Have you ever wondered if your struggle to conceive could be caused by your genes? Today we're going to answer that question and more about genetics and fertility by talking with two certified genetic counselors with CooperGenomics: Sharyn Lincoln and Sheila Johal.
In this episode, we cover:
Infertility is a disease affecting nearly 7% of all couples. It is a highly heterogeneous pathology with a complex etiology that includes both environmental and genetic factors. In this episode we will be focusing on the genetics.
What percentage of infertility can be attributed to our genes?
Genetics and Female Infertility
47,XXX (trisomy X; Triple X)
⁃ What is trisomy X?
⁃ How common is 47,XXX?
⁃ What are the symptoms of Triple X syndrome?
⁃ How common is infertility in women with Triple X?
⁃ Will the children conceived also have this chromosomal abnormality?
Turner syndrome (monosomy X)
⁃ What is Turner Syndrome?
⁃ How common is it?
⁃ What are the symptoms?
⁃ How common is mosaicism with this chromosomal defect?
⁃ How common is infertility in women with monosomy X?
⁃ Will the children conceived also have this chromosomal abnormality?
Single Gene Disorders
⁃ Fragile X (Primary Ovarian Failure)
Polygenic, complex female infertility (environment & genetics)
⁃ Is there a genetic link?
⁃ Is there a genetic link?
⁃ Hereditary leiomyomatosis and renal cell cancer (HLRCC)
⁃ Polycystic ovarian syndrome (PCOS)
⁃ Congenital adrenal hyperplasia (CAH)
⁃ Primary Ovarian Insufficiency (POI)
⁃ Is there a genetic link?
⁃ XXX syndrome
⁃ Fragile X syndrome
Genetics and Male Infertility
⁃ What is Klinefelter syndrome, 47,XXY?
⁃ How common is Klinefelter syndrome?
⁃ What are the symptoms of Klinefelter syndrome other than infertility?
⁃ Is it possible for a man with Klinefelter syndrome to reproduce?
⁃ Will the children also have chromosomal abnormalities?
⁃ How common is XYY syndrome?
⁃ What are the symptoms of XYY syndrome other than infertility?
⁃ Will the children also have chromosomal abnormalities?
Structural chromosomal abnormalities (SCAs) include deletions, duplications,
translocations (balanced, imbalanced, and Robertsonian), and inversions.
⁃ Y chromosome micro deletions
Single Gene Disorders (Cystic Fibrosis)
Why has it been so hard to pinpoint the exact genes associated with male and female
Please pardon the errors, this is an automatic transcription.
welcome everyone to creating a family talk about infertility i'm dawn davenport i am your host and the director of creating a family and we are this podcast but we are also a website full of information to help you in this infertility journey struggle whatever word you want to use for it and that website is creating a family.org so today we're going to be talking about genetics and fertility infertility is a disease affecting nearly 7% of all couples it is a highly heterogeneous pathology that's the fancy way of saying it's complex and it includes both environmental and genetic factors we're going to be focusing today on the genetic factors we're going to be talking today with two experts - genetic counselors sharon lincoln she is a certified genetic counselor at cooper genomics specializing in pgt m. prior to joining cooper genomics sharon worked at the boston children's hospital with specialties in pediatric genetics fragile x syndrome and genomic medicine we will also be talking with sheila joe how she has been with cooper genomics for five years she provides genetic counseling to patients seeking pre implantation genetic testing and is now the manager of the ptt m genetic counseling team she came to cooper genomics after more than nine years at metrohealth medical center in cleveland ohio where she provided prenatal general and cardiovascular genetic counseling services welcome sharon and sheila to creating a family we're so glad to have you here to talk about this complex and really fascinating topic thank you so much thank you so much for having us all right so let's start by kind of getting ourselves grounded and how common this is so what percentage of infertility can be attributed to our genes shayla so right now research suggests that about half of all infertility cases are related to genetic issues but that's not to say that there's one single gene that causes 50% of these issues there are many topics which i know we will cover today that have a genetic component but also have an environmental component and there may be many genes at play but some of the things that we'll be looking at are chromosome abnormalities we'll be looking at inherited conditions that can impact fertility and then conditions like endometriosis where genes absolutely play a role but environmental things play a role as well thank you so now we're going to divide the interview into two sections one who have genetics affects female infertility and then how genetics affects male infertility all right sharon let's begin with trisomy x r 47x x x what is it first of all and then and how does it affect infertility sure so quick crash course with chromosomes
yeah so we have 23 pairs of chromosomes for a total of 46 the first 22 pairs are numbered one through 22 they're the same between men and women that last pair of chromosomes are called our sex chromosomes females typically have 2x chromosomes males typically have an x and a y so trisomy x which is also called triple x is when a female has three copies of the x chromosome instead of two and so that's why you'll see 47x x x 47 total chromosomes extra x chromosome
triple x is actually pretty common it happens in about one and 1000 women there are undoubtedly women out there who don't even know that they have it because the symptoms can be pretty mild so you could have an extra x chromosome and not know it that's interesting yeah so so what are the symptoms so historically people would say oh you know there really isn't anything but as we've looked into this more and more there can be learning disabilities language delay and some social and behavioral issues not ones that are on the autism spectrum but things like attention and executive functioning issues women with triple x tend to have tall stature as well so they may be tall for their age interesting alright so how common is infertility if a woman has 3x chromosomes is she automatically infertile is it more likely and if it's more likely how common how more likely
is not automatically going to be infertile. It's it's actually unclear how common infertility actually is in women with trisomy x or triple x. There's evidence that shows that women with triple x have lower Hmh levels. That's one of the hormones that's looked at infertility workups. But it's really not clear whether this correlates with an increased risk for primary ovarian insufficiency. One of the causes for fertility, further research is definitely needed. So, you know, kind of long answer short is that, yes, there probably is an increased risk for infertility. But what that risk is, we don't actually know.
