least one of the three labs flagged as a potential arrhythmia risk. But beyond that, there was almost no agreement.

Roden: One of the pressing problems in modern genomics is to figure out what to tell people when we find a rare variant in a gene where we know other rare variants can cause very serious health problems so we have this set of 48 variants. In fact, the three labs only agreed in four cases.

Pence: That kind of uncertainty makes Clayton wonder about the value of looking for disputable incidental findings at all, or of telling a person when something is found.

Clayton: Is it appropriate to be looking for variants in this gene in people without a family history in the first place? So that’s the first question. The second question is if you’re going to look, what you tell them, and that becomes a really complicated issue because to call somebody up and say, ‘You have a variant that we think can cause disease but we don’t know if it’s going to cause disease in you,’ you know, I think is a really difficult thing to tell people because then there have the sword of Damocles over their head.

Pence: In the case of some genes, a positive finding can prompt a doctor to order definitive testing such as an EKG for heart arrhythmia. Or it can trigger more intensive screening for things like breast or colon cancer. Yet if a sizeable proportion of the population has an occasionally suspect genetic variant, as is the case with the two heart genes, extra surveillance could cost the healthcare system plenty without saving many lives. But testing is likely to become more and more common in the future. It’s imperative to figure out what it means before then.

Roden: There’s a school of thought that says at some point, we’re all going to have our entire genomes sequences and somebody’s going to tell us what we’re at high risk for and what we’re at low risk for. The counter argument to that is that there’s so many variants in the genome who’s function we don’t understand that opening up a huge can of worms is dangerous and I think somewhere in the middle is going to be the truth, if there is an absolute truth, and the truth is going to be that we have to understand these risks a little bit better and then we’ll understand how best to use genetic information to actually help take care of individual patients.

Pence: We’re still in the infancy of decoding genetic information and it’s proof that a little knowledge is a dangerous thing.You can find out more about all our guests on our website, where you can also find archives of our programs. They’re also available on iTunes and Stitcher. I’m Reed Pence.


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