Ep 265: Genetic Testing Decoded: Making Sense of Genetic Results Before Pregnancy

Have you ever wondered if genetic testing before pregnancy is something you should consider? In this episode, we chat with Dr. Millie Thakur, a reproductive endocrinologist, medical geneticist, and founder of Genome Ally, a telemedicine reproductive genetics company. She breaks down the many reasons why someone might want to see her before trying to conceive. Maybe you or your partner have a family history of genetic conditions, a newly discovered genetic mutation, or have experienced recurrent pregnancy loss. Or perhaps you are just curious about genetic testing on embryos and what it all means.

Dr. Thakur also gives us the scoop on the kinds of tests she can order and how they can provide valuable insights for hopeful parents. Plus, we talk about the cost of a visit, the benefits of speaking with a specialist before pregnancy, and what to expect from a consultation. If you have ever had questions about genetic counseling but didn’t know where to start, this episode is a must-listen. Join us as we dive into the fascinating world of reproductive genetics and learn how science is helping families make informed decisions about their future.

Today's episode is brought to you by Receptiva, US Fertility, and Shady Grove Fertility

Transcript

Susan Hudson (00:01)

You'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.

Abby Eblen MD (00:56)

Hi everybody, we're back with another episode of Fertility Docs Uncensored. I'm one of your hosts, Dr. Abby Eblen from Nashville Fertility Center. And today I'm joined by Dr. Susan Hudson from Texas Fertility Center.

Susan Hudson MD (01:06)

Hello!

Abby Eblen MD (01:08)

and Dr. Carrie Bedient from the Fertility Center of Las Vegas.

Carrie Bedient  MD (01:11)

Hi, how's it going?

Abby Eblen MD (01:14)

Great. And today we have a very special guest, Mili Thakur. She is a physician, a reproductive endocrinologist, and also boarded in medical genetics, which that is not an easy task to be boarded in both. She's also founder of Genome Ally, which is a telemedicine reproductive genetics company. And so Mili has really helped us out with a lot of people who have really complicated genetics issues. And we're going to talk a little bit about that just a second. But first, Mili, you were telling us a little bit about your background and where you grew up and some interesting things you've encountered.

Dr. Mili Thakur (01:45)

Yeah, hello everybody. I'm excited to be here. Thank you for having me as a guest. I was born and raised in India, and I was telling before we started that growing up in India I did my medical school there and then I did a residency in OB-GYN. As part of that residency, I also volunteered and I was telling stories of these amazing opportunities that I got to volunteer in the foothills of the Himalayan mountains. As you know, the Himalayan mountains is the highest elevation. So some of the villages there, we would go on these missions and one of the pediatricians from our hospital would arrange those trips. So they would have me as our OBGYN, and then she was a pediatrician and her husband was a pediatrician as well.

And then we would have a surgeon and eye doctor and few nurses and we would go out and be in these remote areas. So there are very good fond memories from there, especially for obstetric and women's care in such remote areas.

Abby Eblen MD (02:47)

I've done medical mission work, but mine was more just upper respiratory infections. like more as a generalist. Can't imagine doing OB in a really remote area with no resources, no backup.

Dr. Mili Thakur (02:57)

Yeah, and I think that's what I learned in those trips is that, as humans, we are very resourceful and depending on where that situation is, the women around that community actually build that community in that way. So one of the examples was I had this trip one time where we went and I was, I remember they put us in a really nice guest house, the best that they had where the chief minister of the state would come and stay.

And I was like, okay, where's the population? Where's all the people that live that we are gonna see in the camp tomorrow? And they showed me out of this window, gorgeous panoramic view of the mountains. And they said, oh, there's a village four hours from here. There's so many families there and then there and there and there. So in the mountains, they showed us how there are these small hamlets, maybe like 300, 400 people live in those places. And so I asked them, I said, are we gonna meet the person who delivers the babies in these areas. So she was a trained midwife who would go from village to village. And then when I met her, I was like, how do you deliver the complicated ones? And she said, I have a lot of experience in delivering breech babies. They get used to delivering all that. And then whatever she can't deliver, they just put the patient in the hospital and go to the nearest hospital, which is six to eight hours away.

Abby Eblen MD (04:19)

And how transportation, how did they get around there in those mountainous areas?

Dr. Mili Thakur (04:24)

I think mostly walking, but then they would have two wheelers, lot of scooters and motorcycles now. Amazingly, even at that time, and I'm talking about, I've been in the US for 15 years, so this is before that, they would still have cell phone towers. There would be cell phones, so for a while, what we did was we would go out to these places, have these different camps that were set up and do examinations. So I would do pap smear for women on a stretch, or we would do different things. But then we also set up something that was almost telemedicine. And what we did was we found out that there were these young boys and girls, the ages of 16 to 18 years old, who were still part of the community, haven't gone out for jobs yet.

