#96 Genetic Testing: What it Means for Families and the Future

Stacy Hewson, Director of Genetic Counselling at the Hospital for Sick Children, and Program Director for the Master of Science in Genetic Counselling at the University of Toronto


May 5, 2021

The Human Genome Project -- to sequence all genes in human DNA -- took over a decade and about $5 billion dollars to complete. Today, we can get the same results in 2 months for about $5000, or even over a weekend if we really need it. As a result, more and more people have access to genetic testing. For many families affected by inheritable conditions, these tests can be invaluable. But is this the precision medicine revolution we've been promised? In this episode of Raw Talk Podcast, we gather experts in genetic testing and genetic counselling to find out. We'll explore what genetic testing really looks like, what the results can mean for families, and learn about the growing field of genetic counselling. First, we spoke with Dr. Raymond Kim, medical geneticist at the University Health Network, who told us about the history and future trajectory of medical genetics. We also sat down with genetic counsellors Stacy Hewson and Laura Zahavich, who direct and lecture for the genetic counselling master's program here at the University of Toronto; they shared with us their challenging but rewarding experiences supporting families to order, interpret, and process genetic tests. Finally, we heard from Huntington's Disease researcher and carrier Dr. Jeff Carroll, who shared his story with genetic testing personally and while family planning. We hope to shed a light on the exciting fields of medical genetics and genetic counselling, and the growing number of genetic tools that might truly revolutionize healthcare as we know it.

Written by: Adrine de Souza

Dr. Raymond Kim - Webpage
Stacy Hewson - Webpage
Laura Zahavich - Webpage
Dr. Jeff Carroll - Webpage
University of Toronto MSc in Genetic Counselling Program
Article - Prioritizing diversity in human genomics research
gnomAD: Genome Aggregation Database
Raw Talk Podcast - Season 5 Listener Survey

Jenna Park [0:01] Before we begin, we would like to acknowledge that here in Toronto, we are on their traditional territory of many indigenous nations, including the Mississaugas of the Credit River, the Anishinaabe, the Chippewa, the Haudenosaunee, and the (Huron-)Wendat. This meeting place is still home to many First Nations, Inuit and Metis people, and we are grateful for the opportunity to live and work on this land. as we explore stories of medical science, we also ask our listeners to learn about and reflect on the long history of science and medicine as tools of oppression against indigenous people, and the complex perceptions of and barriers to healthcare that are still experienced by indigenous peoples in Canada today.

Jason Lo Hog Tian [0:44] We also wanted to remind you, the listeners, about our Listener’s Survey. We are constantly trying to improve the show and we really value your feedback helping to make that happen. You could also win one of three cool Raw Talk tote bags, you can find the link to the survey in our show notes.

Jenna Park [1:00] Most grad students today would tell you genetics began with pea plants in Gregor Mendel's garden some 200 years ago. We've come a long way since then, genetics now plays a growing role in modern medicine, from prenatal testing, to whole genome sequencing and beyond. As we'll learn today, these technologies provide huge amounts of information that we're only beginning to apply to clinical practice.

Jason Lo Hog Tian [1:23] And yet, patients are not always well equipped to understand the health implications of these highly personalized data, not only for themselves, but in many cases for their families as well. To help them navigate testing options and results, genetic counselors are essential members of the care team, alongside medical geneticists, who order the tests, and integrate test results into patient care.

Jenna Park [1:46] In this episode, we'll hear from experts in genetic testing and counseling to learn about this exciting and at times challenging field. I'm Jenna.

Jason Lo Hog Tian [1:54] And I'm Jason, and welcome to Episode 96 of Raw Talk podcast.

Jenna Park [2:08] First, we sat down with Dr. Raymond Kim, a Medical Geneticist at Princess Margaret Cancer Center. Dr. Kim's clinical work focuses on complex multidisciplinary care and adult hereditary disorders. While his research aims to incorporate new genomic technologies into clinical care, like whole genome sequencing and circulating DNA, we asked him to briefly describe the history of the field of genetics.

Dr. Raymond Kim [2:33] BRCA 1 and 2, you know, is arguably one of the first genes maybe NF1 was one of the first genes cloned in hereditary cancer, but BRCA1 was probably one of the first genes to be used pervasively in genetics, and that was in the 1990s. So the cloning of genes is probably a milestone, the next milestone would probably be sequencing of the Human Genome Project, which occurred in the early 2000s, or mid 2000s. That was one thing, the next thing that happened was with what we call Massively Parallel Sequencing, or other people call it Next Generation Sequencing. But that's pretty much where instead of using a traditional, old school Sanger sequencing, when use dideoxynucleotides, you use small bits of fragments about ranging from 50 to 100 base pairs, and you pile them on top of each other. And you can sequence very quickly a large number of genes. To give you an idea of the scale, it took about 20 years and $3 billion to sequence an entire genome and the Human Genome Project back in the 1990s and early 2000s. Now, it costs about three grand or five grand to sequence someone's entire genome introns and exons included, and it takes about two months, some hospitals have what they call a Rapid Whole Genome that takes 48 hours, that technological advance has really changed genetic medicine, because we're not going in blind. Before there was nothing much to look at, because we couldn't assay the genes very quickly. Now it's the opposite. We can assay the genes very, very quickly. But we actually don't know what it means because we don't know all the genetic variation and how that causes disease. So you're you have this massive data genomic firehose that you don't know how to interpret. So you're only actually greening what you can from the previous knowledge. So that's a big genetic advances, whole genome sequencing, the baby step of whole genome sequencing was exome sequencing. So exome sequencing was where you only sequence part of the genome that codes for the protein. The other big advance in modern medicine is probably newborn screening. So newborn screening screens for a lot of inherited genetic disorders that occur in childhood. There are some that are not genetic like where they come in and check you're hearing the baby's hearing, but others are genetic where they do a heel prick on the baby and look for, on the blood spot, signs of a childhood metabolic disorder, whether it be sickle cells, cystic fibrosis, or some sort of rarer, inherited metabolic syndrome. That has, and a lot of these are actually manageable very early in life take newborn screening has really changed the life-expectancy of a lot of children who otherwise would have died if they weren't diagnosed at birth. I think that is truly revolutionary. And the last is, of course, the cell-free DNA, which is being used in the pregnant space to diagnose patients with diagnose fetuses who have a chromosomal problems such as Down Syndrome, then that just to give you an idea how rapidly things change, exome sequencing was probably in the scientific literature in 2010 ish. And then within 10 years, it got used in routine clinical practice, cell-free DNA in pregnant women probably took about three years to be implemented in the clinic, because it was so powerful, those things move very quickly making the field again, genetics very exciting.