Okay, so but but that is something that is commonly done in a genetic workup for somebody who is seeking infertility treatment, that a chromosome analysis should be done for somebody who is seeking infertility treatment to look for not only triple x, but some of the other sex chromosome abnormalities that we'll be talking about. Okay. So one of the things that infertility patients have to wonder is if I have a chromosomal abnormality, such as trisomy x or triple x, the is this going to be passed to my children? And if so, then I need to think through whether or not this is something I want to do. So what is the likely Yeah, I mean, it's a real quick conundrum. So what is the what is the likelihood that a woman would pass trisomy x down to their child, female child, obviously. So there actually doesn't appear to be an increased risk of having a child with a chromosome abnormality if you have triple x?
Okay, well, that is like really good news for anyone who has that. Okay. All right. So Sharon, we've talked about having an extra X chromosome. What is it possible to have less or not most women, genetic women, genetically, women have x x is the chromosomes on their last of the DNA strand. But is it possible to have a single x?
Yes, it is. A single x or monosomy. x is also called Turner Syndrome.
Yeah, I've heard of Turner Syndrome. So what it what it? How common is it? And what are the symptoms? Let's talk about that.
So Turner Syndrome happens in about one in 2000 to one and 4000 women. You know, that sounds like a really broad range. But part of that is there may be girls and women out there who haven't been diagnosed. And so the studies themselves vary in terms of how common it is versus not. Yeah, it's an interesting thing with genetics, isn't it? Because we, we don't automatically test our genetics do our genetic testing, unless we usually have a have an issue have a problem, in this case, women seeking are men seeking fertility treatment. So it's like our population that we test is skewed towards those who have issues it would seem to me is that exactly. Yeah, that is absolutely true. Yes. So it makes it hard when people like me ask how common it is? Because the truth is, we don't know. Yeah, go ahead. And not only that, it makes it hard to when you look at historical literature or historical information about certain conditions, because historically, we were looking at the most severely affected, we weren't looking at the milder end of the spectrum. And now, with genetic testing becoming more frequent and more common, we have much more of that spectrum. Oh, that's fascinating. That makes so much sense. Yeah, because in the past, it would only be the more severe that would bring somebody into the well, and let's be honest, that the ability to do genetic testing is a relatively we take it for granted now, but it's relatively new in the in the scheme of medicine.
So yes, definitely. What are the symptoms of Turner Syndrome are monosomy x? Yeah, so Turner Syndrome can be can have some signs and symptoms prenatally so on prenatal ultrasounds, you may see an increased nuchal translucency and that's the kind of space between space at the back of the neck that is sometimes measured in early ultrasounds that can be increased in girls with Turner Syndrome. You can also see what we call lymphedema which is fluid buildup in other parts of the bodies and that can be seen both prenatally and after birth, particularly in the hands and feet. So girls with Turner Syndrome may have puffy looking hands or feet because of this
lymphedema. Interesting and the thing about the extra space in the neck, how is that seen after? Is it noticeable after birth? That's a great question. So it actually isn't necessarily noticeable after birth. Women with Turner Syndrome can have a webbed neck, meaning that there's kind of more skin connecting the neck to the shoulder area, that may be a result of this kind of lymphedema in that neck area. But that's not a definite correlation. So just because there's an increased nuchal translucency on ultrasound, doesn't mean that you're going to see anything after birth. Interesting. So that you've talked about some of the things that that are present in ultrasound, so pre birth, what about children and babies, children? And then adults who have Turner Syndrome? Are there symptoms to be looking for there? Yes. So a decent number of girls with Turner Syndrome have congenital heart defects. And so that's something that can be again, detected prenatally, but may not be something that's noted until after birth. They can also common features include short stature, so poor growth, they can have chronic ear infections, which can cause hearing loss, congenital kidney abnormalities, their autoimmune disorders, particularly with hypothyroidism and celiac disease as well. Girls with Turner Syndrome do not have intellectual disability, this was something that was, again historically thought that they might, but they do not have intellectual disability. But they do have a very specific learning profile that can cause pretty significant learning disabilities, particularly with nonverbal communication and spatial relationships. So girls often need support. So cool, I think you're meaning that when you say that that would be a learning difference. I mean, they have a learning profile. It's not that their intelligence is less, it's that they're there. They learn in a different way. I'm trying to say, Yes, yeah. Okay. Yeah, they have they have weaknesses in certain areas that need to be addressed in learning. Correct. Okay. All right. And then the big issue, especially related to the talk today, is they can have delayed puberty and fertility issues and the fertility issues are extremely common. Okay, and is it that they have primary ovarian insufficiency, so that they maybe subfertile early but able to get pregnant? But then if if they wait, their fertility will decline rapidly? Or is it that they do not have healthy ovaries? are what what is there a particular aspect of infertility that they're more likely to suffer from?
