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Overwhelm. Anxiety. Cases that stay with you.
That’s how some of the field’s most experienced professionals describe genetics in reproductive medicine today.
In this episode of Inside Reproductive Health, we brought together leaders from RMA, CCRM, Shady Grove, and GeneScreen to talk about the genetics overload in modern ART.
They talk with Griffin about:
The liability landmine that genetics has become
Why one lab’s “positive” is another lab’s “negative” (The Panel Paradox)
Real cases where rare findings blindsided experienced REIs
Smart strategies to stratify counseling (Without missing critical risks)
The growing complexity of third-party reproduction
The coming wave of whole genome sequencing and polygenic risk scores
This isn’t a high-level overview. It’s a blunt conversation about the real risks, broken workflows, and what’s coming next for your lab and patients.
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Kate Devine (00:00)
We are responding to patient demand in genetics and living in a world where more is more in many ways, not just on carrier screening panels, but we're entering, I think, into an era where our patients are going to be requesting whole genome sequencing of their embryos and so on. And so we are in a challenging place where we're using tests that are probably more than our patients need. And then sometimes not clearly even understood by anyone in terms of what all of the results mean.
Griffin Jones (00:42)
Overwhelm anxiety cases that stay with you. These are some of the words I heard while learning about how fertility professionals are drowning in seas of 700 plus gene panels, variants of unknown significance, and patients are now starting to demand whole genome sequencing for their embryos. We've assembled an all star panel Dr. Shefali Shastri from RMA, Dr. Deb Keegan from CCRM, Dr. Kate Devine from Shady Grove, and Jill Chisholm from GeneScreen.
That's US fertility, IVIRMA, CCRM, wrapped on one podcast. It's actually probably Jill and the GeneScreen people that deserve the credit because GeneScreen was clearly the bonding agent. They're all using them. They all have a lot of positive things to say about GeneScreen, but let's pretend it was me. Pretend I was the reason four very busy people from very different companies contorted their schedules to have this conversation. We talk about the liability landmine.
Why genetics has become ART's biggest source of risk and how clinics are protecting themselves. The Panel Paradox, why one lab says a patient is positive while another might say it's negative and what to do when that happens. Smart workflows, how top clinics stratifying genetic counseling to move patients faster. smart workflows, how Shady Grove is Stratifying Genetic Counseling to Move Patients Faster Without Missing Critical Risks.
The rare case trap, real examples of one-off genetic scenarios that blindsided experienced REIs. How third party reproduction has become a genetic counseling maze, and the coming tsunami. I hold genome embryo screening and polygenic risk scores are about to change everything. This isn't your typical genetics overview. It's a jam session about the messy realities of practicing reproductive medicine in the age of genetic information overload.
Deb Keegan (02:43)
fastest advances in change I've seen, I think, since I started this about 20 years ago. The complexity, the amount of information that we as providers and patients need to distill to understand what their risks are.
what the testing means. So if we're gonna talk very concretely, I would say, use an example, like when I had my first child 22 years ago and 23 years ago was getting tested, all they offered was cystic fibrosis because I was a Caucasian, right, of Caucasian ancestry. By the time I got to my next kid, almost two years later, they added this thing called Fragile X testing.
And that was, she's 19. Now, 20 years later, there are panels that are screening for 700 plus of these genetic mutations, right? That, you know, if we identify, we can act and prevent the transmission of diseases. So going from two to over 700 and what that means and what the severity of the diseases are and what the impact is,
It overwhelms me on a daily basis because if you think about the patient load we're all seeing and how many people are getting tested and what the current recommendations are and keeping track of those recommendations because they do differ between different bodies, different guidelines and recommendations. think tracking that information and understanding the impact of the results has changed a lot because many, many years ago we really just didn't do it.
That would be my biggest thing is just being overwhelmed by how much information is there and what to do with it.
Griffin Jones (04:31)
Shefali, you're nodding your head.
Shefali M Shastri (04:33)
Yeah, so well, first of all, I'm thrilled to be here with all of you. And, you know, just to sort of ditto what Deb was, you know, articulating. I think that the expanse, the depth of genetic screening that's available today is amazing. I mean, I remember probably like 15 years ago, early in my practice, I remember seeing a few couples who had come to see me after they had babies or young toddlers who had passed away. And at that time,
unknown reasons they couldn't identify after going to every pediatric top pediatric hospital in the country, they couldn't identify the cause. And when they presented, you know, a few years later, when they were able to come in for fertility treatment with a simple carrier panel, we were able to identify what happened previously. And so to me, that honestly was the, I think one of the biggest realizations in terms of the power of a carrier panel and what it has today in genetics.
⁓ And then on top of that, obviously in our lifetime, it's amazing where we went from day three embryo transfers to blastocyst transfers to PGT testing. And now it's not just single gene testing or gender, you know, ⁓ selection to reduce the chance of disease transmission, but it's really, you know, developing probes for single gene diseases. And obviously we can talk so much more about ⁓ what's on the horizon in terms of
know, next gen sequencing and, and, you other capabilities. Um, but it's pretty, you know, in our, and I feel like in our lifetime, our careers, genetics has been the, has propagated us forward so much and helped us sort of realize, um, the ability to have not just a baby, but a healthy baby, healthy baby, healthy mom. Um, and you know, it's a reality for the large majority of our cases.
Griffin Jones (06:18)
You mentioned that it's overwhelming, Deb. What's the overwhelming part that you're not sure what prognosis or excuse me, maybe what plan to pursue or that there's ⁓ a thousand different options that someone could take? What's the overwhelming part?
Deb Keegan (06:35)
I think the first thing I think of are the number of diseases that we can track, that we can test. And I don't know the names of most of them, right? So I'm ordering these panels and there's hundreds of things on them. And when they come back, what I'm really looking for is, you know, is the patient, what is the patient positive for?
what is the partner positive for, what is the donor positive for, right? I'm looking specifically at reproductive risk, but there's probably so much more that I'm not thinking about, right? It seems like it should be so much more complex than that. And so the moving parts too of helping the patient understand in the event that they are at a higher risk. And hopefully we'll talk about that later.
