Ep 339: Unlocking Embryo Genetics: The Future of Whole Genome Sequencing

0:00You're listening to the Fertility Docs Uncensored Podcast, featuring insight on all things fertility from some of the top-rated doctors around America. Whether you're struggling to conceive or just planning for your future family, we're here to guide you every step of the way.

0:21Dr. Susan Hudson: This episode is brought to you by Receptiva DX. What if unexplained infertility isn't actually unexplained? For many women, hidden inflammation associated with endometriosis and other uterine conditions can go undetected for years, even when everything else appears normal. For more than a decade, fertility specialists have trusted Receptiva DX to provide deeper insight into the uterine environment, helping women and their physicians uncover answers and make more informed treatment decisions. Hello, everyone. This is Dr. Susan Hedson from Texas Fertility Center with another episode of Fertility Docs Uncensored.

0:59Dr. Susan Hudson: I am here with my amiable and amazing co-host, Dr. Carrie Bedient from Fertility Center of Las Vegas. Hello. And we're so excited to be joined by Maria Katz from Orchid Health. How are you doing, Maria? I'm doing well. Thanks so much for having me. Absolutely, absolutely. So Maria is a board-certified genetic counselor, and she is the director of clinical product at Orchid Health. And so we're going to talk about some very exciting things today, whole genome sequencing for embryos. And I know that's a lot of big words that we just mentioned, but we're going to break them all down. But Maria, tell us, what exactly is a genetic counselor?

1:42Dr. Susan Hudson: Because I mean, Carrie and I send our patients to genetic counselors all the time. And usually when we do, the patients are like, what am I getting into? What exactly are we getting them into? Definitely. I appreciate the question because we're a pretty niche field. There's not a lot of us out there and we're very specialized. So our master's program is in genetic counseling. What we're focused on is the clinical side of genetics. Genetics is very complicated, even just talking about whole genome sequencing. What is that? What we're trained in is being able to make complex information easier to digest.

2:16And of course, we are often meeting families when they're in very emotionally charged situations. So we can be in many different areas. We can be in cancer. We can be in prenatal, preconception, pediatric. So we're in really heavily emotionally charged situations. So that's the counseling side is being able to support families when they're in challenging, emotionally complex situations. When we're thinking about sending patients for genetic counseling, often in the fertility space, it's to review things like carrier screening. So we often are reviewing carrier screening results with families, helping them understand what next steps are available, or if there's any other sorts of family history that we would have other genetic testing recommendations for.

3:03And then, of course, for me, I'm in the PGT space. So explaining what embryo screening is to families and helping them make a decision that's right for them and their family and their values.

3:12Dr. Carrie Bedient: So what's the difference between a genetics counselor and a medical geneticist in what they do and how they get there? Yeah, excellent question. So a medical geneticist goes through medical school and then specializes in genetics. And often medical geneticists, what they are doing is really a full medical assessment, including a physical assessment of families. When we think about the stereotypical medical geneticist, we think about a pediatric medical geneticist who is reviewing a child who may have signs and symptoms, doing a physical assessment, really assessing everything that is their needs and helping them make the right genetic testing decision with often a genetic counselor.

3:54So the genetic counselor is usually there to help support the family, explain these very complex genetic concepts to them, and then again, help them make a decision that's right for them. Because, of course, genetic testing has, one, complexities, but also what's unique with genetics is it often impacts the entire family. So if one person may have a condition, there may be other family members who would be interested in that information as well. And so there's a lot of layers to think about. But in short, medical geneticists are doctors who then specialize in genetics. And then genetic counselors, we specialize in specifically genetic counseling to really translate that complex information and support families.

4:36Dr. Susan Hudson: What type of training does a genetic counselor do? So we typically all do very similar undergraduate degrees, but there's a range. So usually it's something related to the sciences and or psychology. So for me, for example, I studied biology, psychology and statistics in my undergraduate degree. And then I went to get my master's in genetic counseling. And a lot of my colleagues had similar backgrounds. Some had more science background, biochemistry or straight biology, and others had more of a psychology background. And then our programs really help us understand all the science of genetics and then also the counseling foundations.

5:17That's pretty cool.

5:18Dr. Susan Hudson: I actually don't think I've ever had anybody fully explain those two pathways. I mean, I figured them out for myself, but I mean, it's really nice to have it very clearly laid out. This is what that role is. This is what this other role is and how they interplay together. Exactly. And especially because it depends on what field you're in and interacting with a genetic counselor. So, for example, in the reproductive field, genetic counselors are usually very isolated and away from medical geneticists. So often if I see a patient and they're completely out of scope of what we should be touching, I'm referring them far, far out to a medical geneticist.

5:57We don't really work side by side when you're often in the reproductive space.

6:01Dr. Carrie Bedient: As part of your training, do you have classes in how to communicate and explain to patients these really highly technical and complex? I mean, there's a lot of doctors who barely understand what it is that this is doing. But do you have technical art classes of how to draw things and education classes and how to explain these concept topics to people with extremely wide variety of educational backgrounds? Yes. And I love the way that you described the class should be called that. But yes, that is that is exactly what we're doing. So we have some classes that's making sure we understand the technical part.

6:41So we're tested quite extensively. But the other classes are often a lot of role play where we have a patient who has XYZ symptoms and then we're needing to describe to them in a way that they can understand. And usually there's some sort of blurb about their background to help them think about how will I be framing this information? And often it's a lot of training in what questions to ask the patient to make sure that you're meeting them where they're at, because that's a big part of it, too. is if I'm explaining like a fifth grader to someone who has a PhD in genetics, they're not going to be very happy with me.

