Navigate Your Genetic Landscape For Fertility

Noor Siddiqui

Yes. Thanks so much for having me. I think this is an amazing platform that you guys have developed. It’s an honor to be here and to get to chat.

Aumatma Simmons, ND, FABNE, MS

Yes. What is the genetic testing that’s available on embryos currently?

Noor Siddiqui

Yes. The current type of genetic testing that’s available is called PGT-A. It’s pre-implantation genetic testing for aneuploidy. What it is, you’re evaluating chromosomes. When you think about the genetic code, there are 23 pairs of chromosomes—just like the company 23andMe —that you might have heard of. That’s what’s referring to your chromosomes. It’s from largest to smallest. Chromosome 1 is the largest. Your sex chromosomes per 23 are the smallest. What PGT-A is telling you is: do you have the correct or abnormal number of chromosomes in a specific embryo? If you have an abnormal number of chromosomes, unfortunately, that usually results in a miscarriage. 

Most of those are not compatible with life, a very small fraction, or with life ones that you might have heard of, like trisomy 21, or Down’s syndrome. You have three chromosomes 21. Again, the reason why it’s compatible with life is because it’s one of those smaller from the 21: on the smaller side versus if you have trisomy 21, just one close of one that’s, unfortunately not compatible with life. PGT-A was the first round of genetic testing that became available. The way that you can think about chromosomes is like a chapter in a book. Do you have the correct or incorrect number of chapters? You want to be able to evaluate something so that you can have the highest pregnancy rate or the most successful implantation when you go to transfer those embryos and move on.

Aumatma Simmons, ND, FABNE, MS

So PGT-A testing is widely offered in the reproductive endocrinology world. I’ve heard some debate around it as far as how useful this is. Are we damaging the embryos? Do you have any thoughts on that?

Noor Siddiqui

Yes. I think PGT-A, or the biopsy or the sample that’s taken from the embryo, comes from a structure called trophectoderm. The trophectoderm goes on to become the placenta. The inner part of the embryo called the inner cell mass, goes on to become the fetus. The edge of the embryo is four to six cells that are taken, and that procedure has been by embryologists over the last 10 to 15 years. You shouldn’t worry about it, your babies don’t have these, and the samples taken are smaller. They don’t hurt as much. So that can give you an idea of how the genetic testing of embryos first started. It started on day three. When you only had eight cells and were taken to a much larger fraction than taking four to six, or 120. The sampling thing much later, yes. Millions of babies have been born that have been genetically tested at the embryonic stage. Those are two; they give folks a little bit of comfort. Then the third piece is just that the cells that are being sampled are from the placenta rather than the ones that are from the ICM that are fated to be the baby itself. 

Just to wrap up the discussion about what types of embryo testing are available. PGT-A chromosomes by assessing chapters. Other types of testing are available. It’s called PGT-M. It’s looking for monogenic disorders. If you go in and say that you have a condition like cystic fibrosis, you can go in and design a probe to look for that one specific gene. That often requires sequencing mom, sequencing dad, and sequencing grandparents. Because what you’re trying to do is grab flanking regions so that you can assess, carry, or not carry that damage or mutation. What we’ve been able to do at Orchid is to move far beyond both PGT-A and PGT-M. PGT-A, we’re looking at chromosomes, which are chapters, and PGT-M to locate one specific gene. There are 20,000 genes; only look at one of them. What Orchids can do is we’re able to do the entire genome. Instead of looking at a tiny fraction of the genetic makeup of an embryo set, both PGT-A and PGT-M look at well under 1%, closer to a 10th of a percent in terms of the amount that’s being evaluated. 

When you do a full genome, you’re looking at over 99% of the embryo’s DNA. You’re talking about looking at billions of letters, or what we were talking about earlier, the analogy of chapters instead of just some chapters, or the table of contents. You’re reading every single letter and doing a spell check on every single letter in an entire book. You’re getting much more data. You’re getting 100 times the data on the embryo. You can think of it. That’s the type of information that you’d be able to get from an adult. We’ve been able to show for the first time that you can get a similar sense of activity, specificity, and accuracy as you would on blood or saliva on that embryo trajectory in the biopsy. 