Going to school so they can read and write and understand things. So we went and we trained them. So then what they would do is we would be in the city and they could actually send us stuff from there. So if there was a diabetic in the village, they would do the blood sugars. And if it was going high or low, we would prescribe something. And then the doctors who were working with us who were used to organize these camps would actually, they bought from the US they had bought these snake venom kits. So we gave those kits to these kids essentially, right? They're 16 to 18 year olds and they would take care of snake bites as a first responder and then the person would be sent to the hospital. The gist that I got from that is every community has those resources that they develop. They might not be top class as they are, but every simple action can then go into the community. So the midwife that I talked to you about, she has developed the resources, living in that community, taking care of these women. Yeah, yeah. And it's always good to have the person trained from the community because they live there. They believe in that.

Abby Eblen MD (06:12)

The team to take care of everybody as a group. That's awesome. That is very cool.

Susan Hudson MD (06:22)

They know what's normal, they know what's not normal, they know what that person's like on a daily basis. And that's invaluable.

Abby Eblen MD (06:25)

That's right.

Dr. Mili Thakur (06:27)

Yeah.

Abby Eblen MD (06:29)

That's great. Well, tell us a little bit about your company. I'm really impressed. Tell us about what you do.

Dr. Mili Thakur (06:35)

Yeah, so when I did my fellowship, I was fortunate to get into a fellowship which was reproductive endocrinology and infertility, which is a three-year fellowship. But I also did medical genetics as part of it. So the amazing thing was at that point, we were able to develop a combined fellowship, which is a four-year fellowship with two years dedicated over genetics and two years on reproductive endocrinologists. And this gave me a very good area to focus on where family building and genetics coincide together. And right after my fellowship, I worked, I live and work here in Grand Rapids. So I worked at a fertility center here. I built a genomics program here. And then in 2023, what I did was I created a telehealth genetics practice, is Genome Ally.

And I see patients now from 21 different states from other providers. Our main mission is to improve access to genetics during family building. So we see patients who are on a family building journey and have found either new information that came through testing while they were doing the fertility testing, or they already knew that there was a family history of some sort of genetic risk. And we address that risk, discuss the options with the patients, and then we help them make the right choice of what works good for them to reduce that reproductive risk. We also provide counseling about abnormal test results like genetic testing on embryos like mosaic embryos or segmental aneuploid embryos, and also address reproductive failure type of situations like recurrent pregnancy loss or implantation failure.

Susan Hudson MD (08:16)

Whew, that's a lot.

Carrie Bedient  MD (08:17)

So we, as REIs, we very much appreciate you because we have sent many people your way. Susan was mentioning this before we started where oftentimes we send patients to talk to genetics counselors or geneticists and they come back and they are just terrified and overwhelmed. And the patients that we send to you come back and they understand and they know, okay, here are my options forward.

This is what might be going on. This is what we might have to do to move forward. And when you're talking about PGT-M especially, which is pre-implantation genetic testing for single gene mutation, so different than PGT-A, we are very, grateful that you and Genome Ally are out there and exist because you save us a lot of time and explanation and you save our patients a lot of heartache by being able to go through all of this because PGT-M is more complex than PGT-A. There's more nuance to it. The setup is more complex. And so we are very much hoping that you can explain that to our listeners here so that they get the right information from you, not us.

Susan Hudson MD (09:24)

Before we jump down the PGT-M rabbit hole though, we need to do one question, okay?

Starting a family is one of life's greatest adventures, but sometimes the path to parenthood isn't as straightforward as expected. Shady Grove Fertility is there to guide hopeful parents every step of the way, offering compassionate care and advanced fertility treatments to help make parenthood possible. With their exclusive 100 % refund program for IVF and flexible monthly payment options, Shady Grove Fertility makes treatment more accessible.

Visit ShadyGrowFertility.com to schedule a consultation and take the first step, because the adventure of a lifetime starts at Shady Grow Fertility.

Alright, so our question for today is how hard or dangerous is it to move frozen eggs versus embryos from one state to another? I'm thinking about moving and wonder if my eggs would be portable. Thanks.

Carrie Bedient  MD (10:18)

So the short answer is everything's portable. It's just how much effort you have to expend to make it portable. There are specialty companies that work to move eggs and to move embryos. And so the cryo storage and sperm, and sperm, can't forget the sperm. I just got a necklace recently that looks like sperm and I will have to show it to you girls later because it's not intended to be sperm, but it is a little indecent.

Abby Eblen MD (10:39)

If you say it's unintentional, it's supposed to look like sperm or it just does.