Who's best equipped to help guide those patients? Who is most informed to answer the questions about impact of disease and what if I do this and what if I don't? Who can talk to someone who chose a donor where the donor wasn't screened necessarily for a similar mutation? And then there's the whole question of
how the mutations were screened. Were we looking for the most common mutation or was it sequencing and the existence of different panels too that aren't always the same? I think you guys get what I'm talking about, right? So the nuances in the testing themselves and what that means for the results you get, because I've had patients where somebody screened positive on one panel.
but not on the other. And then when we retested them on another panel, they were positive. So like, who's choosing what? maybe somebody can shed some light on that. are there so much variance in the different panels that are out there? 400, 500, 700, this gene or not this gene? That's overwhelming to me.
Griffin Jones (08:35)
Kate, how do you deal with that?
Kate Devine (08:36)
I couldn't agree more.
And you know, at the end of the day, the American College of Medical Genetics is recommending, you know, their tier three panels that have 97 disorders tested, which, you know, that is an evidence-based recommendation, but We are responding to patient demand in genetics and living in a world where more is more in many ways, not just on carrier screening panels, but we're entering, I think,
into an era where our patients are going to be requesting whole genome sequencing of their embryos and so on. And so I think that the timing of this podcast could not be kind of more timely in that we are in a challenging place where we're using tests that are probably more than our patients need. And then sometimes on the embryo genetic side, really sort of not
clearly even understood by anyone in terms of what all of the results mean.
Griffin Jones (09:36)
Dr. Keegan asked the question, why is there so much variance between panels? Let me tackle that question by phoning in my phone a friend, Lifeline. Jill Chisholm, why is there so much variance between panels?
Jill (09:45)
⁓
So I think the issue is that there's different labs that do different things. And so some unmask certain things and some don't. So it's not so much that each lab can't actually run these mutations. It's that some choose to unmask certain things and some don't. A lot of it could be cost to the lab where they can run certain things to such level of detail. And then they have
Some that have, you know, confirmation, what's the Sanger sequencing to make sure that their actual results are reported accurately. Some use next gen sequencing to confirm next gen. So it's just different ways of confirmation, different, how they run different mutations. So I think that also can lead to results being a little different. Also in terms of variants.
you know, there are so many different variants of undetermined significance that we don't know about. And so when we are looking at the whole exome, whole genome, we have to deal with a lot of these unknowns, right? Where we have these variants that are change in the gene, but not necessarily a pathogenic or benign mutation. We don't know that yet. So we, there's a lot of still research that needs to be done. And I think that these targeted panels that we're using,
Deb Keegan (10:43)
Okay.
Jill (11:01)
I just think some labs will report certain things that others won't. And so it becomes a little challenging. And then some will do smaller panels and some want to do the largest what we should be focusing on is really what is clinically significant to the patient or what's medically actionable. And so I think a lot of times that what we're running sometimes isn't always actionable. And so it becomes a challenge.
⁓ but I, but I do feel very strongly in what Kate and Deb and Chef were saying, which thank you all three so much for being on. I'm excited to have you guys. You've always been like such, big supporters in genetics and to be honest, ⁓ no more than you all think, because there's a lot of out there that there's a lot of unknowns and you guys are always so knowledgeable. but what I, what I think is going to happen is, ⁓ as kind of Kate mentioned with the whole exome whole genome on embryos, actually think at birth, we're going to start to see.
more babies just being, you know, they're going to sequence ⁓ the genome and we're headed in a direction where I believe it's just going to be coming more mainstream ⁓ where everyone's going to want more and we're going to have more. So it's important that we look at that and make sure we know who's interpreting those.
Griffin Jones (12:06)
What?
For those doctors that have had that experience where one panel says that someone's positive for a particular disease and another one says it's negative, what do you do in that situation?
Kate Devine (12:22)
I mean, I think in general, we consult our friendly genetic counselor and depending upon the ⁓ size of our clinics that may be somebody in-house for, you know, clinics, larger networks, maybe a clinical genetic counselor who is, you know, in clinical practice outside of one's own institution or, you know, it might be GeneScreen because there are services
Shefali M Shastri (12:26)
you
Deb Keegan (12:28)
you
Kate Devine (12:48)
available thankfully that are remote and easily accessible and highly expert. so genetic counselors can help us determine whether again, as Jill was just saying, the result is clinically actionable. Sometimes when it's positive on one and negative on another, the reason is that a certain testing company has chosen not to include that variant in their reporting because it has very low clinical penetrance or low
Shefali M Shastri (13:06)
you
Kate Devine (13:15)
clinical significance and maybe that patient just needs to be counseled that that PGTM isn't really indicated for that particular variant or mutation in combination with the sperm source as the case may be.
Deb Keegan (13:28)
And Kate, that goes back to what you said about if we look at guidelines or what's recommended by the ACGME, why are we doing those then, right? Because a lot of those mutations that are not clinically significant or that have variable penetrance and we don't know what it means, and you said it yourself, nobody necessarily knows. It causes a lot of anxiety, I think, for patients and providers.
to come up positive on these things. And we're like, yeah, well, you're positive and we don't really know what that means. So I do think often about, this expanded as expanded as it's become, what are we creating on the side? Like what is the collateral damage to the patient and furthering our understanding because
And there is because we're so caught up in a lot of things that maybe aren't clinically significant. Right?
Griffin Jones (14:22)
Are all
three of you GeneScreen fiends? Do all three of you use GeneScreen or just Kate?
Deb Keegan (14:29)
No, we do. We do.
Griffin Jones (14:31)
Tell me how you use them.