What you can do with that information is, instead of waiting until, after the baby is born, find out that that child was affected by a certain disease. You can, before that pregnancy even begins in the embryonic state, learn about pediatric and hereditary cancers. You can learn about neurodevelopmental disorders; you can learn about birth defects. Again, all of these have a track record. But over the last two decades, since the human genome was first sequenced in 2000, millions of people have been sequenced, and academic and medical geneticists have been working together to catalog what all these different types mean and how they are associated with disease. What we consolidate are the most severe, catastrophic illnesses that could affect a newborn, during the pregnancy itself as childhood and up to adulthood, depending on how much, that, the parents are interested in receiving.

Aumatma Simmons, ND, FABNE, MS

Amazing. It sounds like whole genome sequencing is so cool on so many levels, the cutting edge of what’s available as far as the information that we can gather. What’s the best used-case scenario? Let’s say couples are going through IVF. We want to do genetic testing on the embryos. What are my options? Why would someone choose whole genome sequencing over PGT-A?

Noor Siddiqui

Yes. Unfortunately, right now 30 million Americans—about 10% of the population—are living with a rare disease, and the vast majority are genetic. Among those 30 million Americans, 95% of these conditions don’t have any treatment options. I would say close to 99% don’t have a cure. Unfortunately, there’s an orphan drug problem where, pharma isn’t motivated to address each of these diseases because, by definition, since their genetic track disease is less than 200,000 people are affected. But if you add up all the thousands of genetic diseases, you get to those 30 million Americans. If you want to think about the context of a baby, between 3 and 6% of babies are born with birth defects or neurodevelopmental disorders that are either diagnosed in the first year or the first ten years of life. 

What’s valuable is being able to get that information at the embryonic stage, because then the couple can decide together: do they want to proceed with that pregnancy with the child? Maybe they have a higher medical need. Maybe they already have a child with high medical needs or the need to, consider how that would affect their license. They may already know that the disorder may already be something that the parents have experienced. or it may be something that they think is too severe, and they want to prioritize another embryo for transfer. But what’s valuable is just having that information earlier and being able to make a conscious decision about which improvement they want to transfer based on the genetic risks that they find out about rather than being taken by surprise, which is, unfortunately, what’s been happening because there wasn’t a way to detect it at the earliest possible time. 

Not developed and to go into the decision of which number to transfer the most possible information to be able to mitigate the most risks, whether what the parents want to prioritize or just birth defects. These are things: congenital forms of blindness, hearing loss, skeletal dysplasia, and meeting babies that have no properly formed skull. or heart. When you’re talking about developmental disorders, these are typically the most severe forms of autism, epilepsy, intellectual disability, or developmental delay. These are typos or genetic variants that are associated with some of the most severe syndromes. That’s just information that we have. When they’re deciding which number to transfer.

Aumatma Simmons, ND, FABNE, MS

For sure. I think it offers, it sounds, it just opens up the floodgates in terms of how much we have access to and control over as far as the genetic destiny of the child.

Noor Siddiqui

Yes. I do it. It’s clear that there are genetic forms of birth defects, and there are also physical forms of birth defects. If mom drinks, there’s going to be fetal numbers associated with that. When we think about whole genome screening, we should be thinking about it as mitigating risk. Reducing the chance of genetic forms of birth defects reducing the chance of genetic forms of neurodevelopmental disorders, and boosting the chance of pediatric and adult-onset cancers. But unfortunately, these aren’t all fully genetically determined. There’s a fraction that is genetically determined. There’s a fraction of such factors as environmental lifestyle and, unfortunately, unknown factors. I mean, science goes on every day, but there’s a frontier of knowledge that’s always expanding, but we don’t have knowledge for all of these. Of course, it’s important to just frame it in the context of, This is 100 times the amount of information. There’s a huge amount of risk that you can mitigate. But it’s still not, even though you have the whole genome.

Aumatma Simmons, ND, FABNE, MS

Yes. In terms of the controversy between genetics and epigenetics, To a certain extent, we have genetic predispositions. But then our nurture and nature-nurture controversy. If we want to go back to the days when our lifestyles impacted genetics, how much of that do you see as important to mitigating risk from the beginning versus, This isn’t a genetic thing? It’s just something that you’re going to need to regulate through your lifestyle.

