Geneticist Dr. Tamar Goldwaser joins Dr. Fox for an updated discussion on carrier screening and how it is recently changing and becoming more accessible. In previous years, different genetic tests were offered to people based on their reported ethnicity, but self-reported ethnicity is not always accurate. By looking at carrier frequencies across demographics, Dr. Goldwaser and a team of medical geneticists in the American College of Medical Genetics and Genomics compiled a list of 113 genes that every patient should be screened for during their prenatal care.
“Carrier Screening Revisited: The case for universal, expanded carrier screening” – with Dr. Tamar Goldwaser
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Dr. Fox: Welcome to today’s episode of “Healthful Woman,” a podcast designed to explore topics in women’s health at all stages of life. I’m your host, Dr. Nathan Fox, an OB-GYN and maternal-fetal medicine specialist practicing in New York City. At “Healthful Woman,” I speak with leaders in the field to help you learn more about women’s health, pregnancy, and wellness. Dr. Tamar Goldwaser. Tamar, welcome back to the podcast. How are you doing?
Dr. Goldwaser: Thanks, I’m great. Thank you. Thanks for having me.
Dr. Fox: So, we’re here to talk about the wonderful world of genetics, the WWG, the best world there is. And we’re doing an update on carrier screening or carrier screening phase two or carrier screening advanced level course. We did a podcast three years ago now in July of 2020 on sort of the basics of carrier screening. It wasn’t a basic podcast, we went pretty deep into it, but sort of like an introduction to it. And so, our listeners can obviously refer back. But we got more to talk about. Carrier screening is really front and center now, yes?
Dr. Goldwaser: Absolutely.
Dr. Fox: Beautiful.
Dr. Goldwaser: My favorite topic.
Dr. Fox: You know, it really is fascinating because there’s like the science behind it and the medicine behind it and sort of like the practical nature of it. But there’s so much else. There’s sort of, you know, there’s cost, there’s different labs, there’s geographic variability. There’s all this confusion and disagreement about what to do with, you know, race and ethnicity. And it gets confusing with carrier screening. It seems like a very simple concept, but it gets really confusing out there. And I know that it’s so different all over the country.
Dr. Goldwaser: Yeah, that’s one of the craziest things, is that depending on where you get your care, you’ll get offered a lot of carrier screening or no carrier screening or somewhere in between. Yeah, it’s, it’s definitely disparate at this point.
Dr. Fox: And, I know that you were part of, I guess, a committee or a group or something, a consortium to address this on a national level. So, talk about that a little and impress all our listeners with how cool you are and famous.
Dr. Goldwaser: Okay. Yes, So, my pleasure. So, in 2021, I was part of a group, and we put out a new practice resource titled Screening for Autosomal Recessive and X-linked Conditions for the American College of Medical Genetics and Genomics.
Dr. Fox: I’m gonna stop you right there. Tell me about this group. How did you get selected to be in this group, this super high-powered group?
Dr. Goldwaser: So, I’m a member of the American College of Medical Genetics because I’m a board-certified medical geneticist, and I’ve stayed involved. It’s how I keep connected and learn what’s new in genetics. And I’ve always been part of different..there’s a group called the Practice Guideline Group. And I’ve been involved in several of them, and this was the most recent one. I think that they asked me to do it because, you know, I represent the OB side of genetics, whereas some other people do genetics from the pediatric side or from the lab side. So, I spend all day with the OB department or OB patients. And so, it brings a different piece to the puzzle.
Dr. Fox: Okay. So, you’re part of this elite squad of medical geneticists, like the A-Team of medical geneticists brought in, and you guys are sitting around a table. And what is the problem you’re trying to solve while you’re sitting around talking about this?
Dr. Goldwaser: All right. So, the problem is that the old model of carrier screening had some issues. So, it used to be, and it probably still is in a lot of places, that depending on your reported ethnicity or reported background, you were offered different tests. And this was done initially because genetic testing in general was very, very expensive. And so, public health and doctors wanted to be mindful of the cost and not recommend expensive tests in groups of patients who are very unlikely to need the test or to have a positive result.