Shefali M Shastri (14:33)
Yeah, so we have, so at RMA we have a small in-house genetic counseling team who really works primarily with our single gene cases. So our patients who present or who are found to be carriers at high risk for a single gene disease and who will be, excuse me, utilizing IVF with PGTM. And so we just, and we put that into place more recently to mitigate risk just to make sure
Deb Keegan (14:36)
Okay.
Shefali M Shastri (14:59)
Everyone's on the same page. There is counseling prior to the actual PGTM probe development IVF cycle. And then once we get the results back, prior to embryo transfer. And so that's really what the focus of our in-house counselors are for. We use GeneScreen for all of our, for the most part, for our routine counseling. And we really highly, highly recommend that every patient and partner undergoes
extended carrier panel screening. And so, you know, I don't think that you can offer something like that without having a counseling session to review those results. And to Jill's point and to Kate's point, there are a lot of nuances, there are a lot of gray areas that come up. in order to, you know, we don't want to overwhelm patients with sort of background noise, but we want them to really understand what's relevant and clinically what's going to make a difference in their care. So that's how we utilize, you know, genetic counseling in our practice.
But I have to tell you, I think it's definitely a work in progress. It hasn't always been, you know, as such, and I think we're continuously growing. So we currently have two genetic counselors in-house for all of our PGTM cases. We also work closely with Juno, and they have their genetic counselors. So I think that the genetic counseling component is so important if you're offering this type of technology and treatment.
Griffin Jones (16:17)
You recommend that extended panel for all patients, Shefali? How common is that and why do you do that?
Kate Devine (16:17)
Yeah, and we recently.
Shefali M Shastri (16:21)
We do. We do.
We do that primarily because the way I'll counsel my patients is this is something that's available and this is something that we highly recommend. If you're going to be going through all of this treatment, ultimately, I want to give you your best shot of having a healthy pregnancy, healthy baby, healthy outcome. And so if there is something as basic, I think that 15, 20 years ago, sure, let's test for the basic fundamentals, cystic fibrosis.
at SMA, at Fragile X. There's so much more available today. I also think when you talk to our patients and you think about an individual or a couple that's going through IVF, they're thinking that you are doing everything. You've done all of this, so I'm going to have this perfect outcome. And so that's not reality, right? And I always try to bring people down and say, hey, listen, once you get pregnant, unfortunately, anything can happen. Our goal is to try to mitigate your risk, to give you your best chance of having a healthy outcome.
And part of that risk mitigation is having genetic care panels on. Let's get some more information. I always try to couch it as, let's do this screening test, let's see what we find. You'll have a conversation with the genetic counselor to review this in conjunction with your family history. If there's something that comes up that's uncovered, we'll talk about it in more detail. So we recommend it really to give our patients the best outcome.
Kate Devine (17:41)
you know, I agree with everything you said, Shefali. That said, we've taken a little bit of a different approach of late, actually working with GeneScreen in that, you know, there's the risk to our patients, right, of course, and that's the reason we're getting and recommending these panels in the first place. There's also risk taken on by the physicians and the clinic, and actually, I think we'd all agree that genetics and all of its
uses in ART is sort of our biggest source of risk, actually. And while we need to make sure that our patients are well-counseled in response to these results that come back, you know, we've sort of taken it onto ourselves to counsel patients about their every type of genetic risk that could possibly exist. And that wasn't really always the case. And when we decide that that's our responsibility,
we take risk on ourselves as well. And so this is something that we've thought about a lot and kind of struggled with. And the other piece is that to mandate genetic counseling for every single couple slows patients down. And as we all know, all of our patients want a baby yesterday. And so when, for one thing, they come back and they're not mutual carriers on a panel that has four, five, 600 disorders on it, as we've discussed.
then they have to wait for an appointment while they may be able to get in relatively quickly with some of the services we've already discussed, you know, then they may have to start their IVF cycle, one menstrual cycle later, which is a source of disappointment for them and also may induce extra costs. So we've actually taken an approach where we have gene screen review for us, all of our results, and we have a
low intermediate and high risk stratification. And for patients who are low risk, they receive that result as low risk that's been reviewed and signed off on by a genetic counselor. But then the couple needs to sign off on their residual risk. So we have a residual risk acknowledgement that they understand exactly as you said so eloquently, Shefali, is that, look, we can't promise you that your baby's going to be healthy, have no medical problems, have no genetic problems.
But this result really has not indicated any increased risk for you. And so it's a green light to proceed once you acknowledge, again, your residual risk.
Deb Keegan (20:02)
I think that is an incredibly efficient approach, especially given all that we're talking about as the results come flooding in. We're pretty similar in that we counsel and offer expanded carrier screening to everybody. We don't require it. If we find that the patient has, for whatever reason, they don't want to proceed with it despite our counseling, before we...
them, we will bring in the genetic counselor to talk to them about what that means to decline it. What could they be missing? So there's that piece that we use GenesCrene for too, because ultimately what we do every day is share decision making, right? And there is patient autonomy that needs to be considered and respected. But if I'm not getting through pointing out the things that we feel are important to mitigate risk.
then we at least have them agree to see a genetic counselor to talk about it further, because I think that expertise might help them understand better. We're not trained to do that. So that's one way we add, ⁓ you know, Gene Screen in to help us, patients that just don't want to do anything. Regarding our PGTA and and who does the counseling, we have in-house at CCRM,
headed up by Mandy Katz-Jaff in the reproductive genetics lab. So her team helps with A The carrier screening pretty much is mostly through GeneScreen. And GeneScreen is able to see our results. They interface with our resulting labs, and then they reach out to the patient and they do the counseling session and we get that report.
And it is stratified in that way. And anything that's flagged that needs further discussion with physician or plan, it's very clearly outlined and discussed and kind of moves up to the front of the line. So that if you need to do PGTM or something like that. So many ways we're using gene screen because we don't have in-house genetic counselors per se hanging around like RMA does.
to where heavily rely on Jill. Thanks, Jill.
Griffin Jones (22:10)
Kate, you said that genetics in art is the biggest risk in art or something like that. What was it that you said and unpack that please?
