Myriad Live - Let's talk hot topics in prenatal genetics!

Myriad  Live episodes are recordings of an open-forum webinar hosted by Dr. Thomas Slavin. The opinions and views expressed in this recording do not necessarily represent those of Myriad Genetics or its affiliates. To participate in a future recording, visit myriad-oncology.com/myriad-oncology-live for a list of dates, times, and subjects.

References for this episode:

Open Access: Addressing Reproductive Healthcare Disparities through Equitable Carrier Screening: Medical Racism and Genetic Discrimination in United States’ History Highlights the Needs for Change in Obstetrical Genetics Care https://www.mdpi.com/2075-4698/12/2/33

ACMG poster. eP336: A tale of two HBs: DNA Sequencing and hemoglobin electrophoresis. https://www.gimjournal.org/article/S1098-3600(22)00388-4/fulltext

The Evolving Role of Next-Generation Sequencing in Screening and Diagnosis of Hemoglobinopathies. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8353275/

Transcript

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0:00:13.3 Dr. Thomas Slavin: Welcome. This episode of Inside The Genome is a recent recording on Myriad Oncology Live, a webinar hosted by me, Dr. Thomas Slavin, Chief Medical Officer for Myriad Genetics. The opinions and views expressed in this recording do not necessarily represent those of Myriad Genetics or its affiliates. To participate in a future recording, please visit Myriad Live for a list of dates, times and subjects. I look forward to exploring the world of genetics with you all.

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0:00:40.7 DS: Hello everyone. Welcome to Myriad Live. This is a fun one today. We're gonna be diving into the world of prenatal genetics, so I have to dust off my past knowledge of prenatal from clinical genetics. Although, I still get a healthy taste every time I have to redo my board questions every six months, and also my pediatric questions, which are due for my continuing education fairly soon, [chuckle] quarterly. We have Deb Brugman helping us today, so she is the Medical Science Liaison for our women's health business unit, so, so excited to have you on, and I believe you have some special guests as well. I'll turn it over to you in a second. I'll do a little housekeeping first. And so if this is your first time to Myriad Live, which it very well may be, since this is our come out for not being totally oncology-focused. So if it is your first time this is a... It was weekly... We try to do about two a month now, but it is just a pure educational session.

0:01:51.1 DS: The goal here is for everyone to learn and have a safe environment where they can ask whatever questions are on their mind, there is no judgment here, and we do these theme-based. This week is really down here, so we're talking hot topic, it's in prenatal genetics, Spring Conference review. However, if you wanna go back into oncology type question, that's fine too. Feel free to unmute yourself, ask whatever you want, feel free to interrupt us, we're here for you. And just note the following schedule, so yes, today we're doing hot topics and prenatal genetics. Oh, and I should mention this. We do record these, and I'll get to that in a second, but in April, we're gonna have E. Smith on, we're gonna be talking Advanced Practice Provider Genetics Practice Education Certification. She's also gonna have a special external guest, and then we're gonna come back to... There's just so much going on with conferences right now and research coming out, we're gonna come to oncology conference review at the end of April, and that's being spearheaded by Shelly, who is also running our chat today. So if you don't wanna unmute yourself and ask questions, feel free to send a chat question to Shelly.

0:03:10.1 DS: So Shelly Cummings is our Vice President and Medical Director of our oncology business unit. And then in May, and we'll continue to build this out, but in May... May is Mental Health Awareness Month, and so we're gonna talk mental health genomics. And we're gonna have an external guest on for that one as well. So very exciting. We do put these up, as I mentioned, they are recorded, just the audio, so not the video. And we put the audio up on Inside the GENOME. And so you see there's a lot out there. So we just put this really good one up with Allison DiPasquale. This was the last one we did with the Myriad Live with Dr. Rick Boland, that was a really good one. They're all great. So you can't go wrong. And the difference is, if they say Myriad Live, it just means it is one of these types of recordings, and if it doesn't say Myriad Live, that just means it's me sitting down, usually, or myself and Shelly sitting down with one or two experts in the field, and those are only about 20 minutes long, but you can see there is more than enough content for your summer... For your summer break. Alright. So let me now get back to Deb and the plan for today. So Deb, yeah. You are already unmuted, if you wanna introduce yourself to the audience and talk about what you have planned for today, the walkthrough.

0:04:43.1 Deb Brugman: Yeah, thank you. I'm really excited for this opportunity and stretching across different areas of genetics. So today, for our prenatal intro, we have Dr. Liz Collins with us. Liz is a PhD in Cellular and Physiological Dynamics. She's also a member of our Myriad Clinical Genomics team. So I know this isn't typically myriad-focused but she is... Well, she... And she is amazing, she had a poster presented at ACMG that I think is a really interesting take on a topic that's familiar to a lot of us, and that Liz will take us through her poster and kind of a deeper dive in how they got to the content for that paper. So welcome Liz, talking about...

0:05:31.7 DS: Yeah, and side fact, I threw axes with Liz's husband two days ago.

[laughter]

0:05:37.9 DB: Yes, I was gonna leave that to her, but yeah for sure. So Nick Collins, Liz's spouse. He's on the line as well. Welcome Nick. And he's an amazing RMS out of the Chicago area. So he also knows the prenatal land very well. So Liz will...

0:05:58.2 Dr. Liz Collins: So just to be clear, that was part of a game, a competitive, safe environment throwing axes at a board. Just clarifying for the recording.

[laughter]

0:06:08.3 DS: We should be clear there.