7:17They're going to want me to meet them at their level. So it is really important too, to build rapport with families to understand, okay, not only how should I explain this information to them, that's the short of it. But yes, that's exactly what our classes are doing. And it is really challenging with some really complex genetics where sometimes you have to be comfortable not talking about some of it to make it more digestible. And that's part of the balance too, which I see nods because I'm sure you deal with this every day because you talk about very complex things as well. It's really just trying to find that healthy balance.

7:51Dr. Susan Hudson: That's amazing. That's very good. Very good. RMA of New York is a global leader in state-of-the-art reproductive medicine, serving as Division of Reproductive Endocrinology and Infertility at the Icahn School of Medicine at Mount Sinai. Led by an integrated team of physicians and scientists, RMA of New York is renowned for its pioneering research in the field and for delivering high IVF success rates. With locations across Manhattan, Brooklyn, Westchester, and Long Island, RMA of New York has helped thousands to build the families of their dreams for more than two decades and counting. Well, let's do a question of the day for today, and then we'll get to our main subject.

8:30Dr. Susan Hudson: Question today is first pregnancy no heartbeat no heartbeat at nine weeks at the nine-week ultrasound stopped growing at seven weeks doctor said everything looks good and to try again after a cycle or two but on my ultrasound report there was a mention of a posterior fundal subserosal fibroid what is that

8:51Dr. Carrie Bedient: and does that have any effect on fertility that is an excellent question and it is a very very common one. To break that down, first of all, what a fibroid is, it is a monoclonal expansion of tissue, which really means one cell went rogue. And instead of growing in that very nice controlled manner where it coordinated with everything around it to make muscle cells that interacted nicely to expand and contract and do what the uterus needs, they just went rogue and they multiplied and multiplied and multiplied until you get this ball of muscle. And sometimes that ball can be the size of a pea and sometimes it can be the size of pretty close to a basketball, depending on how big it is.

9:35Dr. Carrie Bedient: As with many things in life, size matters. And also with real estate, it's location, location, location. Subserosal refers to being just under the serosal layer of the uterus. Now, when you're looking at the uterus and you go from the outside in, you've got the pelvic cavity where all the intestines are rolling around and it's a big bowl full of spaghetti. And then you've got the serosal layer, which is the outer film covering the uterus. You've got the muscle, which is the myometrium. And then you've got the endometrium and the cavity. From outside in, there's usually about four or so layers that we're thinking about placement.

10:17Dr. Carrie Bedient: Subserosal means it's the part furthest from the cavity. And in terms of fertility, if you have to have a fibroid, this is the place to have it because it is as far away from the luxury mansion that we're looking for as you can get. There are times that these are really big and that they are pushing on the cavity such that your luxury mansion has had a room crashed in. But a lot of times they're big and for fertility, they have a considerably minimal impact. Certainly if they're causing symptoms for you, we want to get them out. But if we can leave these guys alone, we do because we don't want to cut into the uterus if we don't have to.

10:52Dr. Carrie Bedient: Other locations of fibroids that can cause more drama are cavitary or submucosal fibroids. So in this case, the mucosa refers to the lining of the uterus. And what that means is that the fibroid is either completely hanging into the cavity and providing a blockage and less space for the embryo to implant onto healthy endometrium, the lining of the uterus, and less space for it to grow. Sometimes it's called intramural, which means it is in the wall of the muscle, but you can have intramural where it's completely contained within the muscle. You can have intramural where it's also submucosal as well, so it's really pushing into the cavity.

11:37Dr. Carrie Bedient: And you can have intramural where it's subserosal as well, where it's more on the outside. And it's mostly in the wall, but it's pushing out outside. And again, the sizes and locations of those make a huge difference. If we've got a fibroid that is cervical, for example, those tend to be very challenging to remove because we want to keep the integrity of the cervix intact. So the cervix is very good at keeping a baby located in its house. And if you cut down part of that door, you are making it a little bit easier to rob and for the inmates to get out. And we don't want that to happen. A cervical fibroid is a very different story than maybe a tiny little P-shaped fibroid in the wall, which is a very different story than one that's the size of a huge grapefruit that is pushing into the pelvic cavity.

12:27Dr. Carrie Bedient: And how we handle all of those is very different. The hope is that we've got submucosal fibroids because frankly, those are the easiest to get out. They're incredibly satisfying to remove because you just go and you play Pac-Man and you go chomp, chomp, chomp, chomp, chomp, chomp, chomp, chomp, chomp, and you can completely clear it out. And they're pretty minimally invasive procedures for patients. They're very satisfying for the docs involved, and they can really make a huge impact. The intramural and subserosal fibroids, there's much more variability. Some of them have a huge impact on fertility, and some of them don't have much at all.

13:02Dr. Carrie Bedient: And the process of getting them out, the surgeries to get them out are far more invasive and involved. They require a lot more skill. They require a lot more recovery. When we have patients who need myomectomies, which is the formal name of that procedure, there tend to be surgeons that we directly send to of people who really like doing those surgeries who are really good at it. So it may be that your REI, reproductive endocrinology and fertility specialist, doesn't take those out. And it's not because they're not good at what they do. It's because it is a very distinct skill to do that. And we want you to be in the best hands possible.

