Rescripted S02E09_Genetic Testing 101: Audio automatically transcribed by Sonix

Rescripted S02E09_Genetic Testing 101: this mp3 audio file was automatically transcribed by Sonix with the best speech-to-text algorithms. This transcript may contain errors.

Kristyn Hodgdon:
Hi! I'm Kristyn Hodgdon, an IVF mom, current IVF patient, and co-founder of Rescripted.

Lucky Sekhon:
And I'm Dr. Lucky Sekhon, a board-certified reproductive endocrinologist at RMA of New York.

Kristyn Hodgdon:
Welcome to Dear Infertility, the first-ever podcast that doubles as an advice column for the millions of people globally who have trouble conceiving.

Lucky Sekhon:
We're here to answer real questions from real fertility patients about what to expect during each stage of the fertility journey and to provide you with the patient-centric advice and guidance you need to be your own advocate when trying becomes trying.

Kristyn Hodgdon:
Now, let's dive in and help you feel more empowered during this overwhelming process.

Kristyn Hodgdon:
Hi, everyone, and welcome back to a new episode of Dear Infertility. I'm your host, Kristyn, and I'm here with Dr. Lucky Sekhon. Hi, Lucky!

Lucky Sekhon:
Hi! How's it going?

Kristyn Hodgdon:
I'm doing well. How are you?

Lucky Sekhon:
Good. I'm really excited to nerd out for this episode.

Kristyn Hodgdon:
Yes, we're talking all about genetic testing. So from carrier screening to PGTA, we're going to kind of cover it all today, I'm excited.

Lucky Sekhon:
I'm excited, too, because I feel like this is such an area of confusion because we use the word genetics to talk about so many different types of testing and screening tools that we have. So I think it's good to just kind of put it all in one place and really lay it out there for everyone.

Kristyn Hodgdon:
Yeah, definitely. I do see a lot of confusion in the community about if, as a sort of initial step at the fertility clinic, they did, both partners did the genetic carrier screening, which is the blood test, they don't really understand why they have to do more genetic testing down the road. Can you kind of go into the differences?

Lucky Sekhon:
Yeah, definitely.

Kristyn Hodgdon:
The blood versus the genetic testing of embryos?