Jenna Park [6:09] We asked Dr. Kim about how genetic testing is used in a clinical setting.

Dr. Raymond Kim [6:14] So here's an example from my cancer practice. And I'll use an example from another practice. Let's just say somebody comes in young breast cancer patient, please say 30 something. So that's a pretty young age to develop breast cancer in any jurisdiction, we would do genetic testing on them. And then let's just say we find a TP53 mutation she was born with that puts her at increased risk of breast cancer, and that's why she got her breast cancer. You're born with a TP53 genetic change or mutation. So what do we do after that? We tell her you have this, this explains why you have your breast cancer so early, you are now at risk of developing a breast cancer, another breast cancer, you're at risk of having a brain cancer, and you're at risk of having colon cancer and a sarcoma, and other types of cancers. And that's quite scary. She will invariably say, Well, what are we going to do about that? Do I just live in fear of this cancer ticking time bomb, and we say no, in these types of patients, I follow them annually with a brain MRI, every year full body MRI from their neck all the way down to their feet, which is done in no other field of medicine, nobody gets a whole body MRI, it's just not done. And then, you can remove your breasts so we can put you under high intensity breast screening, and you start doing colonoscopies every two years. And with that, we hope to detect cancer early. In this type of case, we would say okay, well, we're going to do that, and we're going detect your cancers early, and we'll see how you do. Then she has her sibling who also are hopefully healthy, if they can identify it and they're at 50% risk of having the same genetic change if they are identified as a carrier also, even though they haven't had cancer, they're in put under that intensive surveillance. So we can detect cancer early and prevent it if it indeed happens. So it's kind of like preventing cancer and detecting cancer early. Of course, she's 30, and may want to have kids. And simply because she had breast cancer doesn't mean she can't have kids, depending on the therapy she is getting. She may say, well, I don't want my child to have this disorder. I would like to engineer my embryos not to have that genetic change, we're able to prevent the cancer risk from the previous generations on subsequent generations. And in my mind, that's almost a cure for cancer for this family unit. If we are able to predict their genetic change or identify their genetic change to prevent it from happening in the future. That's how it happens in the cancer space. The same thing happens in a rare disease. If you have somebody or a child coming in with developmental delay, severe epilepsy or some other severe condition, if you identify a genetic change that affects some other part of their body, whether it be their heart, or their kidney, or something else, because we know that genetic change, and we know what it does to the rest of the body, we can take care of them in a different way, than they had then they were being taken care of before genetic testing.

Jason Lo Hog Tian [9:11] We also spoke with Laura Zahavich, a genetic counselor at the Hospital for Sick Children, and lecturer with the University of Toronto genetic counseling master's program. We'll learn more about genetic counseling a little later, but first, we asked Laura to help us understand the different types of genetic tests and why they might be ordered.

Laura Zahavich [9:30] Genetic testing is kind of a broad term for testing that's done on a sample of a person's DNA. So that's the typical test that we would do. There is a fairly large range of tests that we tend to order in my clinic, there's a few that are sort of the more common tests that we would do. So when a child is born with physical differences at birth, or think there's concerns around development then a typical test that's ordered would be a test to look at their chromosomes. So something called a chromosomal microarray. Another test that's become clinically available from the past few years is something called Whole Exome Sequencing where, rather than looking broadly at the chromosomes, we're looking in finer detail at the specific genes. And we're actually looking at someone's entire sequence of their DNA. Those are patients who have mainly more than one physical difference or concerns with their development. Within cardiology, we tend to order what are called gene panels. And those are panels of you know, a number of genes ranging from five genes to up to over 100, depending on the condition that you're looking at. But they're more targeted. So looking for specific, inherited cardiac conditions.

Jason Lo Hog Tian [10:41] And so what actually happens in the laboratory as part of the test, what do we look for, and how do we find it.

Laura Zahavich [10:48] The genetic testing that's done, depending on so for doing a, what we call a molecular genetic test, where we're looking at specific genes that's done by sequencing, but really is just looking at the spelling of genes looking for any spelling differences in any of the genes, the laboratory will report back to you. Not every spelling difference in every gene, because many of them are benign, and the laboratory has tools to look at whether a change is likely to be benign, but they will report back any spelling differences in any genes that are either pathogenic, so meaning there's enough evidence to say that they will cause disease, or that they are not and there isn't enough evidence to say that they're harmless, so they're called what we would call variants of uncertain significance. So that's the information that we would get back on a molecular test. For what are called cytogenetic tests, and that would be the chromosome microarray or even that kind of older school test, that's the karyotype, where you would see the picture of the chromosomes that everyone sort of seen in their science textbook, those are looking specifically for extra or missing pieces of the chromosomes. It's not done in quite as fine of detail. But what the report will go back to the laboratories, it will really show areas for which there is more than expected a certain area of the chromosome or less than expected, which would be a deletion.