13:35Dr. Susan Hudson: And most of the substerosal fibroids aren't going to have a major impact on fertility. That's probably why it wasn't necessarily verbally shared with you is what we would call an incidental finding. So definitely talk to your doc, make sure that they don't have any concerns, but it's probably one of those, yes, it's there, but they really don't think it's a major player in what's going on and probably had minimal, if any, effect on the outcome of this last pregnancy. All right. Well, Maria, Let's kind of start talking about this long phrase that I just mentioned, the whole genome sequencing. What does this mean?

14:14Dr. Susan Hudson: And in what relationship for people who are trying to do IVF does this have any implication? Definitely. I think somewhere that's helpful to start with is what traditional embryo screening is doing, because we can talk about whole genome sequencing for children and adults. We can talk about it for embryos, but I think let's focus on embryos and let's start with what are we currently doing with embryo screening and work up from there. Typically, when we think about embryo screening, we think about chromosome screening or PGTA aneuploid screening. What that is doing is saying, does an embryo have the expected number of chromosomes?

14:57We typically have 23 pairs of chromosomes and that's what we're looking for. Is there 23 pairs or is there more or less copies of chromosomes? That's really just looking for very large obvious differences. The genome, when we are thinking about other types of embryo screening, it typically is for a specific need. So if there is a patient who has a genetic condition themselves, for example, if they have hereditary breast and ovarian cancer, BRCA1, BRCA2, they may want to screen embryos for that very specific condition they have because they know the gene, they know the change, and they want to look embryos for that difference.

15:36So the reason I'm kind of jumping to that is that there usually is a specific question that embryo screening is answering. For chromosome analysis, it's saying, is there expected number of chromosomes there? For PGTM, when there's a known condition, it's saying, is there the presence or absence of the disease that we're looking for. When we move to whole genome sequencing of embryos, that is changing the way that we're thinking about testing embryos, is instead what we're shifting towards is saying, can we look across all genetics, with an asterisk, I'll come back to that, all of our genetics or the entire genome, and look more broadly to see if we can see many differences and other differences that are just not visible by the other tests.

16:25So with whole genome, it can do the chromosome analysis. It can do PGTA. It can look for a known condition and say, is it present or absent? But it can also look for thousands of other conditions simultaneously. So it is kind of like running many, many, many, many tests at the same time. That's what whole genome sequencing is doing. is we really have billions of letters that make up our DNA and make up our genome. And what whole genome sequencing is doing is actually reading all of those letters rather than counting chromosomes.

16:59Dr. Susan Hudson: What are some of those other medical conditions that this could be looking at? Yeah, excellent question. And when we think about different conditions, and this is why genetics is so complex, is there's many different types of genetic conditions or chromosomal conditions. When we say chromosomes, we're talking about those 23 pairs that I had mentioned earlier. They host a lot of genetic information inside of them. There are some chromosome conditions that are missed by PGTA. So PGTA, as I mentioned, is counting. It's saying, are we seeing two copies of chromosome 21 or 13 or 18, or are we seeing an extra or a missing copy?

17:39So that's quite similar to, for example, non-invasive prenatal screenings. what would be offered during pregnancy. But we actually can have very small changes in those chromosomes that are extra or missing that are too small to be able to be visualized with this PGTA technology because the goal again is to look for these large obvious differences. So there are small changes that are called microdeletions or microduplications that are just missed by the standard platforms and they're missed because they're not being looked for. It's just different tests are answering different questions. So one part is these very small changes.

18:17And then the next part is the single gene disorder. So I had mentioned the example of someone who has a hereditary cancer condition. They were tested for it. They tested positive and now they know about their genetic condition and they're provided the option. Do you want to screen embryos? Yes or no? And if the answer is yes, then they can learn that information. But we all have many genetic conditions we either may not know about, but there's also genetic conditions that are very severe and can happen by chance in the embryo. So those are the types of conditions that you can look for with whole genome sequencing, and there's a lot to break down there.

18:52Dr. Susan Hudson: So when you were talking about these micro deletions or additions, how does that kind of make it or break it on whether a baby is going to make it to be an embryo that is going to develop into a baby? Do these have health consequences? Why do those things matter? Excellent question. So it depends on what the extra and missing chromosome is. There are some that may result in a child who may have mild health concerns. So an example of that, which is honestly a range of symptoms, is 22Q or DeGeorge syndrome that's starting to be talked about a little more because it's offered on non-invasive prenatal screening, but there's a really wide range of symptoms where some people may have the condition and not know about it, whereas others may have a heart defect, may have mental health or learning disabilities.

19:47So it's a wide range of symptoms. So 22Q or De George syndrome would be a good example of, you know, wide range, but there could be a child who has mild to limited health symptoms. On the other side, there are more severe conditions such as Wolf-Hirshorn syndrome or Cretaschot, where if the child is born, there's typically very, very severe health concerns like birth defects and neurodevelopmental disorders. So they can be very severe and sometimes more severe than the whole chromosome difference that we think about. For example, I know it's starting to be talked about more and more is Down syndrome.

20:25Down syndrome is a perfect example of a chromosomal difference where, again, really wide range of symptoms, But there are adults who are walking around who have Down syndrome who do have health concerns, but are still able to live a relatively supported life, but a life, whereas some may not make it past childhood because they're very severe conditions.