Kate Devine (22:17)
So in terms of the risk that we take on by, for example, telling our patients they need an 800 mutation or 800 disorder panel, is that we then need to be able to interpret it appropriately and explain it such that if they have a child that's affected by something that we should have known that they had risk for and didn't appropriately explain to them.
you know, then that's actionable on the part of the patient. If they have a sick child, it's a tragedy as well. And so the more that we send and even discuss in terms of patients' familial and actual genetic risk, the more the clinic is responsible for. And so we really do need the help of genetic counselors in the position that we're currently in. Some of us deal with this by, for example, and Jill mentioned this earlier, unmasking.
using the kinds of panels where all of the information is there for pretty much all of the disorders that any of the panels have, but we don't report everything and we're able to unmask, for example, in the setting of if they have a sperm or egg donor that has mutation that they weren't originally reported on. And that's a very nice way to keep the panels a manageable size, but also
be able to access that information if we need it. And again, a huge source of risk is having the wrong staff members being tasked with reviewing these results. And so when one thing that we really wanted to solve for in our protocol is that we have our genetics, our carrier screening lab do one pass. So they do again, an automated review.
they identify mutations that are not just carrier-carrier, but also carriers at risk for symptoms, know, manifesting carriers, some people will refer to them as, and also then having a live review by a genetic counselor. So by the time it's reviewed by, for example, a medical assistant or a nurse, or even a physician that might not have, you know, as none of us do, perfect genetic knowledge, it's already been twice reviewed.
so that we can't miss something that could potentially impact these patients or their child.
Griffin Jones (24:29)
to move on to PGT in a second I want to stick with care screening for the moment what are the consequences that you see that come from these risks
Jill (24:39)
Yeah. I think, you know, I feel for the REIs and the IVF docs, I feel it's tough. They're getting these like patients that have gone through OB-GYN, some of them haven't had carrier screening. And so it kind of gets dumped on when they're ready to have a baby. And they want like, as Kate mentioned, they want to have a baby tomorrow. So it becomes challenging because it really has kind of like should be done earlier on in some ways. And then it becomes a
Kate Devine (24:40)
it.
Jill (25:05)
know, mad rush to get things done. And I will say one of the things that I, you know, I do pride myself in being able to do having an experience of an IVF background is knowing that there's a workflow that needs to happen, that needs to go quick. We can't delay these cycles. They want to have these, these are very anxious patients. so the reason we created the model that we did, and I think Kate's model even of mitigate, stratifying the risk and mitigating
still be able to mitigate risk is helpful because it allows people to get through the system a little faster. And so we can also still have a live genetic counselor's eyes on it, which is really important because you just don't want that to get missed. So I believe that that will be helpful in getting patients through. And I think our technology, we've been able to, while we have in-house counselors that are amazing and...
great, as everyone mentioned, they can't always see everybody, right? So we have to find a way to make sure everybody has access, not just because we don't know. And so I think the answer to that is everyone having access is where I've seen where you might've thought that somebody may have been a low risk patient that we've now determined from when we looked at everything that maybe they're a little bit higher than we thought. so a couple of incidents, I mean, I'll give you one case which was very interesting and I...
I still think this is a valuable lesson in terms of where we can incorporate potentially more technology to build into some family history. But we had a patient that had Lynch syndrome, risk of colon cancer, developing colon cancer herself. And so when we met with her, we just kind of talked about, and this is the downside of eliminating hereditary cancer, which I don't think is our problem.
⁓ when it comes to your reproductive risk, except for now there's PGT that you can do on the embryos for this. And so when we were meeting with this patient, we turned out, we let, checked the partner. The partner said, I, by the way, have my father died of colorectal. We tested him for Lynch syndrome. And as it turns out, they both were carriers now in, a, in a world of dominant disorders, you think, okay, well, they both have a risk of developing.
you colon colorectal or for the female, you know, uterine ovarian or colorectal with Lynch syndrome. Both of them being carriers though cause what's called CMRDD, which is constant mismatch repair syndrome. And that actually one in four chance one in, sorry, children usually have a chance of a recessive. It's a turns into a recessive condition where they can have a childhood cancer by the age of 10. So in, and they have cafe au lait spots, they have some, symptoms. So
when this couple went back and they looked at their child at home, that they were in for secondary infertility. So they already had a child at home. When they went back and they looked at their child at home, they said, you know, she has these spots, let's get her checked. They went to an oncologist. Turns out she does have CMRDD. So it ended up being where they were able to put her into a protocol and just understand now what was wrong with her all this time. And then now do PGT on the embryos for Lynch syndrome. So.
I know it's a rare and unusual case and we do have some of those that are very unusual, but our goal is to figure out like, you where those little gaps are. And I do think that ⁓ one of the other things I feel very good about is that since we have come in to give access to everybody, we feel very strongly that we've mitigated risk for a lot of practices.
Kate Devine (28:24)
Thanks.
Jill (28:36)
They came to us, there was some issues and then now we felt very strongly that we haven't seen that in a long time. So we're hoping that like just stay on top of these things and really just going with the, with the, trying to understand a little bit more about how we can build in technology and tools with AI potentially, or things that can help assist us to get to that level quicker so that we can move these workflows along. Because the goal is not to have these.
patients not wanna have their consultation, not wanna see somebody. And I understand that you're going through fertility. You don't wanna have to talk to a genetic counselor for 45 minutes. It's like the last thing you wanna do. So I think there's ways like we built with Kate, which I think has been great. I'm excited about it. Hopefully that we can build in some more even family tools around that, that maybe we can even identify maybe some more challenging patients like you said, that could be a risk that we miss.
Griffin Jones (29:29)
Jeff, the example that Jill just told about Lynch syndrome, is that something that most REIs or the counseling that comes with most CARES screening panels would have picked up on?