Jason Lo Hog Tian [11:58] So we're looking for differences, either in the spelling of certain genes, or perhaps larger sections on chromosome. But what are we comparing it to?

Laura Zahavich [12:07] I think what you're referring to is there's these big population databases, one called gnomAD. And that's actually something that they use probably universally, the labs use in order to assess pathogenicity of variants. So they'll go in, they'll look into big databases and say "okay, we have somebody with it, what we think is this rare disorder, they have this variant", so they seen in the population databases, because if it is, then it's a lot less likely to be disease causing. So it's absolutely extremely valuable, and has made a huge difference in our ability to interpret genetic variants. And one of the downsides of that is that populations within those databases are not very diverse, it works well for people of European background, it doesn't work well for people of minority backgrounds, because there just isn't that large amount of data. So you might be able to say, yes, this variant is rare in someone who's European, but this person is not European. And so I have actually no idea how common it is.

Jason Lo Hog Tian [12:59] To address this concern, researchers around the world are now trying to build more complete genomic databases in terms of race, ethnicity, and ancestry. To learn more about these efforts, check out some of the links in our show notes. Next, we heard from Dr. Jeff Carroll, a researcher and advocate in Huntington's disease or HD, who shared with us how HD has affected his family, and led him to pursue a career in genetic research.

Dr. Jeff Carroll [13:26] Yeah, when I was a kid, I didn't really know anything about Huntington's disease. I mean, I should have obviously, my maternal grandmother was quite sick. Even when I was a young kid. She lived for a long time, pretty advanced state of HD ultimately, she was pretty impacted even when I was young kid. Nobody really told us what was going on, you know, it's like a lot of families like grandma's sick, and no one really has a clear sense of why. My mom had some mental health stuff that was confounding, it was hard to know, you know, we didn't have a clear sense of what's going on my grandma. And eventually, my mom stopped having us hang out with my grandma, my grandma kind of stopped coming to events and then kind of went away from it and was living my life and doing my own thing and wasn't thinking about my mom, my grandma's situation at all, didn't really know anything about it. And honestly, I hadn't really thought about my grandma because my mom really compartmentalised it, and then I got orders to go to Europe, and my then girlfriend was like, Hey, I'll come visit you. We'll hang out in here for a little while. While we were there. We have this crazy plan to get married, because then she could like move to Europe, stay with me while I was in the army, wrap up my army career and right about that time we came home and my dad, I think, because he heard I was getting married, even if it seemed a little bit like random ever getting married or fast or whatever. I think at that point, he decided to like, tell us about my mom's situation. And so my dad sat us down in his kitchen, my dad told me, like, you know, listen, your mom's not only at risk for HD, but she's actually started showing signs and she might have to like not be able to live on her own anymore pretty soon and stuff. And I just like freaked out and my wife Megan, she had no idea what's happening because she didn't know what Huntington's disease was. I never mentioned it to her. And so that was that, I got out and came back to Vancouver, which was always my plan, ended up just fortuitously and really luckily ended up at UBC, started taking undergrad classes. You know how my G.I. Bill and I always wanted to finish college. I didn't have a clear plan to do science, but I just, it just was bugging me that I couldn't really understand what was happening. Yeah, I just started taking biology classes, I kind of talked my way in and I didn't have any prerequisites. So for me, it was a little bit sink or swim, like, like, see how this goes. And I didn't really feel like I could be a scientist, I didn't know anyone who was a scientist or like an academic. I didn't know that people got paid to do science. I didn't understand that that was a career path. And so for me, it was really weird to even think about what I was going to do with my life. But I was young enough, that didn't really matter, either. Like we were children in Vancouver, we had this great life and it was fine. So just started going to school. And then during my second year of undergrad, I got my predictive test. I found out that, you know, like my mom, I had inherited this mutant gene, and that given enough time, I would develop HD and then sort of kind of ask for a job. I sort of said: "How can I help?" and by then, I had heard about Michael Hayden, because, you know, he's a very prominent, you know, medical geneticists, but particularly around Huntington's disease he's been working for decades on HD in Vancouver, it turned out to be real luck that I ended up at this university has this incredible HD researcher here.

Jason Lo Hog Tian [16:12] Dr. Carroll told us more about his experience testing for Huntington's disease.

Dr. Jeff Carroll [16:16] You know, when Megan and I went through the process of getting predictive testing done for me, we had to have genetic counseling, and I was so cocky, I was like, horrible. I'm so smart on science now. You know, I was like as an undergrad, I didn't know anything but I felt very smart. I felt like I didn't need this counselor, you know, and we had this amazing counseling experience, we got a lot of good advice about family planning. And it was actually as part of this conversation that they really prompted us to do that. Megan, and I started talking about kids again, because the genetic counselor was like: "Well, what about kids?" And I was just like "No". And she was like, "Well, how do you feel Megan?" And Megan was like, "Well, I don't know, maybe we should talk about it." And then like, that sparked a conversation. So I'm just I'm always amazed that the tough work that genetic counselors have to do. They sort of get none of the glory in the sense of like, they do all the really hard, emotional and intellectual labour, they don't always get the credit they deserve. So I'm glad that you're having a genetic counselour on, they do really amazing work.

Jenna Park [17:12] Genetic counselours are integral to the world of genetic testing. Next, we spoke with Stacy Hewson, a genetic counselour and director of genetic counseling at the Hospital for Sick Children, and program director of the Master of Science Program in Genetic Counseling at the University of Toronto.