20:48Dr. Susan Hudson: Let's play a game. How many tabs do you have open right now about IVF? One says your chances are great. Another says they're terrible. Reddit has one opinion. TikTok has another. Facebook is full of horror stories. And somehow, after two hours of searching, you have more questions than answers. Sound familiar? That's exactly why we wrote the IVF Blueprint. This isn't another fertility book filled with opinions or miracle cures. It's an evidence-based guide that walks you through every stage of IVF, from understanding your fertility evaluation and choosing a treatment plan, to medications, egg retrieval, embryos, genetic testing, transfers, and the two-week wait, and beyond.

21:32Dr. Susan Hudson: Because the last thing you need during IVF is more noise. Close the tabs, put down your phone, open the IVF blueprint instead. Available now wherever books are sold.

21:46Dr. Susan Hudson: Can you tell from this testing, when you have a disease that has a range of severity, Can you tell from this testing where a child or future adult may fall upon that continuum? So it's nuanced. The answer is yes and no. Yes, in the sense that you can target the regions you're looking for. So we all have changes in our genetics that we don't know about. And we may have symptoms, but we may not have symptoms related to those changes. But there are other changes that are really well documented, such as 22Q. What 22Q is, is a change on chromosome 22 on the Q arm, which is the long arm of the chromosome.

22:30We know the region and then we know that there's a range of symptoms. So I can tell you that general deletions of this size may be more severe or less severe, but in the range of the condition to George syndrome. But what I can't tell a family is definitively your child would have a less severe or more severe. It would be this is the range of symptoms that we see. It is easier to talk about it when it's a very severe condition, like the ones I mentioned before, Wolf-Horscher and Acreta-Shot, where they're almost all more severe. And it's when we're talking about the range, of course there's a range, but it's kind of all skewed towards the more severe.

23:08For us, when we're doing whole genome sequencing, we actually target regions where we know there are disease-causing microdeletions and microduplications. So that if there is a finding, it's one that's been well-documented so that We can have this conversation with patients of this is the range. What are your thoughts? Let's talk about it further. But this is a well-documented condition.

23:29Dr. Carrie Bedient: So how do you approach the areas that are not well-documented? Do you try not to look at them in the first place? Because if you don't see it, you don't have to talk about it. Or does it just plunge patients into this black hole of what ifs and maybes? So it's blacked out. We genuinely don't look at it and we don't see it. which is the case with a lot of tests. There is one, a limit of detection. Not any test can test for everything, and every test has a targeted purpose. But sometimes, yes, you can accidentally see something that wasn't the purpose of the test, but there are guardrails for every single screen to reduce the chance of seeing things that are outside of that scope.

24:12So that's one part, is that not every platform can see everything, and whole genome sequencing is the most advanced genetic platform that exists, but there are changes we just can't visualize. It's not physically possible. And then the other parts is we have everything set up. So a patient is consenting to these 50 regions. We're going to report out on these 50 regions. We're not going to go exploring elsewhere.

24:35Dr. Susan Hudson: So for our listeners, the testing that we're talking about right now is testing that is only available if you do in vitro fertilization or IVF, where we can tangibly have your embryo at the stage where we can tell what parts are going to become the baby and what parts are going to become the placenta. Some cells are taken from what are going to become the placenta. The embryo is cryopreserved. And then that sample of cells is sent to a specific laboratory like ORCID to run this type of testing. Now, I'm curious if somebody does this testing through a company like ORCID and they end up having a child that has a condition that was not in those 50 regions you tested for.

25:22Dr. Susan Hudson: And we figured this out later. Okay. Babies two, three years old, not making developmental milestones or something like that. Can they come back and do testing on some of those blacked out regions? Or I mean, essentially the testing's been done, but it's unblinded? Yes, really, really great question, because that is what's unique about doing whole genome sequencing of the embryo sample to start with, that there is, in air quotes, unlimited additional analyses you can do. So you can look at the data many different times in many different ways. And yes, you can unblock regions as long as it's within the technical scope, as I mentioned before.

26:02So if it is physically possible to be visualized, it just wasn't looked at from a clinical perspective. Yes. And this is really helpful for families who may have a child that has a health concern and wants to go back and look at their embryos. So we have had families who have consented to some publications we've done on this. I can speak a little bit more freely about it. But they've done testing just PGTA previously, had a child, had health concerns, and they wanted to go back and screen their embryos for the condition that was found. they had to get a new sample from that embryo and then go through that whole process again.

26:39What is helpful with whole genome sequencing is the data that you are getting is a hundred times more in terms of the visualization than you would for something like PGTA.

26:50Dr. Carrie Bedient: Can we talk a little bit about the names and the titles that we're throwing around? So there's whole genome sequencing. Yes. There's PGTA. Yes. PGTM, PGTP, PGTSR, NGS. yes yes all of those things get thrown around when we're talking about an embryo yes can you lay out for our listeners the kindergartner's version and i'm not saying that to insult anybody's intelligence i'm mostly saying it because i deeply hope that i can steal whatever example you're going to give us so that i can use it to explain to my own patients but can you can you lay that out simply as to what those things are what they refer to and what they don't refer or two?

27:31Yes, definitely. And I will start off by saying I'm not an analogy person and I loved your analogies and I think they are excellent and my analogies are never very good. I'm going to describe it. And if you want me to go in deeper, let me know. I can play with an analogy at the very end, but I think starting with the end acronyms, which was NGS and SNP, I think that's a good starting point because, well, actually, I think I want to go even further back when we're talking about the placenta cells and the cells that become the baby. Because when we're thinking about embryo screening, that is a good place to start, which is the cells that any embryo screening company receives from an IVF center are coming from cells that become the placenta.

