Genetic Testing & Technology – with Dr. Jim Evans

Ron Falk, MD: Hello, and welcome to the Chair’s Corner from the Department of Medicine at the University of North Carolina.

This is our series where we discuss genetic diseases with physicians who treat patients with these conditions. We start off our series with a discussion on genetics, new research, and the amazing new technologies today available for testing and treatment of disease. We’ll also talk about when someone should think about getting testing, or getting their child tested, for a genetic disease. And—when should people buy genetic testing kits like “23andMe” or “Ancestry.com?”

We welcome Dr. Jim Evans, Bryson Distinguished Professor of Medicine and Genetics in UNC’s Department of Genetics. Dr. Evans is the Director of Clinical Adult and Cancer Genetics at UNC. Welcome, Dr. Evans.

Jim Evans, MD, PhD: Thank you.

Defining some key genetic terms

Falk: As we start thinking about genetic diseases, there are certain words that may come to mind and are used frequently. One of those words is “mutation.” What on earth is a mutation?

Evans: Mutation, in the purely genetic technical sense, is any variation from some consensus or standard sequence of your DNA. Unfortunately, the term “mutation” has gained a rather pejorative meaning, and people think of a mutation as bad. In a technical sense, that’s not true. Mutation can be any change. For that reason, because there’s some confusion, the field is actually changing the nomenclature and we try no longer to use the term “mutation” when dealing with human genes and diseases. We talk about “variants”—for a variant in the sequence, and if that variant is associated with or causes disease we now call that a pathogenic variant. So, mutation really is an older term that is less and less in use.

Falk: Because there are variants that actually are protective or are useful in some circumstances, and may be pathologic in others.

Evans: Yes, exactly. One of the focuses of modern genetics is to find those variants that actually benefit, protect against disease. There’s some good examples of those with certain variants that protect, for example, against HIV infection, etc, and I would just mention that the entire process of evolution really rides along with variants that end up conferring some advantage in a given environment.

Falk: You can have a sickle cell variant and survive malaria, if you’re living in Africa. Or, sickle cell disease if you have more than one copy.

Evans: Yes, there are a whole host of both globin, beta globin variants—that’s one of the constituents of the machinery in your red cells that hang onto oxygen, as well as blood groups that protect against malaria. If, for example, as you mentioned, certain mutations are present in two copies instead of just one copy, then that can actually cause problems to an individual, so there’s an intricate balance there.

Falk: Let’s talk about some other words. Let’s talk about the words “genotype” and “phenotype.” What do those words mean?

Evans: Really, the phenotype is what you see. Your phenotype is how tall you are, what color eyes you have, perhaps your proclivity to certain diseases, or perhaps resistance to certain diseases. Your genotype is what underlies that, and there is not a clear or an exclusive one-to-one relationship between your genotype and your phenotype. You may, for example, have genes that would, under certain circumstances, make you very tall, but if you’re malnourished, in a certain environment, that genotype won’t be manifest in your phenotype and you’ll end up short.

So, the phenotype is what you see, the genotype are the underlying genes that tend in very broad terms to guide what you end up as, but I think this is a good opportunity to stress the fact that as that distinction that I just discussed would imply, your genotype isn’t everything. Our genes are important in who we are, in our medical status, what we look like, etc, but our genes aren’t the whole ball game—our environment and sheer chance are also very important.

Falk: There are other words we need to talk about, including the words “autosomal” and “recessive” as ways that genetic information is passed from one generation to another. Help us understand.

Evans: Autosomal simply means that a gene that we’re talking about is on one of your autosomes, that is most of our chromosomes. We have twenty-two autosomes that the bulk of our genes reside on. We can look under the microscope and see those chromosomes.

There are two other chromosomes that are called sex chromosomes. They differ in the way they are transmitted from the autosomes basically, or their effects. If a gene happens to be on one of those sex chromosomes—for example, you’ve heard of “X-linked diseases”—hemophilia is a good example. Color blindness—I’m color blind—that’s because I have a mutation on my X chromosome. Because the X chromosomes determine what sex we are, any variant that is on one of the sex chromosomes that causes disease will have a different pattern of inheritance in the family.