Noor Siddiqui

Yes. when you think about the monogenic panels, Orchid screens for over 1300 genes that are definitively associated with severe diseases. One of the ones I would say parents are most interested in is autism. These are very severe forms; typically, there are other symptoms as well. Seizures and other types of development are highly penetrant. Meaning if you have this variant, you unfortunately have that syndrome. Similar to the genes that are looking for birth defects, pediatric cancer, or other developmental disorders outside of autism. Those are kinds of aneuploidy or abnormal chromosomes, where if you have an abnormal trisomy 21, that’s Down syndrome. There’s, your epigenetics are going to be able to, get you. Epigenetics plays a larger role, which I would say, is not on the monogenic side of some diseases but on the polygenic side of diseases. 

With full genome sequencing, you could use something called a genetic risk score. This is a way to quantify genetic predisposition to disease in a way that is a little bit more foggy. Previously for genetic risk, because you would just say, Do you have a first-degree relative of a disease? then they would calculate, okay, empirically, you’re at this higher rate of disease, but they weren’t able to raise it specifically to you. To make it more relatable, you might know a family where one sibling develops breast cancer, diabetes, or a heart attack. The other one doesn’t. That’s similar to the setting of IVF, where you have multiple embryos, but one embryo, by chance, has inherited more risk or a higher genetic predisposition to disease than the other embryos. That’s what the genetic risk scores can reveal: yes. I think, are you South Asian?

Aumatma Simmons, ND, FABNE, MS

Yes, I am.

Noor Siddiqui

Yes. We’re both South Asian and unfortunately, we get heart disease about 10 years older than any other ancestry. We’re twice as likely to die from, so even within, even when you, either from an S3 perspective or as an individual, have a disease like schizophrenia or bipolar that doesn’t have a single but is driven by the cumulative, yes, I go from dozens to thousands of variants. You can learn which embryo has a higher or lower genetic risk, but you shouldn’t think of it as a diagnosis in the same way that you would with Down syndrome, because it’s more of a risk factor for smoking. 

If you smoke, that’s not a diagnosis of lung cancer. It just means that you have a much higher risk of developing lung cancer. Similarly, certain people or embryos inherit more risk variants from both of their parents just because they just got that embryo. If the parents are in the position where they have multiple embryos, they have a choice of whichever to prioritize, they may consider prioritizing an embryo that has a lower genetic predisposition to a specific disease, either run in the family or that they might be affected by.

Aumatma Simmons, ND, FABNE, MS

If an embryo has low genetic variants, did I say that correctly?

Noor Siddiqui

You can think of it as a percentage of the genetic risk of the parents, and maybe they are. One might be in the 60th percentile. One might be in the 98th percentile. One group could just get lucky and be in the 90th percentile, the other in the 70s, and the 60th in the 50th percentile. This is a lifetime risk for that disease. One embryo might have a 36% lifetime risk for breast cancer, and it might have an average of 12 to 13% lifetime risk. It’s basically when you have a family history or are at a higher latent genetic risk. But there are still differences between the embryos; there are just differences in you, and you’re something who develops the disease. Some of that is controlled by genetics, and some of it is controlled by cell factors. It also depends on the disease rates for something like schizophrenia or bipolar. There’s much less known about mitigation factors in terms of okay changing, diet changing, or exercise, and how that might delay or reduce the onset of that disease is much more driven by genetics than if you have type 2 diabetes, which has a much larger impact on avoiding that disease, even if you do have a higher latent genetic risk for it. 

Aumatma Simmons, ND, FABNE, MS

Yes. I’m trying to sift through all of it because it’s all very new to me. But I’m very excited to talk to you about it. In terms of PGT testing, at least my understanding of it, which is very rudimentary, is that it helps determine which embryos are likely to have the best chance for implantation and full-term development. Would all genome sequencing be able to give that information as well, or do people just need to start doing both? 

Noor Siddiqui

Yes. Sequencing is the maximum possible information that you can get. Every other type of testing is a subset or a smaller ratio that holds. When you, or can you get you to do the whole genome? You find out about your chromosome count. But make a duplication of deletions. You don’t need to design a new probe for PGT-M. If you’re looking for a specific familial variant that you’re looking for, are you looking for BRCA? If so, you don’t need to sequence relatives or any other parent because we’re sequencing that embryo directly. What’s interesting is that sometimes people find out information about themselves from their embryos. A parent might not know that they carry a cancer risk variant by sequencing their embryos, one thing that one of the partners carries carries a risk. 