28:14They're not cells that eventually become the baby. So anytime we talk about embryo screening, it's a screening test. It will never replace diagnostic testing during pregnancy because there's always a chance that although egg and sperm make both placenta and cells that become the baby, there's always a chance there could be a difference between the two. So that's one place that I want to start off is that it's a screening test. No matter what acronym you use after, that is always important to know. So the next part is what actually happens when an embryo screening company receives a few cells. So really the first step is making many, many, many copies of those five cells because there needs to be more copies to be actually able to do anything with that sample.

29:01And there's a lot of complexities there that I will skip to get us to NGS and SNP. So once we have enough of a sample to perform an analysis, and that's really being able to perform a test, is there's many different platforms that it can be done on. So NGS, next generation sequencing. SNP is talking about single changes across the genome and looking at each individual spot. With whole genome sequencing, the way to think about it is it's kind of both. It is next generation sequencing, but the idea of these SNPs is that you're able to see actual changes in the genome, but you're targeting them. Really to kind of take it back is for the listener, you don't need to know all the technical ins and outs of what is the PGT company choosing for NGS or SNP?

29:50What is their platform? The question is, is what are they able to visualize? And that's why that matters is the platform really just indicates what can be visualized. So when you had mentioned, are you blacking out part of the analysis? And I had said, there's just things that are out of our scope. The same goes for every single test. If the PGTA company, and there's the next acronym, is choosing to do NGS or SNP or both, that's going to change what they're going to be able to visualize when they're doing the analysis, which means that an embryo that screens negative may have a different meaning depending on what went behind the scenes.

30:32So to go to that acronym, PGTA, pre-implantation genetic testing for aneuploidy, it really should be PGTS, not PGT. Joy really drives me crazy with the testing part because it's a screening. But I think PGT has gone through so many different acronyms by itself because that's part of it too. Change names so many times.

30:54Dr. Carrie Bedient: We just did an episode on PCOS versus PMOS and Susan has her own named, labeled, painted, lacquered soapbox for how we all hate PCOS as a name. And so we identify very deeply with the desire to change the PGT to PGS to PGD to PGU, whatever. Yes.

31:16Dr. Susan Hudson: I remember the ASRM I went to and it was like the world had changed. We went from PGD and PGS to PGTA, SRM, all those types of things. And it literally in one day, one three to five day meeting, the world in that acronym changed overnight. It was crazy. Yes, which is why I'm pro not changing the acronyms again, because no one needs that to happen. As long as we say it's PGT stands for preimplementation genetic testing, but it is a screening test, then I'm happy. But the PGT part really just means embryo screening. It's the acronym for embryo screening. The A stands for aneuploidy, which is the chromosome differences that we had mentioned earlier.

32:04So we typically have 23 pairs. Sometimes we can have extra or missing chromosomes. Many of those extra and missing chromosomes would be unlikely to result in a pregnancy because there's so much that's inside a chromosome. There's thousands of genes, and if they have way too much or way too little, it can't result in implantation. And if it does, it's usually a very early miscarriage. Where there are other differences in chromosomes, for example, an extra copy of chromosome 21, which causes Down syndrome, which can result in a pregnancy. It may result in a miscarriage, but could also result in a live-born child who would have the condition Down syndrome.

32:45So when we're thinking about PGTA, it is screening for extra and missing copies of chromosomes.

32:52Dr. Susan Hudson: To go back and talk a little bit about NGS and SNP. Yes. When we're talking about pure NGS, are you saying with pure NGS, all we can see is whole chromosomes versus you have to have some level of SNP to be seeing the smaller pieces of chromosomes or the microdeletions, those types of things? So with NGS, you typically can see what we call segmental aneuploidy, which is large, extra and missing copies of chromosomes. And what typically is missed when SNP is not added to it are conditions like polyploidy, which a common example would be triploidy, when there's an extra copy of every single chromosome, or a molar embryo, which is when, for example, an empty egg is fertilized.

33:46Without the SNP analysis, it just looks like it's a chromosomally typical embryo because the way that PGTA works with NGS is it's really dosage. So it's really just comparing everything together. So that will, from the laboratory's perspective, look normal unless there's this additional analysis that's added to it. So that's kind of that blacked out piece that I was mentioning that it just will look normal because it's not within the limits of what that test is able to do.

34:17Dr. Susan Hudson: So when we're talking about whole chromosome sequencing, we're using NGS with SNP layered over it to be able to catch more and more information.

34:29Dr. Carrie Bedient: Yes, exactly. I apologize. I'm going to ask you a really terrible question. I'm sure it's not terrible. Which one is best? Yeah, see, it really is terrible. No, it is terrible. I take it back. It is a terrible question. No, but it's a good question. And I think everyone wants to have the best test. I think there's a lot of layers to it that are very complex. So, for example, mosaicism. Depending on the platform you use, there could be a higher likelihood of getting a mosaic result than a euploid or aneuploid result. So what mosaicism means is it's kind of an in-between result. The genetic council community also wants to step away from the term mosaicism, speaking of trying to use different terms.