Carrie Bedient  MD (10:42)

No, not even a little. So I think I might need prior approval before I put this thing on. But you can move anything anywhere. There are specialty companies that are designed to do cryo transport. Now, the question here is how dangerous is it? So in general, it's not dangerous at all. Anything can be moved. The problem is, what is the risk if something goes wrong? And the risk if something goes wrong is that you lose it all. And so that happens very, very rarely, but it is possible. And so a lot of us tend to prefer to keep whatever eggs, embryos stored in whatever location they originated. Now there's always exceptions to that because you may find a clinic that is better suited to you that maybe has better success rates than the one you originally started at, that has a better offering. It is more logistically possible for you to work with them than anyone else. And in which case transfer to your heart's delight.

Some things to consider. Do you want to transfer into shipments? It might be more expensive, but if one goes wrong, you don't lose everything. I think I've only seen one or two bad things happen over the course of my career, but man, it sucks when it does.

Abby Eblen MD (11:54)

Yeah, I would add to that. think the risk are really, really low. I I'm not overly concerned about that. curious, I mean, anything can happen. That's what you learn in medicine over the years. Anything can happen. But I think the chances of that happening are exceedingly low and hopefully getting even lower as more people understand about the importance of timing and liquid nitrogen and all that when they transport embryos and eggs and sperm.

Susan Hudson MD (12:18)

And I mean, this leads into the discussion of long-term storage versus local storage. I mean, I can say that I am generally in favor of long-term storage. You have an entire storage facility that all they do is store reproductive materials. I mean, the amount of backups and alarms and security for those types of systems. I mean, we do a great job in our labs for our local storage, but I don't think that it's as secure as long-term storages. And I think there's risks to everything you do, but in general, I mean, we ship sperm and eggs and embryos across the country on a regular basis. And for the less than 1 % that's going to have something bad happen.

I mean, that's not really a big deal. The biggest thing is that generally the best place to have your eggs or embryos thawed or warmed is the place that they were cryopreserved. So not everyone does everything exactly the same. And what we do at our lab may not be the same as what somebody does at their lab. And it can sometimes have an impact. And so I think most reproductive endocrinologists would would say yes, under most circumstances will accept most other eggs and embryos from other places. There's always exceptions to the rule, but that the best place for something to be warmed is the place that it was cryo'd.

Carrie Bedient  MD (13:50)

When embryos are being transferred from one place to the other, there's some clinics that will not accept all embryos because the criteria for freezing and biopsying at one clinic may be very different than another clinic. There's also quite a lot of risk and liability for the receiving clinic because if the shipping clinic didn't do something quite right, it's the receiving clinic that's going to take the flak even if they had nothing to do with it. And to go back to amend my prior statement, when I think about it, all of the stories that I have from this tend to be international shipping. And so that is definitely a different ball game, but I don't think I've had any, knock on wood, problems with domestic shipping.

Dr. Mili Thakur (14:31)

Also the insurance that you can buy when the specialty carriers are moving the tissue.

Carrie Bedient  MD (14:39)

Mm hmm.

Yep. Yep. All right. Cool. That was a good question.

Abby Eblen MD (14:44)

Well, very good. Mili, tell us a little bit about how things work with you. Do patients contact you directly? Do patients come through their physicians or how does that work when they get in touch with you?

Dr. Mili Thakur (14:54)

So we do online booking and majority of our patients either come through their fertility physicians. So they are going through the fertility treatment or going through IVF and the physicians would send us the referrals or they can reach us directly. Many of our patients come through social media, like they've heard or worked with a patient of ours before. Because we do online booking, they are able to go to our website, which is genomeally.com and they can book their appointment by making an account with us. I would say most of our patients are in that family building process. Rarely would we see somebody who's thinking about it in a year or two. Most of them are actively trying to have a family in the next year.

Abby Eblen MD (15:39)

And are these people that have known conditions or are they coming to you for initial testing or how does that work?

Dr. Mili Thakur (15:45)

So there's three, four different indications of why they come. A majority of them would be coming because something new was found while they were doing the fertility testing. So most of these patients are healthy. They are thinking of having a baby. And then, as part of the fertility work-up, most of the doctors are doing carrier screening. So they do a panel of genetic conditions are looked at, usually these panels can be between 100 to 600 plus conditions. And then now the couple has been found to be at risk for the condition. Common conditions that are found are cystic fibrosis or sickle cell anemia, because it's a condition that you don't have a family history for. And now these couples just have some sort of an issue.