[chuckle]

0:06:13.2 DB: Very good. And we have Deanna Darnes also joining us from Texas. Well, I'll give her full intro here. Deanna R. Darnes is the Director of Genetic Counseling and Services at Fetal Care Center, Dallas. Deanna received her Masters of Science degree in Genetic Counseling from the University of Texas Graduate School of Biomedical Sciences, Health Science Center in Houston in 2010. Since that time, she has worked in both pediatric and prenatal care, and she's practiced as a clinical pediatric genetic counselor at Children's Hospital, Colorado in genetics and inherited disease, and she's currently a clinical prenatal genetic counselor where she also provides the only prospective genetic counseling student shadowing program in North Texas. And so she's involved with students as well, which is great. And Deanna provides speaking engagements for various laboratories, universities and hospitals, and on the importance of genomic equity, which is key to our discussion today. She's a member of the American College of Obstetrics and Gynecology, the Texas Society for genetic counselors, the National Society for Genetic Counselors, and she's a mentor of the Minority Genetics Professional Network. Thank you so much for joining us, Deanna. And she's gonna be talking about a collaborative paper that was published just recently on...

0:07:36.2 DB: I thought I had it at my fingertips for the full title. Addressing Reproductive Healthcare Disparities Through Equitable Carrier Screening: Medical Racism and Genetic Discrimination in the United States' History Highlights the Needs for Change in Obstetrical Genetics Care. And that was co-authored with Aishwarya Arjunan and Deanna herself and Katelynn Sagaser, I hope I'm saying that right, and Ashley Svenson, who I think I saw Ashley pop on as well. I've had the pleasure of working with both Ashley and Aishwarya and I welcome Deanna in your comments a little bit later as well.

0:08:11.0 DS: Yeah. Nice to meet you, Deanna. Thanks for coming on. And Liz.

0:08:15.1 Deanna R. Darnes: No problem.

0:08:17.6 DB: So we can call... And then as time allows, there's another article that caught my attention and I had the opportunity to share on an internal journal club recently about changes in prenatal genetic counseling in the era of increased and improved treatments for spinal muscular atrophy. So as time allows, I'll touch on that article as well. The author for that paper was unable to join, so if I don't get to it, maybe we'll be able to have her join in a future or maybe both and... But maybe we'll be able to have her join in a future Myriad Live.

0:08:52.7 DS: Yeah.

0:08:54.9 DB: So I don't know that we decided but we could start with Deanna, I know you had prepared some slides that maybe you wanna take us through and we can pop in with some questions.

0:09:06.3 DS: Yeah, feel free to share your screen, Deanna, at the bottom if you wanna show some slides.

0:09:16.3 DD: Sure, I'm a kid of the '90s, so of course we love a good PowerPoint, so I went that way for us as well. But, of course, as they just talked about, it's supposed to be pretty lax, so if there's anything that comes up during any of the slides that I'm posting, feel free to pop in, I'm good with that and ad libbing as we go. And so thank you so much, Deborah, for that introduction. And yes, the title is perfect, but the authors, as Deb just mentioned, and those are our lovely faces, so myself, Ashley, Katie and Aish. This project was started by Ashley and Katie as they worked together with trying to get Medicaid coverage in Maryland for extended carrier screening panels, and then Katie saw the call for this type of paper.

0:09:57.3 DD: And we kind of all met together in a very 2021 fashion, which was on Twitter, 'cause some of us haven't met in person, but that's how we got together and copious amounts of Zoom calls commenced after that to talk about this paper and what we really wanted it to be. And so with this paper in mind, it was... That was the basically the main focus of this society special issue, which was gonna be racial equity in public health, policy and reproductive health rights and justice, with the focus being, of course, reproductive rights, health and justice. And what better way to kinda go about that would be carrier screening. Carrier screening is kinda always looked at as sort of the gateway to genetic testing, while, of course, we would love for there to be genetic counselors and genetic testing, more marketing-focused in the family, basically general family practice clinics as that would be pretty much the best place to be.

0:10:49.3 DD: We know that genetic testing isn't as ubiquitous as that just yet, and so your average person doesn't get a lot of information about those opportunities until they start talking about the idea of becoming pregnant and starting a family. And so in the reproductive setting, one of ACOGs guidelines is you start to talk to the patients or patients who may be planning a pregnancy and asking them if, "In a year or in the next couple of years are you planning a pregnancy? What are your thoughts on that?" And if a patient happens to say yes, then there's a really, really big conversation that takes place as far as what's appropriate for a healthy pregnancy, what are things that they need to think about, but also they get off for genetic testing in the form of carrier screening. Now, of course, if you say no to that, then there's not a back-up plan or another if-then statement to say what type of genetic testing are those individuals offered.

0:11:40.3 DD: So even if from the onset, we do see that there's this barrier already in place for the individuals who do get this robust conversation and those who don't have that opportunity. So even another reason why carrier screening is a great way to go about equity because it's something that should be talked about more frequently and has the ability to affect a lot more patients than what we can currently deal with at this time. And so throughout the paper, we kind of focused on what were some of the discriminatory practices that we see when it comes to genetic testing, and the big ones are people being offered genetic testing in the first place, if they have appropriate informed consent for that testing, what type of testing is offered and whether the person has adequate insurance to cover that testing, depending on what lab you utilize or what test you order, of course, genetic testing isn't always cheap, so sometimes that in itself is a huge barrier that some people can't overcome.