35:10And the reason being that what euploid means is that there's the typical expected number of chromosomes. What aneuploid means is that there's an extra or missing copy of at least one chromosome. What mosaicism looks like from the laboratory's perspective is instead of seeing two copy numbers, because everything's kind of plotted on a line, if it's aneuploid, you're going to see a full extra one, so it'll go to three. Or if it is monosomy, there's going to be a dip, so it'll go to one. What mosaicism is, it's in the middle. That is what we're actually seeing, and then we're calling it mosaic. What mosaic means in the prenatal setting or in the pediatric setting is that we all have many, many cells that make up our body.

35:53And typically, we expect if someone has the typical number of chromosomes, every single cell that you test should have the right or correct or typical number of chromosomes. Mosaic means that you would take a sample from an individual, and some would have the typical expected number of chromosomes, and some would have an atypical, for example, a monosomy or trisomy. So that means that what mosaicism actually is, is someone has different cell lines in them. In embryos, we thought that's what it meant. So a decade ago when we started talking about mosaicism, wow, we just didn't visualize these before.

36:30We're really excited about mosaicism. But as the years have gone by, we're noticing that this may just be either an artifact of testing. So is NGS, is it a ray? Is it the more historical methods that were being used? mosaicism some may be true i'm not saying all of them are not true we are seeing that when mosaic embryos are transferred they may have different outcomes than euploid embryos that could be a whole topic on its own but when we're thinking about what platform is better a good question to ask the embryo screening company is what is your mosaicism rate what is the size of extra and missing copies of chromosomes can you actually see because there's going to be differences across platforms.

37:13Some will only be able to see very large differences that are looking at 10 million letters or bigger in size, whereas others, it's 5 million letters or bigger, so much smaller changes. So those are the questions that you need to be asking the embryo screening company to give you a good idea of which one is better. So long-winded, long-winded answer, but it's complex.

37:37Dr. Carrie Bedient: Now, Susan, I don't know if you noticed this, but this is how we know that Maria is truly masterful at her craft, the entire conversation, she has never once said the words normal or abnormal. That is absolutely true. So once you've made the decision to do IVF, once you've made the decision that you want additional information, if you say, I want PGT. Yes. And you say, I want as much information as possible from that. What does that mean you're going to most likely need to do next as a patient? Well, if you want the most maximum information from PGTA, it would be talking to your doctor about what companies they use.

38:19And I recommend that patients always look into as much information as possible so that they can make informed decisions. Obviously, I'm a genetic counselor, so I feel that way. But there's only so much information you'll get from PGTA is really what I want to take home here is that PGTA has a purpose. It's been here for a long time. And some patients may say, I want PGTA or I don't, and I don't want to do any testing. And then the next step is, is PGTA enough information that I am happy with? And for many patients, that's the answer. Yes. I'm interested in chromosome results because I'm interested in thinking about differences in chromosomes that may result in failed implantation or miscarriage or health concerns.

39:03But there are some patients who say, I want more information that goes beyond the scope. And that's really where whole genome embryo screening comes in, is there's definitely clinical indication, specific needs that someone may have that are not being covered by PGTA. But there also are families who want more information. We know a lot about genetic diseases. Really what whole genome sequencing is doing is putting that information that we know about diseases and bringing them to the embryo stage. So that may be something in a type of patient who may be interested in this.

39:36Dr. Susan Hudson: In addition to the indication of, I really just personally want to have more information, which that is one indication, what are some of those other indications that you were alluding to? Yes. So I think a big topic is the age of the potential father. We are very comfortable talking about the age of women, but also men play a big role. They're 50 % of the embryo. And as men get older, there is an increased chance of having an embryo or child who has these conditions that are not being visualized by PGTA. So those are single gene disorders or to kind of break it down again, chromosomes, we have those 23 pairs.

40:22Inside of them, we have genes and genes provide instructions for different tasks in our bodies. And sometimes we can have a change in one of those genes. It's just a spelling mistake and it can cause different organs to not work. There'd be an increased risk for cancer. And we see those changes happening more frequently as men get. So that's one group. Yeah.

40:43Dr. Susan Hudson: I have so many questions, but we're actually going to dedicate an entire episode. So keep your eyes and ears out for that episode that we're going to dive into that in so much. Oh my goodness, as you're talking, I'm just like, ooh, ooh, ooh. Yes, that is a big one and there's a lot to dissect there. Another group would be families who've already had a child with a condition that was not inherited. So before I worked in the PGT space, I worked in the prenatal space. So I worked in high risk obstetrics. And my job was to counsel families that typically had very severe birth defects that were seen on ultrasound.

41:24That is what my job was. I would meet with these families and we would talk about options for genetic testing. And sometimes there would be a finding, a genetic single gene finding in that pregnancy that did not come from mom or dad. And those families now know a lot about genetics. These are families who have a lot of heightened concerns about conditions that happen by chance and are not covered by PGT. And this is an option for them. That's honestly why I moved into this space.

41:56Dr. Susan Hudson: So in that type of scenario where, say, a couple has a child who has some sort of disorder due to a single gene defect, neither the source of the egg or the source of the sperm had that defect, it's not actually to make sure it doesn't have the same thing because the chances of that being a reality are slim to none. It's just really making sure that future children have a lower risk of other random things happening. Is that correct? It's a bit of both. So the reason why it's very hard to counsel families and to anyone who's listening who has been in this situation, I know it's hard when you've had these conversations where you will talk to a genetic counselor or another provider and they will say, there is a very, very low chance this will happen again.