Yeah, so it's more
the sub fertility is is not really there. It's more that the ovaries could be absent, or there's, there's such significant ovarian insufficiency that it just occurs very, very early on. And so spontaneous pregnancy in women with Turner Syndrome is is actually pretty unusual. It's rare, that occurs in about five to 8% of women with Turner Syndrome. But there can also be some other issues, particularly with hormone balances because the ovaries really aren't working. And also there can sometimes be some uterine abnormalities. And so even in women who do get pregnant, there's a high frequency of miscarriage because of the uterus is also not functioning in the in the correct way. or correct. is some of the I have heard that mosaicism is more common with Turner Syndrome can first of all, is that true? And then can you explain what mosaicism is? Yeah, so mosaicism is quite common in Turner Syndrome. mosaicism is where we're seeing some cells in the body have a normal number of chromosomes. And some cells in the body have this monosomy X or or have the chromosome complement we'd see with Turner Syndrome. Most often we're seeing a mix of normal female chromosomes and the Turner Syndrome karyotype or that 45x. But you can also get women who have Turner Syndrome who are mosaic for 45x, that monosomy and 46x y. So when we have a mosaic Turner Syndrome, or Turner Syndrome, really in general, it's actually really important to test for the Y chromosome
terial because women who have or girls who have Turner Syndrome and have this Y chromosome material are at risk for a specific type of tumor called ganando blastoma. And so if they have this y material, the management of those girls is going to be different.
Does the having the presence of the y and imos in a person who has mosaicism? Is that also impacting the success of fertility treatment? It may, it's, it hasn't really at least that I have been able to find it hasn't really been broken down as much into, you know, what is the difference between women who have kind of full Turner Syndrome, those who are mosaic with normal 46x x versus those who are mosaic with 46x, y versus mosaic for some other chromosome abnormality? Yes. And it could be others as well. We've just mentioned those. It would seem to me that again, if women were able to get pregnant, a question they would need to ask is, what's the heritability of this chromosomal abnormality?
And we don't really know and part of that is because most women with Turner Syndrome will need an egg donor in order to conceive, okay, for those who are able to use their own eggs, either for spontaneous pregnancy or they have enough follicles to to use their own eggs in a fertility treatment, there is an increased risk for chromosome abnormalities over all, not just Turner Syndrome. Okay. Okay, that makes sense. At that Now, moving on to single gene disorders at the beginning, Sheila mentioned that one of the issues with infertility as it relates to genetics is that it is often not just one gene that is causing the problem which complicates the and increases the need for sophisticated genetic testing, and it complicates the diagnosis. But there are some single gene disorders. Sheila, I'm eventually going to get to you. But I'm going to direct this question to Sharon as well. What are some of the single gene disorders where we've got an issue with one gene that can cause a disease or cause an abnormality that would impact fertility. So Fragile X is one of the most common single gene causes for primary ovarian insufficiency. galactosemia is another galactosemia itself isn't common, but it's another I would say known cause for primary ovarian insufficiency. Other common genes may not actually cause additional symptoms, other than the primary ovarian insufficiency, or ovarian failure. And those genes can include ones called BMP, 15, and OB o x, nr, five, a one, an F, phi g, l. a, those are kind of some of the other ones that that range anywhere from, you know, one to 10% of the genetic the known single gene causes for primary ovarian insufficiency. Let's talk about Fragile X, is it more common? You've mentioned that the others, the others that you've mentioned are fairly uncommon. But what about Fragile X? And what what is it first and then how common is Yeah,
so fragile X is a from a genetic standpoint, it's relatively complicated. It's what we call a triplet repeat disorder. And what that means is in the gene, there's this section of DNA that repeats itself over and over and over again, most of us have between 10 and 45 of these repeats, individuals who have Fragile X have over 200 repeats. When that happens, the gene gets shut off, it gets turned off. So it's not making any Fragile X protein. And it results in primarily developmental and behavioral issues. So individuals with Fragile X do have intellectual disability, most often in the moderate range. And that's further complicated by things like ADHD, autism spectrum disorders, sensory processing issues, and anxiety and all of that can tie into behavioral issues as well. So it is tends to be a more developmental disorder physically, they tend to be fairly healthy most of the time. In between this normal and fragile X is what we call a pre mutation. And women and men who have a pre mutation have between 55 and 200 of these repeats,
Women who have a pre mutation have about a 20% risk of having primary ovarian insufficiency. And that's where the fertility issues come in. Again, the the how common are the pre mutations? And and would a person know that they they're not full blown Fragile X, but they have pre mutations for that that repeat, would a person be aware with a woman be aware of that other than infertility or their symptoms? Not necessarily. The other things that we can see with a pre mutation are things we see in the general population. So there is an increased risk for anxiety and depression. But those are also relatively common in the general population. The pre mutation in the United States in women is about one in 200. Women give or take a little bit that differs from a little bit from country to country. So in places like Israel, the pre mutation frequency is about one in 100. And in other places, it might be a little bit less. Why would it differ? If I would assume that, that less genetic pool to select from would would be an influence for the increase? Why would it be less some places? Same idea, actually, that the genetic pool if if it started, and there weren't that many individuals with a pre mutation, then it's not going to be as prevalent.
And if you if it is common in a population to, to move and to be then selecting partners, for from a more diverse gene pool than that would probably Exactly, exactly. Yeah. Yep, that makes sense. All right, excellent. This show as well as all the resources we provide at creating a family is brought to you by our partners. These are organizations that believe in our mission of unbiased medically accurate information to the patient community. One such partner is cryo international sperm and egg bank. They are dedicated to providing a wide selection of high quality extensive screened frozen donor sperm and eggs from all races, ethnicities and phenotypes for both home insemination, as well as fertility treatment. cryos international is the world's largest sperm bank and the first freestanding independent egg bank in the United States helping to provide the gift of a family.