But a lot has changed. So, first of all, genetic testing has become much more efficient. The technology has advanced tremendously in the past 10 years, and it’s also become much, much more economical. And so, testing is not as expensive as it was. Instead of thousands of dollars, it’s down to just a few hundred dollars.
And the other thing that changed is that, actually, we’ve learned through some of the direct-to-consumer testing genetic labs like 23andMe and Ancestry, a person’s self-reported ethnicity is notoriously flawed and wrong. And people are learning, “Hey, I have this in my background, or I have 20% of this ethnic group or country of origin in my background.” And this is because, over the past several decades, there’s been a lot of population mixing or blending. So, it’s a beautiful thing in this country, but people don’t live in their silos the way we used to think of it.
And so, for those reasons, we said only offering genetic testing to some patients was not fair or equitable. You know, it wasn’t providing good care to all of our patients. And it was also just scientifically flawed because we know actually people may not know their true ethnicity or their ethnic background. And so, you may be missing genetic carriers because you ruled it out from the beginning.
Dr. Fox: Right. So, just to sort of state it again, you know, just to clarify, because this is a really important point. We were training sort of, and it’s still again, it exists in many, if not most parts of the country. They would say, “Okay, every pregnant person, you know, who we’re checking for genetics, we’re gonna check for this one condition. And if you’re, let’s say, black, we’ll check for these extra two conditions. If you’re Mediterranean, we’ll check for these conditions. If you’re Ashkenazi Jewish will check for these conditions. If you’re Asian, we’ll check for these and.” You know, sort of like go through it and say, “All right, what are you?”
And okay, so I say, “All right, I’m Ashkenazi Jewish.” Great. But I don’t know. Like, that’s just what I am. That’s how I identify, that’s how I think I am. And maybe it’s true maybe it’s not true. But for all I know, my great-grandmother was Mediterranean or Asian or whoever. And so, this is really an issue, like you said, not just on the sense of like, you know, what we talk about, like being equity, like someone’s not getting tested for things and we’re sort of like not doing right by them, but also this idea that you can sort of determine what someone’s at risk for by asking them, “Hey, where are you from? What’s your ethnicity?” And like that doesn’t like…someone says like, “I’m black.” Like, okay, well, you could be from like 100 different places, right? And you could have a crazy different ancestry. That doesn’t mean much. I say I’m Jewish. What does that mean? Like, I’m converted, you know?
Dr. Goldwaser: Yeah. People have no idea. Right. People really, really have no idea. And it ended up being… You know, it’s even hard when you’re trying to do research. I’m sure you’ve encountered this. You usually have to try and define the demographics of your patients. And sometimes it’s hard to decide what category to put someone into because of that exact problem.
Dr. Fox: Yeah. So, that was the problem. And what solution did you come up with?
Dr. Goldwaser: Okay. So, there was actually a paper that was a joint statement that was put out by ACOG and the which is the American College of OB-GYN and the Society for Maternal-Fetal Medicine, and also the Genetic Counseling Society a few years ago that basically offered a suggestion of screening for any condition with a carrier frequency of greater than 1 in 100. So, that would mean that if you sample 100 people in the United States, 1 is supposed to be a carrier or is expected to be a carrier. And that was the beginning of how we approached this.
So, we had a team of nine of us, and what we decided to do was comb something called ClinGen, which is a database of all the known genes and look for any gene that is known to have a carrier frequency of 1 in 200 or greater in any population in the United States that has reasonable representation. So, any gene or gene that’s that we know to be mutated or an issue with a specific gene, with a frequency of anything more than 1 in 200, and it doesn’t have to represent the entire United States, but any population that represents more than 1% of United States, like Ashkenazi Jews or Puerto Rico, for instance, those groups were also taken into account. And so, with that, we devise a list of 113 genes that we recommend every single patient to be screened for when they’re preparing for a pregnancy.