Most genes will reside on autosomes, they are transmitted in ways that have nothing to do with your sex, and the two things to pay attention to there are, there are diseases called “autosomal recessive,” and for such a disease you have to inherit a pathogenic variant from both mom and from dad. That’s the only way you end up with the disease.

There are other diseases called “autosomal dominant,” where if you inherit that variant from mom or from dad, just one copy, you will then have that disease. A good example of that would be Marfan syndrome—people who are tall and have certain risks of aortic rupture and eye problems, or Huntington’s disease. For those kinds of disorders, you only need to inherit one mutation and it can come from either mom or dad. There, I slipped up again and used “mutation,” just to reinforce to you that we are in the process of kind of changing that nomenclature.

New technology to sequence genes

Falk: The technology used to understand genetics has tremendously changed over the last few years. What kinds of studies are occurring worldwide?

Evans: The advances in the technology of genetics have been breathtaking. When I was a fellow about twenty-five years ago, we could sequence a gene—that is, to define each of those rungs on the DNA ladder, usually in the range of a few thousand, to see if we could find a mutation—that is, a misplaced rung, an incorrect rung, or a missing rung on that DNA ladder—but doing so was a real challenge. It was not a trivial thing to even sequence a single gene.

We now can sequence all twenty-two thousands of a person’s genes in a matter of a week or two. We can now sequence the entire genome—that is, define every rung on your DNA ladder, all three billion of them. This has been due to advances in sequencing—called massively parallel sequencing, where we can do millions of reactions at the same time, and thereby define one’s genomic constitution.

The important thing I would mention is, that as is usual in science, our technology has outstripped our understanding. I can sequence your genome, define all three billion rungs on your DNA ladder. Making head or tails of that is a whole other ball game. We are only in the very earliest stages of beginning to really be able to understand your genome, and what it means for you and your health.

Falk: Other words—“massive parallel sequencing,” “next-gen sequencing,” “whole exome sequencing.”

Evans: Next-gen sequencing is usually used synonymously with massively parallel sequencing. I like the latter term, because it actually describes what we do—we’re doing massive numbers of reactions in parallel. I don’t know when “next generation,” will be the next “next generation,” right? You will hear “next generation sequencing” very commonly, probably more commonly than massively parallel sequencing.

“Exome sequencing,” also called “whole exome sequencing,” is basically looking at all of the expressed parts of your DNA, all of your genes, and we have about twenty-two thousand genes. It takes about twenty-two thousand genes to make a human, and an exome sequence is defining those. That’s commonly done because the exome is where the variants that matter for us medically, that we understand, reside. In a clinical setting, when we think somebody has something genetic, we might do an exome—sequence all twenty-two thousand genes and look for the culprit. In research, we sometimes do whole genome sequencing which also sequences all of the DNA material between genes and in the nonexpressed regions of genes.

Planning a family & newborn screenings

Falk: If you were thinking about starting a family and you know, for example, that you’re a carrier for a specific disease—let’s use cystic fibrosis as an example. How can this kind of testing and meeting with a genetic counselor help?

Evans: Many of us carry variants that can cause disease in a child of ours if our partner also carries such a variant and transmits it to the child. Like you said, cystic fibrosis is a good example of that. Among the Western European-derived population of the United States, about one in twenty of us have a pathogenic variant for cystic fibrosis. Now that doesn’t do you any harm at all, if you are a carrier. But, if your partner happens to be a carrier, and you both happen to transmit that pathogenic variant to a child, then that child will have those two pathogenic variants, what’s called the CFTR gene, and will have cystic fibrosis.

Now, you might be very interested in understanding whether you’re both carriers because it could give you a heads up on what to be prepared for with your child. Other individuals might wish to terminate a pregnancy that has two mutations, or pathogenic variants, in the cystic fibrosis gene. It can basically help with reproductive decisions and with planning. Some people wish to avail themselves of that information, and some people don’t, and as you know that’s a highly contentious issue right now in our society. This is an example where genetics, and our technology and being able to define variants runs right up against hot buttons, social issues as well.