0:12:34.2 DD: And so we found that extended or not... Well, carrier screening of barring the extended portion. It should be something that we talk about in more detail and in depth. Because it has the ability to transcend those kinds of barriers if everyone of course works together and buys in. Now a big passion of ours was the historical contacts of thinking about where this information comes from. A lot of times you'll hear, especially in the past two years with, of course, dealing with the pandemic, is people talking about why don't people trust the healthcare system? Why don't they trust the science? Why don't they trust the people in charge? Where quite frankly, if we just look at the historical context, are we trustworthy? And to be frank, there's been a lot of medical atrocities that have happened that deem us not as trustworthy. And so it's really not or shouldn't be not understandable to understand why people are a little bit skeptical. So a big passion of ours was going back and looking through the history, not only for medical atrocities, but laws that were in place, especially when it comes to immigration acts, to understand how we got from point A to point B, where we are now. And so when we think about those things, we think about systemic racism and how these types of policies are really just deep, baked in, woven into every part of our societal policies and practices that affect our healthcare system today.

0:13:50.0 DD: One of the questions that I was asked while I was doing this presentation was, were we surprised about any of the atrocities that we reviewed or any of the laws that we came across? And all of us, I would say for the four of us, really weren't. We're all big admirers of history and love reading different articles and books, especially going into detail about how that connects to our current healthcare system today. But what we probably would say is that we're very surprised that this hasn't been integrated more in med school curriculums or genetic counseling programs. We, of course, all get that little bit of information when we're doing our IRB practices and learning about the US syphilis study. And that's pretty much where it stops. And we don't get to learn about all the other things. But while these were the main anchors that we focused on in the paper, we of course could have talked about the Puerto Rico birth control studies of the 1950s, the Cincinnati radiation experiments of the '60s to 1971, the XYY aggression studies, which unfortunately, if you are prenatal genetic counselor and you have a patient who has a positive non-invasive prenatal screen for that particular condition, those studies still appear when a person does a basic Google search. It's something that patients still talk about.

0:14:57.0 DD: We can discuss the HIV drug and vaccine trials on foster children, the measles vaccine on black and brown children in LA. But we can also look to today, right now where there was Ivermectin studies done on prisoners who did not have proper informed consent. So again, these all anchor back to what we're dealing with today and how we can kind of move forward.

0:15:18.7 DS: Yeah, this is really incredible. And so you've put all this... You and your co-authors really aggregated all this information for the paper? 

0:15:27.9 DD: Correct.

0:15:28.8 DS: Yeah, that's really impressive. That's a lot of work.

0:15:31.4 DD: So one of our... This is one of my absolute favorite diagrams or tables from the paper. And Aish did a really great job with this. This was definitely 100% all her. And I'll give her all the credit, in especially tracking down all of these different guidelines from ACOG, ACMG, NIH, all over the years, so since 1991. And what we found, of course, there's a lot of difficulty in tracking deck down some of these articles that are no longer available, or are behind a paywall. And it really comes down to who you know. And if you have good relationships and networking skills and you know who might have a certain paper from 1998 that's no longer available, you're able to get that. And so this is one of my favorites because one, it condenses everything down into one space. And so there you have... You don't have to search through multiple different papers to get all this information. It's right here, right in front of you. So it gives a good overview of where we've... How far we've come, the thought processes, how it's changed over time. But it also kind of tells us how far we haven't come, especially with the advent of various technologies that we currently have available to us, and have had available to us for quite some time. When looking at this, my very first thing to think about is in 1997, NIH was discussing CF screening for pretty much everyone. And it wasn't until 2011 that ACOG jumped on board.

0:16:47.5 DD: So in those 14 years, how many families didn't have the opportunity for adequate testing or adequate just information about what was or wasn't available to them? And I love this table as well. Because it gives a better overview of what was offered to who, and really... And of course, what wasn't. And who was kind of left out. And you can see just very blanketly with the check marks, who was getting a lot of opportunity and who really wasn't and what disorders were talked about more frequently and with what particular groups. And so another question that I was asked was, "How do you manage the difficulties, and especially in a clinical setting with all these kind of differing professional society statements?" And on the left hand side is gonna be ACOG's, which was from 2017 and then re-affirmed back in 2020 to the current ACMG one that we have from 2021. And of course, with ACOG, they're still with the idea that pan ethnic and... Or not pan ethnic, but ethnicity-based carrier screening is still okay or acceptable versus ACMG that's stating that's not helpful anymore. We're definitely in a place where we have the availability of technology to offer more testing to more people.

0:18:02.8 DD: Of course, obviously that has its own drawbacks when it comes to variant analysis and the fact that historically excluded groups are more likely to have variants of unknown significance, just because we haven't studied those variants enough, and how we haven't seen them enough. Because again, it hasn't been offered to people. But one of the biggest sticking points in the ACOG guideline that always kind of lingers in the back of my head is that re-testing with larger panels isn't recommended. And the reason why that sticks with me is because you can have a person who's had CF testing, but it really wasn't that great or adequate. And so why wouldn't you, especially when you know that there's well over 2000 known mutations associated or variants associated, that we should actually go back and maybe at least talk with patients. As we know in the clinical world, not everybody accepts everything. And they don't have to. That's definitely their own agency not to do so. But we at least should talk about it. And the reason why that sticks in...

0:18:53.3 DS: Yeah, that is an odd statement. Does anyone know why that is in the ACOG guideline? 

0:19:01.0 DD: So it goes into a little bit more detailed thinking... And the idea was that the yield for finding maybe a positive variant would be rather small, so basically not worth the money, so to speak, if you were to put it in more layman's terms. However, I'll talk about in just a quick minute why that is still something scary as heck to me that you wouldn't wanna do that. Because you can also get really, really caught up in a really bad situation when you heed that idea that it's not a big enough yield.

0:19:29.7 DB: In that someone addressed... I know you haven't gotten there yet. But it's on your slide, the ACMG 2021 guidelines. Do you have some caveats for re-testing? So I was at least glad to see that, whether it's a new partner pair or a new partner in the pair, the couple with maybe new information or like you said, new genes on the panels or new genes available. They do have some carve outs and caveats for that. So I was glad to see, among many things, ACMG's moving forward, which I think is great and helpful.