Of course, just to be clear, all that counseling happens upfront We have a genetic counselor discuss the implications of holding and sequencing on the embryos so they can request any amount of information, so they can request just PGT-A or just a chromosome count. They can request a monogenic screening for those severe infant early-onset diseases, which would be neurodevelopmental disorders, autism, and birth defects. They can all ask for just pediatric cancer. They can ask for pediatric and adult scores, and then they can extend it to also include those polygenic risk scores, which aren’t binary in the sense that if you have that, that doesn’t mean the child is going to be affected. It means that there is an elevated risk. Any amount of information can be requested, and any amount of information can also be restricted. It’s just up to the parents to decide what information is going to be most valuable for them. Most of the people today who are or who are using it want all the information because that’s how and why they came to us. But certain folks are interested in just the childhood-onset rather than the maternal conditions. 

Aumatma Simmons, ND, FABNE, MS

Yes. Okay. Fascinating. In terms of access to Orchid testing, from my understanding, you guys are the only company that offers whole genome sequencing. 

Noor Siddiqui

That’s correct. 

Aumatma Simmons, ND, FABNE, MS

Can a patient who’s going through IVF request Orchid testing through their clinic or do they go to you directly? How does that work?

Noor Siddiqui

Yes. We’re available at IVF centers nationwide. But so you can ask the doctor for it. But we do recommend that you just contact us directly so you can go to www.OrchidHealth.com and you just meet with one of our genetic counselors. You talk about your situation, and you get up expectations around. What you can learn, you can see in a report, and then, depending on where you live, we can recommend an IVF center near you. If you’re already at one, we can usually onboard that IVF center if they’re new to the technology. You should just plan on that being, from 2 to 4 weeks for us to onboard a new center that we already have. But we’re already, I would say, the vast majority of IVF centers, just, I guess, by metro area.

Aumatma Simmons, ND, FABNE, MS

Amazing. This is so cool. It’s so cool. I’m a little science nerd at some level. Even though we do a lot of natural functional medicine, this area of progress is just mind-blowing. It’s exciting that you guys have this and that people can access this level of information before a child is even fully born or conceived.

Noor Siddiqui

Yes. No, I think it’s valuable information because it doesn’t always have to be that you’re choosing one embryo over the other. Sometimes it’s just the case that, if you’re able to avoid a diagnostic odyssey, Unfortunately, newborn screening is becoming more common. But, unfortunately, a lot of the time, symptoms will emerge sometime in childhood, and then they’ll just pop from specialty to specialist and get different treatments. Sometimes those treatments will aggravate rather than alleviate because they don’t understand what the root causes are. Even being able to know what could potentially affect a child at that earliest possible stage can avoid all of the misery of seeing a child with, say, five seizures to 10 to 100 seizures a day because they’re not getting what they need. 

Yes, we’re excited about it because it’s just that knowledge is power. Being able to treat symptoms that emerge. It is just huge. Some of these, unfortunately, are fatal. Saving your family from that heartbreak is powerful because a lot of times people are going through IVF. You’ve had multiple miscarriages; you might have had a stillbirth; you might have had a child with a severe disease. Being able to avoid the genetic components. Huge. But, even in the case of just being able to be alert for potential symptoms, it can also be super valuable for families.

Aumatma Simmons, ND, FABNE, MS

Valuable. I know you said your website is orchidhealth.com. Are there any other resources or things that you want to share with our audience that they can find and connect with?

Noor Siddiqui

Yes, we’re on Instagram, I think, @orchidinc, and Twitter, Orchid Inc. as well. We also have a podcast series where we have a lot of different genetics experts and fertility experts. A lot of different folks come and just talk about the experience and how genetics can impact your life, either during pre-pregnancy planning during the embryo stage or as an adult. There are some nice education resources that we have, just depending on where you are in the process.

Aumatma Simmons, ND, FABNE, MS

Yes. Beautiful. Well, thank you so much for joining us today. This was awesome. Thank you for sharing all of the amazing work that you’re doing in the genetics world. We’re happy to have you here.

Noor Siddiqui

Thank you so much. It’s such an exciting conversation and a cool platform. Thanks so much for putting this together.

Aumatma Simmons, ND, FABNE, MS

Yes.