42:48However, we can't say anything other than it's probably less than 1 % of the concept of mosaicism that I mentioned earlier. Sometimes it's in the eggs or the sperm and not in the rest of the cells. And therefore, the chance is higher than the average person in the population. And that is really, really hard to hear when you've had the worst thing that could happen to you happen because these are very severe conditions. For these families, they're looking for, are there options to screen embryos for this specific condition? Even though I know there's a very, very low chance I want to screen for this condition.

43:25And also simultaneously, I want to screen for more because now I know this can happen and I want to reduce risk. So that's why this is a group of families where it's complex. I have a question and this is a very delicate question, but Carrie and I have both had patients that have been in this type of scenario.

43:44Dr. Susan Hudson: Does the affected child still need to be alive for them to do testing for future children? So that is why whole genome sequencing is so helpful. The answer is typically no for whole genome sequencing. So that's why this technology is so helpful because often the child is not alive and often there's no sample available. And emotionally, that is a horrible conversation to have with these families. And also, I can see in both of your eyes, you remember those conversations. Then there's no other options that are available to them because everyone is saying, no, I'm sorry, but don't worry. It's a low chance.

44:26That is unfortunately not what they need to hear. They want to have this additional option. Again, this is for the family where they want to do screening. There's, of course, families who are saying, this is not what I want to do. But for the subset of families where they are thinking about this, it's something that's really important to them.

44:45Dr. Susan Hudson: Is whole genome sequencing helpful for somebody who has a family history of imprinting disorders like Angelman's? So it depends is the answer is that there are some regions that can be visualized and some that can't. And especially when we think about imprinting disorders, we're talking about complex genetic topics. Imprinting would be at the top of that list. It depends on what the underlying reason for the imprinting disorder is because the test that's done to see if there is some sort of imprintation difference is called methylation. It's looking to see how genes turn on and off. And that is not possible on an embryo sample.

45:24So it depends. It depends on what the change was, because there are some changes that cause the imprinting disorder that could be screened for. But if we're just looking at, can you do methylation? That's typically a no. And that's why no tests can screen for everything. And that is an important piece to highlight. So a very practical question.

45:44Dr. Carrie Bedient: Someone listens to this episode, they decide they want to do whole genome sequencing. And they are already planning IVF. They're already planning PGT of whatever variety. So they already know they're going to get the biopsy done. And what else has to happen? Is there additional testing on the patient and partner or donors that need to happen? Is who carries the pregnancy relevant here? How do they find the companies that do this? Because not only do most companies not do it, but there are differences in the companies that do do it. How do they make this happen? Yes. So from a practical perspective, starting from the biopsy and then we'll move to the pre-biopsy, the biopsy itself is the same.

46:31It's just where it gets shipped to that differs. So that is helpful to know because that is one of the main questions that families ask is, does something different need to happen? The answer No, it just gets shipped somewhere else. No, there does not need to be any unique or additional screening of intended parents or donors to do the testing. With the caveat that to now move to what typically happens before, for us, we do pre-test genetic counseling for every patient who meets with us. And if they tell us that, for example, they have a family history of autism and they saw that we offer screening for neurodevelopmental disorders, we're going to have a long discussion about what that actually means.

47:11So if there's a family member who has an autism spectrum disorder and they're interested in what is the options for embryo screening, genetic testing needs to happen for that individual for us to have any conversation because we don't know what was the cause of the autism spectrum disorder. So about 30 % of individuals who have a clinical diagnosis of an autism spectrum disorder actually have an underlying genetic cause. So that would be an example where we would say testing needs to happen for that individual for us to have a conversation about how do we fit.

47:42Dr. Susan Hudson: And that testing would be ordered through a medical geneticist? Yes, exactly. And that was the example I was alluding to of when we say we refer out and we wait for tests to come back. Exactly. So typically it's a child in the family and we would say meet with a pediatric geneticist and then we can go from there. But one of the points that you had specifically mentioned was donors. And that actually is another group of patients that we find are interested in whole genome sequencing. And that's because we have limited information from egg donors and sperm donors. Because obviously there's a lot that goes into getting the information from donors.

48:22And you're getting that information at one point in life and their life continues and their family's life continues. So there's diseases that have not appeared yet or people have small families. Carrier screening is typically the test that's performed prior to IVF, which I know that you've touched on before, but kind of the really short of it is that carrier screening is looking for single gene disorders that we've been talking about here, but ones that are inherited. So examples are conditions like cystic fibrosis, where we have two genes called CFTR. If someone has a change in one of those genes, they would be called a carrier of cystic fibrosis, and they typically would not have the classical signs of cystic fibrosis.

49:05But if them and the reproductive partner are both carriers of cystic fibrosis, that's when there'd be a one in four chance for an embryo or a child to have two non-working copies and therefore have symptoms of cystic fibrosis. So what I want to highlight with carrier screening is it actually only includes conditions that are autosomal recessive, like I just described, or X-linked. So they're actually missing a large amount of conditions that may appear later in life for the donor.

49:36Dr. Susan Hudson: So is whole genome sequencing a potential replacement for PGTM, which is when we're testing for specific matches in that situation? Can you do it that way? So there are many families who are being offered PGTM as an option for them, and they decide, yes, I want to do PGTM. And then, yes, they decide, well, I would rather do whole genome sequencing and add PGTM because I'm going through this anyways, and I'd rather screen for that disease and many more. Yes, that is something that many families are choosing to do. But again, it really goes to decision making for that family if it's right for them.