0:20:06.2 DD: And so this is why, like I said, it sticks in the back of my head. And it's kinda really scary to me. And so these are three different labs, one who does a 32 variant analysis for CF. And this is all CF 78 variants and then full sequence analysis. And I had a patient a couple of years ago who this was her fourth pregnancy. Everything's pretty routine. No ifs, ands, or buts about it. Had CF testing in her first pregnancy, which was about four to six years prior. And she had a CF 32. And everything was negative. So no one thought twice about anything during pregnancy number two, number three. But she had a different OB for pregnancy number four. And during that time, they talked with her about further genetic testing. And she did a bigger CF panel, which happened to be 600 variants. And of course, lo and behold, she came back positive. Then, of course, we needed to test her partner. But what was a big barrier to that was the fact that she ways living at that time in a pretty rural area. And transportation wasn't on her side, as far as being able to get to a clinic, an MFM Practice like ours, as quickly as possible. So while she found out she was a carrier roughly around 15 weeks, it wasn't till about 18-19 weeks till she was able to be seen. And then of course, we did partner testing, partner testing roughly about two weeks. So then we're putting at 22 weeks.

0:21:21.2 DD: And lo and behold, he was a carrier as well. Actually, pretty classic, delta F508, our old good friend. And they went on to do diagnostic testing. And baby inherited both mutations. And so that, of course, in the state of Texas, for those of you who may be here, of course, have heard about us greatly in the news, that makes things a lot of difficult when it comes to reproductive options when it comes to abortion. So that was a patient that unfortunately had to travel to another state to seek that appropriate care. But again, because of the fact that she was put in a situation where no one had talked with her about what her carrier screening was, she was in that situation where she thought she was negative. And she was correct in providing that information to her providers. But what's very important as health care providers and labs to understand is what those variants mean. And while yes, you can say that you fulfilled your criteria to say that, "Yes, I've offered a patient CF screening," if that CF is 32, when it comes down to thinking about detection rates and detection rates for different backgrounds or ancestries, that negative 32 for somebody can be great, while it can be really, really bad for someone else. And so that of course goes in to more evidence why I expanded our carrier screening as it stands now, is more important to be offered and discussed with more patients.

0:22:40.8 DD: And so with those difficulties, when it comes to those societal guidelines is of course how big of a panel you should go to, what's actually on that panel. And that's of course difficult in a prenatal setting. Because you think that, "Okay, if it's the first panel, it's covering the things that are "recommended" but depending on what guideline you go by. You should be good from there." But you really do have to start getting down into the nitty-gritty of what is actually on those panels. In our highlight which ones include HPV and HPA moving forward or screening for hemoglobinopathies. Because 7% of the world's population is a carrier for a hemoglobinopathy. That's pretty big. Again, global population. So if those things even are on the basic or on the tier one panel that, again, more credence as to why carrier screening then involves more conditions is more equitable than just the basic that we've been going along with.

0:23:32.8 DS: Mm-hmm.

0:23:36.0 DD: But of course, we can't do it alone. And a portion of our paper towards the end that Ashley was great with was talking about concerns and coverage. And that's how all of this really started, was trying to get as much access to patients as we possibly can. It was noted in our paper that Blue Cross Blue Shield has the most coverage as far as a commercial insurance is concerned. And then when we go to Medicaid plans, only about 29 out of 50 cover carrier screening. But again, that's ethnicity-based on your CF and your SMA and not expanded carrier screening. And currently fewer than 5% of those with commercial insurance and then 2.5% of those with Medicaid have that coverage. And as we know, when it comes to those community-based and federally-based with Medicaid plans, that those are the ones that affect those individuals who are of minority status. So therefore those are the ones that are most greatly impacted with the fact that they don't have access to appropriate genetic testing when it comes to carrier screening.

0:24:34.8 DC: Deanna, I'm afraid I might have the answer on the back of my mind. But when it comes to that... Excuse me. I mean, I understand somewhat from the insurance plan carriers in a perspective, the more we test for, the more we might find, the more we want to do. But when we think about inherited cancer in particular, and cancer risks, more screening. But when it comes to carrier screening, it's a very different ball game. That's not exactly the same price. So what kinds of, I guess, hesitation, pushback barriers are we getting? I mean, is it purely an economic decision that the plans just don't...

0:25:14.0 DD: Sometimes.

0:25:14.7 DS: Yeah.

0:25:15.2 DD: When you see... Yeah, sometimes with insurance companies, definitely as it goes down to the bottom line. Sometimes they will have questions as far as the clinical utility of that information and what patients will do with it afterwards. But of course, we've seen through numerous studies through the past years. It's looked at almost in the same way you would use a non-invasive prenatal screening result. So there's definitely clinical utility there. We'll get on to that part of why that's still concerning as well. But there definitely is utility there. And the price is definitely a big sticking point, but also with understanding of the phenotype, there's still a lot of disorders that we have that we don't know exactly what the phenotype is, or what all the different management concerns would be or the interventions that would be available. But I often wanna challenge the idea of thinking in that manner because carrier screening is not just for reproductive decision-making options. While, yes, that is something that we talk about quite a bit in the paper. We also should make it known that it's about the person as well. There are plenty of individuals who are carriers for excellent conditions that have features of that disorder. We can think of Duchenne muscular dystrophy and the concerns for cardiomyopathy.