Stacy Hewson [17:29] Genetic counseling is defined as the process of helping people to understand and adapt both to the medical, the psychological, and the familial implications of a genetic disease. That process usually involves a number of things. But first of all, interpretation of the family and medical history in order to assess the chance of having a genetic condition or passing it on to your children, education to patients and families about the inheritance, the testing options, management and prevention, as well as resources and maybe research opportunities for individuals based on that. The counseling part of the genetics is to help families adapt to a diagnosis or to a risk of diagnosis and make informed decisions, both about testing or preventative options or screening.

Jenna Park [18:19] We asked Stacy why individuals or families would be referred to a genetic counselour specifically in pediatrics or children.

Stacy Hewson [18:26] If we focus on pediatrics, often we're seeing families with new genetic diagnosis, to help them adapt to that diagnosis, understand what's going on with their child, and then provide information about recurrence risk of whether that could happen again, then any testing options that might be available for them, their future children or their family, their extended family. Sometimes we see individuals with unclear genetic testing results, someone may have genetic testing results, but it's not clear whether or not that's causing the condition. And so genetic counselours can help interpret or try to do further testing in the family to try to clarify genetic results that are not certain or that are uncertain. In pediatrics, genetic counselours can spend some time talking to youth about their own genetic conditions, what that means, what that means for their health, their future health and their reproductive health, empowering youth to understand their own genetic condition and be empowered as they go forward into adult care.

Jenna Park [19:23] What does a typical session look like in a genetic counseling appointment?

Stacy Hewson [19:26] For a new family, the typical start to a session would be understanding, having a discussion of whether the family understands why they're being seen for genetic counseling, because sometimes it's an aside or it's not quite clear to families, why they're coming to genetics in the first place, and sometimes it can be quite scary for families. A lot of the initial discussion is to understand what their understandings are, what their perceptions of the appointment are, what their main questions are, for the counselour to be able to explain to the patient and family what their goals are. You are kind of goal setting at the beginning, what are the patient's goals? And what are your goals and how you meet those goals together. It also gives counselours an opportunity to understand the patient's perspective and where they're coming from, to be able to gauge where to start the discussion. If a family has a very good understanding of genetics, you're going to start at a different spot than a family who's doesn't have any clue why they're there, and what type of testing may be offered or done. It's all about goal setting at the beginning and understanding where they're coming from. And genetics referencing take a family history, because obviously we want to be sure that we're talking about we're collecting all of the family history information that might be valuable for the assessment, there might be discussion of basic genetic concepts like genes, chromosomes, DNA, what genetic testing is, and then the types of results you can get from genetic testing. Many people come to genetics because they want genetic testing to rule out a condition which unfortunately, is not very good at. Currently, we are very clear with families that we might get a positive and negative or an uncertain result. Having that clear discussion in advance is important for families to understand what types of results can be obtained afterward, we obtained consent for genetic testing. So written consent is usually required for genetic testing. Currently, we're doing everything virtually. So virtual consent, but certainly a consent so that families understand what they're getting into before testing is initiated, make a plan for follow up. And the follow up, the results session, reviews kind of the basics required that you did in the first session, an overview of the result. And then a really an explanation of what those results mean, in whatever category you fall into. Certainly, if it's positive, we talk a lot about what that means for the family and the child and discuss the condition and the prognosis, and if there's any referrals that need to be done to other specialties or other services, and try to really support the family in providing the amount of information that they want about the diagnosis and any other resources or supports that might be valuable, connection to support groups or connection to other families with the same condition.

Jenna Park [22:07] A newly diagnosed genetic condition can take a huge toll on families, especially when the diagnosis affects a child. Stacy shares with us some common challenges that families face when undergoing a genetic diagnosis.

Stacy Hewson [22:19] I think one of the biggest things is uncertainty, because your families are provided with a genetic diagnosis, and maybe a spectrum of where kids might fall within that medical spectrum. But the uncertainty of not knowing what will happen for your child, or what might happen is very scary for parents, I try to normalize that with families in the context of any child, we don't have a crystal ball to know exactly what's going to happen. But I think for families where children have been identified with concerns, it's much more scary to not know the trajectory that that might play for their child and what kind of concerns might come up in the future. So I think that probably is the biggest thing. Sometimes it's very hard for families to accept a diagnosis and to accept that their child will not be "typical", that can be very hard. And certainly I have spent time with families where the diagnosis is significantly challenging in the context of it's not, it will shorten the lifespan of that child. So those families enter into a period of what's called anticipatory grief, because you anticipate that at some point, you will lose your child. And that's a very hard journey for families.

Jenna Park [23:37] Receiving a genetic diagnosis sounds like an incredibly emotional journey for families. Despite this, are there benefits to undergoing genetic testing and obtaining a result?

Stacy Hewson [23:47] I think from genetic testing perspective, there are definitely all of those things. So I think for families, sometimes obtaining a genetic diagnosis provides a great relief. So there's lots of literature about the distress families go through in this diagnostic odyssey to try to find an answer for their child's condition. And certainly finding an answer can provide a lot of benefit. Even if it doesn't change the management. Often a genetic diagnosis doesn't change what the family's has already been doing, or the medical staff has already been doing. But it really does seem to improve family's comfort to have a name to be able to give and to advocate based on that condition, as well as to know that they're not missing something that would change the trajectory of their child. If you don't know what your child has, you can't be for sure that you're not missing something. The diagnosis really does help that for families and I'm sure it helps in adulthood as well. There are significant impacts that can be obtained from predictive testing in areas where we can ensure that individuals receive treatment in advance to prevent further complications, cardiology is a good example, there are conditions where families can have this fatal rhythm problem. But if you know in advance, you can have interventions. And there's a lot of really important health scenarios where you can make a difference with genetic testing. A dad said to me once that it just gave him a thread of hope to follow in the future, to know that there are other either scientists or families that are working on potentially trying to come up with a intervention for his child's condition. And at least to know you're on the right road, as opposed to not knowing what road your child is on.

