“Fragile X Screening” – with Dr. Tamar Goldwaser

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.

All right. Tamar, Dr. Goldwaser, thanks for coming back to the podcast. So happy to have you.

Dr. Goldwaser: Thank you. Happy to be here.

Dr. Fox: Wonderful. So we’re going to be talking today about fragile X and screening for fragile X in pregnancy, which is a very interesting genetics topic.

Dr. Goldwaser: Yes, it is. Yeah, we could screen for it in pregnancy or, you know, even better, to screen for it before you’re pregnant.

Dr. Fox: So, what exactly is fragile X as a condition?

Dr. Goldwaser: Fragile X is the most common inherited form of intellectual disability seen in boys. And so that’s, in general, it can manifest as more severe or less severe, but usually will either have intellectual disability, behavior issues, or sometimes autism features as well.

Dr. Fox: And the interesting thing is that the reason it’s more common in boys is that it’s one of the genetic diseases that we call X-linked, which people may be getting flashbacks to high school biology, and maybe sweating a little bit. But just, can you explain what that means to be an X-linked disease and why that would be more common in boys rather than girls?

Dr. Goldwaser: So X-linked means that the gene responsible for the condition is found on the X chromosome. And so an X chromosome is one of the sex-determining chromosomes. Most of the time, females have two X chromosomes, and males have one X and one Y. And so if you have a change in a gene that’s going to give you a disease and it’s on the X chromosome, then it’s going to show up more often and be more severe in a boy because he doesn’t have a second X chromosome to fall back on. And so if a girl has two X chromosomes, one has a mutation, but the other one doesn’t, she’s more likely to at least have 50% normal functioning of that other gene to carry her through. Whereas a boy has nothing else to fall back on. Every cell in his body is going to have just one X chromosome, with that one mutation, and so you’ll see the manifestation either more severely or at all. Sometimes girls can just be carriers of an X-linked condition.

Dr. Fox: Right. And before we, sort of, had the molecular genetics understanding of this, this was just known for certain conditions and was, sort of, mapped out on what we call a pedigree where you see, in a family, that it only affects boys and, you know, that it’s passed from, you know, mother to son, and not from father to son. And so this is one of the things that they, sort of, worked out conceptually but then figured it out molecularly later. Like, hemophilia, for example, is one of them.

Dr. Goldwaser: Right, exactly. So the royal family had hemophilia, and they were able to trace it back with a family tree or a family pedigree that showed, yes, that it was inherited through the mothers, and you saw it manifested in their sons. And then even their daughters could have sons who could also manifest the condition.

Dr. Fox: Right, exactly. And it’s one of these things that they teach you, that the reason it’s not passed from father to son is because if the father has the condition, that means his X chromosome has the mutation, but if he has a son, he’s passing on his Y chromosome and not that X chromosome. So he would only pass it to a daughter, and that daughter would typically be what we call a carrier, sort of, like, not have the condition, because one of her X chromosomes should be normal, presumably.

Dr. Goldwaser: Right.

Dr. Fox: This is where you gotta, sort of, really draw those trees to figure it out.

Dr. Goldwaser: Sometimes, like, let’s say colorblindness, you know, classically, you see it in men, but it’s because there’s a gene on the X chromosome that is responsible for certain types of colorblindness. So if a female inherits that mutation, then she might actually sometimes have some level of colorblindness, but because she has another X chromosome that’s functional, she may not have it as severely. There’s also this really cool concept of X-inactivation mosaicism, where females do have two X chromosomes, but in each individual cell of her body, she’s only manifesting one of those X chromosomes. And so it can get really interesting with these X-linked conditions.

Dr. Fox: Right, because, sort of, the first, sort of, level of thinking about it is, conceptually, like, when you’re learning biology, is you say, “Okay, it’s like a recessive condition, but it’s on the X chromosome.” But it’s not really like that because most recessive conditions where you need two copies of the gene to be abnormal that don’t have this inactivation, and most of the time, carriers have no manifestations. But with the X ones, they can have some because those chromosomes act a little bit differently from the other 22 pairs of chromosomes. Yeah, interesting. And then, for this particular condition for fragile X, the gene in question, they call it the FMR1 gene. It’s an unfortunate name because it stands for fragile X mental retardation, which is, sort of, how they name these. So typically, we just call it FMR1. And one of the really fascinating things I find about this is it’s not actually a mutation as we think about mutations. Like, it’s not a change in a base pair in the DNA. Can you explain exactly what’s going on in this gene that makes it so fascinating?