0:26:20.9 DD: So we're not just talking about health for our offspring, our children, but for ourselves as well. I often think about the idea that heart disease and the umbrella term that that is of how many people suffer from that, especially in adulthood, and what factors that there are. How many of those people may be carriers for a neuromuscular condition and then don't know it, and that's a contributing factor. We're now learning about people who are CF carriers that may have some medical concerns, I've got a patient coming up who is a galactosemia carrier and she has liver issues that we don't think are anything new to any environmental factors or her job or alcoholism or any run the gamut. So is it possible that the two could be related, we don't know, and the reason why we don't know is because, again, a lot of people have been historically excluded from having the ability to undergo testing, and so therefore that wealth of data that we would love to be able to evaluate and identify. We don't have yet, because again, people haven't had access to testing.

0:27:18.4 DB: And I'm not sure if everybody saw Ashley Svenson, so also an author there. She chimed in that payers are also concerned about OBs being overwhelmed with information. So I mean, education is always what pops into my mind, and how of course, a lot of us here on the call are genetic counselors, and come from an area where we would love to help with that, but I get that that's a barrier, perceived barrier, anyway.

0:27:45.8 DS: Yeah, and making sure patients have access to education as well, from the front end and the back end, yeah. I'm surprised to see that 29 out 50 state Medicare plans. I would have assumed it would be a lot higher.

0:28:02.0 Susanna: Yeah, and can I add something? 

0:28:03.5 DS: Go for it.

0:28:05.8 Susanna: Yes, my name is Susanna I'm with Medical Services here at Myriad. And I attended the ACMG conference last week, and they talked about a very interesting study, and this was hereditary cancer. So yes, it's a different area, but they had this really interesting study where they talked about how actually people, these communities that are of lower socioeconomic status get offered less testing by physicians, so there is a bias there from the healthcare provider's side that we can actually help with, which I thought was really interesting, they actually get offered testing a lot less than in communities of higher income. So I just wanted to add that as a potential barrier too.

0:29:05.2 DD: No, 100%. And that's something that we also mentioned in the paper as well, that as a patient, you're almost certainly at the mercy of your healthcare providers' biases, what they think a patient may or may not be able afford or what they think they may not be interested in, based on things of what insurance do they have, what is their social economic status and background. And so sometimes decisions are made prior to even being seen a patient, so that again, greatly impacts what patients have access to, so definitely you have a great point. And so as we're wrapping up towards the end of our paper, we're really talking about what it would mean to strive towards equity and those important factors, and really what it is is good old-fashioned teamwork, and really understanding that this is not just one prong of the healthcare ladder that has to do all the work, it's not just about patients and thinking about that they need to advocate for themselves more, because most certainly you can't advocate for what you don't know that's out there, or what's accessible.

0:30:02.0 DD: It's about healthcare providers, and unfortunately, as Jess mentioned, there's sometimes not a lot of education that's available. On average, your healthcare provider gets about 36 hours in med school about genetic counseling, not counseling, but genetic testing options and what's available. So that's not a lot in a four-year medical school career, so education has to be there, talking with insurance companies about what the importance is of covering these types of tests and why it is beneficial, not only to the patient themselves, but to their family members, because of course, if they are a carrier, other family members could be a carrier and that's affecting other units that's in society, as well as, like I say, the earlier, their own personal health, because we're now learning that there's... Not consequences but ramifications to being a carrier as well. So it is really a community concern that we need to address and take care of for all of us, because again, we're all gonna be patients someday. This very well may be us.

0:30:55.3 DD: This very well may be some people in this chat right now that are affected in this way, and if we don't have all the information or all the data, because of the fact that most GWA studies are very European-based and therefore a lot of variants, we can't give patients additional information to, or if we have a situation where insurance won't cover certain testing because they don't see the clinical utility or efficacy behind it, we're not gonna move forward, and so that's why we think from the historical aspects that we mentioned, why it's so important to understand that some of these things are beyond a patient's control, and so therefore the people who are stakeholders, who are in power, it's very important now to come together and move the needle forward. And by offering this type of testing, while, yes, it's not the panacea, it's not the catch-all, it's not gonna remove all the healthcare disparities that we know and have in society today, but it can help and it's one way that we can move forward.

0:31:47.0 DD: And so speaking with that clinical utility, that is a big thing that gets discussed regarding what do you do with those results, whether that be prenatal diagnostic testing, or that be IVF with PGT, which of course, are quite costly and are out of reach for many, many individuals and so that's why it's a good team effort to talk with all these different prongs and areas to get together to say that this isn't just about one area of life. We should be striving toward making genetics, of course, precision medicine about everyone's life as early as possible, so that way, yes, we can get more data and information, but two, we of course can improve what we understand about the data that we're dealing with right now.

0:32:26.4 DS: Mm-hmm.

0:32:27.1 DD: And so that is the end of my...

0:32:27.7 DS: Yeah this is great work. Yeah, thank you so much. This was fantastic. Yeah, it's really impressive to see how you laid out the historical context, and it really puts everything into perspective. So any questions for Deanna? Then we can pop over to Liz. We're probably not gonna get to the spinal muscular atrophy today though, Deb, [laughter] but this was great.

0:33:00.1 DB: We could plant the seed, right? [chuckle]

0:33:01.8 DS: Yeah. Planting the seed.

0:33:02.7 DB: Absolutely.

0:33:03.5 DS: Great. Liz, do you wanna share your screen? 

0:33:07.6 DC: Absolutely.

0:33:08.7 DS: Yeah, and maybe if we have some time at the end, we can just pause for other questions and go back to Deanna's as needed.

0:33:18.6 DC: Alright. Let me get into Presentation Mode, are you guys still seeing a presentation? 

0:33:23.0 DS: Mm-hmm, big blood cell.

0:33:25.8 DB: A blood cell.