Shefali M Shastri (29:39)
No, so it's interesting. when we talk about, I mean, I feel like we've had a number of like one-off cases over the last 15 years working with gene screen, you know? But so one thing is, so hereditary cancer screening, not routine and standard, especially for fertility practices. We do try, I mean, especially like when we're talking, know, between Kate, Deb and I, we're talking about these three large networks, we have lots and lots of
Deb Keegan (29:40)
Yeah.
Shefali M Shastri (30:06)
practices that are part of our networks. So even our practice patterns may not be consistent from location to location in terms of the medical practices. So we have definitely gold standards that we have tried to confer throughout our physician interactions. So for us at RMA, it's routine and standard that you get a family history. Are we all the same? we all have the depth of our family history consistent across?
Physician to physician, I hope so, but let's see. And so if someone's identified at risk, then what we do at RMA, we have a pretty strict algorithm. That patient should have comprehensive genetic counseling, not just results review for their carrier panel. And the purpose of the comprehensive counseling is to try to identify or prevent cases like this. But part of the problem is as a physician,
I don't know how many physicians would have known about this, you know, the recessive disorder associated with both parents as Lynch syndrome carriers. That's not something that I'm well versed on, and I think I'm very in tune to genetics. It's just, I don't have the bandwidth to keep up with all these mutations and these, you know, manifestations that have been found. And so I think that to me, if you...
Deb Keegan (31:24)
Thank you.
Shefali M Shastri (31:24)
We try to trigger the right algorithm. When you take your patient's family history, if they are high risk or there's a question of anything, we're sending them to comprehensive counseling. Kate, to your point, it does slow things down and it does. So everything is a sort of risk benefit ratio. Like everything in medicine is risk benefit ratio. And I try to discuss that with the patient and counsel that appropriately. don't want to mandate everyone has to do something. But if you're considered high risk and there has to be some way to...
sort of identify that, then you may benefit from this. I mean, we've all seen patients who have regret. Early on, I remember before SMA was part of a routine carrier panel, I had a couple who had two children, healthy, no issues. This patient was now in her 40s. They got pregnant with their third on their own without any fertility treatment. And the baby was born with SMA. If you go through those OB records,
They declined, declined, declined over and over again despite counseling, SMA screening, because it was now standard. And this baby, oh my gosh, God forbid, was born with SMA and passed shortly thereafter. I mean, these cases stay with us, right? And so if you've been burnt once or you've been burnt, you are going to ask those questions and you're going to send them for counseling and ideally screening. So.
Deb Keegan (32:33)
Yeah.
I
had a patient that saw just on TikTok a story like that. And their new patient visit was because they wanted to have genetic carrier screening and counseling to determine their risk before they started, you know, before they started trying to have a family. In my perfect world, a genetic counselor sits in my consults with me and, and, you know, grabs that family history and then does part two.
Kate Devine (33:05)
Thank
Jill (33:06)
Yeah.
Deb Keegan (33:11)
and we determine it right then and there. What do we need beyond carrier screening and do we need to do comprehensive screening and every patient, because we are an entry point. I know that we focus on what is the reproductive risk, but if you think about things like hereditary cancer screening, we talk about mitigating risk for future generations, right? Like where does the responsibility begin and end when we are talking about potential development of disease?
in the families, the kids we help create, right? So my perfect world would be that person or that entity like for every single patient and then the shared decision-making about how far do they wanna go down the road? Do they wanna talk about the cancer screening? Yes or no, right? And I think in that way, we're taking an opportunity to...
to reduce risk in future generations, but also if you pick something up in someone now, putting them in a surveillance program that will help prevent progressive disease, some sort of cancer. So there's a lot of opportunity there, but unfortunately it is not efficient to Kate's point in a reproductive medical setting.
Kate Devine (34:27)
I love that the genetic counselor on your shoulder, know, ideal world. I think that would be great. And also, Chef, it couldn't be more true that it all comes down to that family history. People need to be stratified even in advance of the care screening being sent. And there are some patients that need to have a comprehensive genetic consult, you know, regardless of even their care screening decision.
Griffin Jones (34:50)
The risk benefit calculation is complicated a little bit by another pillar, which is public relations. And there's a sociological phenomenon that the rarer something becomes, the less acceptable it is. And you can think of that in a number of different cases. Childhood mortality, for example. 200 years ago, if you were having five children, two of them weren't living till their 10th birthday and everybody understood that. that...
if that came anywhere close in a population of 100,000 today, we would be up in arms and sick about it. now the same thing can be said in genetics as well. And you talk about how rare these different cases can be, Jill, and they're one-offs. But as Shefali says, there's one-offs that add up over time. And it seems to me like the genetic counselor exists for
this world of one-offs, don't they?
Shefali M Shastri (35:45)
They do. I'll tell you something to add. I know, so offline, we'll talk very frequently with GeneScreen when we get results back. One of the things specifically for these one-offs or to address some of these potential risk cases, internally, we have a team of two three genetic counselors at the RMA Network. One of the things that we established was a genetics ethics committee. And I would imagine you guys may have the same.
And so there are definitely cases where we see these, not just, they started off as one-offs and then you see it every couple of months as we grow and we have more and more patients, we see that result again. And so instead of sending them all to genetic counseling or immediate genetic counseling, PGTM, or scaring the patient or not having an immediate answer, we will, do we require a PGTM? Can we be that authoritative as a practice and say,
you came up as a carrier of X, and Z, you must do PGTM. Or it's your option, whether you do PGTM or not. How do you identify what is mandated, what is not? You don't want to be so paternalistic and you want patients to have autonomy, but what's sort of the right balance there? And that goes, Griffin, when you talked about the risk benefit ratio, we put together this genetics ethics committee that's run by Amber, who is the head of our in-house genetic counseling.
This is for our providers, our medical providers, so we can have a discussion around, have we seen this before? Has this been vetted out before? This, like an example, would be non-syndromic hearing loss, right? There are certain cases that are severe. are certain mutations that are associated with mild. If this has been vetted out before, we have a catalog of scenarios that has been vetted out before. So if you review those results with your patient, they're going to speak with a genetic counselor, but up front, you have information for them.