Falk: What you’ve just described though, is different than newborn screening. Newborn screening happens to pretty much every child born in North Carolina, if not the United States.

Evans: Every child who is born in the US gets a heel stick within a day of being born. The drops of blood that are obtained from that heel stick are then analyzed—actually not through genetic analysis, it’s through something called tandem mass spectrometry—to detect diseases that could cause catastrophes in that individual if there wasn’t an intervention enacted.

The perfect example of successful newborn screening is PKU—phenylketonuria. If it is detected within the first month after birth, and the child is put on a special diet, that child will be fine. On the other hand, if it’s not detected within a month, the child will have severe cognitive impairments and have a very compromised life.

There are a set of diseases that we now screen all newborns for with the hope of intervening early and preventing them. Most of those disorders are genetic, and there’s interest now in seeing how we can use massively parallel or next generation sequencing in order to augment newborn screening. There are some disorders that we can’t pick up through tandem mass spec that would be good candidates for using sequence analysis for. I think we’ll see this kind of DNA analysis helping with traditional newborn screening, but it won’t replace it.

When genetic testing is most helpful

Falk: Jim, you’re a practicing clinician. When do you think genetic testing is most useful for a patient?

Evans: Like any medical test, we generally in clinical medicine don’t do medical tests simply for curiosity’s sake. What people want is, whether they’re coming to the doctor for a sore throat or a cough, or because of a possible genetic disease, they want information that’s going to help them make decisions, help them get better, etc.

Right now, the most appropriate use for genetic testing is when someone manifests symptoms, or say an inheritance pattern in their family that says, “Gosh, there might be a genetic disease going on.” By doing genetic testing and defining that, we can often times really improve somebody’s health.

An example I would use is, most of the listeners have probably heard of BRCA1 and BRCA2. These are genes, that when they have pathogenic variants in them, greatly predispose to breast cancer and ovarian cancer. So, a woman with a BRCA1 pathogenic variant will have a lifetime risk of breast cancer that is from sixty to eighty percent. Her risk of ovarian cancer approaches fifty percent. Knowing about that can help immensely because she can either undergo enhanced surveillance to try to catch the cancer at a much earlier and more treatable stage, or many women choose risk-reducing surgeries, like mastectomies like Angelina Jolie did, oophorectomies—removing the ovaries.

We apply genetics typically when there’s reason to think that there’s a genetic process or disease going on, or the person is at risk for something that we can act on. Sometimes that action is, as we just discussed, reproductive decision making. Even if we can’t do anything about a really awful disease like Tay-Sachs disease, there are parents who wish to know whether a child that they’re conceiving has Tay-Sachs or not. If you want, we can talk a little bit more about what the role might be in the future for DNA analysis of healthy individuals. That’s not something we’re doing a lot of now but there’s promise.

Falk: Let’s take a tangent from that and ask the question. If you are part of a family and you are an adolescent. Let’s use the example of polycystic kidney disease for a moment—you know your parent had polycystic kidney disease, it’s an autosomal dominant disease for the most part, and do you want to know with genetic testing whether you are going to get polycystic kidney disease, or not? What do you tell the parent and the child?

Evans: Right. When it comes to children and adolescents, we do genetic testing when the disease can have an impact on that individual during childhood. So, for polycystic kidney disease, which can manifest in young people, it’s often times beneficial to know whether they carry a pathogenic variant for that disorder, because if they don’tcarry it—let’s say dad has polycystic kidney disease and they have not inherited that pathogenic variant—they can dispense with the usual screenings we subject people to—ultrasounds, really careful control of blood pressure, etc.

On the other hand, if they find when they’re seventeen or fourteen years of age, that they are at risk for polycystic kidney disease because they’ve inherited dad’s pathogenic variant, then they know, “I need to be getting renal ultrasounds, I might qualify for certain studies of investigational agents that show promise in stalling the disease.”

Falk: Tolvaptan has just been FDA approved.