All right, now we're going to be talking moving to Polly genetic complex, female infertility. And Sheila, I've saved the best for you.
I'm going to give you the more common Amelie the hard stuff. So we've talked at the beginning, you talked about the strong possibility that that that some genes, that some infertility could be caused by an easy to identify genetic connection. But some is far more complex. And it's a mix of things. So that's what we're going to be talking about. Now. When we say poly genetic, what do we mean?
So apologetic is really just a fancy way of saying that there are both genetic factors that contribute to a certain disease presentation, as well as environmental factors that can contribute. And in a lot of cases, we don't have either of those headings very well described. We just know that it's that it's both.
And but we're not sure, necessarily even which of the things would be, which of the environments, environmental factors are which of our genes is necessarily controlling? That's correct. So in a lot of cases, we don't know exactly. We don't know exactly what genes might be influencing or contributing to the problem. We don't we don't know if it's one gene or many, the environmental factors, we again, we may or may not know what some of them are, we likely don't know what all of them are. And we don't know in a lot of cases, which one is more heavily weighted? Like is genetics more important for a certain condition? Or is environmental factors more important for a certain condition. And so these these poly genic findings are, for the most part, there really isn't a specific genetic test you can do to diagnose them.
Hence that the one of the most important things to realize is that there's not a genetic test, you're not going to be able to go through genetic testing and kind of come out with a definitive answer. And that's something it's important for both medical professionals and for patients to realize,
but Okay, so if we don't know for sure how much genetics are contributing, how Why do we even think and we're going to be taught we're going to move into talking about
four common diseases endometriosis, fibroids, peace
polycystic ovarian syndrome and primary ovarian insufficiency. But before we talk about that, if if we don't know how much genes are impacting what makes us think genetics is is even potentially involved? That's a great question. And the answer is that for these conditions that we're going to talk about in a minute, in almost all cases, we see that for many of the women affected by say endometriosis, or by fibroids, that there are other women in their family who have the same finding. And in many cases, you see more affected women in a family than you would expect if this was happening by chance alone, which leads you to the conclusion that there must be some genetic factors that are playing a role. Okay, perfect. Well, let's dive in endometriosis. Is there? Is there a genetic link? Yes, there certainly does seem to be there have been several studies that have been completed for women who have been diagnosed with endometriosis. And what they were really looking for is, is there aggregation of this condition in your female patients side of the family. And in several of the studies, what they've done is they've looked at the women in the family of the index patient. So the patient, the female patient who's presenting with a diagnosis of endometriosis, her female relatives have been evaluated. And when I say female relatives, I mean, close relatives, sisters, Mom, aunts. And what they found is that if you compare the frequency of endometriosis and female in the female relatives of a woman who has endometriosis, to the frequency of endometriosis in a family, that doesn't mean that there isn't like a primary female index patient, we see that the relatives of the female patient are more likely to be affected. And in a lot of studies, what they did was they use the male partner as the control. So they looked at the women in the female patients family, the women in the male partners family and and said like, do we see more endometriosis on the female side than the male side? And that answer is often Yes.
What has been done to try to find the genes. And I'm assuming that if they're what we don't even know, it could be one gene, or it could be multiple genes. But what is being done to try to trace the gene or genes that would be causing endometriosis? So some of the older studies, scientists were using something called linkage analysis and linkage analysis basically evaluates segments of DNA that family members have in common because family members don't share 100% of their DNA, they share a proportion. And how much DNA you share in common with a relative just depends on how closely related you are to that person. But what they did was they look to see okay, in our female patient who has endometriosis, in her sister who has endometriosis, and her mom and their aunt or whoever else in the family might have had that diagnosis. What what segments of DNA? Do they all share in common? And from that, there, there have been studies to say like, Are there genes in this area that have a role in things like uterine lining, and there have not been any single disease causing genes identified to date. So there still has not been one gene that has been described as with certainty causing endometriosis? There are several what we call candidate genes, which means genes that might be involved. But that has not been definitively shown. And as I mentioned a minute ago, so right now, what that really means for patients is that there is not a genetic test that you can do that will diagnose endometriosis, there is only the histologic testing. So often, that is some value evaluation of the uterus and potentially a biopsy. And I know that that can be frustrating, because I think in this day and age, everyone sort of expects there to be a genetic test for everything. But the reality is that we don't we don't have that yet. What we do know from these studies is that there's unlikely to be just one gene that causes endometriosis, it's almost certain that there are going to be multiple genes.