So basically we would find them and they would come to us because there was a known risk that was found. The other thing is that they have a family history of the disease. Things like some sort of neurological conditions like Huntington's disease or frontotemporal dementia runs in the family or the person has a personal history of disease like Marfan syndrome or osteogenesis imperfecta or achondroplasia. So these children have now grown up. They always had the diagnosis, but with improving medical care, they are healthy. Even with the genetic condition, they are healthy. And then they are now thinking of having a baby and they want to prevent the risk of passing that genetic condition that affects them or a family member and not pass that on. So that's the second group. The first group is where they were seemingly healthy, but they are now asymptomatic carriers and there is a risk to the pregnancy. The second group is where they have a personal or family history of a genetic condition. The third group is when they've had recurrent pregnancy loss and the IVF doctors or the fertility doctors have done a thorough workup. They've looked at the chromosomes of the patient. They've done other blood clotting factors and the assessment of the cavity and still there are no answers.

And then we will do some specific genetic testing that's on a deeper level to figure out why this is happening. So that's another group of patients that we see. And the fourth group of patients that come to us is that genetic testing was done on the embryos. And now there are some results that need to be interpreted in light of what was found on the embryo. So either it could be PGT test results that are not clear cut, chromosomally normal and have some sort of abnormality. We call them mosaic embryo counseling or segmental aneuploidies. More and more information is coming for those kinds of embryo test results. So that's the fourth category where they are coming to discuss the test results of embryos.

Susan Hudson MD (18:26)

So let's go back and talk a little bit about carrier screening. So I know we all offer carrier screening and I would say the majority of my patients take me up on carrier screening. I always explain to people, because sometimes people are like, well, I wouldn't do any different. And I'm like, there's power in knowledge. And so even if you decide not to do something like PGT-M, which we're going to talk about in a few minutes, is that if you know you have a 25 % chance of having a child who's going to need specific medical care or have special needs, whether it's medical needs, educational needs, just general social support needs, that might point you in different directions of what you would do in preparing in your pregnancy, delivery, what you're planning on doing postpartum and those types of things. But when we do that carrier screening, what are the chances that you end up with testing that may lead to a recommendation for something like PGT-M.

Dr. Mili Thakur (19:22)

So it depends on a few things. When we do carrier screening, right now at this time, we are offering something called pan-ethnic expanded carrier screening. Years ago, the type of testing that was done for carrier screening was they used to base the test or the diseases that were being tested on an ethnic group. So for example, there are some conditions that are very common based on the ethnic group of the person like hemoglobinopathies like sickle cell or your thalassemias are very common in those with Southeast Asian descent or African American descent. Cystic fibrosis is very common in Northern European descent. And then, we used to have certain panels for those with Ashkenazi Jewish population and others for Southeast Asian and others for the regular population. So what we have done now is we've gone away from that. We do a pan-ethnic carrier screening and the risk of finding a carrier-carrier couple, because the majority of disorders on these big panels are autosomal recessive, is about one in 50. So one in 50 people would actually match up. Yeah, so they would match up for the disorder, not knowing that each one of them carries the mutation for the same exact gene. And then one in four of their children will be at risk.

Abby Eblen MD (20:27)

Wow.

Dr. Mili Thakur (20:41)

And then many of these panels, I know the panels that all of us are using have about 30 to 40 X-linked conditions. And it's very surprising that about 2 % of women can actually be carriers and they are silent carriers of conditions that are X-linked. They never manifested because the X-link conditions can manifest differently in boys and girls. So one of the common examples of these silent conditions that are sometimes picked up only by carrier screening is like Duchenne and Becker muscular dystrophy. So, it affects boys, but many a times we would now pick those up on carrier screening and alert the mom that they are a carrier of this condition. And then they are able to pick up the reproductive options much better. And the reason why carrier screening is so important and a big advocate of carrier screening is we have now treatment for many of these conditions.

But many of these treatments, including gene therapies, have a timeline of when they work best in a little baby. So if somebody hadn't done the carrier screening and then their child is born and has the rare condition, it takes an average of two to three years for the health care team to find out what's different about the child. Many a times for Duchenne muscular dystrophy, is gene therapy available now.

But by the time the child is actually diagnosed, which is five, six years of age, they are actually no longer candidates for gene therapy that starts around four or five years of age. So by doing this kind of carrier screening before somebody gets pregnant, they can actually know what they are at risk for, if at all, and then go forward with the decision-making. So on a carrier screening, one in 25 people will be carriers of cystic fibrosis, but only one in 50 couples would actually be at risk for something where both partners are carriers. So I think it's a good thing to consider it before the pregnancy actually starts.

Abby Eblen MD (22:43)

Absolutely.

Carrie Bedient  MD (22:44)

So if we find that one of our patients is a carrier-carrier couple, they both carry a gene that is silent in them, but in combination may cause a one in four chance, 25%, which is a huge percentage, of having their child be affected, and we send them to you, what do they do next? What happens?