Dr. Goldwaser: Yeah. It’s very cool. The building blocks of DNA are made up of these base pairs made out of nucleotides. There are only four of them, and we could name them as A, C, G, and T, for short. And in the FMR1 gene, there’s a region where there are these multiple repeats of CGG, CGG, CGG. And you could have up until 45 of those repeats and it would still be considered a normal version of the gene. But once the number of repeats gets higher, so when it gets up to 55 or it could go all the way up to 200, then you could be called either a premutation carrier or you could have the full mutation causing fragile X.

So those repeats exist, and in people who are not even carriers, they have these certain number of repeats. It could be 30 repeats, it could be 29 repeats. But once the number of repeats gets to be too many, that section becomes what’s considered unstable. And it means that when you pass on that gene to your progeny or to your children, it’s a little shaky and that it’s more likely to increase the number of repeats. It’s almost loose and the repeats increase. And so a mother can have 30 repeats, and as long as it’s under 45, it’s considered stable, and she can pass it on, and it’s not going to increase. But once she has 50 repeats or 55 repeats, then when she passes on that gene to her children, it gets a little more unstable, and the number of repeats can start to increase as it gets passed along through the generations.

Dr. Fox: Is the instability of it the reason it was called fragile X, like, why the word fragile was used?

Dr. Goldwaser: Yes.

Dr. Fox: It’s like an odd name for a condition where it’s like they’re saying the disease is the X chromosome, the X chromosome is fragile, which is an unusual…we don’t normally refer to genes that way. It’s so interesting because, again, everything we learn in biology, it’s always this idea that you carry something, that you have this single mutation, one of those letters is wrong, and because of that, it throws off the whole gene, and you pass it on this. But here, we’re talking about, essentially, the gene looks exactly the same for everybody except it’s just how many of those repeats are in the middle there. Is it, you know, is it 10? Is it 20? Is it 30? Is it 40? And if someone has a very long one, then what happens is we’ll talk about what it means with that person, you know, herself or himself, but then when they pass that on to the next generation, it gets longer. And so it’s only at risk for getting longer and getting worse, so to speak, based on the starting length

Dr. Goldwaser: So what happens is this. We call it an allele. An allele is a variety of a gene. And so as long as your allele is under 45 repeats, you’re considered to not be a carrier. When you have 45 until 54 repeats, it’s called an intermediate allele. And then when you have 55 all the way up to 199, it’s called a premutation allele. Then this other crazy thing happens, that once you get to 200, the entire gene gets turned off, and then you get fragile X syndrome. So once it gets to be too big, there’s a process called methylation where carbon atoms are attached to the DNA itself and shut off the expression of that gene. And so once you get to 200, you have the gene, it’s turned off, and then you see children who have fragile X syndrome.

Dr. Fox: So if the boy has a Y chromosome and then his X chromosome has over 200 repeats, he will have fragile X syndrome, he will have the condition. And if he has under 200 but over 55, it’s called a premutation, and he does not have the syndrome. There are some health effects on him from it, but essentially, he does not have the condition at all. And if he’s under that, he basically has no manifestations whatsoever. That’s for him, for the child. But for the mother, right, so the mother, it’s not so much what does she have, it’s what is she at risk of passing on. So if the mother has a number that’s over 200, right, she essentially has the condition on one of her X chromosomes, and she may or may not have full fragile X syndrome, but she may not because she has the other X chromosome and it’s, sort of, unique to each person and different, sort of, degrees compared to a male. Correct?

Dr. Goldwaser: Correct.