Jason Lo Hog Tian [25:40] Thinking about his future children and his HD carrier status, Dr. Jeff Carroll and his wife were among the first patients to go through in vitro fertilization to avoid passing along his Huntington's Disease mutation.

Dr. Jeff Carroll [25:54] When I found out about HD in my family, I just sort of told my wife, okay, well, we can't have kids, obviously, because I'm glad I'm born, and I don't think that people with HD mutation should like not be born just a different time, we have different kinds of knowledge now. I felt that we couldn't, I couldn't make the same decision my parents did, because I had better information then they did at the time. And so that, we just kind of shut it down, and you know, we're both studying anyway, so it wasn't a big deal until my granddad got sick, he had glioblastoma. He was in his 80`s, but he passed away, and I think that really influenced us of like, life is short, and like, what are you doing and started doing a little more reading and thinking and heard about prenatal testing and things like that, which at the time we weren't interested in doing. And then we heard about this pre-implantation genetic diagnosis or PGD, where you can just do a genetic screening of embryos and have been done on a research level for a long time and at the odd clinic. At the time, there were no clinics at BC doing it commercially, and we happen to be the first successful cycle maybe in BC, but with this commercial access, I know how long ago was my kids are 15 now, so that was 16 years ago.

Jason Lo Hog Tian [27:00] It's really amazing to imagine the potential implications for families living with genetic conditions everywhere.

Dr. Jeff Carroll [27:06] Yeah, well, people say these are incurable diseases, and that's true for the people that have them, but for families that are affected, we really have options. I'm still working all the time and so it's a lot of people to try to develop treatments for HD for patients now, but you can do something about your family already. And yeah, it can be expensive. And unfortunately, as far as I understand, at least in BC, whose the last family I was talking to, it still wasn't covered. And this was in Canada, we paid something like $25,000, or something, so it wasn't cheap. We were in a position where we were able to do it luckily. And and I have to say, we got lucky, too, we we've met lots of families now who have gone through repeated cycles and struggled for various reasons to successfully have a baby. And we had twins on the first time we tried, it worked, we didn't know how lucky we were, having twins is tricky and my wife was on bed rest for three months, and the kids are in the NICU not because of the HD, but just because of they were low birth weight. So it was a weird year, let's just say but it came out well. And now when I look at my kids, I don't think about HD, you know, now they're 14 almost 15. So I mostly think about if they shower or clean their room, but I never like think about them and wonder, you know, whereas I think that's always the thing is you're like looking at your kids all the time and wondering, and you can never not wonder if and when there'll be affected. So it's a real gift to not have to do that.

Jason Lo Hog Tian [28:24] As we've learned genetic counseling has tremendous potential to help families navigate difficult diagnoses for genetic testing is a complicated process. And perhaps surprisingly, the results are not always as precise as you might think. Stacy Hewson tells us more.

Stacy Hewson [28:39] I think from my perspective, one of the clinical issues about genetic testing, which I already alluded to a little bit is uncertainty of results, there are a large group, and I'm not talking about uncertainty of diagnosis, because you get a diagnosis, there could be some uncertainty, but really, it's about interpretation of genetic results. And sometimes we just don't have enough data to determine whether a result is normal or abnormal. That can cause a lot of clinical issues about not knowing what to do with those results, as well as anxiety for families where the results are unclear. It's hard to have an unclear results, meaning you don't know what to do with it, whether it's positive or negative, or whether you need to continue being screened, safe, or yearly cardiac assessments or whether you're actually not at risk at all, the uncertainty really is a clinical challenge. And we'll hopefully reduce over time as we get better at understanding different genetic variants. So sometimes we have very clear understanding that a genetic variant is causing a problem. And sometimes we don't, and it can be based on the fact that we all have thousands and thousands of variants that are not doing anything. But we're not always good at figuring out which variants are a problem and which aren't. Many of our population databases that try to help us determine whether a variant, it's kind of common, are not ethnically diverse. So we tend to be able to interpret variants that are from European Caucasian backgrounds, because we have a lot more data, as opposed to populations where there isn't a lot of data to determine whether variants are rare, but like are normal in those populations. That to me is a big clinical issue and hopefully, we'll get better as we learn more about genetics. And as we get better at interpreting variants from our genomic data. Some of those problems with the uncertainty of results are challenged for individuals when they're interpreted by non-genetics professionals. So genetic reports tend to be very wordy, and, and full of acronyms, and are not very patient or professional friendly. So I think that also needs to change because I think sometimes uncertain results get interpreted by non-genetic professionals as being certain. And that can cause harm if they're actually not really the true result. That's sort of one area which I find an issue. I think some of the other kind of ethical issues sometimes that we get into is certainly the privacy of genetic information. Certainly, you know, genetics falls into all of medicine, where the individual, the privacy of the information is very important to the individual. However, genetic information is also shared with your family members, there may be other individuals whose health is at risk, and who, as medical professionals we might have, we feel a duty for them to be informed of that risk, and balancing that duty to warn other people with the privacy and confidentiality of the individual patient. So certainly, what we do in genetics is really tried to encourage families to share information that would be valuable to other family members' health and provide them with documentation or make it as easy as possible for them to share that information because it can be very important, in certain circumstances could be very important for others. It's sort of balancing those two ethical principles of confidentiality, and then our kind of duty to others, and the harm that can be caused to others with this information or not sharing the information can be a little bit of a challenge.

Jason Lo Hog Tian [32:13] So how do genetic counselors navigate these challenging situations and best support their patients?