Evans: Is that right? That’s exciting. That actually highlights an important thing about genetics and that is, it’s far from a static field. We tell the people we see, even when we can’t help them right now or can’t figure something out, please stay in touch with us each year because there are new therapies being developed for genetic diseases, there are new tests that can shed light. We often times do test some people, who, three years before there was no test available, and now, we can tell them something important.

Direct-to-consumer genetic testing

Falk: Dr. Evans, you’re spending a lot of time trying to explain the process, the thinking process that goes into whether you’re going to do a genetic test or not. At the same period of time, if you flip on your TV, you’ll see an ad for “Ancestry.com” or “23andMe.” Tell us what those tests really are and what kind of genetic test is being done, and then let’s chat for a bit about the ethics of doing those tests.

Evans: I’d love to address both of those things. The offerings that are out there for genetic analysis—we call it “direct-to-consumer” or “DTC” genetic testing are extraordinarily wide and heterogenous.

They really vary from the ridiculous to the sublime. In the ridiculous category, you will see promises of genetic testing that will tell you who you should date and marry—they’ll do matchmaking with genetics. You’ll see offerings that purport to tell you what kind of sport you should encourage your child in—whether they should be a sprinter or a long-distance runner. You’ll see reports that people can analyze your DNA and tell you what you should eat. All of that is hogwash. It is complete and utter nonsense. There’s an offering out there to analyze your DNA and tell you what kind of wine you will like. My retort to that is, you’re far better off spending that same money on some bottles of wine and trying them, you’ll get a much better beat on what you will like, and it will be more fun and accurate. There are a lot of offerings out there that are just plain ridiculous and you shouldn’t go near them.

On the other end of the spectrum, there’s ancestry testing, for example. It’s very accurate. It’s frankly not going to surprise most people, because most of us, simply from family lore or looking in the mirror can guess what continent our ancestors were from, but it’s interesting. It’s pretty accurate. Sometimes people get surprised. More often, they don’t. One of the things you might want to think about before you do any direct-to-consumer genetic testing is that your DNA typically enters databases when you do that. These companies are in business primarily to get data and sell your data. So, you should just know that your privacy is being compromised when you do such testing.

Falk: Including if you’re the Golden State Killer.

Evans: Exactly. That’s how the Golden State Killer was found. They submitted a sample for ancestry testing and said “I want to find my relatives.”Sure enough, the Golden State Killer wasn’t in that database—apparently he had not availed himself of that testing, but relatives of his had, and they were able to find his relatives and it pointed directly to him. The other thing I would just, warn you about if you pursue ancestry testing, you do want to have in the back of your mind that you might find out Dad isn’t Dad. That happens right along with ancestry testing. Ancestry testing is valid, it’s quite interesting, and it has relatively low downsides, unless you start to think about some of those broader society and privacy issues.

In the middle somewhere is this murky area of wellness—medical, direct-to-consumer genetic testing. I would generally tell people that the claims made by 23andMe and other companies that purport to tell you about your health, your wellness, your risk of disease, are largely unreliable. There are a few tests that have been FDA approved and you can see if you’re a carrier for this disease or that disease, but like any complex medical test, I think you’re better off talking with an expert about what test actually makes sense with you, before you just sign on to a test that someone is pedaling. You should probably speak with a genetic counselor. I’m not a genetic counselor, so I’m not feathering my own nest there—but in general, people are best off talking with a professional who isn’t pedaling a given test, before they send their money in and get a test that’s being marketed.

Falk: Do any of the current, direct-to-consumer tests identify the breast cancer gene?

Evans: That’s a very nuanced answer—yes and no. The FDA recently approved 23andMe’s assay for three particular pathogenic variants involved in breast cancer predisposition for BRCA1 and 2. Here’s the problem with that: There’s been a lot of concern, that it will do a lot more harm than good, and I tend to agree with that grim assessment. The three pathogenic variants or mutations that 23andMe has been cleared to test for constitute a tiny fraction of the pathogenic variants that can cause predisposition to breast and ovarian cancer. It’s only sensible to assay only those three in very narrow circumstances—that would be somebody who is Ashkenazi Jewish, who doesn’t really have a strong history of breast and ovarian cancer in their family. Otherwise, it’s an extremely incomplete test.