And just in closing into matrices does affect fertility. And you can get more information on that. That is a that is a course unto itself. And you can get much more information on that at our website, creating a family.org. You will also get information there about the lifestyle and environmental factors that can influence endometriosis as well. All right, now let's talk about fibroids. Is there a genetic link?
fibroids. I certainly know that there is a it does tend to be connected. If your mother has fibroids, you are far more likely to have fibroids. But I guess that answers my question is if there's Is there a genetic link, but she like go ahead and talk to us about five that genetic connection with fibroids? Yes, you're 100% right there. There absolutely is a genetic link. It's a little different than endometriosis in the sense that, um, fibroids themselves are very common, even in the general population. And not all fibroids are created equal. Many women who have fibroids will have small fibroids that don't ever impact their fertility or their activities of daily life. And then there are some women who have fibroids that they have a lot of them they get very large, sometimes they can be painful, and so they certainly can impact fertility as well as again activities of daily life. In general. Yes, if you have a family history of fibroids, your risk as a female to have fibroids in your life is increased. It's not clear exactly what that specific increase is the studies the studies are different. And again, because fibroids are so common, it can be really challenging to figure out that number. Environmental factors certainly do play a role. And like endometriosis, this is a condition that we don't have a predictive genetic test for. So same thing you can't go and get a genetic test that will diagnose you with fibroids. You only really get that diagnosis by actually looking at the uterus and evaluating usually by ultrasound for fibroids. I will add here that for fibroids in particular, there is at least one inherited what we call single gene condition that is known to be associated with fibroid. This is really not a very common disorder. And so the vast majority of women who have fibroids are not going to have this. But this is a condition that has a long name. It's called hereditary leiomyoma ptosis and renal cell cancer. It's often abbreviated h l RCC and this is caused by a gene called f h. And this is actually a hereditary cancer predisposition, like the name implies. People who have this condition, male or female have an increased risk to develop renal cell cancer in their lifetime. But women who have this also have a very high risk of developing multiple uterine fibroids. And not a small number of families with this condition are identified after the identification of multiple generations of fibroids that are again impactful.
And so again, while it's certainly not the most common explanation, something to always keep in mind and one of the reasons that a family history is so important, really for all patients but particularly for patients who are seeking an evaluation for infertility. Okay, and again, you can get more information on fibroids, environmental factors and impact on fertility at creating a family.org. Now, polycystic ovarian syndrome or polycystic ovary syndrome, I've seen it both ways PC o s. What is it the genetic connection with pcls Shula? So again, this is this is very similar to the other two, it's going to start sound like a pattern
the poly genic pattern go ahead is it It absolutely is now I will actually take a step back and say that when someone has a diagnosis of pcls, it is important to make sure other genetic conditions that can masquerade as pcls are being evaluated for and the condition that comes to my mind is congenital adrenal hyperplasia. That's a condition that has what we call a classic form, and a non classic form. And in the non classic form, one of the main findings are problems with infertility. And in some women who have non classic congenital adrenal hyperplasia, they can actually be diagnosed with PCL, when in fact, there's something else going on. So it's really important to make sure that that has something that is being considered. But just for pcls, in general, same thing there are with virtual certainty, multiple genetic factors playing a role, because again, if a woman has pcls, she's more likely to have a family history of pcls. But again, we have not yet identified a single genetic cause. And we certainly know that there are environmental factors that predispose to this, um, obesity is one that we know can sometimes increase the risk for pcls. And if you have pcls, you also have an increased risk for other medical conditions such as diabetes, that's a common finding and someone who
pcls but again, not a genetic test that you can do that will diagnose this, this has to be diagnosed using other methods. Yeah, and this, of course, that one of the real struggles for people with PCs, women with PCs is that it tends to lead towards weight gain, and weight gain is also exacerbates it. So it's a bit of a closed loop there. Yep. It's a it's a cycle. It's a certain Yeah, exactly. All right. And again, more information on PCs, the environmental factors and its influence on infertility at the creating a family website. Now let's move and talk about primary ovarian insufficiency. We've already talked about trisomy x or triple x as well as fragile X, both being chromosomal abnormalities that can lend that may cause infertility. Are there other genetic links other than those two that we know of that might lead to a diagnosis of primary ovarian insufficiency? So yes, as Sharon covered earlier, when she was speaking, there are some genes that have been identified as causing only primary ovarian insufficiency without other findings. So as you mentioned, things like Fragile X and sex chromosome abnormalities. They are both associated with primary ovarian insufficiency. But if a woman is a fragile X carrier, or if there is a chromosome abnormality present, there are often other findings. It's not just the ovarian insufficiency, but there are some genes that we know if those genes are not working, really the only finding is that primary ovarian insufficiency. So those are sometimes called nonsyndromic findings. It's not completely clear how often these genes are involved in primary ovarian insufficiency, likely because while there may be testing for some of these single genes, it's still not really standard of care. It's not something that's done routinely in a practice. If a woman comes in and she's diagnosed with primary ovarian insufficiency, often there will be a kerio type dot, often there will be Fragile X testing done. There's often not testing done beyond that. And so without that testing, we really don't have the data to say exactly what percent of women with with primary ovarian insufficiency has one of these other causes. Yeah, that makes sense.
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Okay, now, we've talked about genetics and female infertility, we're going to move to be talking about genetics and male infertility. Sharon, I think a lot of people have heard of kleinfelder syndrome. First of all, what is it and how common is it? How does it affect fertility in men? So kleinfelder syndrome is 47x x y. So these are males who have an extra X chromosome. It's actually quite common. It happens in about one in 500 to one and 1000 males. And fertility is one of the major major features of kleinfelder syndrome.
Is there other symptoms that people would see would notice if they have it? There can be it's actually often not recognized prior to adolescence or adulthood. And what may prompt kind of a workup for kleinfelder is failure to progress through puberty, or coming through for infertility and specifically a xo sperm iya or lack of sperm in the semen. Other features that we can see include tall stature, they can have something called gynecomastia, which is basically breast development. And they can also have fat deposits similar to what we see in females. There can be some learning issues as well. Again, not intellectual disability, but a specific learning profile that may need some additional help in school. How common is it in men?