[chuckle]

0:33:25.8 DC: Excellent. Yeah, yeah, I'm gonna become oddly fascinated by blood cells as this goes, so just heads up on that. So my name's Liz, I'm a Manager with Clinical Genomics on the Foresight Panel, and I'm gonna present the work that we did at ACMG recently. Our poster was called A Tale of Two HBS: DNA Sequencing and Hemoglobin Electrophoresis. So I'm just gonna give a little crash course in hemoglobin, and hemoglobinopathies. We'll talk about how that played into the Myriad Foresight Panel and where my just unnerving fascination with red blood cells was born. And then what was actually presented at ACMG, which was this HBS-mimicry case. So red blood cells are simultaneously probably the simplest and most complex cell in the body, depending on which way you're looking at it. You probably know their primary function is to carry oxygen and carbon dioxide. The most important features they have are two things they actually have, and then things that they don't have. So they have hemoglobin, and they've got a lot of it, about a third of the contents of the cell is hemoglobin. And I just read last week that the average red blood cell has 300 million hemoglobin molecules, which just blew my mind.

0:34:44.5 DS: Yeah.

0:34:46.0 DC: The other thing they have is the membrane, and basically a red blood cell is a membranous bag of haemoglobins. The membrane is important in the sense that it's actually the recipient of most of the damage in hemoglobinopathies. So it has a lot of important kind of aspects that look at the pathophysiology of these conditions. And then the big things that are kind of important about red blood cells is they don't have a nucleus and they don't have organelles. So when they are out in circulation doing their job, they've got a life span of about 120 days. They get a lot of mechanical and physical stress, and then biochemical stress, like oxidant damage and they have just no way to repair themselves, so they're like a plucky little cell. So I talked about hemoglobin, it's a tetramer of two alpha globin and two beta globin molecules. And they themselves are very small, alpha globin is about 142 amino acids. And I think beta globin is 147. And by most gene standards, that's actually tiny, but they manage to pack a lot of disorders into those small amount of amino acids.

0:35:50.8 DC: So we've got the thalassemias where you lose the expression of one, and that's a disorder of imbalance. You've got a structural hemoglobinopathy where you're not changing the expression level, but you're changing the behavior, how it polymerizes. HBS that leads to sickle cell anemia, I think would be the most well-known example of that. We also have unstable hemoglobinopathies, thalassemic hemoglobinopathies, you've got alterations to behaviors like oxygen affinity, which lead to polycythemia and erythrocytosis, and then you've got things like methemoglobinemia, and these are such a fun set of disorders if you trip over words like I do. So the alpha-like and beta-like genes are expressed in two clusters. All of the alpha-like are up on chromosome 16 and all of the beta-like are down on chromosome 11. One interesting tidbit that I just think is, again, fascinating, is that the order they appear on the chromosome are the order that they're expressed from embryonic through fetal to adult, and there's no real known reason for that, but I just thought that was interesting.

0:36:56.6 DC: The biggest thing you're gonna notice is that alpha-globin has two identical genes and they're actually surrounded by regions of identical homology rather than beta, which has just one copy of beta-globin. And because you've got all these regions of homology, you get a lot of crossover events and a lot of just gene deletions or deletional variants. So about 90% of alpha-globin related hemoglobinopathies are these thalassemias, which are just caused by deleting out one or both copies of alpha-globin. So I talked about deletional alpha-thalassemia, like I said, the thalassemias are disorders of imbalance, the alpha and beta need to be expressed in near perfectly equal amounts, and the cells don't tolerate an imbalance of that, so if you delete a copy of alpha-globin you're gonna tip that balance.

0:37:45.6 DC: And a thing that I also think is fascinating is that the destruction bit to the cell or the damage to the cell is not caused by losing the alpha-globin, it's caused by the activity of the beta-globin that's now... You've now got too much of. So like I said, these are expressed in near perfectly equal amounts, and alpha-thalassemia doesn't have a fetal version, so there's no real modifier, so it's got a really linear and predictable relationship between the hematology and the phenotypic severity and the gene dosage. So if you delete one alpha-globin copy, you're called a silent carrier, which is unaffected and we can't... The hematology is actually pretty similar or can't be distinguished readily from that of a wild type. Two copies being deleted is a trait carrier, so still unaffected but we can now look at the hematology and see a change.

0:38:41.7 DC: Three deleted copies is required to give you a clinical condition, which is HBH disease, and if you have all four copies deleted, you get HB-Barts, which is also sometimes called HB... Oh, I'm sorry, called alpha-thalassemia major. Up to 2020 at Myriad, our foresight panel looked at a targeted panel for nine of those deletional variants or CNVs that you lose one or both copies of HBA2 or HBA1, the alpha-globin genes. And then we also had one common non-deletional variant that we looked at, which is called Hb Constant Spring, this is a stop-loss variant, and that we knew that that particular variant had a more severe behavior than these deletional variants. So like I said, with the deletional variants, you need three copies affected to get a clinical phenotype. We know that Constant Spring, having two copies homozygosity can actually give you a HBH disease or a clinical phenotype.

0:39:41.9 DC: So in 2020, we added full sequencing of HBA1 and HBA2, the alpha-globin genes. All their exons, the intron [0:39:49.5] ____ and their UTRs, and that allowed... We did this because, like I said, 90% of the variants are caused by these deletions, but so this allowed us to get our detection rate up to greater than 99% for high risk ethnicities. We had to ask the question, do these other non-relational variance behave like CNVs? Do you need three impacted copies to get a clinical phenotype? Or are they gonna behave like constant spring? And have that elevated severity where only two effective copies allow you to get a clinical phenotype. So while everyone was baking or learning languages during the lockdown, my 2020 sort of starter was reading through at least fully four text books, a couple of bits sections of other ones, all the lecture and reviews, and primary lecture I could get my hands on.