Dr. Fox: But if she has that 55 to 199 and she’s a carrier, again, there are some health issues for her, which we’ll get into, but the big issue for her is she’s basically fine but she is at risk when that X chromosome gets passed down, if it’s a boy, that it’ll then become over 200, meaning what she has, which is 112, for example, will then be 200. And the risk of that happening is, what? Like, how likely is it if she has that 55 to 199 that, when she passes it on, it will then bump up to over 200 for her son?

Dr. Goldwaser: So the risk increases depending on the size and depending on the number of repeats that she has. So if she’s on the lower end and she has maybe 57 repeats, then there are studies that have studied different groups of these repeats that show it’s a still very low likely chance that, in that next generation that she passes it on, it’s gonna get all the way up to 200. If she has something over 100, if she has a repeat that’s over 100 CGG repeats, it’s much more likely to expand to a full mutation in the next generation. So it becomes more and more unstable with an increasing number of repeats. And then we always have to add into the calculation, she still has another allele that’s normal. So if she passes on just randomly, half of her children will get her stable allele or, you know, the one with the normal number of repeats, and only half of her children will be predicted to inherit her expanded allele and would be at risk for having fragile X syndrome.

Dr. Fox: Right. So when a woman gets screened and finds out what her fragile X gene status is, and she finds out that she does carry this premutation on one of her X chromosomes, in terms of the counseling, it’s what the likelihood she’ll pass it on to a child. So number one, it’s 50-50 whether the child will get the good X chromosome, so to speak, versus the one with the premutation. Number two, it’s also 50-50 whether that X chromosome is gonna get paired with a Y chromosome, putting the boy at risk, versus another X chromosome, so that’s another 50-50. And on top of that, there’s the percent of it expanding to the full mutation or the full fragile X based on how many, like, what her number is. So meaning, if she’s at 60, it’s much different from if she’s at 160. And also, that 50%, 50%. So it’s always a math game in terms of the percent likelihood that she’ll have a son with the condition, correct?

Dr. Goldwaser: Yeah, exactly. Everyone gets a slightly different counseling depending on what their finding is. In general, for doctors, learning about this condition, if someone has over 100 repeats, it’s very likely to expand to a full mutation versus if it’s under. So you could think of the 100 a some point of reference. But again, there are tables that you can look up that will tell you. So there’s like a list for repeats 55 to 60 and then 60 to 65. So there are differences. It’s definitely a worse condition and more severe condition in boys, but there could be girls who have severe fragile X syndrome as well. So it’s classically thought of as a syndrome of boys, but there are girls with fragile X syndrome who have pretty severe difficulties and learning issues or behavioral issues that are classic for fragile X.

Dr. Fox: Right.

Dr. Goldwaser: Again, we’re more worried when it’s a boy.

Dr. Fox: Right. And there’s also…aren’t there other factors regarding the gene that might help predict the likelihood of the condition in the children, you know, in terms of like the methylation tests? There’s other nuances that are there that affect it beyond just the number of repeats. Correct?

Dr. Goldwaser: Yes. So, well, what happens is, for whatever reason that I don’t understand, I’m not sure if it’s been out there, but after you get to 200 repeats, then the whole gene gets methylated and it gets turned off. And the genetic testing to count the number of repeats is actually complicated because they have to figure out how large is the protein product, and based on the size of whatever test they do, they could do DNA testing, RNA testing. They have to predict based on that size the number of repeats. And so, sometimes they’ll say it’s, give or take, one or two repeats. And once it gets to be really large, it gets even harder to give you an exact number. So you’re not commonly gonna see a number like 180. They’ll just say it’s very big, and then they have to check to see, is it methylated or is it not methylated? So that’ll be like the next level of testing to say, “Are we there yet, or are we not there yet?” Because it’s hard, based on the different genetic testing methodologies to give an exact number of repeats. As it gets bigger, it gets more difficult, and so then they’ll add methylation testing because we know once you’re at 200, the gene gets methylated, gets turned off, and then you have the condition.

Dr. Fox: Right. And so this is really one of those tests where the results, unless they’re like normal-normal, need significant counseling afterwards to sort out exactly what it means because I find that a lot of people don’t quite get it after they get the results.