It's about one in 500 to one and 1000. Okay, interesting. All right. And
So a sperma is the most common sign that a man is infertile have his kleinfelder syndrome. impact the sperm is what I'm trying to ask.
Yep, so it's a what we call a non obstructive azoospermia. So there's not an obstruction or something blocking the path of the sperm, we're still not entirely sure how the aser sperm yet occurs, what we've seen is that in early adolescence, the sperm count may actually be normal, but then it drops off very rapidly. And so by the time a young man with kleinfelder, reaches adulthood, they may have very few or no sperm in their semen. Okay, and so then that would be and then so is there is it possible to use XC, is there any Is it possible to reproduce?
It is possible. It often requires, you know, preparation and some intensive assisted reproductive technology. One thing if the diagnosis is known, and you know it's being discussed with a young man is that you can do what's called cryo preservation of sperm, basically getting a sperm sample in adolescence, when we know the sperm count can be higher and freezing that sperm for future use.
If you know it early, yeah. If you know it early, exactly. The other big thing that's being used for men with kleinfelder is a testicular sperm extraction, where they're going and getting the sperm directly from the testicles rather than through semen. So even though a person with kleinfelder might well have ACS bermeja, they are still able to do the sperm extraction from the gonads and would have the ability then to reproduce. Is that correct? Correct. Correct. Interesting. Okay. Excellent. And then let's, let's talk about the possibility of passing this chromosomal abnormality on.
So there is a higher risk for having children with X or Y chromosome abnormalities. That risk hasn't been quantified very well. We just know that the risk is there. Okay. So it's something to be aware of going forward if a man has klinefelter syndrome?
Correct. Okay, excellent. So we've talked about where we would have an extra with a man having an extra x. What about if a man has, is it possible for a man to have an extra Y chromosome? So it would be x y y? Yes, it is. And that is basically what the syndrome is called. It's called XY syndrome. And it's an extra Y chromosome, as you mentioned. Okay, so how common is that? x, y, y is also relatively common. It's it's about one and 1000 men as well. Maybe a little bit rarer. Okay, but but similar? What are the symptoms? So actually, a lot of times, just like with kleinfelder, and some of the other sex chromosome abnormalities, men with XY syndrome may be missed, because there aren't really a lot of of issues that we see. The biggest things are, again, with regards to the learning profile, where there may be ADHD and some learning disabilities, but in general, it's it can definitely be missed. Both kleinfelder and x, y y are something that could be picked up prenatally if prenatal testing like a CVS or an amniocentesis is done, but also could be completely missed unless something triggers them to come to clinic or come to a genetics clinic for testing. Yeah, is this for pre implantation genetic testing? This could also be picked up but again Is it is it normally looked for? Correct it can be picked up by pre implantation genetic testing. And when you do PG TA, which is looking at the chromosomes via the pre implantation genetic testing, it it will be picked up and reported as long as sex is being reported. Okay. And what are the symptoms that would impact fertility is ACS bermeja. The again, the symptom as it is with kleinfelder syndrome or is it just reduced? sperm mortality, our quantity, so actually 47x by y rarely causes fertility issues. It's it's a little unusual in the sex chromosome abnormalities for that
regard. And so most of the time, this is not a discussion we would necessarily be having with a young man or an adult with x, y y syndrome. Certainly they come through, but it's not thought to be really a cause of the syndrome itself. Interesting so that you probably would not even necessarily know about it other than the fact that you're in fertility treatment for some other reason. And you're doing genetic testing then. Correct. Okay. I guess that's it. That's good news for someone is at this point. Yeah. Finally, we have some good news for you there. All right. Now, let's talk about structural chromosomal abnormalities, which would include things like deletions, duplications, translocations, and things such as that. Sheila, what are they structural chromosomal abnormalities, and how would they impact something like fertility?
So a structural chromosome abnormality is really any chromosome finding, that results in some sort of either imbalance depending on what the finding is, or the person who has the structural chromosome abnormality may themselves have a balanced set of chromosome material. But because of the arraign, the rearrangement, they themselves have an increased chance of having a baby with a with an unbalanced form. So you're talking balanced and unbalanced. What do you mean by that? So great question. So a balanced chromosome rearrangement would include things like a balanced reciprocal translocation, or a balanced robertsonian translocation, or a balanced inversion. That means there's a rearrangement in the way the genetic material is present in that person. But even though it's, it's in a different order, all of the information is there. And so there's nothing missing or extra to result in any sort of significant significant findings for that person. So unless they were having fertility concerns, or unless there was a suspicious family history, which often there is not a person with a balanced chromosome rearrangement is not going to know they have it. Okay, so would it be like this, if the normal arrangement was a, b, c, d, the somebody with a balanced rearrangement would be something like a D, C, B, so that it would be bout the same that the quantity of material and the actual material would be there, it's just in a different order is Am I understanding it correctly? Yeah, that's that's a great analogy. Okay. So that's balanced. And and it sounds like that would have less impact, because the material there is there, it's just not in the right order, is in my Is that correct? Well, it has less impact on the person who carries the rearrangement. But it's actually very impactful for reproduction. Because if somebody has a balanced chromosome rearrangement, when they are making their gametes, so when they're making egg or sperm, their chromosome pairs have to divide. And if their chromosome material is in a different order, while that doesn't impact them, it really impacts the way those chromosomes pull apart to make a mature egg or a mature sperm cell. And so the result is often either an egg cell that has too much or not enough chromosome material, or a sperm cell that has too much or not enough chromosome material. And if that egg or sperm is used in a conception, then you have an embryo and potentially a pregnancy that is affected with an on balanced rearrangement. So having not enough or too much genetic material, and that is very impactful. It can either result in pregnancy loss, or in some cases, the birth of a baby with special needs because of the imbalance in chromosome information. And so that goes back to my simplistic analogy, imbalance would be the normal one being ABC D imbalance would be ABC or ABC, D, or ABC, or something. Yep, exactly. Yeah. Okay. So that would be an imbalanced and an imbalanced arrangement has more direct impact, or has a direct impact on the person who is carrying it, which means the child that would be conceived or the human, the person who's coming in, correct. If it's unbalanced, those effects are going to be for the person who has the unbalanced form. Because they're missing something. There is some unnecessary chromosome, there's something part of the DNA that is not that is missing. Correct. So what is a robertsonian? a structural chromosomal abnormality? Yep, so a robertsonian translocation refers to a very specific set of chromosomes. So there are five chromosomes that are what we call Afro centric, which just means that the top part