Lucky Sekhon:
Yes. Sounds good. So let's go in order of what happens logically. So you're trying to conceive, you come in for pre-conception counseling with your OBGYN or your fertility doctor, and we often will very much recommend carrier screening. And what that is, is basically a blood test that you do yourself. If you have a partner that you're trying to conceive with, you have them do it at the same time, I think that makes the most sense because the blood work takes about 2 to 3 weeks to come back, and I think it's very helpful to just do it simultaneously because it's all about doing a risk assessment. It's looking at what your reproductive risk is of having both of your DNA combined and having a child with a potential disorder or problem. And originally, like two decades ago even, I think we were only testing for four major disorders, one of them being cystic fibrosis, because that has such a high prevalence, especially in Caucasians. And there are a bunch of different disorders that are more prevalent in certain populations, like those who are Ashkenazi Jews. But now we've realized that you can't really use ethnicity to delineate who's at risk for what. And there are these big monster panels now that will cover up to 500 different diseases. And a lot of these are diseases that would require both copies of the gene to become nonfunctional or mutated. There's a lot of redundancy in our genetic code, and a lot of genes, there are two copies that are functional, and if one copy is mutated but you still have a functional other copy, you're going to be fine. So this type of carrier screening isn't directed towards trying to diagnose or find problems in the individual who's having the blood test. What we're trying to figure out is, is there any chance that both of you could carry the same mutation? And if you do carry the same mutation, which in my experience, 2 to 4% of couples that walk through my door end up being what I call joint carriers. Then you have a one in four chance that you could have a child with two copies of the mutation and it would actually manifest as a disease. There are also some diseases on the panel that are what we call X-linked, which doesn't involve the male partner. Basically, this is something that a mom can pass on to her son because her son will only have one X chromosome. So if the mutation's on that X chromosome, they have the disease. Things like colorblindness, hemophilia are examples. So this is a risk assessment, we do the testing on both of you. If we find that your joint carriers, then you have a couple of decisions to make. But because this is something that could affect the way you do things, I recommend doing it before you get pregnant, a lot of OB-GYNs will just do this testing once you're already pregnant. Either way, if you find out your joint carriers, you could say, Let's roll the dice, one in four, I'm okay with those odds, let's get pregnant and be aware and acknowledge the fact that I have to wait till I'm at least 11 to 12 weeks pregnant to do definitive genetic testing on the pregnancy and then wait for the results. And if I do have an affected child, what am I going to do about it, right? So there's that decision tree, and I think that could be really anxiety-provoking for a lot of people. You could also say, I don't want to go through that. Let's preemptively do IVF and create embryos and genetically test them for that disorder so that we can screen those embryos out and ensure that we're going to have a child who's not affected. So that's what carrier screening is for, and it's only really looking for those particular mutations. When we're doing genetic testing on an embryo, we're not looking for all those different disorders, we couldn't even do that if we wanted to do that as a blanket form of testing, because we don't have a lot of DNA to work with. So it's very helpful to know ahead of time if there's any particular risk, because then we can create a special test that's able to really detect that set of mutations in the embryo. But when we're doing standard PGT to just test embryos as part of IVF, the majority of it is just counting how many chromosomes are in the cells of the embryo, and that's a much easier test to do, it doesn't require a high resolution, we're not looking for really particular specific things. We're just saying, does this embryo have all of its chromosomes? And that's a very different form of genetic testing aimed at helping you to select an embryo that has the best chance of implanting and has a lower chance of miscarrying, because the number one cause of miscarriage is having the wrong number of chromosomes, so that's the distinction. There is other genetic testing which is more specialized, something called a karyotype. And we will do this in prospective parents to see if their chromosomes have any structural rearrangements. There can be a section or an end of a chromosome that breaks off spontaneously and joins another one. It usually doesn't cause any medical problems for that person themselves because they still have all the genes that they need to function. But when their DNA tries to join, when their chromosomes try to join with that of their partner, oftentimes it's going to create a much higher than expected proportion of abnormal embryos that are imbalanced and are missing critical amounts of DNA or having duplicated DNA. So we do karyotypes in patients who have recurrent pregnancy loss because we're trying to understand if their underlying problem is genetic. And I might even do it in patients who come to me, and they have really diminished ovarian reserve at a very young age because there are certain abnormalities that can be found in a karyotype that will uncover a potential reason as to why they are in that situation. So really, those are the main genetic tests that I would say that we run in the fertility clinic setting.

Kristyn Hodgdon:
Ok, and then what about, that's really helpful. What about kind of the differences in the different, and, so there's PGT-A, which I think is probably the most standard pre-implantation genetic testing of embryos. And then can you go into a little bit of the other ones like PGT?

Lucky Sekhon:
Yeah.

Kristyn Hodgdon:
I might be forgetting one.

Lucky Sekhon:
So PGD-A, A stands for Aneuploidy, which is a fancy, which is doctor-speak for an embryo with the wrong amount of DNA. Anything other than 46 chromosomes is not what we want, right? Because it can result in medical problems, miscarriage, or implantation failure. And so that's just the standard counting the number of chromosomes in the embryo, and that's done in the majority of cases with PGT. You can also add on something called PGT-M, and you're only going to do that if you know that there's a risk of having embryos or children that would carry a genetic mutation that could cause a disease. And so that was anything that could be uncovered from the carrier screening. In addition, if you know that you have a strong family history of cancer and maybe you've been tested for a mutation and, you know, I, I carry the brca gene, right? That has implications for your general health, you should be undergoing closer surveillance and maybe even risk-reducing surgery or things to consider. But also, there are implications for what you could pass on to your children. And a lot of these cancer-causing mutations are something called dominant diseases, meaning it's not a, it's not like one in four chance, it's actually a one in two chance that any of your embryos could be carrying that, that gene. And all you need is one copy of the mutation for it to actually manifest as a higher risk of cancer. These are things that you can also test embryos for, which is I think is incredible because I see patients that their family history has been devastated by multiple family members getting colon cancer, uterine cancer, breast cancer, and if they know that there's this tool that they can utilize to prevent their children going through that same problem, I think that's really powerful. So I always screen my patients for their family history. And if I see multiple family members young onset in terms of when their cancer was diagnosed and multiple family members with the same type of cancers, if they haven't seen a geneticist, I'll recommend that they go and occasionally we'll actually uncover that they carry one of those types of mutations. There's also PGT-SR, which stands for Structural Rearrangements. So if your karyotype shows that you have one of those structural rearrangements in your chromosomes, this is a specialized tool that is going to look for any embryos that are imbalanced in the number of chromosomes th<at they have.