Dr. Goldwaser: You know, sometimes people will have their test result, and just because of the way that the report looked, like maybe it wasn’t bolded, it can be looked at and seen as normal because there was no mutation there, but the report might just tell you that there are 55 repeats, that she has 1 allele with 55 repeats and 1 allele with 30 repeats and just leave it at that. So yeah, the doctors have to be discerning when reading the report, and then some people can get counseling that you’re gonna have a baby with fragile X. And so, definitely, these results have to be brought to someone who’s well-versed in genetics to break it down, and each person gets their own individual counseling because as we said, it depends on a lot of factors.

Dr. Fox: Right. I find that one of the confusing things for patients and also for a lot of doctors is when someone gets that result between 45 and 54, what we call the intermediate because it’s not normal, but it’s not even the premutation, meaning the likelihood of an intermediate turning into a full disease in the next generation is essentially zero. I mean, it’s been reported in the history of, you know, humankind, it’s basically zero. But it does put you at risk for passing on the premutation. I mean, the intermediate can expand to become the premutation.

So what ends up happening is when people, sort of, figure out what’s going on, the woman who’s getting tested, and she founds out she’s an intermediate, what she’s finding out is that her grandchild might be at risk for getting fragile X. I mean, this blows people’s mind that they’re thinking about their grandkids when they’re, you know, getting screened for their… they haven’t even had a kid who’s born. But they sometimes think that, “Oh, this is abnormal. My child could have fragile X.” And the answer is, “No, your child will not have fragile X. Your child may carry fragile X.” And again, there is some implication to carrying fragile X, which we’ll get into, but they won’t have the condition. I find a lot of people get confused with that.

Dr. Goldwaser: Yeah, definitely. And then it’s all about counseling, and we’re living in the age of, you know, I feel like the doctors, we have to explain what medicine and what treatments are available. And then different people take this information differently, but most couples, once they learn, “Okay, if I had an intermediate allele, I have 44 repeats, then the chances are maybe I’ll have a child who has a small premutation, you know, in the 50s. It might expand.” And then we do end up talking to people about, well, patients who have a premutation do have some risk for other manifestations when they’re grownups, not fragile X at all, but we can talk about the other manifestations that premutation carriers have.

Dr. Fox: Sure, let’s do it now.

Dr. Goldwaser: Women with a premutation, about 20% of those women are at risk for premature ovarian insufficiency. And in English, that’s just basically premature menopause, where the ovaries stop ovulating and stop, you know, giving you that cycle, and you lose your fertility a lot sooner than your average cohort. So people can learn this, and let’s say they come to start having children at age 35, they may discover that they actually are not producing a lot of follicles and they have low fertility. So that’s one condition that’s definitely well understood and documented in terms of premutation carriers. And then, in men and women, there’s a risk for developing something that can look like Parkinson’s disease if you have a premutation carrier. So it’s called fragile X tremor/ataxia syndrome, and that shows up, again, also, you could think about 20% more often in men than women can develop a tremor and sometimes psychiatric disorders. That usually comes on in your 60s or later. And so those are two conditions that we know about. They’re not something that people really wanna start thinking about when they’re like 10 weeks pregnant like, “Will my child potentially be at risk to develop this when they’re in their 60s?”

So the conversation can get pretty complicated. And also, when people do general carrier screening, like let’s say a couple is getting married, and before they go to have children, they do carrier screening, they’re out there not to look for diagnosis in themselves or to find out that in the future they’re at risk for this or that. They’re looking to see, “Am I a carrier for something that may affect my child if my partner and I are both carriers?” But in this instance, with fragile X testing, you might learn, if you’re a woman, that you’re at risk for early menopause, or you might learn that you might be at risk for something that could look like Parkinson’s disease in your 60s. And at this point, there’s no pill that you would be able to take to, let’s say, prevent that from happening. So it’s a hard piece of information to hear about when you’re thinking about having children.

Dr. Fox: Right. And some women learn that they’re carriers, again, just, sort of, on the screen, it comes up to like, “Hey, you know, who knew? How about that?” And others find out when they’re actually trying to have children and they’re having fertility issues, and then they go for a workup, you know, “Why am I having a problem getting pregnant?” And then, ultimately, it’s found out, “Well, your follicle count is low. You know, sort of, your ovaries aren’t functioning the way they should.” Like, “Wait, but I’m, like, 32.” And they find out that this is the reason. And so it does add a layer of complexity, and it’s something people should know about and, you know, when they screen, like you said, the counseling.