Doesn't really contain any genetic information. It's really all contained in the bottom part. Those are chromosomes 1314 1520, and 21. And so those are the only five chromosomes that can be involved in a robertsonian translocation. And in a robertsonian translocation, what happens is two of those Aqua centric chromosomes join end to end, and they form one long chromosome. So the most common chromosome translocation that we see in the general population actually happens to be a robertsonian translocation. And it's what we call a 1314 translocation. And then someone who has that they have one copy of chromosome 13, that is free and not attached to anything, one copy of chromosome 14 that is free and not attached to anything. And then they have a second copy of 13, and a second copy of 14 that have joined end to end and they have formed one long chromosome. So those individuals actually have 45 chromosomes instead of 46. But they're not missing any information. Or the information from 13 and 14 is present. But they've joined and now they're one long chromosome, do they have any impact from that? for themselves? No. But again, when it comes to reproduction, that impact is very significant. Because that long chromosome where the 213 and 14 have joined end to end, that's not going to divide very well when egg and sperm is being made. And so you can end up with an egg that either has too many number 13 chromosomes or not enough 13 chromosomes. And same thing with 14, you can have an egg or a sperm that has too many or not enough. And if those are using a conception, you're going to have that you're going to have a pregnancy that either has an extra or a missing chromosome. And again, that's either going to result in Nope, no pregnancy like no implantation.
It can result in an early miscarriage or in some cases that can result in a baby that has a pretty significant genetic disorder as the result of an extra chromosome. Can these structural chromosomal abnormalities including the robertsonian, a happen with both male and female? Yes, that's actually a really important point on it's very often that women are having their chromosomes tested. One of the and one of the reasons that we see a preponderance of women having this testing is because a common finding in couples that have a translocation, or an inversion is miscarriage. And often, you know, when we think about an evaluation for recurrent pregnancy loss, it's often the woman that is having that testing. But in reality, her male partner can also carry a translocation. And so testing really needs to be done for both of them. It's called a karyotype, or a chromosome analysis. And even if you test the woman first, and you find she has a translocation, that does not mean that you don't need to test the male partner because there are couples where both members of the couple have a translocation. And that's a really important, I'm particularly for couples who might be undergoing IVF, because that really impacts their chance of having an embryo with a normal set of chromosomes, which is what's going to give them the best chance of success. So it's really important to always test both. And the reason we're talking about it go by essays, but structural chromosomal abnormalities under genetics, the section here in genetics and male infertility is because so often, it's not thought of, because we test the women for this, but we don't test their their male partner in that. And that's an important thing that we absolutely must do, particularly when somebody is seeking infertility treatment. So now let's talk about, we've talked about single gene disorders for females. Let's now talk about single gene disorders that might affect male infertility. Sheila, are there any? There are, Don, if I could back up to the structural rearrangements? I had just had one last point, if you don't mind? No, absolutely, because this is under the male infertility section. So I just wanted to make sure to mention a chromosome abnormality that does really only impact men and those are the Y chromosome micro deletions. So there are areas on the Y chromosome that are important for the development of healthy sperm. And if there is a deletion in any of those regions, there are three main ones if there is a deletion in any of those regions, that is going to impact sperm production and depending on where the deletion occurs, it can result in a zOS bermeja
Sometimes it can result in oligos Urmia, it can also result in problems with sperm formation, which is sometimes called Terada sperm iya can cause issues with motility. And because that happens on the Y chromosome that is something that is very unique to men because, you know, genetic females do not have a Y chromosome. So when you have a male who has an abnormal semen analysis, it's really important to always think about doing those y micro deletion studies because it may give you your answer. Okay, now, let's get back to the single gene disorders. Sheila, are there single gene disorders that affect male fertility? There are and the most common one that that is seen is cystic fibrosis, and cystic fibrosis for those who may know that term or are familiar with that condition. A lot of people think about cystic fibrosis in a way that we often call classic cystic fibrosis where people who have cystic fibrosis have very significant lung involvement, they get very thick, sticky mucus buildup in their lungs, which causes a lot of respiratory problems. And classic cystic fibrosis truly is a multi system disorder, with lung involvement being the most common, there's also involvement of the pancreas and the digestive system. But it also does impact fertility. And for males in particular, who have cystic fibrosis, they have something called congenital absence of the vast friends. And so this is actually the vast difference are the tubes that help to transport sperm out of the body. So these men make sperm, but this is an obstruction. So this, this resulted in obstructive azoospermia, the sperm can't get out. And what we are learning with the continuing evolution of genetic testing, is that the cystic fibrosis gene, that gene