0:40:39.3 DC: And I mention this because in addition to having the sequencing all of these variants, with alpha you actually there's a particularly nuanced need to have correct interpretation, and we basically came up with 20 pages of yes and no to the answer to that question. Some of these variants behave that way, some you need three copies, some you need two copies, and that's critically important because when you're trying to report to a patient what their either personal or reproductive risks are, you need to understand, not just sort of generally deletional or non-deletional, but you need to be variant by variant understanding of what that behavior is gonna be.

0:41:20.2 DB: Okay. Thanks so much, Liz. If you could go back to one slide.

0:41:23.6 DC: Sure.

0:41:26.1 DB: Yeah, I mean this is huge, and it's not something certainly that was part of the curriculum when I was in school. If there was, I don't remember it. Yeah. So it's really a new evolution in hemoglobinopathies altogether, but certainly as you've discussed, as it comes into carrier screening, it changes the dynamic. So doing better for patients of different ethnicities or ancestries, to get better information, but then also then interpreting that is complicated, so I appreciate all the work you've done as well as others undoubtedly, but a lot of work on your part.

0:42:07.3 DC: Yeah I mean this is where I became kind of oddly obsessed with hemoglobin. No, I would say to the point about ethnicities, is a lot of the variants, these non-deletional variants are particularly common in ethnicities that would be traditionally under-served in the US medical systems. So there's a, I think there's a very important benefit there. And I think to your point, alphas is so interesting because in those deletional variants, it's probably the easiest to predict, if you can count as high as four, you can accurately predict phenotype and then, you go, you swing far right to the other extreme where you have these extremely difficult ones. So it's a lot to just dump this on a provider and say they've got this variant, good luck. I think the onus is on us to really fully understand each variant that we're reporting. So in addition to the benefit of having that greater than 99% detection rate, another at least to me, unexpected benefit was being able to resolve false negatives or questions that come out of traditional screening methods.

0:43:14.9 DC: So we've always had these provider requests asking to confirm a true negative for HBS, and where that comes around from is that by traditional methods such as hemoglobin electrophoresis, someone will be told that they are a HBS carrier, and then by foresight, we say, "No, you're not a HBS carrier." And I don't expect a patient to understand which methodology would be more accurate, so they're just left with this very unsettling, he said, she said. And the typical outcome would be that we would carefully look at their result and re-confirm that they are negative for HBS. But now that we have this full alpha-globin sequencing. We're gonna show how with an internal case, we were actually able to not only confirm again that they were negative for HBS, but explain why they had been falsely identified as a HBS carrier by traditional screening, and hopefully just remove fully back that concern or burden from them. We also presented literature support for this phenomenon.

0:44:11.3 DC: So I've mentioned that there are these false positives, so a question you might reasonably have is why are people going through these traditional screening methods? And I think part of that is that the current ACOG guidelines recommend the following for screening for carriers of hemoglobinopathies. And for any biological female who's pregnant or planning to become pregnant, they recommend complete blood counts, and then they also recommend hemoglobin electrophoresis in two situations, either in parallel, if you are one of these high-risk populations, and then if you're not a high-risk population, if your complete blood counts are below certain thresholds, these are MCH and MCV values. Then they will recommend hemoglobin electrophoresis. So we had a recent case, and this is a case we presented at ACMG at Myriad, this person had actually been identified twice as HBS-carrier by Hemoglobin electrophoresis, so they confirmed that result for them. We said that they were negative for HBS by sequencing.

0:45:15.1 DC: So obviously we got the request to confirm that and we were able to review all the variants that were detected by Foresight in all their hemoglobin genes, HBA1, 2 and HBB, and we looked at all of them, including those that are non-reported because they don't have a known disease association of what we found was that this subject was heterozygous for a variant called Hb Hasharon, that's an alpha-globin variant. And when we looked at the literature for it, it was pretty clear that this is actually well-known to behave like HBS on hemoglobin electrophoresis, despite having no known disease association. So we were able to explain to this patient they are in fact negative for HBS, and here's why electrophoresis identified you as HBS carrier. So hopefully, this person is now confident that they are not a carrier. In the bottom panel, we show ideally the NGS only scenario where because we only report parents that are likely pathogenic or pathogenic by ACMG AMP guidelines, they never would have been misinformed by this hemoglobin status in the first place.

0:46:21.1 DC: So the reason it puts a lot of burden on a patient if they think they are a HBS carrier, is that there are personal reproductive and then implications for partners and biological relatives. Even in the carrier state, the "unaffected" state, they're have been reported risk of complications and symptoms. Particularly if you're in conditions that favor sickling. Like high altitude, prolonged physical endurance, dehydration, hyperthermia, etcetera, etcetera. Then if their partner is a carrier of either HBS or another pathogenic beta global allele, they now have a one-in-four chance of a clinically affected child. And they also have a further one-in-four chance of a child who's a carrier for HBS and you're back into that personal risk and management of carrier status. So the partner should be tested. Also for their biological relatives, by then being a HBS carrier, now any biological relatives who are pregnant or planning to become pregnant should also be tested.

0:47:25.3 DC: So there's a lot of down stream testing and management that tumbles out of being identified as a HBS carrier. For Hb Hasharon, which this person actually carried, it's just a straight no across the board. There's no management recommendations because there's no complications in the carrier state. Because this person has a low reproductive risk, partner testing actually becomes unnecessary. So the partner's now represented by question marks. And then for their biological relatives, there's no testing recommended based on this result. So we're able to remove all of those burdens in one foul swoop. We then wanted to kinda turn our attention to a bigger picture. Like was this just an isolated case or is this what's kind of the scope of this phenomenon? So to look at this, we pulled all alpha and beta-globin HBA1, 2 and HBB, variants from HbVar, which is the big database for hemoglobinopathies. And we pulled all of the ones that had reported HBS mimicry. We only looked at the ones we've seen at Myriad.