Dr. Mili Thakur (23:04)

So what we would do is we would actually sit down with them and depending on their situation discuss different reproductive options. So reproductive options that are available to individuals all across the board can range from still continuing to try naturally, be able to now know that there is a risk of one in four children or 25 % of children to have that disease, and in that case, be able to take decisions for the pregnancy and for the baby ahead of time. What I mean by that is if somebody knew that they are a carrier-carrier couple and wanted to test the pregnancy during pregnancy, there are different options like amniocentesis and a test called CVS that can be done. If they choose not to test, then they can actually at least alert the pediatrician team and say, As soon as the baby's here, let's make sure that the baby gets checked out. And then some of these conditions that we check on carrier screening actually can cause diseases, genetic conditions that require something specific being either given to the baby or not given to the baby, because they are enzyme deficiencies. So some of them just means that you eliminate breast milk in the diet. Like phenylketonuria is a common condition that is...if people can be carrier for and in that you don't give them breast milk, you have to give them certain formulas that are very medically balanced. So those kinds of preparations can be made in that natural trying with or without prenatal testing is one option. The second option is you could do in vitro fertilization. So you could do IVF and then do pre-implantation genetic testing for a single gene condition and see which embryo is affected and not affected before a decision of transfer is taken. And in that case, preconceptionally, those families can transfer an unaffected embryo for the disorder. instead of transferring that one in four affected embryo, you can transfer that three of four that are not affected. The third option is they can actually choose to not conceive through their own gametes, but use donor gametes like eggs or sperm, or they can do donor embryo. We talk about that.

Or they can choose to expand their family with adoption or foster parenting or they can choose and decide not to have children anymore. So in that case, what happens is because the carrier screening picked this risk up, at least the intended parents are not blindsided by a sick child coming in. Now they have all options open up and many of the patients that come to us are actually because they're coming from other fertility doctors are anyway thinking of doing IVF for other reasons, say male factor or because of their age, they want to do IVF. And if this additional risk is now found, then you can actually test the embryos for that particular condition in addition to what they were already going to do. And that's where the role of PGT-M comes through.

Abby Eblen MD (25:56)

So Mili, there other, you'd mentioned that you might need some further testing. How does that work? Would that go through the reproductive endocrinologist locally or can you order those tests or how does that work?

Dr. Mili Thakur (26:07)

So at Genome Ally, I ordered those tests and this is for patients who always had a clinical diagnosis of a particular condition, but never got the mutation tested. For us to be able to test the embryos, you have to know the exact mutation or the exact genetic change that has happened in that individual to be able to build a test for the embryos. Many times I will see women or men in their 20s to 30s.

They've always had the diagnosis of that genetic condition. Common things could be like achondroplasia, which is the commonest cause of like short stature. Or they could have like, osteogenesis imperfecta with weak bones. Or they could have, I've had a patient last year who had a extremely severe skin condition. He always had the diagnosis of it. It's called epidermolytic keratosis. And he never got the gene testing checked.

And that's because the manifestation is so obvious that the medical team has always taken care of them as is, but now they want to have a baby and the mutation has to be found. So what I usually will do is I will see them, assess them, and then we will order the genetic testing through medical grade genetic testing labs. We find the mutation and once the mutation has confirmed our diagnosis, then you can move forward with thinking of testing embryos. So, PGT-M cannot work unless the mutation is known. So we ordered that test for them.

Susan Hudson MD (27:31)

And I wanted to mention that sometimes patients come to us and maybe one partner has their genetic testing because they have a family history and they took the testing. But interestingly enough, we usually have to test for that exact same condition in the partner because there has to be proof that they're actually not a carrier of some variant of the same thing or that type of thing.

Dr. Mili Thakur (27:54)

Yeah, and it's very important with some conditions where the patient comes in. So the male partner will come in and we wouldn't find sperm in them. They have azospermia. And when we send them to the urologist and do more testing on that male partner, sometimes we will find that they have cystic fibrosis related condition, which is called bilateral absence of the vas deferens. So they actually have sperm that is formed in the testicles, but the tube that connects it for ejaculation is not there. So in that case, they are now suddenly diagnosed with cystic fibrosis. It doesn't manifest as a typical classic cystic fibrosis, but now we have to be extra careful of how we test the female partner because their cystic fibrosis gene has now to be very carefully looked at and we have to make sure that there is no possibility that they also are a carrier of cystic fibrosis. Otherwise, one in four children could have actually classic cystic fibrosis if those mutations come together. So I think it's really important to understand that there are nuances to the study. And I think as Dr. Hudson said, it's very important for us to do some investigative work and not take it at face value. Another thing that I wanted to point out is some families will come to us and they will say, I had testing through direct to consumer test.