They're not waiting a month just to, you know, on the sidelines waiting to see what happens. And so that's something else we put into place to sort of address that risk benefit ratio, you know, because we don't have access for a genetic consultation for every single patient immediately.
Griffin Jones (37:52)
We've mostly been talking or we've been talking a lot about intended parents. Jill, how are clinics changing their protocols for donor screening?
Jill (38:01)
So donors are actually where we're the busiest. We have an entire genetic counseling team just dedicated to third party egg donation, sperm donation. We have relationships with all the banks. That has become, that was kind of, that's how like clinics kind of start with us because they really need help with it. They struggle in terms of, you know, the recipient might have one test and then the donor has another. And so they're trying to figure out like, you know, we do,
Shefali M Shastri (38:28)
you
Jill (38:29)
consults where we have to say, well, this is the panel that this you had, this is the panel that she had. So how do we compare those two? And what does that mean? Do you need to be tested for anything more? it what's that risk look like if you had a 283 panel versus a 700 panel plus?
So we have to like look at those in different ways. And I think that's what we do well because we're an independent company where we're not really affiliated with one lab. So by working with all the different labs, we can sort of look at it from a unbiased perspective, sort of say, you know, this is what we think based on those things. I also think, you know, I actually worked with, I started a egg donor program years ago when I first got out, when I started at RMA years ago.
And so that helped me a lot learn about the recipients in general and the intended parents and how stressful that process is not having control over what that donor like their donor, what their genetics are. And so that, that conversation becomes really valuable to them because they are so looking for information on, know, I'm, choosing someone to essentially become my egg donor.
I want to know everything about, you know, their DNA, their background, what their family history. And a lot of times, like, I, would say, like, we would go over something and say, okay, well, she has asthma. And the recipient would say, I have asthma too. That's amazing. like, I'm like, you know, instead of being like, well, could be a risk that now you have more asthma. you know, they kind of felt like they could relate to that donor because they had the same thing as them. And so we learned a lot about like, what is really.
Deb Keegan (40:03)
it.
Jill (40:13)
important to these recipients, why they choose certain donors. And now with banks, it becomes more standard practice where they might want to look at, they see everything ahead of time, but they may just have more questions about it. And then they sometimes want to review more than one donor where they can feel like, okay, I'm looking at this donor, but tell me a little bit about this one. And sometimes we help facilitate those decisions based on, you know,
genetic risk or history or something that might just make them feel a little bit better about one candidate versus the other. So we're very strong in our third party counseling. And I think that ⁓ that has helped a lot with ⁓ allowing us to see the patients also later in the process. that the sort of continuity of flow where we've met already with the donor, we met with in some cases, we then we meet with the intended parents and then we can kind of go through.
you know, what that reproductive risk looks like. So I think there's still a big strong need for genetic counselors in the third party arena. And just going back again, I just want to reiterate like what Chef Kate and Deb said in terms of like having the in-house counselors is actually really great for us because we want to make sure that like our goal is just to, because there's not enough just to have that.
increase that access to care. having over, you know, 55 plus genetic counselors who specialize in fertility, being able to come in and say, can we help? But we also like do talk to the in-house counselors a lot about, you know, how can we, we're working with one right now on how we can build that, as we discussed earlier, a family history ahead of time so that then when they come in, we know which ones we have to see and which ones we don't. So we work with the GECs on that. And I think,
it's helpful to have an in-house that then can then also help us understand the clinic and the workflow while we're also helping get and increase the access and the demand of the volume that comes in.
Griffin Jones (42:09)
For the docs, are third-party cases more complicated than they used to be, or is it just that there's more of them?
Kate Devine (42:15)
So they can be, going back to not to beat the same drum, but talk about a challenge to efficiency. Because as Jill said, here we are in a situation where the world is this patient or couple's oyster now, right? They're able to select the donor and with that, the genetics of that will provide half or sometimes if they're choosing an egg and a sperm donor.
Deb Keegan (42:22)
No.
Kate Devine (42:39)
the full genetics of their potential child. And so I do think this is a place where GeneScreen is a godsend. that they make it easy and that they can review multiple donors that once the patient has really narrowed it down at the same time. And I think without question, every single patient that is using donor gametes of any kind needs to have genetic counseling because there's just so much to it.
almost none of our patients are in a position to really be able to fully comprehend without the assistance of an expert.
Shefali M Shastri (43:12)
I would echo
that though. What I would say is there's so many egg banks and there's so many donor agencies and there's not a consistency in terms of what, know, expanded carrier panel they're utilizing, whether or not everyone gets a karyotype. There's not a consistency there. And so for us, what we use as our sort of, you know, screening is gene screen. We have them, they're the ones who sort of this out.
I also think by having a genetic counselor sort of review all of this, it raises the bar and sets a standard amongst egg banks, donor agencies, et cetera, knowing that these are the requirements or these are, and when I say requirements, I don't mean like rigid. I mean, this is what people want. And so it raises the bar in terms of the screening for donors that are available.
Griffin Jones (43:59)
sounds like the gateway drug might be donor screening and then you're getting in more with carrier screening for the rest of the needs. Jill, it also sounds like you might be doing more with PGT. Tell me about where that's going.
jill (44:13)
so we've been getting approached a lot lately on PGT, specifically for pre and post, because we're finding that there's a lot of ⁓ unknowns for the patients to understand what they're doing and what type of testing they're having. In fact, with carrier screening, we do a lot more, you know, because it's sort of mandated or regulated in some clinics, we just do a lot of the post-tests and interpretation of results.