Stacy Hewson [32:19] Yeah, there's a National Society for the genetic counseling profession that's based in the US. We also have a Canadian group and both the American group and the Canadian group have a defined code of ethics for genetic counselours. There is sort of an ethical document for genetic counseloUrs to follow in their context of their interactions, both with themselves, their clients, their colleagues, and society as a whole. That's certainly something we talk at length with about with our genetic counseling students. So as part of the genetic counseling training, it's important to go through all of these codes of ethics and to ensure that students have a good sense of where those boundaries are both within themselves and within our profession and with our patients.

Jenna Park [33:02] Laura Zahavich, who we heard from earlier, specializes in cross cultural communication for genetic counseling, we asked her about the importance of cross cultural counseling.

Laura Zahavich [33:12] I find cross cultural counseling a bit of a strange term, because every conversation, every communication is cross cultural, depending on how you define culture, there's the various sort of new term of someone's ethnic background, but there's really that broad term of all of their experiences, beliefs, values, family structure, everything that can come into play into that. And I think that one of the really unique things about genetic counseling is there are so many products of genetic diagnosis that can be viewed from the cultural lens and be very different for metabolics for example, a big part of that is diet. And that's usually influenced by somebody's culture. There's reproduction, there's beliefs about focus of control, and is it God's will? Or is it something that you can actually control in terms of genetic diagnosis, having another child with a genetic diagnosis, all of those things. Navigating some of those discussions is a big part of what we do, and also just making sure that a decision that's being made is being made based on an individual's values and that we are having a discussion about what that means for that person sort of in all aspects of their culture. We do a lot of that work within our program, within our students and our trainees to try and make sure that something that it is part of every interaction with every patient, there sort of unique experiences are the main reason as to why they're they're moving forward with a certain decision.

Jenna Park [34:30] Laura also told us about a related issue in genetic counseling: representation among counselours themselves.

Laura Zahavich [34:36] We're trying to look at, I mean, one of the things that's widely known within medical research is that patient satisfaction and even the way patients do clinically can be impacted by the providers that they have in terms of whether there's representation within their community group. So one of the things that we're looking at are things like the students that are applying to these programs. Where do they live? Do they live in rural areas or urban areas? Because one of the big parts about genetic counseling applications is not just your academics but also what experiences you have. And we recognize over time that it's really challenging for somebody who doesn't live in a big city, for example, to have experience volunteering in the genetic center. So making sure that we are being more holistic in the way that we look at applications and how we view experience things like the socio-economic status of the students coming in. So if you're expected to have all of this volunteer work, what if you have to have a job while you are in your undergraduate degree? How are you able to get that volunteer experience when you still have to work to pay for your tuition? All of those things together, we're trying to firs, this is sort of the pilot first steps what are the actual issues that students are facing? And then the next step will be how do we address those.

Jenna Park [35:44] Since most genetic testing is currently concentrated in large urban areas, Laura described how patients living in rural or even smaller urban settings face barriers to accessing genetic testing and counseling.

Laura Zahavich [35:56] Since I've been working, there has been an expansion of more genetic counselors available in community hospitals, which is great, but one of the challenges that they tend to face is really long waitlist, they might have a geneticist who comes down to that hospital, you know, once every few months, I've always been a big supporter of telemedicine because my specialty is so specialized. And I work with some cardiologists who work in areas where they're, you know, one of very few within the province that we've have done a lot of telemedicine prior to COVID. But I think one of the things that's really come out of this is just the ease at which now we can do virtual appointments with families are well set up for them to either have blood drawn locally. Or another way that we can do genetic testing is through spit and saliva kits. So being able to have those shipped to families, I think that we are now reaching a much larger patient population than we were previously. And that some other work in terms of research that I'm doing is looking at families that have increased risk for an inherited cardiac condition and what we call cascade screening, including doing these virtual visits for families that aren't local, so that they can at least get maybe they can't get all of the assessment that we would typically do if they were able to come to Sickkids. But at least they can get some preliminary genetic testing and other tests locally so that we can triage them more appropriately.

Jason Lo Hog Tian [37:12] Another issue for the profession is how genetic testing impacts communities or people who are affected by disability. Stacy Hewson tells us more.

Stacy Hewson [37:20] I think that there is potentially if we think about tensions or professional issues within this space. I think within the field of disability, genetic counselors sometimes get into this tension. Because we're balancing our roles as advocates of individuals with disabilities, as well as our role of offering reproductive options to individuals to avoid having children with disabilities. There is definitely like a two sided parts to this. And certainly we have historically, both genetics as a whole and genetic counselours have been criticized by disability groups about this tension. And certainly the profession is trying to sort of build bridges between the two. And as a training program, we certainly incorporate a lot of advocacy and learning about individuals with disabilities, as well as lectures on disability rights and discussion of those tensions with our genetic counseling students as an important source of peace as we go forward and push the profession in that area to make sure that we're covering, we are trying to balance both sides more equitably.

Jason Lo Hog Tian [38:32] In terms of employment and insurance, are there any laws that protect individuals who have received the results of a genetic test?

Stacy Hewson [38:39] The only law which is a big one that that's arisen in this space is the Genetic Non Discrimination Act, it was passed in 2017. It's a federal law. And it prohibits insurance companies or employers from requiring that you have a genetic test or asking for the results of your genetic test. So that can be helpful, particularly for families who may consider what I would call pre-symptomatic testing. So say I have a family history of a genetic heart condition. But before I have a heart problem, I want to have a genetic test to see if I'm going to develop that heart problem, then, my life insurance company and my employer can't force me to have the test or make me provide the results of that testing. In certain areas It has allowed individuals to feel more comfortable to pursue genetic testing, knowing that that information will not be shared with employers or companies.

Jason Lo Hog Tian [39:38] Genetic counselours are healthcare professionals that help individuals and families understand and cope with genetic conditions and genetic testing results.