Falk: You shouldn’t take solace from the fact…

Evans: You shouldn’t, that’s exactly right. What most of us worry about is that people will take inappropriate solace from a negative result—they’ll send their sample in, they’ll say, “Oh, look, I don’t have these mutations,” –that 23andMe has been cleared to test for— “so I’m off the hook.”Nothing could be further from the truth in many of these cases. I worry that people will get false reassurance.

Falk: What do you tell a person, either from one of these direct-to-consumer products, or even through clinical genetic testing, that they have a pathogenic variant or even the possibility of having a pathogenic variant, and become enormously anxious about that result?

Evans: The first thing I would tell people who get results from a direct-to-consumer genetics testing company, or third party, is be careful. There was just a paper published in Genetics and Medicine, the leading clinical genetics journal, that showed that forty percent of direct-to-consumer results were false positives upon reanalysis. Forty percent.

Falk: That’s huge.

Evans: That’s huge. So, I would tell people your result may not be correct. These labs have yet to show they can do a good job at the actual analysis. The second thing I would tell them is, if you have undergone analysis and you have been found to carry a pathogenic variant for this or that, you really need to talk to somebody who does this for a living, to put your risks in context—how big are they, how serious are they, and what are your options for dealing with that risk? What are the various things you can do to minimize problems from that?

Falk: First, make sure you have the risk for real, that it’s a real valid result, and if after you find that out, to determine if there’s something that needs to be done about it.

Pharmacogenomic testing

Falk: One could ask the provocative question of whether people should take drugs of any kind without having had pharmacogenomic testing. In other words, there are enzymes that are really important in metabolizing a variety of drugs, and one can test for those abnormalities by genetic testing. When would you suggest patients have that?

Evans: I think the whole area of pharmacogenomics—this is basically, like you said, we all know that drugs act differently in different people. Part of the reason for that is our underlying genetics. There are a handful of drugs that their use can be tremendously informed by genetic analysis.

A really good example of that is a drug called Abacavir, which is what is called a reverse transcriptase inhibitor, and is used in the treatment of HIV. That is a drug that you really need to have a genetic test before it is prescribed because individuals with certain genotypes will have a very high risk of hypersensitivity—severe reactions—to that drug. So, it is standard protocol when using that drug to get genetic analysis. Now, the hope for the field is that we will be able to productively inform the prescription of many different agents through genetic analysis. That hope has not yet been realized, and I think ultimately, we will see a handful of drugs for which it’s important to do genetic analysis prior to prescription.

Falk: For example, if you’ve have a stint put in for a coronary artery, whether you should take a particular..

Evans: That’s right. There are specific examples. That edges in to another exciting area which is the genetic analysis of somebody’s tumor, their cancer, has begun to be productive in showing which therapies are more or less effective. That, like pharmacogenomics, I would say it’s farther along than phamacogenomics, but those are hopes for the future that we will be able to productively use that kind of information to tailor your prescriptions, but I would tell people for the most part, that is not ready for prime time for most drugs.

CRISPR – what it is and ethical concerns

Falk: CRISPR—it’s all over the news. What is CRISPR? Why should we know about it?

Evans: CRISPR/Cas9, or just CRISPR, is a new technique that has been developed that allows us to very efficiently edit genomes. So, it can be used to go in to cells and actually correct genetic abnormalities. It’s very exciting to think about the possibility of using it for gene therapy, think about someone with cystic fibrosis. The problem that ends up causing them to need lung transplant, and have a very difficult time of it, the whole reason is they have this error in their cystic fibrosis genes.