There are different companies that offer testing and it's part of a little bit of ancestry and genealogy, but also some sort of genetic testing. And patients think that, that was adequate enough for us to prevent any risk passing on to the children. And you have to really carefully look at as to what was done. And many of these tests are not to the level of medical grade testing.

Then what we end up doing is doing a more thorough analysis and making sure that we are reducing the reproductive risk as best as possible.

Carrie Bedient  MD (29:48)

So why can't we do this on every single embryo that goes through? Like instead of testing the parents, which, okay, maybe you do, maybe you don't, why can't we just test this on every single embryo that we get and just confirm it from the very beginning that no kid is gonna have whatever issue?

Dr. Mili Thakur (30:05)

Yeah, so I think there are two factors involved in this and it comes to the point of how small the embryo is. So I like to show a picture to my patients and I'll show it to your audience too. This is the journey of how the egg gets fertilized and then it develops and this is a day five embryo. It looks great in these big pictures, but this is smaller than the tip of the hair. And in a PGT testing, we're taking a few cells out from this outer shell.

About four or five cells are being taken out because we can't take too many. Otherwise it would cause issues with the embryo. And then we send it to the testing lab and the type of technologies that are being used for embryos have to be different from what we used on adults and children. So in an adult or a child, there are millions of cells that are available from blood draw or saliva testing. And you can double check the mutation that you're looking at. But in an embryo, because the DNA is so low, we have to add something more called linkage on mutation analysis. So first point is that there is less DNA and we have to be very specific of what we ask the lab to look for and how accurate the test result is. The second thing is that the technologies that are available right now for whole genome sequencing and whole exome sequencing, they are available for adults and children.

But they've been developed in an environment where there is a phenotype. That means the child or the adult is sick. We know what they have, what is their manifestation in their body. And then we are trying to interpret the genetic results for that. In an embryo, we are trying to take decisions when the phenotype hasn't developed yet. And if we try to do whole genome sequencing at the current time on an embryo, we are going to find a lot of gray zone test results and we won't be able to tell which embryo is actually able to be transferred.

Abby Eblen MD (31:57)

Tell us what whole genome sequencing is.

Dr. Mili Thakur (32:01)

So basically what it means is that, when we talk about our chromosomes, we have 46 total chromosomes that have about 25 to 30,000 genes are written on them. And whole genome sequencing means that they are trying to read every readable gene in the genome on a grand scheme of things and being able to interpret it to figure out what is different in that individual.

And whole exome sequencing means that all the protein making genes are being looked at with great accuracy, with lot of coverage on those genes. And then we are trying to look at the manifestation of the individual and trying to match up to a certain gene. Most of the common reasons of why we do whole exome sequencing is either somebody has birth defects or they have differences about their development. They have like cognitive impairment, seizure disorder, autism.

Some sort of manifestation is happening in an adult or a child and we're trying to look for answers. But when we try to do this, as Dr. Bedient said, if we were trying to look for this in an embryo, we have very little amount of DNA at the same, at this time. And then we also have the limitation of interpreting what we are going to find if we start to look for every single gene, because the parents that created them may not have any manifestation.

And the embryo itself, it's hard to interpret that in something that doesn't have a phenotype yet.

Carrie Bedient  MD (33:29)

So how accurate are these tests? Let's say you've identified, both whoever's providing sperm, eggs, carries whatever problematic gene, they wanna do PGT-M, they wanna identify which embryos are gonna be affected ahead of time so they can then not transfer them. What do they have to do?

Dr. Mili Thakur (33:47)

So what they have to do is that we have to build a test for that couple for that condition. The testing of embryos cannot be done at your regular hospital lab or any sort of different lab. You have to be only testing embryos through specific labs that have developed methods of testing embryos and these are called PGT labs. There's about like eight to 10 of PGT labs in the country, and you have to actually have a packet of documents to submit to them. So each case is then on a case by case basis analyzed by the lab, and then they will give us an acceptance of that case. The packet will include the need for the test, that there is reproductive risk and we are trying to reduce it. It would have the mutation that that person is needing, and then a family history of who's available to be able to participate in the test building of the test.

Then what these labs do is once they have accepted our case of that patient, of that family, they say, okay, we have the mutations. It looks like this is going to be beneficial for testing to your embryos. It's going to be reduced risk to the embryos. Then they will start working with this family and they'll send out DNA test kits. So in an embryo, because we have to establish something called linkage on top of direct mutation analysis, you actually have to link the chromosome that has the mutation in that individual.