Kristyn Hodgdon:
Okay! How does that differ from the karyotype?

Lucky Sekhon:
Well, the karyotype is looking at the parent's blood work to look at the structure of their chromosomes, and so this isn't looking at blood. This is testing based on the cells of the embryo. So it's just a different technology.

Kristyn Hodgdon:
Ok, got it. So once the embryo is actually created, then they would check for those.

Lucky Sekhon:
Exactly.

Kristyn Hodgdon:
I'm learning so much. So I know PGT-A is sort of becoming the standard of care in a lot of clinics for IVF patients, especially of a certain age. In what cases do you sort of strongly recommend it?

Lucky Sekhon:
Well, I think anyone over the age of 35, because the thing that you're testing for becomes much more prevalent in your second half of your thirties and beyond. I think there's a good, a good case to do it. So I would definitely recommend it in anyone that's had multiple miscarriages, and we suspect that this could be because of their age or because of egg quality and resulting embryo quality issues. I think for cases of male infertility where we know that there's a Y chromosome micro deletion or problems with the karyotype and some severe male factor cases, there might be quality issues that extend to the embryo. So I always feel more comfortable doing genetic testing of the embryos. So those are just a few examples. But I think really it comes down to age and also it comes down to goals as well. I think anyone who's banking embryos for the future, I'm going to feel a lot more comfortable if they're using PGDT. I know it's not perfect and it's not going to tell you everything there is to know about your embryos and whether they'll one day implant, but it gets you pretty far. And I think the implications of someone banging embryos at 34, 35 and saying I might come back in 3 to 5 years to use them, I'd rather know upfront what they have. I don't want to blindly bank embryos that might be abnormal, and then they find out about this after many failed transfers in their late thirties. And then it's harder to make more embryos at that point.

Kristyn Hodgdon:
Now, that makes total sense. So someone asked this next question, which is really interesting to me as well, because I've done this, which is thawing, testing and refreezing your already frozen embryos. So I, when I first went through IVF, I was only 28 and it wasn't strongly recommended by my fertility doctor that I test my embryos, I ended up having success, but then the second time around, when I went back to transfer again, I had a miscarriage and I said, you know what? I have nine embryos left, I really want to know which ones are genetically normal. So I had them thawed and tested, but now I've had two failed transfers since. So I'm obviously concerned that the embryos might have taken a hit with that process. So what is the truth behind that?

Lucky Sekhon:
Well, I have a question before I answer your question. How many of the nine came back normal?

Kristyn Hodgdon:
So sorry, one of the nine was the miscarriage. So I tested eight, six came back normal.