And I find another fascinating issue is this is one of the few conditions we check for in a carrier screen where it usually doesn’t matter at all what the father’s status is. Meaning, typically, in a carrier screen, sort of, the tenet is, and we had an old podcast on this, like if the mother’s a carrier and the father’s a carrier, then there’s a one in four chance of the child having the condition, you know, the Punnett square and everything. But for this, it really doesn’t matter what the father is, because it’s not about his X chromosome or his Y chromosome. It’s really just if the mother is a carrier. Now, yes, if the father is a carrier, as we said before, his daughters can become carriers, but it’s not typically part of the screen to see what his fragile X status is. It’s really just the mother’s.

Dr. Goldwaser: Right. It’s very interesting because if couples compare their carrier screening test results, they’ll see that she was tested for one more condition than he was. Because on males, it’s not included on the carrier screen. Another fascinating thing is that the X chromosome allele, the FMR1 allele, is only known to expand when it’s passed on from a mother.

Dr. Fox: Right.

Dr. Goldwaser: When it’s passed on from a father, it stays stable and the number doesn’t increase.

Dr. Fox: It does not expand in sperm, for some reason.

Dr. Goldwaser: So that’s a reason it’s not offered for carrier screening, but men could get tested if either the condition is expected in a boy, they could be tested, but also if someone has a sibling and they wanna know their daughter’s risk to be carriers, men can be tested but it’s not included on your routine carrier screening for men.

Dr. Fox: Right. What typically happens is, you know, a woman comes in either ideally prior to pregnancy or early pregnancy, and we say, “Okay, we’re gonna check you for, you know, your genetic carrier screen.” And so focusing on just the fragile X portion, she’s gonna get tested, and the results are gonna say the length of her repeat region and each of her chromosomes, and she’ll get, you know, “This is the number for one chromosome. This is the number for another.” And most people will get back normal results, and they’re not at risk of having a baby with fragile X, right. That’s just sort of, like, typical.

Dr. Goldwaser: Right, yeah.

Dr. Fox: And then there are some people who will get back this intermediate where, again, they’re okay, their children should be okay, but there is that conversation about there’s a potential for their children carrying fragile X, which might have some implications in adulthood for them and for their own reproduction. And that’s, sort of, the hard one to do. Okay. And the next level is they’ll find out, “Oh, I’m actually a carrier, and I have a certain number of repeats.” And then that’s when you need significant genetic counseling and say, “Okay, what does this mean? How many numbers? What is the chance I’ll have a child? What do I do? If I’m not pregnant, do I wanna do IVF and then PGT, preimplantation genetic testing, you know, to either only select girls or to make sure, if it’s a boy, it doesn’t have, you know, the expanded?” Is that possible for PGT for this?

Dr. Goldwaser: Like, let’s say you have a premutation, so it’s anywhere from 55 to 200 repeats. You can first have a discussion with someone and find out, “Well, what are my actual chances of having a baby with the full fragile X syndrome?” And if you decide you wanna try and see if you could avoid this altogether, you can go have IVF, create embryos in a lab, and test each embryo. And yes, the lab can tell you if the allele that was inherited was the one that carries her expanded allele. So basically, again, because that testing is really tough to count the exact number of copies, they will tell you, “This is the one. You passed on your FMR1 gene that does have that expansion.” And then if that’s what’s identified, they can test for…so they can tell you if they inherited the one that is larger or if they inherited the normal allele.

Dr. Fox: Can they tell you if it expanded?

Dr. Goldwaser: It’s very hard for them to do that count, but you can find out that it inherited the allele.

Dr. Fox: You can find the ones that are certainly normal, and the ones that are “abnormal,” you wouldn’t know for sure if it was abnormal carrier or abnormal mutated. And so you can do that. Okay. And if they’re already pregnant, you can’t change what’s gonna be for the baby, but you could do an amniocentesis, ideally, or maybe a CVS, because it’s like a unique thing, it’s better do an amnio to, sort of, find out, does the baby have the condition or not have the condition?