Stacy Hewson [39:47] Genetic Counselors require a two year master's level program. Currently there are five Canadian programs available. U of T program is competitive, highly academic program, we've had about 22 year history, we accept six students into our two year program. And it's a small program. And that's what makes it competitive, I'm sure. It's a very specialized curriculum that's designed and taught mostly by genetic counselours working in the field. The training involves clinical placements in variety of specialty clinics in the academic hospitals in Toronto, but also specialized didactic learning, that kind of happens at the same time, we incorporate the learning and the clinical rotations at the same time. And sort of the goals of the program is really to foster knowledge, skills and the critical thinking in our graduates, they can function in a variety of work settings, so wherever they decide to go with the field.

Jason Lo Hog Tian [40:44] Laura told us about her journey to discovering the profession.

Laura Zahavich [40:48] Yeah, I started my genetic counseling, I think I was in my third year of undergrad, I knew I wanted to work in healthcare and had initially thought I wanted to work in medicine, and then realize that that's not where I wanted to go. I went to Queens at the time, and they were sort of a health care professionals fair. And genetic counseling was one of the things that were there, but I hadn't actually, I wasn't sure if that was the direction I wanted to go. And then I sort of through a family friend, I had an opportunity to volunteer with the prenatal genetics clinic at Mount Sinai Hospital. And it really, I think, I don't remember being so excited about something. And I really had the opportunity to be immersed in the clinic there and just see the variety of patients, the types of cases, the ethical issues that come up. And I knew that it was something that I wanted to be a part of. And I really appreciated the fact that genetic counseling really tries to highlight everybody's unique experiences, and use those experiences to help a person feel empowered in either making a decision or adapting to a new diagnosis. I think that's something that's really unique to our fields, I just went from there, and then was able to go to the U of T program, which was wonderful. And one of the things that is important is counseling experience. So not genetic counseling experience, but the opportunity to gain experience in counseling, not just to gain the skills, but also to know whether or not it's something that you actually want to do. Genetic counseling from an emotional standpoint can be challenging, we deal with a lot of good news but we also deal with providing a lot of diagnoses and helping people through really challenging times. And so it's important to have had that experience before coming in to know whether it's something that you feel like the right fit.

Jenna Park [42:23] Genetic counseling involves not only a deep understanding of genetics and genetic diseases, but providing compassion and effective communication, especially when children are involved.

Stacy Hewson [42:33] So I think within a pediatric setting, it's important to have a lot of compassion. I think most individuals who go into a health related field have a high level of compassion that gets particularly important in pediatrics, because families go through such a lot with young children and feel a lot of burden and guilt, because particularly with a genetic condition, if they feel like they've given it to their child, and they can't take it away from their child. So I certainly certainly think compassion is important. I think being patient is also important. So sometimes parents can be unreasonable. And so being patient and understanding where they're coming from is a critical key. I think, with my experience dealing with youth, I think you need to be engaging and sort of clear and be able to present information in an understandable and relatable way. I mean, that's not just with youth, but also with parents. And I think sort of being compassionate, but clear and patient and meeting the patients where they need you is the most important skills.

Jason Lo Hog Tian [43:36] Genetic counseling also involves the integration of both professional and personal support in practice. Laura tells us more about the importance of support as a genetic counselor.

Laura Zahavich [43:46] There's a lot of work being done right now in something called compassion fatigue. So recognizing the helping professions, and what that ends up doing, the impact that it has on a person, both professionally and personally. I think for me, and I think for a lot of people I work with the opportunity to just debrief with colleagues is incredibly important. And so we have a monthly or bimonthly meeting where we get together and talk about difficult cases within our group that really gives you the opportunity kind of in a safe space to just talk about, if you've had one of those experiences, or just something that was challenging and what that was like. I still find it hard, I don't think it's something that ever gets easier, and you have to see value in what you do, and the support that you're able to provide to families even in a really difficult time. And then make sure that you have both in professional sports and personally, you know, family things outside of work that you do that help with your self care and other things to focus on.

Jason Lo Hog Tian [44:37] Dr. Carroll then shared his views on the rise of genetic counseling as a career path.

Dr. Jeff Carroll [44:42] I hope and wish that their roles increased because I feel like they have a great skill set and a great compassion that drives them to that career. And it feels like those are folks that we could all you know profit from a lot. It's interesting people don't know about it as a career path. So now that I'm lecturing undergrad, I've had a couple becoming definitely interested in it. One is actually right now at the Johns Hopkins Genetic Counseling Program. And he'd never heard of that, because they just they get taught about science or medicine, they don't really get taught about these other associated really interesting career paths so that's been a fun thing of being a professor is trying to put more people towards genetic counseling as a career path.

Jenna Park [45:16] With the feature of genetic testing and genetic counseling looking so exciting. We asked Laura about where she thinks the field is heading.

Laura Zahavich [45:24] Yeah, I think, I mean, whole exome sequencing is something that's been available clinically, for a few years now, whole genome sequencing is just sort of on the cusp of becoming clinically available. So that will be a big change for us in terms of what we'll be able to find both what we're looking for, and sort of the secondary findings and challenges and interpretation. One of the other things that's becoming more prevalent within the hospital and abroad is things like pharmacogenetic testing, so being able to look for specific variants and which medication to treat somebody with. And so I think things like that will become more prevalent, and then something that parents I don't know much about yet, but I'm learning along with everybody out. So things like polygenic risk scores. So we tend to be, typically you have a change in this gene, and therefore, you have a chance of developing this condition. Polygenic risk scores, just as it sounds is looking at sort of lower risk variants in many genes and putting that together to give somebody a risk factor for developing a certain disorder. And I think that sort of the less rare, more common kind of things are things that we'll be looking at more so in the future.