Lucky Sekhon:
Oh, wow. Yeah. I mean, hindsight's 2020 and now looking back, you're like, well, I could have just gone without the testing because the majority were normal anyway. But if you had had different results, you would say the opposite, right? Like if only two came back normal, which I mean, I wouldn't expect that coming from a 28 year old, but sometimes there's just random skew because it's a small sample size and you're not always going to follow the statistics that are expected for your age. Or there could be things going on that make you not fall into those standard statistics. But if you had that information in front of you and said oh, six came back abnormal, you'd be like, Thank God I didn't just blindly keep transferring them, that's a lot of transfers to go through. So I think it's hard to know what the right answer is for people that aren't clear on why you would freeze, thaw, and then re biopsy, it's not just it's always an afterthought, but sometimes new information might come to light about your genetic history and you might say, oh, I just found out I'm a carrier of the brca gene and I want to screen my embryos. So there's a lot of ways that this can come up. And I think it depends on how compelling the argument is, like, I have patients that do this, I don't tell them not to do it. I think that you have to weigh it against, I think you have to weigh a few things. One is, how suspicious are you that there's something else going on and what is the potential benefit of doing it? Could it really decrease future disease in your future children and generations? Could it diminish your chance of having another miscarriage? Is there new information that you have that you didn't have before? And I think you have to weigh all of that against are there potential risks of the additional exposure? Because if you're freezing it initially and then thawing it, testing it and then refreezing it, that's two freezes and two thaws. And I think logically, you might make the assumption that that additional exposure could make the embryo weaker, or definitely we have some data that shows a slight reduction in thaw survival, but we don't have great data to look at the chance of it implanting being different. I actually did research on this that I presented at ASRM, it was an oral presentation, but I had admitted at the end of my presentation that the data is flawed because I compared two groups of people, those that, and this was actually a different topic. It was more about like double biopsy versus single biopsy because sometimes you get, you get indeterminate embryos, but it's a similar concept. And I did see a slight difference in implantation rates, but I was like, the populations are different. People that are using a double biopsied embryo are in a different position than those that maybe have multiple embryos to choose from and they have a bunch of single biopsies. So I think it's hard when you look at two different groups head to head in any study because there's so many different factors that go into the outcome that's being studied. But I think if you have a good enough reason, it's not something to be afraid to do. I think that there is every logical reason to assume that maybe it could affect the overall outcome, but not enough for it to be something that we wouldn't do at all, right? And so there are no major trends coming from the data to suggest that this is detrimental and you shouldn't do it, I think it just depends on the situation.

Kristyn Hodgdon:
Yeah, for me, I had a decent amount of embryos and didn't want to just keep transferring them blind.

Lucky Sekhon:
That's totally fair.

Kristyn Hodgdon:
Without having the knowledge. And I feel like in this process, if you have to do IVF, sometimes having that technology available to you is.

Lucky Sekhon:
Yeah.

Kristyn Hodgdon:
Is a great tool. And so why not have the knowledge if you can, but like you said, it depends on the situation, you have to weigh all of the pros and cons.

Lucky Sekhon:
Yeah, I definitely don't recommend it across the board for everyone. I counsel every single patient about it as an option, but I don't work at a place and I don't practice in a way where I'm like, everyone just do it because I know that it's not a perfect technology, it's really good, but it doesn't tell you every single thing that you need to know or that you would like to know about an embryo. And you know, it's possible that when you're using this technology in a much younger population that is anticipated to have a very low rate of these genetic errors or imbalances, that the benefit might be marginal and you're just adding costs to someone's treatment. So I think it's, you know, it's all about being logical and looking at the patient as an individual. And I don't necessarily disagree with you not doing it at 28, I think that was very reasonable. But then it's also very reasonable to revisit that as a decision after you go through something traumatic like a miscarriage. So I totally understand both perspectives.

Kristyn Hodgdon:
Absolutely. No, this is really, really helpful. So we also got a lot of questions on Mosaic embryos. Can you speak a little bit about that and whether you sort of recommend transferring a mosaic?