And so, the list was put out and we understood it was gonna take time for things to pick up. But slowly, labs have adopted and are using that list to create a carrier screening panel that will be offered. And at least they could say, “Here, this list or this group of genes, you can offer it to your patient and you’ll be covering all of the conditions recommended by the American College of Medical Genetics.”
Dr. Fox: And then, so just to be clear, until this or if people aren’t doing this, you may be tested for 0 conditions, 1 condition, 5 conditions, 12 conditions. Those are the numbers you’re talking about. And you’re saying that you guys recommended that every person who gets screened, every person should be screened, and that panel should have at least these 113 conditions because they’re prevalent enough that no matter what your ancestry, if you’re sitting in the United States, you’re going to pick up something that’s not crazy, crazy, crazy rare, but, you know, prevalent enough that it’s reasonable to be screened for it. And that every lab that has a panel should include at least these 113 conditions.
Dr. Goldwaser: Exactly. Sorry, one more thing. So, we chose the genes not just by the prevalence like the carrier frequency, but also by severity. So, the genes that were selected were also, these genes should be very strongly correlated with disease. It shouldn’t be confusing. And it should also be very strongly correlated with things that are considered to be, you know, relatively more severe or, you know, significant in terms of the impact on a person’s life.
Dr. Fox: Right. I mean, we’re not screening if this kid is gonna be a lefty or righty. We’re not screening this is gonna be, you know, 5-7 or 5-10. We’re screening for, you know, is this kid gonna have a disease? And again, the tenet is that if the mother is a carrier and the father is a carrier, then each child has a 25% chance. There are some exceptions based on the exact gene, but basically, that’s the autosomal recessive model. So, the sort of what happens is, typically, one person, you know, the mother gets screened first and anything she screens positive for, they screen the father to make sure that, you know, that they’re a match, so to speak. There’s other sort of ways to do it, but that’s the most common.
Now, essentially, what you’re saying before is that doing this, the cost is really not different than having 2, 5, or 12 tested. Meaning whatever the cost is to the insurance company or if someone’s paying out of pocket or their co-payments or whatever might be, is really not markedly different.
Dr. Goldwaser: Right. Yeah. Because what happens is the way that they do carrier screening in a lab now is that they’re using something called next-generation sequencing for the most part. And whether they report 14 genes or 10 genes or 100 genes, it’s usually already data that is available from their testing procedure. It’s just a matter of how many things they’re gonna report on. So, yeah, the cost is actually not different.
Dr. Fox: Yeah. And, I think that’s something, yeah, that’s a massive difference. And, I remember, you know, when I was getting screened 150 years ago, you know, I get married and there’s like five genes. I’m like, yeah, that’ll be $1,800. Like, what? Yeah, like, say what?
Dr. Goldwaser: Just crazy.
Dr. Fox: Like, Oh, my God. And so, you can understand why. Like, listen, man, we got to really limit this. Like, we cannot have… Like, first of all, it’s just not tenable. You can’t get everyone to, you know, like, you know, I was a med student, they cut me a deal. I dont think I was… Was I? Yeah, I was a med student. So, it’s just such a difference. And so when people are thinking, is this, like, wasteful? It’s really the same cost. And we’ll talk about it at the end of the podcast, like, some potential. I wouldn’t call it a downside because I think it’s important, but some sort of consequences of knowing more about your genetic makeup than not knowing.
But it’s not an issue of cost. It’s not an issue of availability. Like, you can get these tests pretty much anywhere in the country. There’s lab you can… You can go online and like have this done. It’s not complicated logistically to have your carrier screen done. It just has to be something that your doctor or midwife offers. That’s really it. It’s not particularly complex. And yeah, that’s a big message.