And for that, both male and female partner or the sperm and egg provider are going to be sending out DNA kits. It's almost a test build, which will be close to like your DNA fingerprinting in forensics. They're going to put markers on those chromosomes and read them well. And then if a good test is built, then most of the families would have an accuracy between about, I would say between higher than 90%, between 93 to 98 % is common.

Abby Eblen MD (35:38)

How long does it take to build the test? And is there ever a situation where the test can't be built?

Dr. Mili Thakur (35:44)

Yeah, so usually I think the for common conditions. So even though these are all rare genetic conditions, some of them are, more prevalent than others. So cystic fibrosis, sickle cell anemia, these conditions are very commonly being requested for. So for those conditions, the test build time is shorter. Many labs can actually build it under four weeks, and some of them are even building them up in two or three weeks, the answer would be there whether or not this can be done. Sometimes they don't even have to build a test. They just know that this is some mutation that they have looked at it before. But for some families, the challenge is that they don't have enough family members to participate in the test. So for these conditions, especially the conditions that are X-linked conditions and have repeats on them, like fragile X syndrome is one of those. So if somebody has Fragile X pre-mutation and they want to make sure that that's not passed on to their embryos. They would require parents on each side of the family, at least on the side of the woman, to be able to build the test. And in some families, that's just not an option. So linkage-based testing becomes harder if family members are not available. So Dr. Eblen, to your point, there are some families where tests cannot be built. And most of the common reasons of those are…Number one, that the mutation is very specific and in an area that can be actually not tested in an embryo. The second thing could be that there is some limitation in technology to give an accurate test result. If we want the PGT lab to build the test, we want an accuracy that's not lower than 90%, right? We want to make sure that yes, of course we are testing it. And the third thing is that there are not enough family members available to build the test.

Susan Hudson MD (37:33)

So how many family members are typically needed for a test? This is something that, as you know, as a reproductive endocrinologist, a lot of our patients may not have shared any of their fertility journey. And when we first share with them that, hey, we may need DNA samples from parents, siblings, grandparents, whoever may be related or have the condition or those types of things, a lot of people are taken aback from that.

Abby Eblen MD (37:51)

Yeah.

Susan Hudson MD (38:01)

Do you always have to have samples from other family members or is it specific ones and how many do you actually need a lot of times?

Dr. Mili Thakur (38:11)

Yeah, so I think usually for the conditions where it's a carrier-carrier couple and the mutation is known, in those families, less family members are needed just because we would be able to work with the PGT lab and they are able to usually build it without much difficulty. But when there are disorders that are...triplet repeat disorders, I said, fragile X is one of them. Myotonic dystrophy is another one of them. In those kinds of conditions, in triplet repeats, it's really hard to do direct mutation analysis. In those families, it's an absolute necessary thing. And the PGT lab will usually guide us to say, for this kind of mutation, we do need these two sets of family members or four sets of family members that have to be there.

Other times what can happen is if the parents are not available, so the male and female partner's parents can be involved in those kinds of conditions, there could also be an affected child. Like if there was a child of that couple that is already affected by the genetic disease and that's why now they are doing the testing for a future baby. In that case, if the child is able to participate, that is sufficient because in that case, that child is affected. So we already know which two mutations came through and they can be, then the lab has to set something called setting phase and they can figure out which phase of the chromosome is there. Another thing that is very important to mention is that it's easier to build a test when there are inherited risk. That means either both partners or one partner is a carrier.

What I mean by that, if both partners are carrier, there is a risk of autosomal recessive condition. When one partner is a carrier of something autosomal dominant, then also it's easier to build a test. But sometimes there are these families that come to us where their child, both partners don't have anything, but their child actually got a de novo condition. So de novo conditions are one that happened for the first time in that affected person, are not inherited from the family member.

Abby Eblen MD (40:05)

Yeah.

Dr. Mili Thakur (40:13)

But now because that family got affected by such a rare condition, they want to make sure that it doesn't happen to their future child. In a de novo condition, it's really difficult to build the test for the family because we don't have other reference family members who are affected in that same family. So those kind of cases, the test build in the PGT lab is usually on a case to case basis. We can't guarantee that the test can be made.

And sometimes, the risk is so low for recurrence that their family may not choose to do it.

Susan Hudson MD (40:44)

I know we recently shared a patient that had a, I believe actually an autosomal dominant mutation. And fortunately it wasn't one that had caused her much issue, but because she has diminished ovarian reserve, this particular couple decided not to move forward with PGT-M testing because they're like, well, we know we kind of have an uphill battle on just creating enough embryos to hopefully give us a family.

I've lived with this condition my whole life and it hasn't caused me that much issue. And after counseling with you, they decided, hey, we're just gonna move forward.