0:48:31.0 DC: And then we also, from that list, removed anything that's pathogenic or likely pathogenic by ACMG AMP guidelines. Although, it's not HBS it might be a long walk to what would be clinically useful information. And we also pulled any where we couldn't find primary literature support for this HBS mimicry. What we were left with was a collective frequency of about 1 in 2100 in our sampling population, which are extensively healthy individuals. That would be 1 in 2100 for the general population. We felt that this really demonstrates kind of an alarming potential scale for hemoglobin misidentification by electrophoresis. So we have a very simple take-home that NGS offers superior sensitivity and specificity.

0:49:18.1 DC: Jenny Gold from our company presented the sensitivity piece at ASHG last year, and obviously in this poster we're honing in on the specificity part. The low specificity of traditional methods really has this risk of putting an undue pressure on patients for both their personal and their reproductive management, and then triggering a lot of unnecessary testing both in their partners and their biological relatives. NGS sequencing did have this kind of unexpected benefit of being able to mitigate the burden that was caused by a false positive. But really, the adoption of NGS is either the primary or sole hemoglobinopathy screening method would be in the best interest of the patient. So I just wanna thank my co-authors. I wish I'd put photos up like Deanna, that was a lovely touch. And with that, I will thank you.

0:50:12.4 DS: Yeah. No, that was great. And yeah, those were some nice photos, Deanna. I don't know. Your team must have good access to photography. [chuckle] But no, that was really a good presentation. Do you think the paradigm will shift over time, thinking through this research a little bit on how we're looking at carrier screening for hemoglobinopathies? 

0:50:41.4 DC: I hope so. I'd have to actually turn to my other half to really talk about that one as he's the provider for ACIN1. There is a lot of evidence, but it does seem to be somewhat [0:50:54.3] ____ in terms of shifting to sequencing, which has been around for a while now. I would have hoped it would have been further by this point. I think people might be hesitant to change to new things. But they're certainly unquestionable that that would be the better option for patients.

0:51:13.8 DS: Yeah, yeah.

0:51:15.1 DD: And I agree, but from a habitual standpoint. There are still a lot of providers out there who are still doing hemoglobin solubility screening instead of even a hemoglobin electrophoresis. So even trying to get those individuals to change over. And again, you see those more in community hospitals, county hospitals, the ones where they're impacting the people the most that should be having the next generation high-throughput style sequencing.

0:51:40.7 DS: Yeah, and then Deanna, on your side, you still highlighted the barriers to even access and payment for carrier screening. So Yeah, clearly much to overcome.

0:51:53.4 DC: But I mean as I think Deanna touched on, like the hemoglobinopathies are the most common monogenic disorder worldwide. And I mean I talked about the silent carriers. Which if it's a deletion, it's not gonna show anything on a hemoglobinopathy gel. And alpha-3.7, which is a single deletion of alpha-globin, is the most common pathogenic variant on the planet, period.

0:52:18.6 DS: Yeah. And it takes up a lot of genetics resources. When I was at the University of Hawaii, we had a whole alpha-Thal or hemoglobinopathy clinic, and that was, if I remember off the top of my head, it was one day a week. It took a lot of resources to keep that going just because 10% of people are gonna flag positive of the couples.

0:52:42.3 DC: Yeah. And then the alpha-3.7 carriers won't flag at all 'cause it's fully silent.

0:52:46.0 DC: Right. So great. No, these were really fantastic presentations. Thank you both. Any questions out there, or anything else that anyone wants to talk about as we're thinking through things that they've seen in spring conferences? And then I'm just gonna pull back up Myriad Live real quick. Let me move my screen. Alright. Can people see that? 

0:53:32.5 Susanna: Yeah.

0:53:33.4 DS: Okay. Yeah. Okay. Yeah, just another plug then for April 12th. We're gonna be talking about Advanced Practice Provider Genetic Spatial Education Certification. So please join us for that one. And ED will be on. It will be great. She's bringing an external guest, and then we'll close out April with the oncology conference reviews. So really exciting. But today, yes. Thank you so much, Deanna, Liz, great presentations. I learned a lot. It's amazing. Hemoglobin, it's one of those... It's like a foreign language. I mean I... Just speaking from personal experience. I even taught the medical school courses on hemoglobinopathies, and we had an entire lab and everything, and then when you're talking, it's jogging all these things back in my brain and things that I had forgotten over the years. So it's good to see it every so often and think through the two alpha genes and the beta and all the different types of hemoglobinopathies that we see in the world.

0:54:38.8 DS: And Deanna, this was an excellent presentation. Really appreciate you coming on, walking through just the inequities that have led to where we're at today, and we clearly still have work to be done. So very exciting research, and I'm glad that there's such an effort going on right now and that you're part of it. And Deb, thank you so much for coordinating these two folks, and sorry, we had to bump your spinal muscular atrophy [chuckle] discussion.

0:55:09.8 DB: That's okay. Bethany, the first author on the paper I briefly touched on, and she'll be delighted actually she was really bummed she had a prior engagement. So it might work out for the best.

0:55:20.4 DS: Yeah, we can definitely plan something in a few months and then come back to... Maybe we'll do a fall prenatal conference review. Maybe we can...

0:55:24.6 DD: I'd love it.

0:55:25.1 DS: Take her in there. Alright. Well, thanks everyone. Have a great rest of your day, and yeah, join us April 12th. Thanks Shelly for running the chat and putting some of those things in there as well.

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