Dr. Goldwaser: It’s a huge message. I think it’s a huge message for doctors too. I think that we all grew up and trained and had experience with genetic testing being so expensive and cost prohibitive that we were trained to be selective about when to use it. But the message is the cost is much, much lower than you remember, and it’s recommended for every single patient.
Dr. Fox: Yeah, I mean, it’s just… Listen, for most couples, it doesn’t matter. Meaning most couples when they go through this testing are gonna find out that as a couple they’re compatible. Meaning one may carry something or likely will carry something and one will likely carry something else. But it’s not the same thing, then it’s fine. And so, had they never done it, they’d get away with it. But the problem is if you happen to be in that one or two or three or whatever percent of couples who it is an issue, there is no way to know about this other than doing screening or having a baby that’s sick, that’s it. Right?
Dr. Goldwaser: Absolutely. You can’t rely on your family.
Dr. Fox: Because these things, they don’t pop up in your family history because you have to actually procreate with someone who’s also a carrier. So, if, like, if I’m a carrier of Tay-Sachs, I very likely will not have anybody that I know about in my family who ever had Tay-Sachs. The only way I’m gonna find out is if I get screened or if I have a baby with Tay-Sachs. That’s it. And that’s really not…like that’s best avoided. You know, it’s really something that you wanna screen for in advance because, again, there’s just no other way to find out. And since, you know, you get away with it, 97%, 98% of the time, you don’t hear these stories that often of couples who weren’t screened and they have a baby. But we do hear these stories.
I know people who this has happened to, like I know patients who this has happened to, it absolutely does happen. So, it’s an important message that if you are thinking of having kids or you are in early pregnancy, you should ask your OB, your midwife, your family practice doctor, whoever you’re seeing, “Have I been screened? Have I done carrier screening?”
Dr. Goldwaser: Absolutely. Yeah. And in IVF center too. Yeah. And if you’re preparing for IVF and you’re creating embryos and you plan on going that far to try and have a healthy child, then carrier screening has to be done, and definitely ask for it.
Dr. Fox: Yeah. I mean, IVF is critical because if you’re already doing IVF, like, the only solution if you’re both carriers, other than splitting up, the only solution is, you know, to avoid a possible situation is you do IVF, and you can test the embryos if the embryos have the condition and only put in the embryos that don’t have the condition. Now, if you don’t need IVF and you weren’t planning IVF, that’s a big shift from getting pregnant on your own. But if you’re already doing IVF, it’s almost crazy not to do carrier screening because why wouldn’t you wanna know this in advance? You can actually do something about it. You’re already doing the IVF.
Dr. Goldwaser: Yeah, it is crazy to do IVF without carrier screening. You know, you reminded me that another thing is, usually you would think, “Okay, I did it once and I’m finished and nothing’s gonna change,” because when you do carrier screening, you’re testing your DNA that you inherited from your mother and father when you were born. However, if you did carrier screening more than a few years ago, you might not have had adequate carrier screening given the new guidelines of the 113 conditions and beyond. And so, I think it’s also worth re-addressing, and with each pregnancy, at least, with each planning of a new pregnancy and with each new reproductive partner. So, if you’ve done it in the past with another partner, don’t remember exactly how it worked, but it all worked out, and now you’re having a new reproductive partner, it’s worth taking another look at carrier screening.
Dr. Fox: Yeah. And also, just to be clear, the guidelines that you came out with, which have 113 conditions, that’s the floor, meaning that you’re saying that’s the “bare minimum” that should be tested. But there are panels currently that test over 500 conditions. I mean, there’s a lot more than 113 that are out there. And so, my first question is, why is there so much variation? And my second question is, how did you guys choose to only have 113 and not say you should test as many as are currently available?
Dr. Goldwaser: So, that goes back to our selection process. We called these 113, we called it Tier 3 or Level Three Screening. And then we recognized that there will always be offerings, including more genes. So, we call it anything beyond that as Tier 4. And we knew that that was a moving target because every genetic testing lab does offer larger panels with more genes, hundreds, even thousands of genes, and we don’t necessarily know their selection criteria. And one thing we were really careful about was what we call genotype-phenotype correlation, how tightly linked is this gene to this disease?