But with PGT, we're getting asked a lot on the pre-test side of things because they feel that the patients will then understand what process they're going through, whether it's PGT-A, PGT-M, PGTSR, whatever they're coming in for. They also have been, we've been asked a lot to doing pre post counseling for mosaic embryos because there's so many unknowns. And so even though
We understand the risks are low of certain things. I believe it's just important for the patients to have that information and understand what they're doing before they go in just because of the sensitivity of what is actually going on and in terms of the risks to any potential embryo that could happen or for future offspring.
I think the conversation is now being had more. We've built a whole team of counselors, genetic counselors now for PGT. We're learning a lot more that there's some asking us now for doing whole exome whole genome sequencing on the embryos. Again, I think we're still learning a lot. We're still building a lot and growing with it. But we're being asked not just by clinics, but also by PGT labs to help assist with some of the education surrounding PGT in general.
Deb Keegan (45:52)
Yeah, think the pre to your point, the increasing requests for pre had a lot to do with, you know, patients thinking if I do this and it's a normal result, then it's a perfect baby in pregnancy. Right. So I think that has a lot to do with dispelling the fact that PGTA is going to solve every everything. And I think Shefali alluded to that doesn't mean you're not going to have a miscarriage. It doesn't mean you're not going to have a baby that's affected. And to really, I think
educate the patients about what, you know, are there errors in the lab? Are there things that happen after implantation that, you know, produce a different outcome genetically than what we saw in the lab? I think it's very complex. So I think it is very helpful to have those discussions ahead of signing up for PGTA.
Shefali M Shastri (46:38)
I just, think it's really interesting. Like, Kate, I think that's very, I think the way that you guys are stratifying the risk, yeah, I think that's.
Deb Keegan (46:42)
I love it.
Jill (46:44)
Can you guys hear me?
Kate Devine (46:44)
I love
it so much. It took us like a year and a half to sort everything out. This is just like an idea that I had that it's like, know, first patients get upset when they have to do it and their results are low risk or they're both negative, but we need them to acknowledge the residual risk. Otherwise, you know, we're exposed. So.
Shefali M Shastri (46:58)
Yeah.
Absolutely. Absolutely. That's why we
have them see genetic counseling still. And if they honestly refuse or are ready to go and you don't want to delay them, then it falls back on the doc. Then the doc counsels them and documents it. I love that you have a precise sort of layered system.
Kate Devine (47:14)
Yeah. Yeah.
Well, and then it also the
double check of, cause we have had near misses where somebody signs off on genetic results that perhaps it's an X-linked, they're an X-linked carrier or something like that. And the whomever was looking at it didn't realize, they're not carrier carrier green light. And there that's imposes a tremendous amount of risk for a sick baby. ⁓ And so to have the, you know, two
Deb Keegan (47:43)
terrifying for everybody.
Kate Devine (47:47)
systems to check that we haven't missed anything in these huge panels. And then also, you know, the patient has the option if they're low risk to forgo the genetic testing and but still acknowledge the residual risk we felt was kind of like the best of all worlds in terms of.
Shefali M Shastri (48:01)
best option.
You know, the other loophole is when a patient is a carrier for a recessive disorder and so and the partner is not and so they're considered low risk, but being a carrier for that recessive disorder increases your personal risk of not responding to chemotherapy or not, know, like, yeah.
Kate Devine (48:16)
Right, right. we, yeah, the manifesting carriers are carriers at risk
for symptoms. So they fall in the intermediate risk category. So they still have to do the counseling, but it's a 20 minute session instead of a full hour. So we have, ⁓ you know, different levels too. And then it's all priced in. So everyone pays the same price. The people that need the long consult get it. The people that get the intermediate consult get that. And those that are low risk.
Shefali M Shastri (48:24)
Yes. Yeah.
Yeah.
Kate Devine (48:45)
for the most part don't do a full genetic counseling session.
Deb Keegan (48:48)
And that's
Kate Devine (48:48)
it goes to GeneScreen and they have a genetic counselor review it and certify the report. And then they send a report to the patient and if it's low risk, they also manage obtaining the
Deb Keegan (48:53)
Got it.
Kate Devine (49:00)
⁓ residual risk acknowledgment. So we put together with our legal department, know, verbiage that basically says, yes, your result is negative. This means you're at a decreased risk for the conditions for which you were tested. However, this does not mean that all genetic risk is eliminated or that, you know, it's not possible that your child could have a health condition. Genetic counseling is available if desired, but not required. And then, you know,
Deb Keegan (49:19)
Yeah.
Kate Devine (49:26)
please sign that you acknowledge your residual risk.
Deb Keegan (49:28)
So really by the time it gets to you, that's the third review because if the lab is doing it, presenting it to GeneScreen GeneScreen then looking at it, right? Signing off on it, hits the clinic, you guys are signing off on it. You've seen it three times, plus the patients acknowledged results in residual risk. Pretty amazing. I think everybody should do that because until we have the genetic counselor, you know, AI.
Kate Devine (49:33)
Correct.
Exactly.
Deb Keegan (49:55)
or someone there with you the whole time, it's probably the best I've heard of how it works.
Kate Devine (50:02)
That
AI exists. There are a couple of different companies that offer it, but everyone I know who has attempted to use them, they've had huge problems where it misses
Deb Keegan (50:13)
Mm, not there yet, maybe.
Shefali M Shastri (50:14)
not real time yet.
Kate Devine (50:16)
it sounds like a panacea, but it's so complex that you just, need a real human expert to look at the result and make sure there's nothing that's being
Griffin Jones (50:26)
What is the future of genomics in ART? And I don't mean 30 years out, but three to five years out. And why is it timely? What's the inflection point that's happening now?
jill (50:38)
as we kind of talked about on this podcast, mean, genetics is evolving very quickly. know, ⁓ Deb even mentioned not only being tested for cystic fibrosis, and then of course it was the big three, CFSMA, Fragile X, and then these panels just started exploding. even to the point of prenatal where you're having
NIPT testing, but then there was the nuclear translucency, which again, that only took a certain quick time for it to start exploding and becoming more now a mainstream test that patients have once they become pregnant or couples. So I think that we all covered that where it was when we started GeneScreen from 2013 to now is incredible on what we've seen in terms of these increases in panels.
the the embryo testing, and cancer, hereditary cancer, where that has gone. We're also looking now at cardio and neuro, and I do think that, as I mentioned earlier, there's going to be a point where there's going to be whole-exome whole-genome, not on the embryos, but even at birth. It's happening in the NICUs already, where babies are being tested to make sure.