Jenna Park [46:27] Stacy added her thoughts on the increasingly widespread availability of genetic testing services.

Stacy Hewson [46:33] Direct to consumer testing, I do think we'll continue, I think it's a bit hard sometimes to incorporate that into the healthcare system because sometimes we're used to it being, testing being done when indicated. So when it's sort of done in general, that can sometimes cause a disconnect and not be as easy to interpret. But I think over time, dependent on the quality of the test, it can be incorporated into clinical care, or at least be confirmed and utilized within clinical care. So I do think that space will still continue. But I think within the healthcare system, many more individuals will have the option for genetic testing. And I do foresee certainly at Sickkids, a future where most people who come to the hospital will get genetic testing of some sort, that genetic testing will help guide treatment, management and preventative medicine in the future. So you could utilize your genetic results for your current reason for coming to the hospital, you could utilize other genetic results to plan for the future and have other screening that would help you avoid healthcare risks in the future. So I think it will become much more integrated into all of medicine and utilized by many different sub specialists. Another example would be pharmacists, right? So I think there'll be more and more information from your genetic code that will help determine adverse events to certain drugs that would help guide pharmacists and what medicine you get prescribed based on your genetic code. There's going to be a lot of different areas that will evolve, I think, will also evolve into using genetics for sort of risk assessment in more common conditions that don't have a dramatic or one specific genetic cause, like diabetes or cardiovascular disease, I think will become better at combining your lifestyle score and your genetic score to kind of give more information about whether you might be high or low risk. I think counselors will spend more time doing motivational type counseling in order to explain to families what your genetic and lifestyle risk provides you and then what you need to do to sort of avoid those problems, or try to avoid those problems.

Jenna Park [48:45] Finally, Dr. Kim weighed in on the frontiers of genetic testing, and how we will further incorporate genomics into clinical practice going forward.

Dr. Raymond Kim [48:54] There's a few areas that I think scientifically are going to be the future in genetics like now with whole genome sequencing, we're sequencing all the base pairs of every tumor, every single cell almost in almost every human as great as it is to analyze someone's genome, I don't think that's where the answers are going to finish. Scientifically, I believe the next area of genomics or understanding disease is going to be in the epigenome. The epigenome is where the sequence base pairs are preserved, the "ACTG" are the same, but through some other mechanism, whether it be methylation, chromatin remodeling or something else, but the gene expression is modified not at the base pair or single nucleotide or at the DNA level. There is evidence that epigenetic changes cause inherited types of disorders, you inherit your epigenetics from your parents process called imprinting. It's less known and it's quite complex because it is less known, but I think by studying epigenetics imprinting and those types of genetic regulations are going to open up another field in genetics and genomics. Now, how that will fit in clinically, I think will be a long ways away, what would I like to see in my patients and in healthcare in general, I would like ultimately, maybe in the next 10 years, to really have personalized medicine would be to develop the infrastructure for every patient who is coming in for a health care problem to have their genome sequenced and analyzed, and given back to their medically relevant genetic variants, whether it be their drug metabolism variants, or their traditional Mendelian hereditary variants. And that is not necessarily requiring the heavy input of the genetics professional right now, there are not enough of us to have people even get genetic testing for traditional indications is very difficult. They're just like a family doctor can order a CBC, family doctor can order pretty much any medical tests that they want and are comfortable with and have the education and background and any other primary care provider can do, so much so that even in the cell-free DNA in pregnant women, family doctors, and general obstetricians are ordering that their genetic education can be brought up to speed. I would like that to be even further for everybody just to order genome sequencing and for the laboratories to be able to give back the relevant information in a digestible form that's easily interpretable by the physicians to be incorporated into the patient's care. The problem that the genetics field has had it is that we've kind of built ourselves to be a little bit exclusive. Because traditional geneticists have always said genetic testing is different. It's a little bit exclusive, it's got to be careful in those types of things. So that's why everybody in most of medicine, was saying "Oh, we can't do any of that". And that's basically a little bit of a misconception. Genetics is mainstream, however, to incorporate it more pervasively in modern medicine is going to be a huge undertaking. It's going to take at least a generation for us to do that. That's what I would like to say.

Jenna Park [52:16] Special thanks to our guest today Dr. Raymond Kim, Laura Zahavich, Stacy Hewson and Dr. Jeff Carroll, for sharing with us their expertise and passion for genetic testing and genetic counseling. To find out more about our guests, or for more information about the frontiers of Medical Genetics, check out the links in our show notes.

Jason Lo Hog Tian [52:35] This episode was hosted by myself, Jason Lo Hog Tian and Jenna Park. Colleen Farrell health conducted the interviews and Adrine de Souza was our content creator, Jesse Knight was our executive producer, and Anukrati Nigam with our audio engineer. This is also our last episode in season five, so we hope you have a great summer and we will see you again in September.

Jenna Park [52:57] If you like what you heard this season or if you have any ideas for season six, let us know in our listener survey at rawtalkpodcast.com/survey, or find the link in our show notes. You'll also have the chance to win one of three snazzy Raw Talk Podcast tobe bags.

Jason Lo Hog Tian [53:12] Raw Talk podcast is a student presentation of the Institute of Medical Science in the Faculty of Medicine at the University of Toronto. The opinions expressed on the show are not necessarily those of the IMS, the Faculty of Medicine, or the University. To learn more about the show, visit our website, rawtalkpodcast.com and stay up to date by following us on Twitter, Instagram, and Facebook @RawTalkPodcast. Support the show by using the affiliate link on our website when you shop on Amazon. Also, don't forget to subscribe on iTunes, Spotify, or wherever else you listen to podcasts and rate us five stars.