50:18Dr. Susan Hudson: So it's together, not in replacement of. Okay. And kind of along that line, we're testing for lots and lots of things. Yes. How much does whole genome sequencing generally run? We know that you probably have ideas for your company, but what are general estimates throughout the United States? In terms of the cost of the screening? Yes. So usually somewhere around$2 ,000 to$2 ,500 per embryo. So it is more expensive than traditional embryo screenings such as PGTA. PGTM costs are much more than PGTA, which I do want to highlight, which is also where, as I mentioned, families that are deciding that PGTM is clinically indicated and something they're interested in, they may say, well, we're already choosing this expensive path for slightly more.

51:10you may get hundreds of more conditions, whereas others may say this is information that, you know, is very meaningful to me. And therefore, this is something that I would want to pursue to see more about these conditions that are missed by standard platforms.

51:24Dr. Carrie Bedient: If we have a patient who's likely to get one embryo, if we're lucky, maybe compare to somebody who's coming in who says, look, I am incredibly interested in this genetic testing and they're 31 years old and we've got a very high likelihood of getting a bunch of embryos. The difference in these patients is that one of them, it didn't matter what the results are going to show, that's the embryo they have versus another patient where there is an element of choice. Does the patient who's unlikely to have a choice still need to get this test? Should they get this test? Is it less useful for them? So maybe they don't.

51:59Dr. Carrie Bedient: How do you think about that? So again, genetic counselor, I'm pro everyone hearing about it, getting counseling and then deciding if it's right for them. And yes, the discussions will be different depending on how many embryos they expect to make it to the time of an embryo sample. But sometimes the reasoning of using whole genome sequencing may be the opposite of what you had mentioned. They may say, well, if I'm going through all of this and there may be an older mother and an older father, I don't want to transfer an embryo that is going to have one of these very severe conditions. I would rather know this information than go really far down this path.

52:40So it really depends on the individual. I mean, even starting with some families, PGTA is not right for them. They don't want that information. So that goes every step of the way. I think genetic counseling is the most important part of this is starting with it's a screening test and it does not replace diagnostic testing in pregnancy all the way to what does PGTA actually look at and not look at and whole genome sequencing, is it right for you and your values and what you're interested in learning? So for us, what we do is everything about our screening is opt in. So we have separated the screening out.

53:16So it's not just whole genome sequencing. We screen for a lot. It's here's every single step of the screen and you keep opting in based on what you want to receive and you're comfortable with. So some families may just do PGTM using whole genome sequencing and don't learn anything else. Others may be most interested in learning about very severe early onset conditions and don't want to learn about hereditary cancer conditions, right? So you're opting in to kind of each step with what we had talked about earlier that down the line, they can always go back and ask to get that additional information if they change their mind or something comes up down the line.

53:55Dr. Susan Hudson: Wow, we have covered so much information today. I have to say I am a smarter person after recording this episode. I love it when we have guests like Maria. Thank you so much for joining us, Maria. Thanks so much. I appreciate it. And again, this is Maria Katz. She is with Orchid Health.

54:14Dr. Carrie Bedient: Part of the reason that when we have guests, we're willing to have guests on is because we have used their companies before we believe in them. There are a lot of people who never make it past our screening process because we flat out won't use them. There are some guests who come in because we think the information is worthwhile. We may or may not agree with it, but we want our patients to have that. And then there are other companies where we use it and we know, and Orchid is one of those companies. And so I had a couple patients going through whole genome sequencing at the same time, and Orchid far and away made the process so much easier on them and on my staff, and the patients raved about it.

54:54Dr. Carrie Bedient: And so this is one of those companies. So our listeners know it's not something that's for everyone. But if it is, this is a great company to do it with. And we have personal patient stories to back that up. And I'm so glad to hear that they had great experience and that your staff did too, because obviously the patients care about themselves and their process. We care about the patient and your team. And we do know how hard it is, especially in these really complex situations. And there's so much coordination and so much that goes into it. So I'm glad to hear that too, because we really strive to also make your team's life easier.

55:31So great to hear. Yeah.

55:32Dr. Susan Hudson: All right. Well, Well, thank you to our audience for spending part of your day with us.

55:37Dr. Carrie Bedient: If you enjoyed this episode, subscribe, leave a review, and send us your questions at fertilitydocsuncensored.com.

55:42Dr. Susan Hudson: And if you want even more fertility information, pick up a copy of the IVF Blueprint, our practical guide to understanding fertility treatment, IVF, and the decisions you'll face along the way.

55:52Dr. Carrie Bedient: Before we go, remember, this podcast is for education and entertainment only.

55:56Dr. Susan Hudson: While we are fertility doctors and genetic counselors, we are not ear doctors.

56:01Dr. Carrie Bedient: Nothing we discuss should replace medical advice from your own physician who knows your individual history and circumstances.

56:07Dr. Susan Hudson: Thank you so much for listening. Bye. Bye. This podcast is sponsored by Receptiva DX. When fertility questions remain unanswered, Receptiva DX helps reveal why. Trusted by fertility specialists for over a decade, Receptiva DX identifies inflammatory changes in the uterine lining associated with endometriosis and other conditions that may interfere with implantation and pregnancy. From unexplained infertility, recurrent pregnancy loss, or simply undiagnosed pain, Receptiva DX helps women and their physicians make more informed treatment decisions and move forward with confidence.