⁓ They have you know figuring out what you know what what it is that's that's happening But I think it's going to end up becoming more preventative where they're to do that before they're even Get to that stage, so I think we need to stay on one of the things I'm interested is that genetic counselors Has a two years master program and so they're very specialized in in talking just about this they keep up with their CMEs their CMEs there. They're constantly going to
to conferences to learn more and to stay on top of it. And that is all we do, right? That is all we do is genetics. So I think we're allowing the community, not just in IVF, but in prenatal and oncology and cardiology and neurology to be able to now look to genetic counselors for support and to build workflows to help them see their patients faster and do what they do best. And so.
I believe where doctors need to look now is just finding ways to build it in their workflow where they can continue to do what they do really well and utilizing a genetic counselor or a specialist to be able to build into that workflow in a way that their patients can get the best possible care they can get and understanding the risks that are involved and understanding what this might mean for them ⁓ regardless of,
if it's of a low risk or not, you know, just understanding where they stand. the other thing we have to think about is these longevity programs where patients are now going to programs where they can, you know, get their testing done to see, you know, how long they can live based on prevention instead of waiting for it to
genomics is going to, and genetic testing is going be a part of a lot of different areas of medicine. And so, as GeneScreen, we're here to support that in any workflow that we need to get the patients to get through the system and be able to also support the doctors, the PAs, the NPs, the nurses, the whole staff in evaluating and answering those questions. And I think technology is going to be really helpful in that. And so I do believe that.
AI technology, are all interfacing, these are all things we can do to make this process easier so patients don't have to go through so many different barriers and they can get this access quickly and efficiently.
Kate Devine (54:02)
it is absolutely the case that we will all have to deal with some sort of PGTA that involves whole genome, whole exome, or whole transcriptome evaluation of embryos. And, you know, it's basically all of us REIs putting our fingers in the dam of the tsunami for now.
in trying to mostly hold this off until we understand it better. And then we have all the ethical issues of the cost of this technology. That said, it's coming. Patients are gonna demand it and they're gonna start demanding it in larger and larger numbers. And the interpretation is just gonna be incredibly, incredibly challenging. Again, we will get information that no one knows how to interpret.
Deb Keegan (54:47)
in addition to that, PGTP, or the poly polygenic embryo screening where we're identifying embryos at risk for developing diabetes or heart disease. And I think there was just a paper that came out on that this week or last week as sort of the next frontier and that it's here, but people are doing it. And Shefali and I had a conversation about that earlier.
you know, but where do you draw the line if you are selecting out for those genes, what are you doing to other genes that they may be interacting with that we don't understand? that's going to be another area. I think that's upon us and interesting, but difficult ethically and also scientifically.
jill (55:24)
Okay.
Shefali M Shastri (55:29)
And lastly, what I'll say, what I'll just add, like on the horizon, I think that in addition to ⁓ what Kate and Debra are
referring to, I mean, I think that once PGT becomes, you know, there's a much greater accountability with non-invasive screening tests, I think it's going to be accessed much, much more than it already is. So that's going to increase just the numbers. I also think, I mean, if you think out probably past five years,
If you think out to CRISPR-Cas9, once that is non-invasive or less invasive of a methodology, think that's where we're going to probably be growing. But the question goes back to what Deb referred to, where do you draw the line? It's slippery slope. And so these are some of the questions that come up ⁓ ethically and also in terms of if something is available, do you always offer it?
jill (55:59)
you
Shefali M Shastri (56:18)
you know, and who are
you to not offer it or who are you, you know? And so I think those are some of the questions or concerns that we'll have to struggle with. And I hope that before we, I hope the cart doesn't get ahead of the horse. I hope that before all of this is introduced into the, you know, mass market, there's, you know, more thoughtfulness there.
Griffin Jones (56:37)
gonna have to be a
Kate Devine (56:37)
Yeah, and I would say, you know, to put a positive spin on it, because yes, it imposes a lot of challenges. The pleiotropy issue that Deb raised is a huge thing, meaning like off-target effects when we're trying to, you know, potentially select for health characteristics or even traits. What negative impact could that have on a child's life? That said, you know, was in Esra, you know, last month and
I heard some incredibly exciting talks. The Juniper group, I'm really excited about the approach that they're taking by doing both the whole genome and whole transcriptome evaluation of embryos and specifically looking at variants that are known to be impediments to embryo viability and how they also are able to associate those variants in the parents.
Kate Devine (57:25)
and determine is this de novo, which we know that de novo variants obviously make a lot more sense as something that could potentially count, for example, for things like recurrent implantation failure or embers that don't implant, right? Because obviously the parents are alive and healthy. And then the other piece that they look at is these X-linked inherited mutations that are associated with lack of viability can...
Kate Devine (57:49)
kind of be the answer potentially for a lot of our patients who over and over again fail at IVF and we don't know why. So there's also a lot of exciting technology on the horizon. And I just really hope that these groups, as much as there's this market pressure to become profitable, I hope that they validate them appropriately.
Deb Keegan (58:06)
Yeah, to your point, it also will have to be gated by virtue of the fact that it won't be standard, probably. And how will people afford it? How will it be accessible, universal, available when no one can afford it? So that's going to make it even more interesting as we get into the ethics of it, right? Somebody who has the same risk in, you know, one with one insurance or one income versus someone who doesn't, there's a trade off there,
Kate Devine (58:38)
The ASRM ethics committee definitely has their work cut out for them this decade.
Griffin Jones (58:42)
It's been awesome having all four of you on the program. Thanks for coming on.