And basically, once you get the result, are you able to counsel a family and say, “Yeah, if your child inherits this condition from both of you, they will have X disease and it will look like this?” There are some genes that are newly out there and are less well understood. And so, if you get a result, it’s really hard to counsel the family and say, “This is what the outcome is gonna be.” It’s sometimes there are genes out there where it’s like you could have loose associations with different medical issues, but we don’t actually know the true prevalence and we don’t know how many unaffected people have mutations also. So, we try to stick to genes that have the ability to provide good counseling and thought to be useful. And we also recognize the fact that as more knowledge is accumulated and science progresses, this list has to be updated.
It’s not meant to be static. And we plan to reconvene periodically to, you know, look at it again and reassess. And you asked about the different labs, so, different labs offer different panels of genes. And when we talk about genes, let’s just say, humans have more than 20,000 genes. So, when we talk about carrier screening, it’s not at all fully comprehensive of every gene that can lead to disease. It’s very specific. We wanna look at things that are not really designed to diagnose the parents who we’re testing. So, we’re not looking at dominant conditions, which we could explain, but we’re really just looking at things that are supposed to be more likely to put your offspring at risk, depending on either your partner or if it’s X-linked, depending on how those things go.
So, the different labs all offer a slightly different array, and actually, some of them very, very, very much so. And in our practice had recently switched from one larger panel and, you know, we can discuss. We ended up not using that lab anymore and now we’re using another large panel at a different lab. And the genes are not all the same. And it’s definitely a logistical difficulty. Also, it’s hard to keep track of from pregnancy to pregnancy and from lab to lab.
Dr. Fox: Yeah. Just to clarify a few things. So, you mentioned Tier 3 and Tier 4. So, Tier 1 would be sort of, just like one or two tests for everybody, like old school. And then Tier 2 was sort of what we described before, which is you do one or two for everybody and then sprinkle in a couple extras based on their reported ethnicity. And Tier 3 is sort of what you guys recommended saying, “Don’t do Tier 1 anymore, don’t do Tier 2 anymore. Everyone should be doing Tier 3 or higher,” which is again this expanded panel of 113. And Tier 4 is each lab… Each lab has the right to put whatever genes they want on their tests. It’s not, like, regulated, they’re commercial labs. They could do anything but. But the point of this recommendation is like, “Hey, all you labs out there that are doing this, whatever you do with your Tier 4, you know, crazy expanded panels that are hundreds and hundreds of conditions, please make sure it includes these 113, at least.”
Dr. Goldwaser: Yeah. Right.
Dr. Fox: Got it. And so, because of that, there probably are gonna be someone who’s gonna produce a test that only has 113, but most of them are gonna have, “All right. Ours has 220 tests, but it does include the 113.” Or, “Ours, 508 and it includes the 113,” which is great. It gives some sort of standardization within a system that is inherently different from lab to lab. But you can’t get every lab to do it exactly the same. That’s just not feasible and it’s probably not lawful, but you can at least get them a recommendation that, “Hey, you know, like, at least do this,” right?
Dr. Goldwaser: Yeah. I mean, that actually, I didn’t tell you, that was the other problem that we were setting out to solve. Like, basically, there was no uniform language. And when people said expanded carrier screening, that phrase had no real definition, like, there was no agreed-upon list of conditions that were on that list or who should have expanded carrier screening. And so, it was also a way to sort of get us all on the same page in terms of language and say, “Okay, well, what type of carrier screening has been done, and what is recommended.”
Dr. Fox: Yeah. I mean, in our own practice, I mean, just to give a flavor of sort of the logistics that you mentioned, so, we’ve always been offering, recommending, expanded screening to everyone. But like you said, there’s no real definition of that. It’s based on the lab we chose. So, we were using a lab… We were originally using a test called Inheritest, which was at the time Genzyme, that became LabCorp. And it was like 117 or something conditions. This is years and years ago. Then we switched to lab called Sema4, which is related to Mount Sinai. And their panel bumped up very quickly to 281 conditions. Then they added two more to make it 283 conditions.