Lucky Sekhon:
Yes. So I think this is the biggest hot topic in the last couple of years because, well, let's talk about what a mosaic is for those that don't know. A mosaic is an embryo that has in the biopsied cells that were sent off for testing. There's a mixture of normal and abnormal embryo, sorry, normal and abnormal cells. So some that are 46 chromosomes and some that are not 46 chromosomes. And prior to the technology getting a little bit better and using something called next generation sequencing as the form of counting the number of chromosomes in the sample, we didn't know about Mosaics because we just didn't have the resolution to even detect that when we were using something called PCR, it was just a binary outcome. Either you have 46 chromosomes or you don't, there was no in between, and that probably means that they were being called abnormal, I assume, or maybe some of them are being called normal and that's why they weren't working as as well. I think that there's some data that suggests slightly better implantation rates using this more high-resolution technology. And it's not that mosaic is like this new thing that have been invented or just discovered, it's just we didn't know about them all along. We weren't able to detect it at that level. And now we've gone through this huge shift where it kind of scared us all at first, and we were like, why would we put back a mosaic? We know that there are some conditions, like you can talk to any pediatrician or pediatric genetic person that would tell you certain cases of autism and developmental disorders can relate back to mosaicsm in that child. So we know that it's not completely benign, that this could result in disease. So an embryo has 100 to 200 cells and as it grows and divides into a full pregnancy, some of the abnormal cells could die off and no longer be a problem, it's really hard to predict how things will play out. And so we now know from actual data there was a big paper that looked at at least 1000 embryo transfers of mosaic embryos that we can have healthy, seemingly healthy, live born children from mosaic embryo transfers. A couple of facts that came out of that particular paper is that Mosaic embryos have a lower chance of implantation. So they have overall lower, lower rates of live birth, higher rates of miscarriage. But if a live birth does occur, it was really encouraging that when they tested all of the babies, they weren't able to detect any of these abnormalities. So perhaps mosaic embryos that successfully implant and go on to a live birth, most of them are embryos that self corrected. There's also the chance that some mosaics aren't really mosaics, that maybe there's a testing error, who knows, right? I think there are also a lot of pieces of information in the report that you can get, depending on the lab that's running the testing, some will report the percent of the cells that were abnormal versus normal. We're still trying to understand if that has any correlation with outcome. Like is a high mosaic worse than a low mosaic? That paper that I was referencing did suggest that when the mosaicsm is for a segmental deletion or duplication of a chromosome, not a whole chromosome being involved, those have higher live birth rates. So maybe that's a different entity altogether. I think, you know, we, bottom line will offer it as an option to a patient. Our clinics policy right now and things are always changing is that our preference would be if you have a mosaic versus an embryo that has no question marks surrounding it, it's completely normal as far as we can tell, we'd rather you transfer that. And so for patients who have no other embryos left, they only have a mosaic. We have them see our genetics counselor and the genetic counselor is going to be the most up to date person that can educate them on what's known about mosaicsm of that particular chromosome. Are there any known manifestations or clinical disorders? And I think just having a very thorough discussion and feeling well counseled and if they feel confident, the patient still feels confident and says, you know what, I want to try, this is maybe my only chance, I can't make more embryos for whatever reason, maybe it's just not feasible financially or physically possible for them to do it, it's reasonable and we support them in that decision. But I think there's a lot of question marks and it makes me feel uneasy because you just don't know, and, you know, even the papers that we have out right now, do we have long term health data on those children? No, but I think all of that's going to change obviously over the next few years, so I'm excited to get that data so that we have even more information to counsel our patients with.

Kristyn Hodgdon:
Absolutely. So I do not know if this is true at all, but I've heard from some people in the community that have read articles out there in the world. So this is more of like a myth busting question that, that PGT-A testing can be wrong sometimes. And the fact that it can say an embryo is abnormal when it actually wasn't.

Lucky Sekhon:
Yeah, that can happen. Just like any test, there's always a margin of error, false positives or false negatives. And thankfully that's really, really rare. I've never had a patient with a diagnostic error, knock on wood, but I'm sure it will happen because, you know, we don't say it's 100% accurate. We say there's a less than 2% error rate, and that's why that is possible. But I think oftentimes, hear this concern so much from patients, so it leads me to believe that there's a bias, right? We tend to focus more on those types of cases because they're so disconcerting. But in reality, from my perspective as a fertility doctor in a clinic with a high volume, these cases are few and far between.