Dr. Mili Thakur (41:20)

And I think that's the big factor that we provide in Genome Ally with me being on both sides of things. So I see the genetics aspect of it. So we know how bad that disease can be or what it can do. We understand what the family is requesting. But on the other side, by being a reproductive endocrinologist, I know that we have to work with their egg reserve and what they have for their partner's sperm and how many cycles can they afford because if we are testing for multiple conditions, then you have to also be ready for needing multiple cycles sometimes, one cycle might not be enough.

Abby Eblen MD (41:55)

Correct me if I'm wrong, but I think most of the expanded carrier screening tests that we have available as reproductive endocrinologists generally, as you said, look for X-linked traits or recessive traits, but not so much autosomal dominance. So those are probably people that already come to you because they already have an infected family member, correct?

Dr. Mili Thakur (42:11)

Yeah, so either they will have an affected family member. So those are conditions like Huntington's disorder or frontotemporal dementia, those kind of conditions, or they are personally are affected. They have the manifestation of the condition. So say they have achondroplasia, which has short stature. It's very obvious that they have the disorder, but now they're trying to see if they can prevent that mutation from passing on to a child.

So in those patients, we're still able to build the test.

Susan Hudson MD (42:41)

So Abby, one thing you may have noticed, I've definitely noticed in the last few years on our big panel, sometimes our results will come back and it'll be like, well, this gene may be linked to either an autosomal dominant or autosomal recessive disease because it wasn't something that has affected them yet or had such mild manifestations, that's when things like, going to go see somebody like Mili is very helpful.

Dr. Mili Thakur (43:10)

I also want to point out all of your cancer risk genes, all of the inherited cancer genes like BRCA1 and 2 and PALV2, all of them are autosomal dominant. So one in an autosomal dominant condition, that individual themselves are at risk of manifesting the disease without having the other copy of the gene having any sort of mutation. And one in two or 50 % of their children would be at risk of getting that mutation.

So a lot of families that we see as a fertility specialist now are also coming in for those kinds of autosomal dominant inherited cancer conditions. Now we had also doing egg freezing, right? For these families, for individuals who are at risk for cancer, chemotherapy effects and stuff. They also want to look for those conditions if possible in the embryo, if they're gonna create embryos.

Abby Eblen MD (43:46)

Yeah.

Well, very good. One last question I had for you is what you do, it mostly covered by insurance or not covered or can you make a generalization about that?

Dr. Mili Thakur (44:11)

So for our practice, we have chosen to stay as a self-pay practice. And the reason for that is that we want to give access to care to patients and we want to be quick. So what we usually will do is we will see my consultation would be a self-pay price to them, but then we will work with these labs for ordering their testing. So if I am ordering genetic testing on somebody, that will go through their insurance through the proper prior authorization process.

And then now we are seeing that a lot of these fertility benefits companies are also covering genetic testing, whether it be off the embryos or be off like carrier screening, because those employer-based fertility benefits, are actually looking for making the life of the employee better and healthier. So some of these options actually prevent them from having major health issues later on or their children having health issues. So, I think we are seeing a pretty good coverage of all across the board of acceptance, but still I would say, the important thing is for the IVF doctors and the OBGYNs, all women health doctors to ask patients those questions of like, is there anything else in your family that you would like us to address? And even if they don't have anything that's specific in their family, they can consider carrier screening. That's one of the first screens that they can go through and talk to their doctors about the reproductive risk. And we are happy to see them answer questions, all different types of options. And then if a test needs to be built, we'll help that. And then also for recurrent pregnancy loss, making sure that we do enough testing at that so we can get answers and not have a loss next time.

Abby Eblen MD (45:52)

Well, great. Well, thank you so much. This has been so informative, I know for our audience and for us as well. So thanks for being with us today. To our audience, thanks for listening and subscribe to Apple Podcasts to have next Tuesday's episode pop up automatically for you. Also be sure to subscribe to YouTube. That really helps us spread reliable information and that helps us get to as many people as possible with this information.

Carrie Bedient  MD (46:14)

Visit fertilitydocsuncensored.com to submit questions and sign up for our email list.

Susan Hudson MD (46:21)

As always, this podcast is intended for entertainment and is not a substitute for medical advice from your own physician. Subscribe, sign up for emails, and we'll talk to you soon. Bye.

Carrie Bedient  MD (46:30)

This podcast is sponsored by ReceptivaDx. ReceptivaDx is a powerful test that can help detect inflammatory conditions on the uterine lining that might be preventing you from becoming pregnant or staying pregnant. If you have experienced implantation failure or recurrent pregnancy loss, ask your doctor about ReceptivaDx testing. If found, uterine inflammation can be treated, providing a new pathway to achieving a successful pregnancy.

ReceptivaDx because the journey is worth it.