is called cftr. It doesn't just cause that classic disorder where there's lung involvement, and pancreatic involvement and infertility, you can actually have what's called a cftr spectrum disorder, or cftr related disorder and have only the findings of male infertility. So there are some men who are otherwise healthy. But when they try to have a family, that's not working for them, they go for an evaluation, they have an abnormal semen analysis. And then additional testing identifies either one or two genetic changes in that cftr gene. And that's important for a couple of reasons. One is that depending on what those findings are, that man could potentially have a child who has classic cystic fibrosis, he could also potentially have a male child who also has absence of the vast difference. That would depend both on his genetic findings and the status of his partner. But that's a really important discussion to have. Yeah, that's fascinating. The, the whole thing around genetics and its influence on our health is absolutely fascinating. And it's what is part of it so fascinating. It's it's so new. I mean, we're, we're learning all the time, literally every year that goes by We know, we know more, before we get off of cystic fibrosis. So as a man just it's the absence of the vast death from that is the primary cause they're producing fine. The sperm is not the production of the sperm, it's getting the sperm into the semen. Does CF have any impact on the if the vest definitely is there and there is no obstruction? Is there any impact on fertility at that point? So absence of the vast difference is one of the most common features of cystic fibrosis. So the presence of vast difference is pretty rare. But if a man with cystic fibrosis or a cftr Spectrum Disorder has best deference, then there's not that then there's not really an increased risk for infertility because this, the sperm production tends to be normal. And for men who do have the absence of vast difference, the testicular extraction is something that can be utilized for that. So sperm can be extracted directly from the testicles to use in something like IVF. Got it? Okay. Excellent. All right. So I in some ways have have already answered this question. But my my last question to you and I'm going to direct starting with Sharon. Why is it been so hard to pinpoint the exact genes associated with male and female? infertility? Emmy partly I entered it myself by saying that she does such a new field in many ways, and we're learning constantly, but it other other things that come Why is it so hard to
To to know, it would be so much better if we could just say, Alright, we could do a genetic test, and then we would be great, we could do it when we're, you know, 15. And then we would know, oh, gosh, you know, I'm going to, I'm at risk for losing my fertility early, therefore, I need to start early, or I'm at risk for struggling, therefore, I would fertility so I need to go ahead and start earlier. And maybe I'll do that first before I go to grad school, that type of thing. But that doesn't exist, does it? Not really darn.
For for a number of reasons, you know, it's in genetics, we're very, you know, we try to focus also on the ethical implications of genetics and genetic testing. And that includes autonomy. And so if you think about your typical teenager, they don't, they don't want to know, they don't care. It's not necessarily on the horizon for them. So they're not thinking about it. And you know, when it's for future risk, or, or future health implications, reproductive implications, they really need to have a say in whether they want to have the testing or not. So that's one of the reasons why we don't really just have that baseline population testing for adolescence, in terms of, of finding new genes, finding new genes is hard. It really is, it takes large populations, it takes really comprehensive testing. And it also takes a really good understanding of the genome or all of our DNA, which we simply don't have. We know a lot about a few number of genes, we know a little about everything. And that can make it really hard to be able to narrow down and say, Oh, this section of DNA, or this gene is contributing to X, Y or Z presentation. It's it's we think we know more than we actually do, it's almost like it's we're living in a very tantalizing time, because there's so much knowledge coming in. It's coming so quickly, that we think we know more about genetics than we actually do, which, which is frustrating.
Sheila, I will give you the last word, anything you'd like to add about the progress of genetic testing and how we're moving into the impact on fertility? I think Sharon summarized it very well. And as as did you, Dawn, I think, you know, it's really important to understand that while we're learning new things every day, the more we learn, the more questions we have. And it's tempting to think that we're going to have this sorted out, I hear people say all the time, oh, in five years, you'll have it figured out or Oh, in 10 years, you'll have it figured out. And I I completely agree that in five years or 10 years, we'll know more, we're not going to have it figured out.
So I think that it's really I think that that's a really important expectation to keep in mind. And I would say if we were going to end on any note, I think it's really important for fertility providers and for patients alike, to just make sure that there's a complete review of family history to talk about the genetic testing that is available. Because while we don't have a genetic test for everything, we do have genetic testing for some things. And providing information based on that genetic testing about a cause for infertility can be really helpful if one is identified, both for providing some closure about why this is happening, as well as to make sure that if there is some sort of risk to children say for like cystic fibrosis or a chromosome abnormality, the couples are aware of that, because in many cases, there's testing that can be offered to help them have the healthiest baby that they can. And so it's really important not to overlook the testing that we that we already have. Excellent, thank you so much. She let Joe howl and Sharon Lincoln, both genetic counselors at Cooper genomics for being with us today to talk about in fertility and genetics. Let me remind everyone that the views expressed in this show are those of the guests and do not necessarily reflect the position of creating a family, our partners or our underwriters. Also, this it goes without saying but keep in mind that the information given in this interview is general advice to understand how it applies to your specific situation. You need to work with your infertility professional. Most people learn about specific podcast from friends. So if you're enjoying this podcast, please do us a favor and mentioned the creating a family podcast to someone. We're a nonprofit organization and our mission is to educate and support folks with unbiased medically accurate information. So you'll be helping with our mission by spreading the word. Thanks for joining us and I will see
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