We can now envision a future in which CRISPR could be used to repair those genes. There are a lot of engineering problems to solve before we can do that in a productive way. We have to get the CRISPR tools into all of those lung cells, but it is a huge step that brings gene therapy one step closer in many situations. It’s also a tremendous step forward in making animal models for diseases, because we can, for example, we can accurately mimic the genetic constitution in a mouse of a human disease. It will also be important, because we can do this in animals so readily, it opens the possibility of, for example, designing pigs, that we would be immune-tolerant to their organs and using CRISPR to tweak the genomes of the pig or to remove the retroviruses in other species to make animal organs compatible with us. These things are certainly not a reality at this point but CRISPR will accelerate our abilities and our prospects of doing that kind of thing.

Falk: There is a huge concern with CRISPR from an ethical perspective, however, because you could also CRISPR/Cas9 in a gene for speed or for height.

Evans: Or skin color. It’s very scary. I guess I’d bold enough to say that almost anything that can be done will be done, whether many of us think it should be done or not. There is a real concern that people will use CRISPR in human embryos for enhancement. It’s one thing to say,“I don’t want to give birth to a child that has an awful disease, like Tay-Sachs disease,” or what have you. It’s a whole other ethical dilemma and dimension to begin to say, “Gosh we could make your child taller, we could make your child with a darker or lighter complexion. We could make your child with curly hair.” We’re not there yet—these kinds of traits often include many, many genes and the technical wherewithal isn’t with us yet, but CRISPR brings us one step closer, the notion of designer genes and designer babies, which is troubling to many people.

Falk: I would argue it could be terrifying.

Evans: Yes, I agree.

Falk: If you have a crystal ball, which for most us, happily is cloudy, when do you think that era of designer gene therapy or gene editing, more accurately, would occur?

Evans: I think in the next two decades we might see the kind of technological advances that would lead, in theory, the ability to tweak an embryo at the one or two cell stage, and “enhance” it for various characteristics. I think the most frightening thing about that in many ways, besides the societal dilemmas of “What should we do?” to “What is “enhancement?”It might be different from one person to another. But, to me one of the things that is scary is the realization, the fact, that nothing we have ever done in medicine is without risk or problems. We create problems when we use medicines, even our best therapies and technologies come with baggage. When we start manipulating human embryos, we will now be visiting those errors on future generations.

We have never had to confront this kind of situation before. It’s one thing to say to an individual, “All right, you know there are risks. Do you want this medicine?”People will say, “Yeah. I want that medicine.”But, who are we to decide for generations hence, right? Future generations. This is worth it and I’m going to subject my next generations to the problems, the unintended edits that might go with CRISPR use in an embryo. These are new and difficult ethical problems that we often see with powerful technologies. We’re going to have to grapple with those as we go forward.

Screening adults in the population for preventable disease

Falk: What fun uses of genetic tools are on the horizon?

Evans: One of the things I’m very excited about stems from the following observation. About one to two percent of the population of our country is walking around with pathogenic variants that predispose to serious disease, but is preventable.

A good example is a condition called Lynch syndrome. About one in four hundred people carries a genetic variant that puts them at very high risk for colorectal cancer and uterine cancer, and that’s called Lynch syndrome. We cannot identify all of those people through family history, because families are small, and other things happen to people.

Now through technology we have the prospect of going in to the population and saying, “Who has Lynch Syndrome?”Let’s analyze the Lynch genes. Who has mutations in BRCA1?In other words, analyzing people for diseases that they have a high risk for, that are critical, and we have well-established preventing modalities that we can implement. That could benefit one to two percent of the population. I think of it as newborn screening for adults, and I think we should investigate the notion of that and see whether we might be able to do the population good.

I would emphasize we should investigateit, because there have been times when we’ve had a good idea, and it hasn’t turned out so good. I think we need to look at these exciting ideas and then we need to test whether we’re doing people harm or good.

Falk: Exactly. Thank you, Dr. Evans for spending time with us today.

Evans: Thank you, it’s been my pleasure.

Falk:Thanks so much to our listeners for tuning in. Next time, we will talk about one of the diseases we mentioned in this podcast—that is, cystic fibrosis with Dr. Scott Donaldson. You can subscribe to the Chair’s Corner on iTunes, SoundCloud, or like us on FaceBook. Thanks so much for listening.

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