Kristyn Hodgdon:
Okay, that's reassuring. What did we miss? Let's see. Is there anything that we missed on genetic testing that I wouldn't even know to ask?

Lucky Sekhon:
No. I feel like we covered it all, honestly. I mean, I think and we talked about this in one of the prior episodes, but I think people put a lot of stock in PGT, and if they know that the embryo is tested as normal, I think to a lot of laypeople, patients, they're just assuming that now they're on easy street and everything's going to be totally fine. And I think it's just important to take home that it can get you very far and it's going to weed out a lot of the embryos that would never have made it either to implant or to continue beyond a certain point, mostly the first trimester. And so it's a really great selection tool. But what it isn't is it's not a guarantee because there's a lot of other things that have to go right when it comes to an embryo implanting and staying implanted, and it's not a catch all. A lot of people will come to me and say, I sometimes have consults where patients will say, I haven't even started trying, but I am this high powered insert whatever high powered field they're in, whether they're a lawyer or whatever, and they're like, I just don't want to take on any risks and I'm ready to start building my family and I want to do genetic testing on the embryos to make sure I have the healthiest child possible. And I'm like, okay, well, first off, that's not what PGT is, right? This is a tool that we use to select the best embryo that's going to get you on the road to pregnancy and hopefully minimize your risk of miscarriage, but it doesn't tell me if your kid is going to get into Harvard, it doesn't tell me that your child's not going to have any medical problems or even birth defects. That's another misconception, right? Birth defects are not that common, in the general population t's like 3%. And they can arise from a variety of causes and they're not always genetic. So it's just important to know that it's not a catch all, it's not going to completely minimize risk. And it kind of goes back to just what, you know, this entire journey is, which is the unknown. And I think whenever you're trying to conceive, there are certain unknowns that you have to take on and there's no way to get around that. And PGT helps a lot, but it doesn't address a lot of those concerns.

Kristyn Hodgdon:
Yeah, I think you hit it on the head before when you said it's a, it's a chance of having a baby, it's not a guarantee. And I feel like a lot of people learn that the hard way, and that's not to say that IVF isn't like the coolest science ever. And I have two children from IVF and, but, you know, knowledge is power, and, and that's what I think the beauty of genetic testing is, is that you can kind of know what you're putting back into your body.

Lucky Sekhon:
And yeah, it helps you cut out a lot of the stuff that you would have otherwise had to deal with that I think would make this already long, drawn out, laborious process even more drawn out and even harder. So I'm really grateful that the technology exists. And from my perspective, like when I talk to my mentors who are 10, 20 years older and they've been practicing since IVF first came out, which is crazy to think about. But, you know, they tell me about the early days of IVF where it was single digit success rates. And I'm like, how did you go on? Like, that's so pessimistic, that just would make me feel so negative. I now practice in an era and I feel so fortunate that the majority of the calls that I'm making after a transfer are happy calls, and a lot of that has to do with practice patterns. And for us, we do utilize a lot of this genetic testing and it's incredible. Some weeks there's like 100% pregnancy rates and last month it was like 70 to 80%. So I think it's important to feel positive and optimistic because those numbers are very real. And I do think that at least when you have genetically tested embryos, you've ruled out that really major variable and then that you can really hone in and focus in on the other things that might need to be looked at.

Kristyn Hodgdon:
Definitely. Well, I learned so much today. Thank you so much, Dr. Sekhon, and excited for our next episode.

Lucky Sekhon:
Thanks for having me. Have a good one.

Kristyn Hodgdon:
Thank you for tuning into this episode of Dear Infertility. We hope it helps you feel more empowered to be your own advocate on your fertility journey. Whatever you're currently struggling with, Rescripted is here to hold your hand every step of the way. If you like today's episode and want to stay up to date on our podcast, don't forget to click Subscribe. To find this episode show notes resources and more head to Rescripted.com and be sure to join our free fertility support community while you're there.

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