Dr. Goldwaser: Exactly, because methylation is a process that doesn’t happen at conception, it happens a little bit later. And so we wanna be sure that the methylation process has happened and we’re detecting it. So that’s why, classically, we would do an amnio to check and see if it’s a very high risk.

Dr. Fox: Right.

Dr. Goldwaser: Smaller alleles, they could count. The ones that are getting really close to 200 are harder to count, and then you wanna be able to check the methylation status. So you can have an amnio, and we can tell you, “Okay, this is a boy, 46, X, Y are the chromosomes,” and they look at the FMR1 gene, and it is methylated. And so this is a boy predicted to have fragile X syndrome.

Dr. Fox: And I imagine that, rarely, but you know, ever so rarely, there’s probably someone who gets screened for fragile X and finds out that they actually have a full mutation on one of their X chromosomes, and they’re just one of the people who had very minimal manifestations of it.

Dr. Goldwaser: Yeah, much more common in females. We don’t know, right. We just don’t even know how many women are out there living their life, doing their thing, and they actually have fragile X. They have a full mutation. One of their alleles is completely turned off and not working. But again, probably because of the X-inactivation process, some women, in lots of X-linked conditions, can have no manifestations because it could be that the X chromosome that has the fragile X mutation or that has a full expansion was preferentially turned off in most of the cells in her body, and so she’s actually manifesting or only expressing her normal X chromosome. And so, yeah, it’s actually common, and we don’t know the number of women who are undiagnosed.

Dr. Fox: Right. It’s really a fascinating topic, and I think, for most people, you know, the takeaways that I think are important, number one, this is really, A, interesting, and B, complex. For most people, they’re gonna get screened, they have normal results, they don’t really have to think about this. Like, they’re good to go. But if someone gets a result that’s anything but normal, it’s important to take a step back and make sure that you have the right information about exactly what that means, right, and to make sure, “Hey, how abnormal is this? Is this something where my children are at risk for having this condition? To what degree? Or are they not at risk for having it? And again, if they’re gonna be carriers, what does that mean? If I’m a carrier, what does that mean for my own health?” And have real conversations about that, because it’s not just, like, normal/abnormal. There’s so many levels to this, and it’s important to get very individualized counseling. So this is not something where you really just want to go online and say, “Hey, what does it mean?” You want to have someone who understands that could be very precise with the counseling for you individually based on your results.

Dr. Goldwaser: Yeah, definitely. And you know, once you get tested, these results don’t change, because if you’re born with a certain number of copies, that’s what it is for the rest of your life. And some women might actually use this information to make certain life decisions. So you might learn that you have a fragile X premutation, and you might decide, “I’m not gonna defer trying to have my first baby for the next five years. I might actually just check in with my OB-GYN and see where my fertility status is right now,” because there’s an option for women who have a fragile X premutation in which they may just pursue something called egg freezing so that they at least have a backup in case they do lose their fertility. Because most premutation carriers don’t actually end up with premature ovarian insufficiency. There’s a lot of utility there in terms of the testing, but yes, phone a friend and pursue people who feel comfortable talking about fragile X, which could also be in the pediatric world as well.

Dr. Fox: Right, right. In the pediatric world, that’s certainly for children who have the condition for fragile X. But in terms of, like, interpreting your carrier results, I would probably either start with your OB-GYN or whoever sent the test, but obviously, a genetic counselor or someone like you, you know, a medical geneticist, but certainly, you want it to be someone who can give you personalized, individualized counseling based on all of the relevant factors because there’s a lot. It’s not just, you know, A or B. There’s a lot of options.

Dr. Goldwaser: Definitely.

Dr. Fox: Tamar, fragile X, did it.

Dr. Goldwaser: Fragile X.

Dr. Fox: Thank you so much, and we will…obviously, we’ll speak again.

Dr. Goldwaser: Take care. Bye-bye.

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 hw@healthfulwoman.com. Have a great day.

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