So, now we’re like, “All right, everyone got screened for 281.” Now we got to figure out, are we gonna get them all screened for these next two conditions that got added. And that was its own thing. Then they went to 511 conditions. So, we started screening everyone with that. And then we had the same problem, if someone had 281 or 283, do we check the balance? And then that lab shut down. And so, we went back to LabCorp. And then they have a panel that’s 200 and something conditions. And then we’re like, “Oh, God.” And now they’re having one that’s 500. It’s the same thing logistically, but ultimately, that’s sort of the game. That’s sort of how it is, you know, that each lab is gonna be a little bit different.
But it is reassuring to know both as a doctor but also as a patient, “All right. Like whatever shenanigans are going on with all these different tests and which ones are offered to me, which one I get, you know, which lab, where I am, at least I’m getting these 113, which really a bunch of experts said, all y’all should be getting, just to be sure.” And I think that that’s, like, the major lesson from this for our listeners. You know, again, if you are doing IVF, if you’re thinking of having kids because it’s better to do this before you decide to have kids, or if you’re an early pregnancy, ask, “Am I getting expanded screening that is classified as Tier 3, which is at least these 113 conditions.”
If the doctor says, “Yeah, we use this lab and there’s this 304 and it includes them,” fine, you’re good. Like, could you find one that’s 500? Probably, but it may not be, you know, I don’t know if it’s worth looking all over the country to find the exact lab, but make sure it’s at least above this floor, which is what’s recommended, because otherwise, you’re just missing out on an opportunity to find out potentially something you really, really need to know before you start procreating.
Dr. Goldwaser: Yeah, definitely. I love it.
Dr. Fox: Amazing.
Dr. Goldwaser: Good message. One condition on the list is actually really kind of tricky to test for, and I just wanna give it a shout-out. It’s called hemophilia.
Dr. Fox: Hey, hemophilia, here’s your shout-out. Welcome to the podcast, hemophilia. All right.
Dr. Goldwaser: It’s a severe bleeding disorder where people can’t form blood clots after just minor trauma. And so, that is recommended. And labs are actually having a hard time including it in their panels because it requires a different type of lab test. And so, if you have a family history of hemophilia, then you have to be sure to report it and doctors need to know to ask about it. Or, you know, if someone says that they’re worried about hemophilia, talk to your lab, call them, and see if they could test your patient for that as well.
Dr. Fox: Right. Right. Awesome. What I think we’re gonna do, we’re gonna wrap up this podcast and then we’re gonna do another podcast on carrier screening, which is related to the results that you can get and how they may have implications for your own health and not for the babies. Again, as you said before, the intent of carrier screening is to find out for your children. However, there are some of the tests that have some implications for your own health. And number one, we’re gonna talk about some of those. And number two, on a more global level, why that warrants a standardized and sort of organized way of getting carrier screening where you can get the proper counseling if something like that comes up? So, we’re gonna be back next week with Tamar to talk about the next level of carrier screening. Tamar, thank you. This is awesome. Really helpful stuff.
Dr. Goldwaser: All right. Take care.
Dr. Fox: Thank you for listening to the “Healthful Woman Podcast.” To learn more about our podcast, please visit our website at www.healthfulwoman.com. That’s healthfulwoman.com. If you have any questions about this podcast or any other topic you would like us to address, please feel free to email us at firstname.lastname@example.org. Have a great day.
Man: The information discussed in Healthful Woman is intended for educational uses only. It does not replace medical care from your physician. Healthful Woman is meant to expand your knowledge of women’s health and does not replace ongoing care from your regular physician or gynecologist. We encourage you to speak with your doctor about specific diagnoses and treatment options for an effective treatment plan.